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Ann Thorac Surg 2006;82:1003-1007
© 2006 The Society of Thoracic Surgeons

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Original article: General thoracic

Thoracoscopic Thymectomy Mid-Term Results

^a Department of General Surgery and Liver Transplantation, Fundeni Clinical Institute, Bucharest, Romania
^b Department of Neurology, Fundeni Clinical Institute, Bucharest, Romania
^c Department of Health Psychology and Psychosomatics, "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania

Accepted for publication April 27, 2006.

^_* Address correspondence to Dr Popescu, Department of General Surgery and Liver Transplantation, Fundeni Clinical Institute, Sos. Fundeni 253, Sector 2, 72434 Bucharest, Romania. (Email: irinel.popescu{at}icfundeni.ro).

	Abstract

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BACKGROUND: Results of thymectomy in patients with myasthenia gravis need to be reported in a standardized way to allow accurate comparison.

METHODS: A retrospective study was conducted of 107 patients with myasthenia gravis without thymoma. Patients were followed-up for more than 12 months after thoracoscopic thymectomy and analyzed according to Myasthenia Gravis Foundation of America Recommendations for Clinical Research Standards.

RESULTS: The study population was aged 8 to 60 years old and included 15 men (14%) and 92 women (86%). A right-side approach was used in 36 patients, and the remaining 71 patients had a left-side approach. Mortality was 0% and morbidity was 9.34%. The mean operative time was 90 ± 45 minutes. The histologic diagnosis of the resected thymus was hyperplasia (78.5%), atrophy (15%), and normal status (6.5%). The mean length of hospitalization was 2.3 days (range, 2 to 6 days). The mean follow-up was 36.4 months (range, 12 to 74 months). The rate of complete stable remission was 59.5% by the end of postoperative year 6. An earlier onset age and early operation were significantly associated with complete stable remission and pharmacologic remission. A comparison of right side versus left side approach showed similarities in mean operative time, mean length of hospitalization, histopathologic results, and remission rates.

CONCLUSIONS: Outcomes of the thoracoscopic approach in myasthenia gravis without thymoma were similar to those provided by open surgery, with the acknowledged benefits of minimally invasive surgery and good patient acceptance.

	Introduction

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Video assisted thymectomy was introduced in 1992 as a minimally invasive alternative to thymectomy in patients with myasthenia gravis. Our preliminary results have been previously reported [1]. The purpose of this report is to provide results from a wider range of patients with longer follow-up periods to enable a more accurate evaluation of the approach. Given the heterogeneity of the disease and its unpredictable progress, comparisons of different therapeutic outcomes proved to be very difficult, if not impossible. The Task Force of the Myasthenia Gravis Foundation of America (MGFA) has therefore issued new classifications for the clinical, therapeutic, and postinterventional status [2], which we also used to stratify the participants in our study as a landmark for comparison by future research.

	Material and Methods

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Our study was approved by the Fundeni Clinical Institute Ethics Committee, and the need for informed consent from patients was waved because of its retrospective design. Since April 1999, a thoracoscopic approach has been used in all patients admitted in the Department of General Surgery and Liver Transplantation of Fundeni Clinical Institute with either nonthymomatous myasthenia gravis or stage I thymoma, defined as a tumor size of less than 4 cm with no signs of invasiveness on computed tomography (CT). Those with stage II or III thymoma received the transsternal approach. Between April 1999 and April 2005, the thoracoscopic approach was used in 160 patients with myasthenia gravis without thymoma.

According to the MGFA Recommendations for Clinical Research Standards in the assessment of the postoperative status—complete stable remission (CSR) and pharmacologic remission (PR) of patients—was calculated at the end of a minimal period of 12 months' follow-up. We restricted our study population to patients undergoing surgery between April 1999 and May 2004. We excluded 27 participants with less than 12 months' follow-up, 9 patients with incomplete preoperative recorded data provided by the Department of Neurology, and 17 patients who were lost to follow-up. Our study finally evaluated 107 patients with myasthenia gravis without thymoma who were followed-up for more than 12 months after thoracoscopic thymectomy.

