Ann Thorac Surg 2000;70:918-923
© 2000 The Society of Thoracic Surgeons
Original articles: general thoracic
Thoracoscopic completion thymectomy in refractory nonthymomatous myasthenia
Eugenio Pompeo, MDa,
Italo Nofroni, BSa,
Nicola Iavicoli, MDb,
Tommaso Claudio Mineo, MDa
a Myasthenia Gravis Unit, Department of Thoracic Surgery, Tor Vergata University, Rome, Italy
b Department of Biostatistics, University "La Sapienza," Rome, Italy
Address reprint requests to Dr Pompeo, Cattedra di Chirurgia Toracica, Università Tor Vergata, Ospedale S. Eugenio, P.le dell’Umanesimo 10, 00144 Rome, Italy
e-mail: pompeo{at}med.uniroma2.it
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Abstract
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Background. The aim of this study was to assess the efficacy of thoracoscopic completion thymectomy in patients with refractory nonthymomatous myasthenia.
Methods. Eight patients were operated upon after transcervical (n = 6) or transsternal (n = 2) thymectomy. The mean interval between operations was 129 months. Every patient was completely disabled despite treatment with large dosages of prednisone in combination with pyridostigmine (n = 5) or azathioprine (n = 3) and with repeated plasma exchanges.
Results. Gross (n = 5) or microscopic (n = 3) residual thymic tissue was found in all patients. There was no mortality , but morbidity included 2 patients with postoperative myasthenic crisis requiring reintubation and mechanical ventilation. The mean hospital stay was 4.75 days. The mean follow-up was 28.3 months. At the last follow-up, 6 patients had achieved symptomatic improvement as expressed by significant change in mean Osserman class (3.37 versus 2.12, p = 0.03), and prednisone dosage (43 versus 20 mg/d, p = 0.03). Conversely, there was no difference in dosage of pyridostigmine and azathioprine or in number of exchange cycles.
Conclusions. Our results suggest that thoracoscopic completion thymectomy may be beneficial for selected patients with refractory nonthymomatous myasthenia.
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Introduction
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T herapeutic options are limited in patients with autoimmune myasthenia who remain disabled for years after thymectomy in spite of high doses of immunosuppressive and anticholinesterase drugs. Since complete thymectomy is believed necessary to maximize surgical results, the finding that residual thymic tissue is present in most patients showing partial or no response [1, 2] has led us to hypothesize a role for completion thymectomy. So far, the operation has been carried out in a limited series of patients through aggressive transsternal approaches [1–5]. Though effective, these invasive approaches may lead to high postoperative morbidity [6], particularly in such a delicate patient population. Thoracoscopic thymectomy is being investigated in the belief that it may provide complete thymectomy with the advantages of minimal surgical trauma and superior cosmetic results [7–10]. Having gained confidence with thoracoscopic thymectomy performed as the routine operation in autoimmune myasthenia [9], we have adopted the same approach as a less invasive option to reoperate on patients with refractory nonthymomatous myasthenia. In this study we analyze the surgical and intermediate-term results achieved by this novel approach.
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Material and methods
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Between December 1995 and December 1998, 8 patients, including 5 women and 3 men, with a mean age of 40.3 ± 7.9 years (range 31 to 53 years) underwent thoracoscopic completion thymectomy (Table 1). The ethical committee approved clinical application of the procedure, and informed consent was obtained from all patients. The three inclusion criteria for completion thymectomy were (1) lack of significant symptomatic improvement for at least 3 years after thymectomy, (2) deterioration of symptoms after initial improvement lasting more than 24 months not adequately controlled by maximal medical therapy or requiring repeated exchange cycles, and (3) evidence of residual thymic tissue or thymomatous transformation on computed tomography, magnetic resonance imaging, or both (Fig 1).
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Fig 1. Preaortic residual thymic tissue is suggested by computed tomography in a 50-year-old patient who previously underwent transcervical thymectomy.
