Keating, Cameron P. MBBS, BMedSc*; Kong, Yu X. MBBS*; Tay, Valerie MBBS, FRACP†; Knight, Simon R. MBBS, FRACS‡; Clarke, C. Peter MBBS, FRACS‡; Wright, Gavin M. MBBS, FRACS*
Myasthenia gravis (MG) is a neuromuscular disease that can be controlled but infrequently cured by medical therapy alone.1,2 Therefore, thymectomy has become an important treatment option in patients with MG, particularly in younger patients with generalized symptoms, to achieve symptomatic improvement or disease remission. A meta-analysis of 28 nonrandomized studies by Gronseth et al in 2000 concluded that thymectomy improved symptoms by 1.7 times and increased the rate of medication-free disease remission by a median of 2.1 times but could only recommend thymectomy “as an option,” to increase the probability of remission from MG, because of variability in the surgical literature.3
The initial approach to thymectomy was most commonly by median sternotomy. In recent decades, minimally invasive thymectomy for MG has become increasingly popular, but the optimal surgical approach still remains uncertain. Currently, there are up to 14 different surgical approaches to thymectomy, and they have been classified by the Myasthenia Gravis Foundation of America (MGFA) into five main categories, T-1 to T-5.4,5 In addition to transcervical (T-1), transsternal (T-3), combined transcervical-transsternal thymectomy (T-4), and infrasternal (T-5), minimally invasive thoracoscopic techniques (T-2) include video-assisted thoracoscopy (VATS) from either the right or left side, bilateral VATS, extended VATS (VATET), and robotic-assisted thymectomy (RATS). The benefits of minimally invasive thymectomy include decreased postoperative pain, improved cosmesis, better postoperative respiratory function, and shorter hospital stay.6–8 However, many practitioners still contend that thymectomy by open sternotomy achieves higher rates of disease remission.
Extended sternotomy achieves more complete microscopic thymic exenteration and is still considered to be the gold-standard treatment.9 Recent studies have reported similar clinical remission rates for right and left VATS thymectomy, VATET, and RATS.5,6,10 However, comparability between techniques has been limited by the use of different grading systems and lengths of follow-up. To improve on this, in the year 2000, the MGFA recommended the use of a standard clinical classification and Kaplan-Meier (KM) analysis of remission rates in future research studies.4
Although anatomic studies have demonstrated more complete microscopic exenteration with open sternotomy, it is unclear whether this leads to higher long-term clinical remission rates.9,11 This is critical because cosmetic concerns are important in a disease commonly afflicting young females. Also, because it is uncertain which is the optimal approach to thymectomy, the least invasive technique should be preferred providing safety and clinical outcomes are equal.
VATS thymectomy has been practiced in Australia since 1994, and we described our early experience with 26 patients in 2002.12,13 The purpose of this study was to update our clinical experience in 57 patients undergoing right VATS thymectomy for MG using KM analysis and the MGFA Clinical Classification (Table 1) to assess complete stable remission (CSR) rates in comparison to other techniques of thymectomy.
A retrospective analysis of consecutive patients undergoing VATS thymectomy for MG at two tertiary referral Thoracic Surgery units in Melbourne, Australia, was undertaken. Patients with thymoma or thymic carcinoma (19) were excluded and 2 were lost to follow-up. Fifty-seven patients had sufficient criteria for analysis. Data were obtained by two data collectors and compiled from medical records and neurologist notes. MG was diagnosed by a neurologist, and patients were investigated with acetylcholine (ACh) receptor antibody studies, Tensilon testing, spirometry, and a computed tomography scan of the chest to diagnose thymoma.
VATS thymectomy was performed by a three-port right side technique as described by Wright et al.12,13 Most patients were given plasmapheresis preoperatively and did not require an elective intensive care admission. Pain relief was provided by patient-controlled analgesia.
Both preoperative clinical severity and postoperative clinical outcomes were assigned as described in the MGFA Clinical Classification. Data were collated in a computer database (Microsoft Access version 2002, Microsoft Corp.) and analyzed using GraphPad Prism version 4.0 (La Jolla, CA USA). CSR rates and asymptomatic disease rates over time were analyzed using KM analysis to correct for different lengths of follow-up. Outcome curves of various prognostic factors of CSR were compared using the log-rank test. P values <0.05 were considered statistically significant.
