469
57
Thymectomy for Myasthenia Gravis:
Optimal Approach
Joshua R. Sonett
consistent with level 2 evidence studies.4 Results indicated an overall benefi t for patients undergo- ing thymectomy versus medical treatment, with the following median relative rates associated with thymectomy: medication-free remission 2.1, asymptomatic 1.6, and improvement 1.7. Overall crude uncorrected results of patients undergoing thymectomy resulted in a median rate of remis- sion of 25%, an asymptomatic state of 39%, and an overall improvement rate of 70%. However, signifi cant confounding differences in baseline characteristics of prognostic importance existed between thymectomy and nonthymectomy pa - tient groups. The fi nal conclusion, based on the level of available evidence, was that the benefi t of thymectomy in nonthymomatous autoimmune MG has not been established conclusively, and that thymectomy is recommended as an option to increase the probability of improvement (level of evidence 2).
Perhaps one of the longest unresolved issues in thoracic surgery is the role of thymectomy in the treatment of myasthenia gravis (MG). Persistent questions and issues involve not only the surgical approach to thymectomy, but even the role of thymectomy itself in the treatment of myasthenia gravis. Many of these issues remain unclear because there is no level 1 evidence, and even level 2 evidence available to compare and analyze comparable study populations is limited. Results of many studies are as well not reported using appropriate Kaplan–Meier methodology, making analysis of the results even more challenging or ineffective.1 Additionally, myasthenia gravis is an entity in itself with varying degrees of severity, time courses, and self-remissions. Alfred Blalock, who pioneered and helped introduce thymec- tomy for myasthenia gravis beginning in 1939,2 was even noted in a comment in 1947 to show his doubts about the usefulness of thymectomy: “I thought we had an answer to the thymus in MG, but such does not appear to be the case”3; unfor- tunately this prophetic statement is still relevant.
57.1. Published Data
57.1.1. Thymectomy Versus Medical Treatment
To help analyze the published literature on the role of thymectomy in MG, Gronseth performed an evidence-based review of thymectomy in non- thymomatous MG between 1953 and 1998. In 310 articles discussing MG and thymectomy, 28 arti- cles, involving 8490 patients, were found to be
The benefi t of thymectomy in nonthymoma- tous autoimmune myasthenia gravis has not been established conclusively; thymectomy is recommended as an option to increase the probability of symptomatic improvement (level of evidence 2; recommendation grade B).
Thus, as we in the surgical community debate and analyze the actual different methods and techniques of thymectomy, the debate must be viewed in the context that conclusive evidence of the effi cacy of thymectomy is itself still lacking
many years after it was introduced as a therapeu- tic modality. To help defi ne conclusively the role of thymectomy in nonthymomatous MG, a pro- spective multi-institutional international trial, approved for funding by the National Institutes of Health (NIH), is planned to randomize patients to thymectomy versus medical treatment begin- ning in 2006.5
57.1.2. Surgical Approaches to Thymectomy
The surgical approaches to thymectomy are varied and refl ect the desire to perform a com- plete resection weighed against the magnitude and morbidity of the procedure. All approaches enable complete resection of the capsular thymus;
what differentiates the approaches are the extent of peri-thymic mediastinal and cervical tissue that are excised. To help understand the different approaches to thymectomy and categorize the extent of resections the Myasthenia Gravis Foun- dation of America (MGFA) has broadly classifi ed varying techniques of resection based on the operative approach and extent of surgical resec- tion (Table 57.1).6,7 In the ever dynamic surgical fi eld, robotic approaches (T-2 a) as well as bilat- eral thoracoscopic approaches (T-2 b) are evolv- ing. Overall individual case series have reported data that support the validity and success of all the approaches; however, the lack of prospective, case controlled studies do not provide a signifi - cant level of evidence that one thymectomy tech- nique is superior.4
Given the lack of defi nitive case controlled and prospective studies, this evidence-based review will highlight selective studies that are reported by established centers in the long-term treatment of MG. All data presented represents level 2 evi- dence. Additional literature review will examine the failure of thymectomy procedures, morbidity, and results of anatomical studies of the thymic resection. Simple comparison of reported remis- sions rates and partial remission rates or improve- ment can be and are misleading when evaluating treatment results. Many patients with MG will improve with time, thus any true refl ection of sur- gical results should include time after thymec- tomy. Unfortunately, the majority of the literature does not accommodate for time and are reported as simple crude calculations of remissions (improvement divided by the number of thymic resections). The best method for comparing and understanding results of the literature would be with life table analysis using the Kaplan–Meier method.8–10
57.1.1.1. Extended Trans-sternal Thymectomy Akira Masaoka11 of Nagoya University in Japan and Alfred Jaretzki12 of Columbia University in New York have been amongst the most articulate and persistent leaders in regards to the role extended or complete thymectomy in myasthenia gravis. In 1996, Masaoka and colleagues reported a 20-year review of their experience with extended thymectomy for MG.11 This procedure involves en bloc resection of the anterior mediastinal fat tissue form phrenic to phrenic laterally and the diaphragm and the thyroid gland caudally and cephalad. All adipose tissues in this region is meticulously resected, including around the bra- chiocephalic veins, thymus, and pericardium.
