Study objectives: Minimal-access thymectomy has become increasingly popular as surgical treatment for patients with nonthymomatous myasthenia gravis (NTMG) because of its comparable efficacy, safety, and lesser degree of tissue trauma compared with conventional open surgery. We reviewed and analyzed our data on video-assisted thoracic surgery (VATS) thymectomy and present the clinical outcomes according to the Myasthenia Gravis Foundation of America classification.
Design: A retrospective review of VATS thymectomy for NTMG in a university hospital over a 12-year period. Data were collected from the medical records and supplemented with telephone surveys. The impact of surgery and other variables potentially affecting complete stable remission (CSR) were calculated using Kaplan-Meier survival curves; comparisons between survival curves was performed using the log-rank test.
Results: A total of 38 consecutive patients underwent VATS thymectomy for NTMG. Median postoperative stay was 3 days. Pathologic examination revealed thymic hyperplasia in 61.1% of cases, normal thymus in 22.2%, and thymic atrophy in 16.6%. There was no perioperative mortality; complications occurred in four patients. After a median follow-up of 69 months, 91.6% of patients experienced improvement, with crude CSR achieved in 22.2%. Kaplan-Meier survival curve demonstrated a 75% CSR rate at 10-year follow-up. On univariate analysis, only disease duration [less than or equal to] 12 months (p = 0.03) was associated with a statistically significant improvement in CSR.
Conclusions: VATS thymectomy for NTMG results in symptomatic improvement in the vast majority of patients, with a high rate of CSR. The procedure is associated with low morbidity and no perioperative mortality. Future studies on thymectomy for myasthenia gravis should be reported in a standardized manner to allow accurate comparisons between results in the absence of randomized prospective trials.
Key words: minimally invasive surgery; myasthenia gravis; thymectomy; video-assisted thoracic surgery
Abbreviations: CSR = complete stable remission; MG = myasthenia gravis; MGFA = Myasthenia Gravis Foundation of America; NTMG = nonthymomatous myasthenia gravis; VATS = video-assisted thoracic surgery
Myasthenia gravis (MG) is a chronic autoimmune neuromuscular disorder of the postsynaptic acetycholine receptors resulting in striated muscle weakness and fatigue. In conjunction with medical therapy, thymectomy has been shown to increase the probability of remission and improvement; hence, it is offered as treatment in selected cases of MG. Although various surgical approaches to thymic resection exist, minimally invasive techniques have become increasingly popular due to their low procedural morbidity and mortality, improved cosmesis, lesser degree of access trauma, and equivalent efficacy compared to conventional open techniques. Due to the absence of randomized controlled trials concerning thymectomy in the treatment of MG, no consensus has been universally adopted with regards to the optimum surgical approach. In addition to the patient heterogeneity and fluctuating disease course inherent to MG, the issue of outcomes following thymectomy is further compounded by the use of various classification systems, differing practice guidelines, and lack of standardized reporting of results in the literature. Since 1992, we have offered a right-sided, video-assisted thoracic surgery (VATS) approach for thymic resection in selected patients with MG. Currently, the longer patient follow-up data available enable us to update our series on the outcomes following surgery for nonthymomatous MG (NTMG) reported in accordance with the clinical classification of the Myasthenia Gravis Foundation of America (MGFA). (1)
MATERIALS AND METHODS
A retrospective review was conducted on patients who underwent VATS thymeetomy from January 1992 to January 2004 at a university teaching hospital. For homogeneity of cohort, only patients with histologically confirmed NTMG were included in this study. A review of hospital records and telephone interviews were used in data collection and subsequent analysis. The information gathered was used to reclassify patients according to the MGFA clinical classification (Table 1).
The diagnosis of MG was based on the clinical presentation and supported by one or more of the following: Tensilon test, electromyographic studies, or acetyleholine receptor antibody studies. CT of the thorax was requested in all patients prior to surgery; the presence of an anterior mediastinal mass on CT excluded patients from this study. Criteria for inclusion were patients < 75 years old with NTMG on final pathology. When available, baseline preoperative spirometry was utilized to serially monitor FVC during the initial postoperative period, serving as an indicator of deteriorating respiratoly function. Selected cases of ocular MG were considered for surgery on an individual basis in consultation with a neurologist. In addition to anticholinesterase and steroid medication, preoperative IV immune globulin therapy was provided in four patients with myasthenic crisis requiring mechanical ventilatory support. IV hydroeortisone was administered to steroid-dependent patients immediately preoperatively and gradually weaned after surgeD, when oral steroid medication was resumed.