Comparative studies detailed in Table 2 include a selection of the largest patient series in adults in each thymectomy classification (T-1 to T-5), from the past 25 years. Studies were limited to those reporting either crude remission or KM estimates of 5-year remission according to the MGFA Clinical Classification, in the English language literature. Articles were identified from the Pubmed, Medline, and Google Scholar databases using the search terms: myasthenia gravis, thymectomy, transcervical, VATS, transsternal, maximal, infra-sternal, and MGFA.
The experience with VATS thymectomy at our institution up until 2002 was reported previously.12,13 Updating our results from 1994 to 2007, including operations performed at one additional institution, we reviewed 78 VATS thymectomies. There were 17 thymomas and two thymic carcinomas excluded from analysis. Therefore, 59 VATS thymectomies were successfully performed for nonthymomatous MG. Two patients were lost to follow-up; hence, complete data were available in 57 patients.
Age, sex, postoperative clinical stage, and median length of stay are listed in Table 3. Postoperative histology yielded 18 normal/involuted thymus (31.6%) and 39 with hyperplasia (68.4%). There was a spread of preoperative disease severity from mild stage I disease to severe stage V disease with the highest number of patients in moderate stage II or III disease.
There were no conversions to sternotomy. Two patients experienced myasthenic crisis postoperatively requiring plasmapheresis or intravenous gamma globulin. There were three phrenic nerve palsies; two of these were transient and recovered within the first month. Three port-site infections requiring antibiotics occurred. There was a single mortality, although not during the immediate 30-day postoperative or inpatient period. A 59-year-old man with an 8-month history of stage IIa MG was managed on pyridostigmine and prednisolone preoperatively. He had an uncomplicated operation and was discharged 3 days later. He had achieved an asymptomatic disease state at 4 months on review and remained on pyridostigmine alone at less than one third of his previous dose. Unexpectedly, he experienced a respiratory arrest at 10 months after his operation. The overall morbidity rate was therefore 14% (8/57) and 1-year mortality rate 1.8% (1/57).
The rate of CSR increased over time to 28% at 5 years (Fig. 1): 1 year 5%, 2 years 10%, 3 years 15%, and 5 years 28%.
Asymptomatic MG is defined as patients in CSR off medications; those in “pharmacological remission” on certain medications; or “minimal manifestations” where patients have subtle signs on examination only. More than half of patients were asymptomatic at 5 years (Fig. 2): 1 year 12%, 2 years 24%, 3 years 39%, and 5 years 59%.
KM curves of disease remission stratified for prognostic factors including preoperative clinical stage (P = 0.55), histology (P = 0.25), gender (P = 0.8), age <40 (P = 0.92), and time to operation <12 months (P = 0.08) were drawn. No statistically significant prognostic factors for disease remission were identified, although earlier operation within 12 months of diagnosis did approach significance.
This study has demonstrated a 28% CSR rate at 5 years after right VATS thymectomy for patients with nonthymomatous MG, using MGFA criteria and KM analysis. This is the most important measure of clinical improvement because it implies a change in the natural history of the disease.14,15 Under this stricter definition, patients in CSR must be symptom free for at least 12 months and must not be taking anticholinesterases.4 At 5 years after thymectomy, 59% of patients are asymptomatic. This is another important clinical outcome, as most of these patients can go back to leading a full life. No significant prognostic factors for disease remission were identified. Overall, clinical outcomes after right VATS thymectomy are not inferior to other more invasive thymectomy techniques.
The use of the MGFA Clinical Classification aids comparability to other series. Table 2 lists the remission rates after a variety of thymectomy techniques (T-1 to T-5). Our series of 57 patients is the largest reported in the Australian literature and currently the third largest cohort reported on unilateral VATS using the described outcome criteria.5,16
Our CSR rate of 28% at 5 years is similar to other studies applying the MGFA Clinical Classification and KM analysis of CSR after minimally invasive (T-2) or open thymectomy (T-1 and T-3 to T-5). Reported 5-year CSR rates vary widely between an estimated 10% to 15% remission rate (from published KM curves) in the study by Manlulu et al (T-2a VATS) and 14.9% in Prokakis et al (T-4 transcervical-transsternal “maximal” thymectomy), up to 50.6% and an estimated 45%, respectively, in Mantegazza et al, in both T-2b VATET and T-3b extended transsternal thymectomy.10,17,18
The preoperative patient cohort is more severe in the study by Mantegazza et al10 (88.2%–100% stages III–V) compared with our series (65%), and this may partly explain a higher demonstrated remission rate in their series. It has previously been reported by the American Academy of Neurology that the more severe the degree of MG, the larger the magnitude of improvement after thymectomy.3,11 This rationale may also explain the lower remission rates in both the study by Manlulu et al (35.9% stages III–V) and Prokakis et al (38.5%), because of their milder preoperative MG cohorts.17,18
Furthermore, because there is longer mean follow-up in the study by Mantegazza et al10 (47 months) compared with our series (36 months), this may also explain higher CSR rates, as CSR increases with longer follow-up and KM analysis.