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Preoperative diagnostic tests included spirometry, computed tomographic scanning, and magnetic resonance imaging in all patients. To be eligible for the thoracoscopic approach, patients had to have had no history of bilateral pleurodesis or pleuritis, ventricular arrhythmia, or cardiomegaly. Time elapsed from diagnosis to the initial operation was 15.6 ± 11 months. The initial operation was transcervical thymectomy performed by one of the authors (TCM) in three instances and transcervical (n = 3) or sternal splitting thymectomy (n = 2) performed in another institution in five cases. Time elapsed between operations was 128.7 ± 71 months (range, 62 to 276 months). All patients had a positive edrophonium test and characteristic decrease in response to low frequency repetitive nerve stimulation. At admission, every patient was completely disabled, despite drug treatment with large doses of prednisone in combination with pyridostigmine (n = 5) or azathioprine (n = 3). Six patients were receiving long-term maintenance plasma exchange (Table 2). All attempts to taper medication had been unsuccessful because of patients’ increased fatigue. All patients underwent four exchange cycles over the two weeks before the operation to stabilize clinical conditions and reduce risk of postoperative morbidity. Adjuvant pneumomediastinum was always induced 24 hours before the operation [9].
At histologic examination, thymic tissue was identified by the presence of Hassall’s corpuscles or by immunohistochemical staining with cytokeratin and T-cell markers.
Patients were evaluated at intervals before and after completion thymectomy by means of neurologic examinations utilizing a quantitative clinical grading scale of muscle endurance and strength. The amount of corticosteroids and cytotoxic and anticholinesterase drugs was recorded, as well as the number of plasma exchange cycles. Severity of symptoms were categorized according to a modified Osserman [11] classification (Table 3). Response to completion thymectomy was categorized by both symptomatic changes and changes in medications requirement (Table 4). Postoperative pain was assessed at days 1 and 3 and at subsequent follow-up visits by a standard visual analogue pain scale.
Surgical technique
After double lumen intubation, with the patient lying in a 45-degree off-center position, four flexible trocars were inserted, as previously described [9]. Through the left access site, the mediastinal pleura was incised along the triangle comprising the phrenic nerve inferiorly, the mammary vessels superiorly, and the pericardium anteriorly. Care was taken in recognizing all structures the position of which may have been modified by previous operations. Dissection of vessels and nerves was facilitated by both adjuvant pneumomediastinum and magnified video-imaging. Adhesions are often found at the level of the innominate vein, which was therefore progressively dissected free either anteriorly or posteriorly to exclude the presence of accessory thymic lobules. To improve access to the cervical area in the last 4 patients, we performed a small (2-cm) skin incision enabling us to pass a right-angle retractor behind the sternal notch and lift the sternum. All mediastinal fat tissue including thymic tissue was carefully dissected from the pericardium. Furthermore, fat tissue between costophrenic sinuses inferiorly, aortopulmonary window to the left, pulmonary hilum to the right, and inferior pole of the thyroid gland superiorly was removed as well. After extraction of the dissected tissue through the most anterior port, the anterior mediastinal thymic bed was carefully inspected to assure both completeness of resection and hemostasis. At the end of the procedure, the innominate veins at the junction of the superior vena cava were skeletonized and completely visualized. Finally, one chest tube was inserted in the dissected mediastinal area.
Statistical analysis
Group descriptive statistics are presented as mean ± standard deviation. The Wilcoxon nonparametric test was used to compare data collected before and after the operation. Significance was assessed as a p value of less than 0.05. Analyses were performed using BMDP statistical software (SPSS, Chicago, IL) [12].
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Results
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A left thoracoscopic approach was employed in 7 patients; a right approach was used in 1 patient due to the presence of diffuse adhesions in the left pleural cavity. Mean operative time was 139 ± 38 minutes. At pathologic examination no thymomatous transformation was found, although gross (n = 5) or microscopic (n = 3) residual thymic tissue was found in all instances. That tissue consisted of part of the thymic gland missed at initial thymectomy in 3 patients; in 5 other patients, it was classified as ectopic thymic tissue (Table 1). All patients were extubated within the first 3 hours after the operation. No patients died but 2 required reintubation and mechanical ventilation due to a myasthenic crisis. Subsequently, the 2 patients were successfully weaned from the ventilator at day 3 and 8, respectively, and minitracheotomy was performed to aspirate bronchial secretions. The mean hospital stay was 4.75 ± 2.8 days (range 2 to 10 days). The mean postoperative pain score was 2.5 at postoperative day one, and 1.37 at day three. Two patients had minimal pain (score 1) at one month, but no patient had pain at 6 months. The mean follow-up period was 28.3 ± 15 months (range 4 to 42 months), with no fatalities.