Thymectomy was performed with the patient in the lateral decubitus position utilizing a three-port, right-sided VATS approach in all cases under general anesthesia administered through a double-lumen endotracheal tube. Surgery was further facilitated by rotating the patient slightly toward the surgeon and flexing the table to widen the intercostal spaces. An incision anterior to the scapular tip along the posterior axillary line was made for insertion of a 0[degrees] telescope; the two other instrument ports were usually placed at the third intercostal space midaxillary line and sixth intercostal space anterior axillary line. In female patients, consideration was taken toward placing the instrument ports near the submammary crease for enhanced cosmesis. The operative procedure routinely involved removal of the entire thymus gland including the anterior mediastinal fat, with careful attention to preservation of the phrenic nerve and control of thymic venous tributaries draining into the left brachiocephalic vein. After careful attention to hemostasis, a chest tube was placed to drain the pleural cavity, and the right lung was reinflated under direct vision. A detailed description of the anesthetic and surgical technique was reported in our previous publications. (2-4) Immediate postoperative care consisted of early extubation and transferal to the ICU, where preoperative medications were resumed. Stabilized patients were transferred the following day to a general ward and discharged from hospital when a post-chest tube removal radiograph demonstrated expanded lung fields without significant pleural effusion and pain was adequately controlled with oral analgesia. Patients were followed up at 6-month intervals, where distribution and severity of muscle weakness were carefully assessed by a neurologist with specific interest in MG. The therapeutic response to surgery was determined by comparing the preoperative clinical status with the status recorded at last follow-up classified, according to the MGFA postintervention status (Table 2). This information was used to determine remission and improvement rates.
Taking into account the duration of follow-up, the CSR rate was calculated using the Kaplan-Meier method. Univariate analysis of variables potentially affecting CSR including age at operation ([less than or equal to] 40 years/> 40 years), gender, disease duration ([less than or equal to] 12 months/> 13 months), preoperative steroid use, and histology were calculated using the Kaplan-Meier method and survival curves compared with the log-rank test (Statistical Package for the Social Sciences; SPSS; Chicago, IL); p < 0.05 was considered statistically significant.
VATS thymectomy was performed on a total of 47 patients during the study period, 38 cases for NTMG. Two patients were unavailable for follow-up and excluded from analysis; hence, complete follow-up data were available in 36 patients (23 women, 63.8%). At time of surgery, mean [+ or -] SD age was 33.12 [+ or -] 13.24 years and mean duration of disease was 35.12 months (range, 2 to 204 months). The demographic profile is displayed in Table 3. Preoperative MGFA clinical classification is shown in Table 4. Prior to thymectomy, all patients were treated with antieholinesterase and 69.7% received steroid therapy.
Operative time ranged from 60 to 150 min (mean, 107 [+ or -] 21.7 min). Extension of the anterior wound was required in two cases (5.5%), both due to bleeding from a branch of the brachiocephalic vein that occurred early on in our experience. Median postoperative length of stay was 3 days. Pathologic examination of the thymus gland revealed hypeqplasia in 22 patients (61.1%), atrophic thymus in 6 patients (16.6%), and a normal thymus in 8 patients (22.2%). There was no perioperative mortality. Total morbidity rate was 11% with the following complications: a patient with Down syndrome and history of asthma acquired postoperative pneumonia necessitating prolonged ventilation and subsequent performance of a tracheostomy. Other complications included pneumonia in a patient with MG crisis requiring ventilatory support 5 days prior to surgery, urinary tract infection in one patient, and a case of right chest wall paresthesia. Median follow-up was 69 months, during which 91.6% of patients experienced improvement, with crude CSB achieved in 22.2% of eases (Table 5). The status of two patients remained unchanged after surgery. The first patient was a 42-year-old man with purely ocular MG (MGFA I) refractory to treatment with both anticholinesterase and steroid; this was an example of the unpredictable response of ocular MG to thymectomy. The other was a 46-year-old woman with MGFA IIA symptoms; given the relatively short duration of follow-up (4 months), a longer period of surveillance may be required before she improved. Important to note is that none of the patients experienced deterioration in their postintervention status during the last follow-up.