All of the patients received specific treatment for at least 3 months before surgery in the Department of Neurology of the Fundeni Clinical Institute. Patients were considered suitable for a surgical procedure only when evidence showed good treatment tolerance and a decrease of the quantitative myasthenia gravis score to at least 10. Preoperative clinical staging was assessed by the MGFA clinical classification [2]. Preoperative diagnostic tests included spirometry and a CT scan. Patients were transferred to our department on the morning of the scheduled operation. The surgical technique that we used has been described elsewhere [1, 3].

Patients were extubated immediately and remained in the intensive care unit for 24 hours. They were evaluated by the same neurologist just after surgery and every 6 months during the 6 years of follow-up. Data were collected and analyzed using medical records and telephone interviews. Treatment, morbidity, mortality, and postinterventional status at follow-up were also been assessed according to the MGFA Recommendations for Clinical Research Standards.

The databases were compiled and analyzed using Excel 2002 (Microsoft, Redmond, WA), SPSS 10.0 (SPSS, Inc, Chicago IL), and Epi Info 6.0 software (Centers for Disease Control, Atlanta, GA). The normal sample distribution was measured by using the Kolmogorov-Smirnov (K-S) test. Univariate analysis of variables potentially affecting complete stable remission (CSR) and pharmacological remission (PR), including age at operation, gender, disease duration, and histology were calculated by using the Kaplan-Meier method. We used the log-rank test to compare survival curves, and univariate analysis and ² test were used to calculate the relative risk (RR) with a 95% confidence interval (CI). The Student t test was also used. Values of p < 0.05 were considered statistically significant.

	Results

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The study cohort included 15 men (14%) and 92 women (86%). The average age at the time of the operation was of 28.06 ± 9.97 years (range, 8 to 60 years). The normal distribution of the study population was determined using the K-S test that yielded a nonsignificant p value (K-S Z = 1.284, p = 0.07) showing a normal distribution of the data. The mean duration of the disease was 21.20 months, and it had variations within the study group. No gender-related significant differences were found.

According to the MGFA clinical classification of the maximal severity level in the history of the disease before surgery, 18 patients (16.85%) were stratified in class IIa, 36 (33.74%) in class IIb, 16 (14.86%) in class IIIa, 18 (16.85%) in class IIIb, 16 (14.86%) in class IV, and 3 (2.84%) in class V.

The 107 participants received preoperative steroid therapy. Additional treatment with anticholinesterase was required in 43 patients (40.19%), and 28 (26.17%) required immunosuppressive drugs.

We initially performed a left-side surgical approach for the first 30 patients, followed by right-side thoracoscopy as an alternative intervention. Our decision on whether to use the right-side or left-side approach depended on the CT status of the thymus. Only 2 patients needed the combined cervical and thoracoscopic approach because of the cervical extension of the thymus. There was no conversion to open thymectomy. The mean operative time was 90 ± 45 minutes.

No patients died. Postoperative morbidity occurred in 10 patients (9.24%), consisting of severe postoperative myasthenia crisis in 1 patient who needed mechanical ventilation for 5 days, 2 with contralateral pneumothorax after removal of the drains, 3 with hemothorax that required emergent reoperation, and 4 patients with prolonged pleural drainage.

The three cases of hemothorax were resolved by thoracoscopic reoperation. In 1 patient, bleeding caused by a lesion of the internal mammary vein from the opposite site was stopped with clips applied on the bleeding vessel. Bleeding at the level of the trocar port occurred in 2 patients, one of which required extension of the trocar wound and ligation of the intercostal artery.

The most frequent histologic diagnosis was hyperplastic thymus (78.5%); involuted thymus was found in 15%. The remaining 7 patients (6.5%) in the study had a normal thymus.

The mean length of hospitalization was 2.3 days (range, 2 to 6 days). The average postoperative stay included 2 days in our department and an additional day in the Department of Neurology. The mean follow-up period was 36.4 months (range, 12 to 74 months).

Our study aimed to achieve CSR and PR as defined by the Clinical Research Standards of MGFA [2]. The preoperative status evaluated according to the Clinical Research Standards of MGFA during the 6 years of the follow-up period is shown in Figure 1. The CSR and PR curves have an ascending pattern pointing to the good postoperative outcome.