Our remission rate is also within the reported range for studies using non-MGFA outcome criteria, often with less strict definitions of disease remission, from minimally invasive (T-2), to cervical (T-1), open (T-3), maximal (T-4), and infrasternal (T-5) thymectomy. Reported crude remission rates vary between 15.8% in the study by Meyer et al (T-3a transsternal) and 16.7% in Rea et al (T-2c robotic), up to 57.8% in Huang et al (T-3a transsternal) and 55% in Meacci et al (T-2b VATET).19,20–22
Although life table analysis was performed by Masaoka et al, the reported remission rate has been classified as “crude” in Table 2 because this study was undertaken before the MGFA Clinical Classification in 2000, which defines CSR as requiring 12 months without symptoms or medications, with no demonstrable weakness on neurologic examination.4,23 In the study by Masaoka et al, remissions have been defined as patients without symptoms or medications, but it is not stated whether there was a minimum duration of this state required and whether neurologic examination excluded weakness. Nevertheless, this large series is commendable for its use of life table analysis and long follow-up of up to 20 years. These differences in remission definition and extent of follow-up may account for the higher reported remission rates of 45.8% at 5 years and 67.2% at 15 years compared with our study.23
Jaretzki et al14 also used life table analysis and reported remission rates of 81% at 89 months and a crude remission rate of 46%. However, the definition of remission in this study did not mention a minimum duration of symptom-free disease, and patient outcomes were assessed starting at a minimum of 6 months. Once again, variability in definitions may account for the reported superior remission rate.
Another factor affecting remission is individual neurologist preference for timing the wean of medications after thymectomy. It may be that some patients in our cohort would be classified in remission if their medications were weaned earlier; hence, we have used a broader definition of improvement, measuring those who are clinically asymptomatic. This includes CSR, pharmacological remissions (where patients remain on some medications), and minimal manifestations (where weakness is not noticed by the patient but only on neurologic examination). Our asymptomatic disease rate of 59% at 5 years is comparable to older definitions of remission and suggests that in many patients their MG is not simply improved by a decrease in a symptom grade or in medication dose, but rather they are functionally improved and able to lead a more active life including work.
Complication rates also vary widely in both minimally invasive techniques: 2% in the study by Ruckert et al (T-2c RATS), up to 11% in Manlulu et al (T-2a VATS); and open techniques: 2.7% in Park et al (T-3b extended transsternal thymectomy), up to 16.6% in Huang et al (T-3a transsternal).5,17,19,24 Our rate of 14% is higher than a number of studies listed in Table 2, but this may reflect our conservative approach to reporting all minor and major complications including myasthenic crisis, transient intercostal/phrenic neuropraxia, and minor wound infections.
Previous studies have demonstrated variously that age at operation,10,25,26 time to surgery,23,25,27 and preoperative clinical stage25,28 are prognostic factors for disease remission. None of these factors were statistically significant predictive factors of disease remission in our study. However, our cohort may lack sufficient power to demonstrate a difference or the follow-up time may be too short.
Anatomic studies have shown that combined transcervical-transsternal thymectomy (T-4) achieves more complete microscopic thymic clearance than other surgical techniques.9 However, it remains unclear whether total microscopic exenteration of the thymic bed is required for full clinical improvement. Thymectomy techniques have been grouped into categories based on anatomic clearance of the thymus, from T-1 (submaximal) to T-4 (maximal).4,29 However, there is no clear linear relationship in Table 2 to suggest that remission rates improve for T-2 techniques compared with T-1 and so forth. Future prospective head-to-head trials that diminish the bias produced by different preoperative disease severity, delays before surgery, neurologist practices, and follow-up will help clarify the relationship between anatomic resection and clinical remission.
The benefits of minimally invasive techniques over open techniques for improved cosmesis, less postoperative pain, shorter postoperative stay, and improved postoperative respiratory function are well described.6,8 As suggested by Jaretzki et al,30 the optimal thymectomy, “... balances extent of resection, morbidity, patient acceptance, and results.” Because numerous studies including our own, using standardized criteria, have demonstrated that minimally invasive techniques achieve similar clinical benefit compared with the gold-standard open technique, despite achieving less maximal microscopic thymic clearance, perhaps full microscopic exenteration and the added incisions involved are not required for optimal clinical improvement.