The Kaplan-Meier survival curve for CSR showed a gradual increase at 13 months, rising sharply at 117 months to 75% at 10-year follow-up (Fig 1). This underscores the need for prolonged surveillance when evaluating results of thymectomy for MG, as remissions often occur late in the course of follow-up. Univariate analysis using cumulative Kaplan-Meier survival curves were compared using the log-rank test according to the variables gender (p = 0.82), duration of disease [less than or equal to] 12 months/> 13 months (p = 0.03), preoperative steroid use (p = 0.75), and histology (p = 0.68). Age at surgery > 41 years and atrophic histology were not associated with CSR; therefore, analysis of these variables was not performed. The only factor associated with a statistically significant probability of CSR was disease duration [less than or equal to] 12 months, underscoring the need for surgery to be performed early after diagnosis of MG.
[FIGURE 1 OMITTED]
The lone mortality occurred in a 73-year-old man with generalized MG associated with an atrophic thymus; symptoms did not improve postoperatively, and 8 months after surgery he required readmission for respiratory failure and eventually succumbed. This case demonstrates the unpredictable natural history of patients with late-onset MG and is independent of the surgical approach used to perform thymectomy.
Less invasive thymectomy techniques do not necessarily equate to inferior results; in fact, outcomes for minimal access approaches have been reported to be equivalent to traditional sternotomy approaches. (5,6) This was highlighted in a prospective nonrandomized trial (5) that showed that CSR was not significantly different comparing thoracoscopic and extended sternal approaches. Furthermore, this conclusion was further strengthened by the fact that clinical stage distribution was similar between both the thoracoscopic and sternotomy groups. In addition to being safe and permitting a complete thymic resection, advantages associated with the VATS technique include but are not limited to a significantly less analgesic requirement and shortened hospital stay compared with transternal thymectomy. (7) Only rarely is conversion to sternotomy required (2.6 to 5.5%), and studies indicate a lower procedural morbidity as opposed to transternal thymectomy. Our 11% overall morbidity rate mirrors that of other minimally invasive approaches and compares favorably to the 33% reported for radical thymectomy. (8)
The lesser degree of chest wall trauma associated with VATS has resulted in better preservation of lung function postoperatively. (9) This may play an important role toward earlier extubation and reducing the incidence of postoperative pulmonary infections in patients with severe MG. In addition to the reduced pulmonary reserve as a result of sternotomy, the sternal repair can be complicated by instability, wire protrusion, and chronic poststernotomy pain. (10) Perioperative utilization of high-dose steroids in selected patients would also be a concern due to its recognized negative effects on wound healing. Particularly in young female patients comprising the majority of MG cases, these negative implications of having a sternotomy may serve as a deterrent to undergoing surgical treatment. Despite these issues, advocates of the radical approach claim that removal of ectopic thymus tissue is better accomplished through this technique; however, the actual incidence and clinical significance of ectopic thymus tissue on the subsequent results of surgery have not been well defined. Furthermore, the majority of ectopic thymus tissue is actually microscopic and may even be missed by radical thymectomy. (11) The transcervical approach has been described as an alternative to radical thymectomy; this technique is also associated with minimal access trauma, complete removal of the thymus gland and, importantly, reported remission rates are equivalent with the more radical approaches. (6,12,13) By comparison, VATS offers unique advantages over the transcervical approach. Because of the anatomic location of the thymus being a predominantly mediastinal structure, VATS favors a comprehensive thymectomy as a result of wider visualization of the chest, enhanced optical resolution, and magnification of anterior mediastinal structures. We view these factors as critical to proper dissection and performance of a complete thymectomy. In addition, VATS avoids potential pitfalls associated with transcervical thymectomy such as the crowding of instruments into a narrow access incision and restricted viewing of the operative field. This drawback limits the ability of the team to appreciate the progress of the procedure and may render learning the technique inherently difficult. Other important concerns are a relatively high rate of conversion to sternotomy (19%) consequent to poor exposure (6) and the necessity for re-exploration (27%) because of persistent refractory symptoms. (14) Interestingly, it has been shown that in patients who did not benefit initially from a transcervical or transternal approach, VATS completion thymectomy can be performed to remove residual thymic tissue resulting in subsequent improvement of symptoms. (11)