View larger version (10K): [in this window] [in a new window]   Fig 1. The postoperative status (complete stable remission [CSR], pharmacologic remission [PR]) during the 6 years after surgery (x-axis = time in years; y-axis = percentage).

View larger version (19K): [in this window] [in a new window]   Fig 2. Kaplan-Meier curve for our rates of complete stable remission. MG = myasthenia gravis.

View larger version (10K): [in this window] [in a new window]   Fig 3. Comparative evolution of average quantitative myasthenia gravis (QMG) score and average corticosteroids (CS) doses during the 6 years after surgery (Pearson's correlation, r = 0.956, p = 0.0001).

	Comment

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Although total thymectomy has always been considered to be the goal of surgery in myasthenia gravis, and several studies comparing aggressive with limited resections support the prerequisite that the less thymus left behind, the higher the remission rate [4], the optimal approach that balances the extent of resection, morbidity, patient acceptance, and results remain controversial. Minimally invasive thymectomy techniques do not necessarily equate with poorer outcomes.

Only patients with generalized myasthenia gravis were suitable for surgery. The procedure was not provided to patients with ocular symptoms alone or for those classified with a MGFA clinical status class I, although about 30% of these patients are known to further develop generalized myasthenia gravis [5]. More importantly, in our opinion, surgical intervention should not be imposed on the remaining 70% of these, who would have no benefit; instead, consistent follow-up could enable rapid discovery of those who are going to develop generalized myasthenia gravis. Surgery has also been the therapeutic option for patients with late-onset myasthenia gravis, but only if they were younger than 70 years old or had thymomatous myasthenia gravis, or both.

We believe that surgery is merely one link in the complex chain of myasthenia gravis treatment, and the best outcomes are therefore most likely to be provided only by a coordinated approach of medical and surgical therapies. Practically all the study participants were receiving prednisone at the time of the operation. In our opinion, the very low rate of severe postoperative myasthenia crises (0.93%) is closely associated with the preoperative intensive treatment and with the lower extent of chest trauma related to thoracoscopy.

Yim and colleagues [6] favor the right thoracoscopic approach because (1) identification of the vena cava is a landmark for easier dissection of innominate vein, (2) the confluence of the innominate veins is easier to dissect by using a right approach, and (3) ergonomically, it is easier for right-hand surgeons to dissect the thymus from inferior horns to upper horns with a right approach. To this we would add that the right approach allows a better view in the cervical area.

Irrespective of the patient's anatomic characteristics, every effort is made to perform a full removal of the thymic tissue by clearing the innominate vein and anterior pericardium from all mediastinal fat. We believe a left-side approach facilitates the procedure because most of the mediastinal fat is located on the left side of the anterior mediastinum. The use of a 30° endoscope (Karl Storz-Endoscopy, Culver City, CA) provides significant help. Although we share the opinion of Mineo and colleagues [7] that thymectomy can be performed by either a left-side or a right-side approach, we believe the left-side approach has some advantages. In our experience, the dissection maneuvers are safer when performed on the left side because the right phrenic nerve is situated outside the surgical field, thus reducing the risk of an incidental lesion. It is also easier to perform a dissection of the right side of the thymus by a left approach than a dissection of the left side of the thymus by right approach, especially for the aortopulmonary window.

We have not performed a pneumomediastinum to facilitate thymectomy as have Mineo and colleagues [8], but we have observed that insufflation of up to 8 mm Hg enables pulmonary collapse and enlarges the operating field between the heart and sternum by almost 2 cm, which makes mediastinal dissection easier. Positive pressure is also very useful during the dissection, particularly in the cervical area.

Our reported surgical procedure is not a "maximal" thymectomy as has been shown by Jaretzki [9] or Zielinski and colleagues [10], but it closely matches other published thoracoscopic approaches [11–16] and the "standard extended transsternal thymectomy" [17]. The transcervical approach is also associated with minimal access trauma, and the use of the current technique has yielded remission rates equivalent to the results of more aggressive and extensive techniques [18]. A thoracoscopic approach can provide a better view (thymus is particularly a mediastinal gland) and an easier way of performing the procedure compared with extension of the thymectomy and ergonomics (too many instruments in a single narrow cervical incision).