Cervical neck dissection is performed via the sternotomy incision, but aggressive dissection near the recurrent nerves is avoided. In a cohort of 286 patients, remission rates in nonthymoma- tous MG were 45.8% (5 years), 55.7% (10 years), and 67.2% at 15 years. Similar results have been consistently documented in other series of extended thymectomy. Analysis of multiple pub- lications utilizing extended thymectomy consis- tently fi nd pathological evidence of thymic tissue within the mediastinal fat out side the capsule of the primary thymus (Table 57.2).11–16
TABLE 57.1. Myasthenia Gravis Foundation of America (MGFA) thymectomy classification.6,7
T-1. Transcervical thymectomy a. Basic
b. Extended
T-2. Videoscopic thymectomy a. VATS
b. VATET
T-3. Trans-sternal thymectomy a. Standard
b. Extended
T-4. Transcervical and trans-sternal thymectomy
There is insuffi cient evidence to determine which thymectomy technique is superior in the management of myasthenia gravis.
57.1.1.2. Transcervical Thymectomy
Basic transcervical thymectomy (T-1a) as an alter- native to trans-sternal thymectomy was intro- duced on a large scale by Kirschner and colleagues in the late 1960s.17 However, widespread accep- tance of the procedure only followed the introduc- tion of a more extended and facilitated technique as presented by Cooper: “I do not like to get up and present a paper and look like a blithering idiot by telling people you can take out something through the neck when it is obvious to everybody that it is much easier to take it out through the chest.”18 Utilizing a sternal retractor to improve visualiza- tion and dissection of the thymus as well as peri- thymic fat, a series of 65 patients were presented with a 52% crude complete remission rate. These remission results have been consistently repeated by other groups, including Defi lippi [50% relative risk (RR)],19 and Calhoun (44% RR),20 combined with reports of minimal morbidity and an median length of hospital stay of less than 1.5 days.21
57.1.1.3. Video-Assisted Thorascopic Surgery Thymectomy, Extended Video-Assisted Thora- scopic Surgery Procedures Video-Assisted Thorascopic Extended Thymectomy
More recently, the evolution of videoscopic tech- niques has enabled excellent visualization and
minimally invasive techniques for thymic resec- tion. Early results were initially presented by a con- sortium of minimally invasive centers, describing the technique and safe encouraging initial results.
Mack and colleagues22 described 33 thymectomies (either left or right VATS) performed at three insti- tutions with an 18.6% RR at 23 months follow-up.
Yim and colleagues recently presented the most comprehensive experience with VATS thymectomy in 38 patients at a single institution. In this limited study, a crude RR (CRR) of 22% was achieved and a 75% CRR was found as measured by Kaplan–
Meier survival curve.23 In an effort to mimic the approach of the maximal thymectomy as described by Jaretzki, Novellino has described the VATET approach24: video-assisted thorascopic extended thymectomy, utilizing a small cervical incision and then bilateral thorascopic approach. In a very well- controlled level 2a series presented by Mantegazza, 159 patients underwent VATET, and at 6 years the CSR by life table analysis was 50.6%.25
57.1.1.4. Morbidity and Failures
Results of the evidence-based review by Gorsenth indicate a remarkably low mortality rate for any of the currently used procedures.4 Peri-operative mortality rates were found to be higher prior to1970, but after that time reported rates were found to consistently less than 1%. Additionally, with present day techniques of extended trans-sternal thymec- tomy, particularly with special attention to avoid- ance of injury to the recurrent nerves, morbidity rates for the methods are not signifi cantly different.