During follow-up 2 patients underwent five exchange cycles at 6 and 9 months, respectively, due to the occurrence of a myasthenic crisis. At the most recent follow-up examination, although no patient was in complete remission, 6 patients had significant improvement in bulbar and limb function compared with their preoperative status. In particular, significant differences in preoperative and postoperative values were observed in Osserman class (3.37 ± 0.5 to 2.12 ± 0.8, p = 0.03) and dosage of corticosteroids (43 ± 12 mg/d versus 20 ± 15 mg/d, p = 0.03). Neither pyridostigmine (300 ± 333 versus 180 ± 170 mg/d, p = not significant [ns]) or azathioprine (1.12 ± 1.5 versus 1.12 ± 1.5, p = ns) dosages nor the number of exchange cycles per year (5.6 ± 4.2 versus 1.25 ± 2.3, p = ns) changed significantly (Table 2). All patients in whom gross thymic tissue was removed improved after thoracoscopic completion thymectomy. All improved patients became able to carry out full daily activities and to return to work.
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Comment
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The involvement of the thymus in immune system dysfunction causing myasthenia is suggested by the beneficial effect of thymectomy (producing symptomatic remission or improvement) and by evidence of histologic and functional anomalies such as modified cellular composition, abnormal activation of lymphocytes, and sensitization of certain lymphocytes to acetylcholine receptors [1]. At long-term follow-up, symptomatic improvement has been achieved in 58%–97% [13, 14] of patients who underwent the procedure. Nonetheless, there is a variable and as yet significant percentage of patients who do not improve or even deteriorate further after thymectomy. Chronic immunosuppressive drug treatment is often required whenever disabling bulbar or generalized symptoms persist after thymectomy. However, refractoriness to the tolerated drugs and many side effects, including an increased risk of cancer, may be associated with such therapy [15]. Alternative nonoperative options are limited; they include plasma exchange, immunoglobulin infusion, and even total body irradiation [16]. Unfortunately, the beneficial effect of plasma exchange or infusion of immunoglobulin is temporary, and radiation therapy is only employed anecdotally because its efficacy has not been demonstrated. Radiation therapy may also lead to an increased risk of cancer [15].
The finding that residual thymic tissue is present in 64% [1] to 100% [2] of patients showing no response to or only partial improvement after thymectomy has led surgeons to carry out completion thymectomies. The technical goal of the procedure is removal of all residual thymic tissue that may have been missed in the anterior mediastinum and cervical area [17, 18]. Transsternal or combined transcervical-transsternal approaches have been employed in this setting to maximize radicality of resection [1–5]. Though effective, these aggressive approaches may lead to morbidity rates as high as 33% [6]. Moreover, pneumonia has been reported to occur after transsternal thymectomy in 21% to 44% of patients classified as Osserman grade 3 to 4 [19]. In our series, no pneumonia occurred but 2 patients experienced a myasthenic crisis during the in-hospital stay. We speculate that patients’ unstable clinical conditions may have contributed to an increased risk of postoperative exacerbation of myasthenic symptoms. Nonetheless, aggressive management including selected use of plasma exchange, mechanical ventilation, and minitracheotomy allowed us to limit the mean hospital stay to fewer than 5 days. Furthermore, the thoracoscopic approach may also have reduced postoperative pain, which can trigger the sequence of hypoventilation-atelectasis-pneumonia.
Transcervical thymectomy has frequently been implicated as a cause of incomplete thymectomy due to the poor exposure of the anterior mediastinum provided by this approach [2]. With that in mind, Henze and colleagues [2] performed transsternal completion thymectomy in 20 patients after initial transcervical thymectomy. In that study, gross residual thymus was always found. Standard transsternal thymectomy also has been implicated as a cause of unsuccessful thymectomy [4]. Joseph and Johns [20] hypothesized that the thymus might regenerate from residual cells having proliferative capacity. This hypothesis was also supported by Rosemberg and colleagues [1]. In our experience, 3 patients were found to have microscopic thymic remnants despite the long interval between operations (range, 62 to 180 months). Such a finding seems in contradiction with the hypothesis of a regenerative capacity of residual thymic cells, because if this were the case we should have found gross globular extraanatomic thymic foci in those patients.