The postoperative evolution was satisfactory in 22 (59.5%) of the 37 patients who were in CSR by the end of the follow-up period. Throughout the 6 years, curves for both CSR and PR had an ascending trend, with a 97.19% status improvement at the end of the follow-up. The good outcome after thymectomy was confirmed by the Kaplan-Meier pattern. A comparison of our results with those reported by Jaretzki and colleagues [19] showed that our remission rates were consistent with the estimates reported by other authors at 3, 4, and 5 follow-up years (Fig 1). Our rough rate of achieving CSR was 39.25%, which was in accordance to similar data reported by Savcenko and associates (14%) [20], Mineo and associates (36%) [12], and even with the 33.3% rate of bilateral video-assisted extended thoracoscopic thymectomy published by Mantegazza and associates [21].

Our low remission rates during the first 2 years of follow-up could be explained by the constant use of corticosteroids. The steroid medication dosage has to be progressively lowered, which means that a longer time is needed to get total exclusion and achievement of CSR with a high rate of PR. The slope of the remission diagram shows a sudden increase between years 5 and 6, suggesting that a longer follow-up period might be needed to determine all the beneficial effects of thoracoscopic thymectomy. However, the small number of patients (37) who completed the follow-up period limited the statistical power of our study.

No gender-related differences in achieving CSR existed in our study group. Patients with an earlier onset age had better chances of achieving remission (CSR + PR) after operation than the others (p = 0.04), but the RR 95% CI is not reliable as it ranges from 0.8 to 10.8 (Fig 4). This might become an important issue in the selection of participants for further studies. Patients undergoing surgery shortly after the disease onset might have twice as many chances to achieve remission than the remaining patients (p = 0.03, RR, 1.56, 95% CI, 0.94 to 1.59). Although higher rates of remission in patients with hyperplastic thymus have been reported [21–23], our results did not point to any advantage for this histologic finding, similar to the CMPC study [24]. We therefore believe that the role of histology should be further investigated.

View larger version (12K): [in this window] [in a new window]   Fig 4. Kaplan-Meier curves depending on the age of onset. Solid line = age 40 years or younger; broken line = age older than 40 years.

The mean duration of the disease until patients underwent surgery in our series was 18.8 months, which favorably compares with the mean duration of 42.2 months in our historical series. This suggests that the thoracoscopic approach has a high patient compliance with surgery (we have tripled our experience performed within a similar time interval) because of its better cosmetic results, with the same medical outcomes.

We believe that the thoracoscopic approach in nontumoral myasthenia gravis has several clearly defined characteristics: it has a higher rate of acceptance and may therefore benefit an increased number of patients; the left-side and right-side approaches are similar in terms of postoperative evolution, remission, and status rates; earlier onset age of the disease and early operation are important favorable prognostic factors; the intervention is associated with a very low rate of dramatic postoperative myasthenia crises in patients with preoperative intensive treatment; it provides similar benefits to those of the "standard extended transsternal thymectomy" as it is currently performed, in correlation to the extension of the thymic tissue removal; and, as measured by CSR rates, the thoracoscopic approach proved to be as effective as open extended surgery, with the acknowledged benefit of minimal invasive surgery.

It is important to note that the achievement of favorable outcomes requires highly coordinated teamwork involving a strong collaboration between neurologists, surgeons, and anesthesiologists in making appropriate decisions on selection of patients, therapeutic options, and timing of surgery.

	Interactive eLearning Activities

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The Joint Council on Thoracic Surgery Education was pleased to introduce a series of unique eLearning activities to CTSNet users at the AATS annual meeting in Philadelphia. Sponsored by several cardiothoracic surgical groups, this exciting new educational tool contains narrated videos of actual surgical procedures followed by a series of questions and an evaluation to earn Continuing Medical Education credit.

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Joint Council on Thoracic Surgery Education

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	References

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