In this series, we detailed a crude CSR rate of 22.2%, which is comparable to the study by Savcenko et al, (15) who reported a CSR rate of 14% using the same MGFA criteria and similar operative approach. Both studies are also equivalent in terms of CSR and improvement rates with that of a multicenter trial, (16) suggesting the results of VATS thymectomy are readily reproducible. Although our CSR using the Kaplan-Meier method approaches 75% at 10-year follow-up, we acknowledge that our crude CSR rate appears to be lower compared with other reported studies (Table 6). There are several plausible factors to explain such findings. A review (17) conducted by the American Academy of Neurology reported that the more severe the degree of MG the larger would be the magnitude of improvement following thymectomy. In our patient cohort, 36.1% of subjects were MGFA stage III-V, compared to 55.47% in the series by Mantegazza et al. (5) Thus, the lower rate of CSR in this series may in part be due to the greater proportion of patients with milder disease (stage I-II). Of note, the percentage of patients receiving anticholinesterase and immunosuppressive drugs was greater, at 100% and 69.7%, respectively, as opposed to 46.5% and 53.5% in the study by Mantegazza et al. (5) This perhaps reflects a different medication prescription practice and management strategy among neurologists, the impact on outcome of which is difficult to qualify. A higher percentage of patients receiving medical therapy also translate into a greater number of patients needing to be weaned off medication before achieving CSR; this clearly has implications on rates of CSR and improvement if an aggressive medication weaning practice was adopted postoperatively. It has been postulated that shorter disease duration results in better outcomes after surgery; therefore, earlier thymectomy could theoretically lead to improved results. In our patient population, the mean preoperative duration of disease was 35 months compared with 14.8 months in the series reported by Mineo et al (18) and 10 months in the study by de Perrot et al. (6) The timing of surgery in our institution may reflect a delayed surgical referral pattern or prolonged medical treatment, hence accounting for a lower rate of CSR. Undoubtedly, differing methods of disease classification and outcome reporting render comparisons between thymectomy studies difficult. The effect of nonstandardized classification systems becomes readily apparent not only when attempting to establish initial disease severity but moreover when defining a specific outcome such as CSR. For example, duration of CSR according to the MGFA classification is twice as long as the criteria utilized by de Perrot et al (6) and Shrager et al. (13) Of note, other authors did not specify the time interval in their definition of remission (18,19); this clearly has implications on the overall rate of CSR, as there will be more patients achieving remission given a limited duration.
Thymectomy for MG has been shown to increase the probability of both remission and improvement; this positive effect is more evident in the younger age group, patients with generalized MG and thymic hyperplasia. (20) Consistent with the finding of greater improvement in association with younger age is the fact that all occurrences of CSR in this series were in patients who were [less than or equal to] 40 years old at operation. Another factor causally linked to significantly better CSR rates was surgery performed earlier in the course of disease ([less than or equal to] 12 months) as tested by univariate analysis. Other investigators (17,18) have reported similar findings, and this further lends credence to the concept of early thymectomy.
VATS thymectomy for NTMG results in symptomatic improvement in the vast majority of patients and is associated with a high rate of CSR. The procedure can be performed with minimal morbidity and no perioperative mortality. It is hoped that an effective, less invasive approach will gain increased acceptance among patients and lower the threshold of clinicians treating MG to recommend surgery earlier in the disease course. Future studies on surgical treatment of MG should be reported in a standardized manner to allow accurate comparisons between results in the absence of randomized controlled trials comparing surgical technique.
ACKNOWLEDGMENT: The authors thank Mr. Tse Yee-Kit of the Centre of Epidemiology and Biostatistics, the Chinese University of Hong Kong for assistance with statistical analysis.
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* From the Division of Cardiothoracic Surgery, the Chinese University of Hong Kong, Hong Kong, SAR, China.
Presented at American College of Chest Physicians, Cardiac and General Thoracic Surgery Updates, December 10-12, 2004, Scottsdale, AZ.
Manuscript received March 7, 2005; revision accepted May 1, 2005.
Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml).
Correspondence to Anthony P. C. Yim, MD, FCCP, Professor of Surgery, Chief of Cardiothoracic Surgery, Department of Surgery, The Chinese University of Hong Kong, Hong Kong, SAR, China; e-mail: email@example.com
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