What is clear is that patients undergoing transcer- vical and thoracoscopic thymectomy procedures can be discharged earlier and have earlier return to daily activities and function. Importantly, limited but important data document the failure of initial thymectomy secondary to retained thymic tissue missed at initial exploration (Table 57.3).26–29 TABLE 57.2. Extent of thymic tissue recovered in peri-thymic
mediastinal fat tissue.
Reference Surgical approach Extracapsular thymic tissue Jaretzki11 Maximal 50 patients (98%) Masaoka12 Extended 18 patients (72%) Zielinski13 Extended 58 patients (56.0%) Ashour14 Extended 38 patients (39.5%) Scelsci15 VATET 27 patients (37%) Mineo16 VATS 31 patients (32%) Abbreviations: VATET, video-assisted thorascopic extended thymectomy;
VATS, video-assisted thorascopic surgery.
TABLE 57.3 Surgical resection of persistent thymic tissue after initial thymectomy.
Pathological thymus Myasthenias Reference No. patients Original procedure found at resection improvement
Henze26 20 Transcervical 20/20 19/20
Masaoka27 6 Transcervical 6/6 3/6
Miller28 6 Transcervical (3) 5/6 5/6
Basic trans-sternal (3)
Rosenberg29 13 Transcervical 11/13 6/13
Zielinski13 21 Transcervical (19) 17/21 Not reported
Trans-sternal (2)
57.2. Summary of Published Data
Unfortunately, it is clear that many answers and approaches to the treatment of MG remain unde- fi ned based on a critical analysis of the data.
Although there is no level 1 evidence supporting the role of thymectomy in MG, a preponderance of level 2 evidence supports the role of thymec- tomy in the treatment paradigm of MG. However, recent NIH support for a randomized trial of medical therapy versus thymectomy in the treat- ment of MG highlights the uncertainty of the evi- dence to date. In terms of the different surgical approaches to thymectomy, the literature does not defi nitively support any one particular surgi- cal procedure. This must be interpreted in the context of the preponderance of data being reported as crude data in generally small single- center experiences. These equivocal results must be weighed against clear pathological evidence of extracapsular thymic tissue in the majority of patients and limited but defi ned reports of retained thymic tissue being the cause of some initial surgical failures. Thus some form of com- plete thymectomy should be the goal of any sur- gical approach, and this has been shown to be feasible by all the approaches described.
57.3. Personal View and Clinical Practice
I strongly believe that the evidence to date sup- ports the role of thymectomy in the treatment of MG. This recommendation and practice is bol- stered by the modern day ability to perform the procedure with a very low morbidity and mortal- ity, thus fulfi lling the basic surgical tenant of risk versus benefi t. Given that recommendation and practice, I clearly understand the limits of the data to date, and would support the randomized trial of thymectomy versus medical therapy. But, as with any trial, I would have to bow to some of my biases, and would be reluctant to enter patients into the trial who present with signifi cant respi- ratory failure. In terms of surgical approach, my bias is toward some type of maximal or extended thymectomy. I believe this can be accomplished best by sternotomy or by bilateral VATS with pos- sible cervical exploration. However, this practice
paradigm must be viewed with the understand- ing that the published results to date do not clearly support any one particular approach and transcervical and unilateral VATS resection are used by many accomplished thoracic surgeons.
In the fi nal analysis, the onus is on the thoracic surgical community to investigate the potential surgical benefi t of thymectomy in MG. This benefi t, if proven, will allow us to proceed with further studies to best defi ne the appropriate and perhaps best approaches to resection as well as refi ne indications in terms of symptoms and timing of surgery. I thus would encourage and support the impending trial of thymectomy versus medical therapy in the treatment of MG.