In conclusion, we have demonstrated a CSR rate of 28% and an asymptomatic disease rate of 59% at 5 years after right VATS thymectomy for patients with nonthymomatous MG. When compared with minimally invasive and open thymectomy techniques using both MGFA criteria and older definitions of remission, VATS thymectomy clinical outcomes are not inferior. Longer follow-up would allow better comparison in remission rates between this cohort of patients and other historical studies. However, the literature will remain unclear until a prospective randomized trial of minimally invasive thymectomy versus open sternotomy is reported.
The authors thank the following neurologists who allowed the investigators access to their private patient notes: Associate Professor Richard Gerraty, Professor Mark Cook, Professor Edward Byrne, Dr. Paul Talman, Associate Professor Peter Gates, Dr. Mark Paine, Dr. Katrina Reardon, and Associate Professor Justin O'Day.
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17. Manlulu A, Lee TW, Wan I, et al. Video-assisted thoracic surgery thymectomy for nonthymomatous myasthenia gravis. Chest
18. Prokakis C, Koletsis E, Salakou S, et al. Modified maximal thymectomy for myasthenia gravis: effect of maximal resection on late neurologic outcome and predictors of disease remission. Ann Thorac Surg
19. Huang CS, Hsu HS, Huang BS, et al. Factors influencing the outcome of transsternal thymectomy for myasthenia gravis. Acta Neurol Scand
20. Meacci E, Cesario A, Margaritora S, et al. Thymectomy in myasthenia gravis via original video-assisted infra-mammary cosmetic incision and median sternotomy: long-term results in 180 patients. Eur J Cardiothorac Surg
21. Meyer DM, Herbert MA, Sobhani NC, et al. Comparative clinical outcomes of thymectomy for myasthenia gravis performed by extended transsternal and minimally invasive approaches. Ann Thorac Surg
22. Rea F, Marulli G, Bortolotti L, et al. Experience with the “da Vinci” robotic system for thymectomy in patients with myasthenia gravis: report of 33 cases. Ann Thorac Surg
23. Masaoka A, Yamakawa Y, Niwa H, et al. Extended thymectomy for myasthenia gravis patients: a 20-year review. Ann Thorac Surg
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Myasthenia gravis (MG) spontaneous remission, nonsurgically managed, is estimated to be 8–15% and mostly temporary.1–2 (1. Buckingham JM, Howard FM, Jr., Bernatz PE, et al. The value of thymectomy in myasthenia gravis: a computer-assisted matched study. Ann Surg 1976;184:453–458. 2. Oosterhuis HJ. Observations of the natural history of myasthenia gravis and the effect of thymectomy. Ann N Y Acad Sci 1981;377:678–690). For nearly 6 decades, thymectomy has consistently been shown to improve or reduce the symptoms associated with myasthenia gravis. As the authors describe the Myasthenia Gravis Foundation of America (MGFA) has classified the different approaches and techniques by their capability of allowing perithymic tissue removal. Historically, sternotomy has been the mode of excision most frequently used, but patients and their referring neurologists have been less inclined to have thymectomy performed fearing the pain and potential disfigurement, in spite of the fact that the CR was superior to nonthymectomy-treated patients, at least 2-fold better.3–4 (3. Gronseth GS, Barohn RJ. Thymectomy for Myasthenia Gravis. Curr Treat Options Neurol 2002;4:203–209. 4. Gronseth GS, Barohn RJ. Practice parameter: thymectomy for autoimmune myasthenia gravis (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2000;55:7–15).
Other techniques such as the transcervical and transthoracic approach were developed and appeared to have excellent results, as well. Unfortunately, the different surgical techniques from different institutions were difficult to compare, so the MGFA defined complete remission (CR) as being off medication and symptom-free for 1-year, thus minimizing the inter-observer variability.
The video-assisted thymectomy (VATS) evolved over the last 20 years, but few have used the MGFA criteria to assess the long-term results of the procedure. This article demonstrates that in spite of using the more rigorous MGFA criteria, the VATS approach has excellent results similar to the results of the open sternotomy with minimal complications. These findings should encourage more patients and their referring physicians to consider thymectomy as the primary method of treatment for patients with nonthymomatous MG.
© 2011 Lippincott Williams & Wilkins, Inc.