Removal of only 2 g of residual thymic tissue has been considered therapeutic by Jaretzki and colleagues [4]. In our series, all patients in whom gross thymic tissue was removed improved after completion thymectomy, whereas only 1 out of 3 patients improved after removal of microscopic residual thymus. This result suggests that the beneficial effect of completion thymectomy might relate at least in part to the amount of thymic tissue removed at reoperation.
Improvement rate after completion thymectomy has ranged from 50% to 95% in reports from the literature (Table 5). Similarly in our series, 75% of reoperated patients achieved symptomatic improvement and were able to lower their corticosteroid dosage significantly. All improved patients became able to carry out full daily activities and to return to work. We believe that these results clearly correlated with the reoperation, because symptoms eased soon after the operation and the improvement remained stable during the follow-up. After an initial experience with transsternal completion thymectomy, we have preferred the thoracoscopic approach. We believe that it represents a reliable alternative to transsternal open approaches for several reasons: First, it is associated with minimal surgical trauma that did not compromise wide visualization and dissection of potential sites of residual thymus. Second, reexposure of the anterior mediastinum through the transsternal approach may be particularly demanding due to the presence of adhesions at the site of the innominate vein. On the other hand, it can be facilitated by employing a different route, such as the transpleural approach. Third, since these patients are receiving high doses of steroids, an increased risk of wound healing problems exists if a transsternal approach is employed. Fourth, magnified video imaging may allow better visualization of vascular and nervous structures and may help reduce the risk of injuring them during surgical maneuvers. Finally, the superior cosmetic effect of thoracoscopic completion thymectomy may facilitate acceptance of the procedure, as suggested by the finding that in our series 3 patients had previously refused a transsternal reoperation.
We have always employed adjuvant pneumomediastinum preoperatively, and we believe that this simple maneuver carried out about 24 hours before the operation is capable of ungluing mediastinal fat tissue from the pericardium and great vessels, thus facilitating both adhesiolysis and dissection of residual thymic tissue. To further extend the dissection, we recently employed an improved technique that allowed us to widen the retrosternal space by lifting the sternum, thus enhancing surgical access from the neck to the level of the thyroid gland.
A noteworthy finding in our series is that computed tomography and magnetic resonance correctly indicated residual thymus in 2 patients. Hence, in accordance with Husain and colleagues [21], we believe that radiologic evidence of residual thymic tissue or the finding of newly developed masses in patients with refractory myasthenia should strongly suggest a need for reoperation due to the risk of thymomatous transformation. Additional indications for completion thymectomy might include disabling side effects of immunosuppressive drug treatment, such as osteoporosis, hypertension, obesity, and nephropathy [16].
Thymectomy probably does not represent the sole answer in the treatment of autoimmune myasthenia, as shown by the finding that whatever the surgical approach, remission may be reasonably expected in not more than 50% of patients undergoing the operation [4, 23]. Whether this is due to incompleteness of thymectomy or to the effect of unrecognized factors remains a matter for speculation. Nonetheless, our experience suggests that completion thymectomy may be beneficial for selected patients with refractory myasthenia. This technically demanding procedure does not seem a contraindication for the thoracoscopic approach, since in this series there was no mortality, residual thymic tissue was always found, and significant symptomatic improvement was achieved in 75% of reoperated patients. Due to its low invasiveness and excellent cosmetic results, this novel option might be accepted more favorably than transsternal approaches by patients already frustrated by unsuccessful surgical and medical management.
In conclusion, our results add to the evidence that completion thymectomy may be beneficial for selected patients with autoimmune myasthenia who had required large doses of immunosuppressive drugs for many years after thymectomy; the findings therefore suggest that the thoracoscopic approach may prove as effective as open approaches in this setting. [22]
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Acknowledgments
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This work was performed under the appointment of Dottorato di Ricerca in Oncologia Toracica from Tor Vergata University and received 60% support from a grant awarded by the Ministero dell’ Università e della Ricerca Scientifica e Tecnologica (MURST).
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Accepted for publication March 21, 2000.
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Abstract
Introduction