References
1. Jaretzki A, Steinglass KM, Sonett JR. Thymectomy in the management of myasthenia gravis. Semin Neurol 2004;24:49–62.
2. Blacock A, Mason MF, Morgan HJ, Riven SS.
Myathenias gravis and tumors of the thymic region: report of a case in which the tumor was removed. Ann Surg 1939;110:544–561.
3. Clagett OT, Eaton LM. Surgical treatment of myathenias gravis. J Thorac Surg 1947;16:62–80.
4. Gronseth SG, Barohn RJ. Practice parameter:
thymectomy for autoimmune myasthenia gravis (an evidence-based review). Neurology 2000:55:
7–15.
5. Wolfe GI, Kaminski HJ, Jaretzki A III, Swan A, Newsom-Davis J. Development of a thymecotmy trial in nonthymomatous myasthenia gravis patients receiving immunosuppressve therapy.
Ann N Y Acad Sci 2003;998:473–480.
6. Jartzki A III, Barohn RJ, Ernstoff RN, et al.
Myasthenia gravis: recommendations for clinical research standards. Neurology 2000;55:16–23.
7. MG Task Force. Recommendations for Clinical Research Standards. 2002. Available from: http://
www.myasthenia.org/clinical/research/Clinical_
Research_Standards.htm
8. Masaoka A, Extended trans-sternal thymectomy for myasthenia gravis. Chest Silla Clin Na Am 2001;11:369–387.
9. Jaretzki A III. Thymectomy for myasthenia gravis:
an analysis of the controversies regarding tech- nique and results. Neurology 1997;48(suppl 5):
S52–S63.
10. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457–481.
11. Masaoka A, Nagaoka Y, Kotake Y. Distribution of thymic tissue at the anterior mediastinum. Current procedures in thymectomy. J Thorac Cardiovasc Surg 1975;70:747–754.
12. Jaretzki III, Wolff M. “Maximal” thymectomy for myasthenia gravis. Surgical anatomy and opera- tive technique. J Thorac Cardiovasc Surg 1988;96:
711–716.
13. Zielinski M, Kusdsal J, Szlubowski A, Soja J.
Comparison of late results of basic transsternal and extended thymectomies in the treatment of myasthenia gravis. Ann Thorac Surg 2004;78:
253–258.
14. Ashour M. Prevalance of ectopic thymic tissue in myasthenia gravis and its clinical signifi cance. J Thorac Cardiovasc Surg 1995;109:632–635.
15. Scelsi R, Ferro T, Novellino L, et al. Detection and morphology of thymic remnants after video- assisted thorcoscopic extended thymectomy (VATET) in patients with myasthenia gravis. Int Surg 1996;81:14–17.
16. Mineo CT, Pompeo E, Lerut T, Bernardi G, Coose- mans W, Nofroni I. Thoracoscopic thymectomy in autoimmune myastheni: results of left-sided approach. Ann Thorac Surg 2000;69:1537–1541.
17. Krischner PA, Osserman KE, Kark AE. Studies in myasthenias gravis. JAMA 1969;209:906–991.
18. Cooper JD, Al-Jilaihawa AN, Pearson FG, Hum- phrey JG, Humphrey HE. An improved technique to facilitate transcervical thymectomy for myathe- nia gravis. Ann Thorac Surg 1988:45:242–247.
19. DeFilippi VJ, Richman DP, Ferguson MK. Trans- cervical thymectomy for myasthenia gravis. Ann Thorac Surg 1994:57:194–197.
20. Calhoun RF, Ritter JH, Guthrie TJ, et al. Results of transcervical thymectomy for myasthenia gravis in 100 consecutive patients. Ann Surg 1999;
230:555.
21. Ferguson MF. Transcervical thymectomy. Semin Thorac Cardiovasc Surg 1999;11:59–64.
22. Mack MJ, Landreneau RJ, Yim AP, Hazelrigg SR, Scruggs GR. Results of video-assisted thymec- tomy in patients with myasthenia gravis. J Thorac Cardiovasc Surg 1996;112:1352–1360.
23. Manalulu A, Lee TW, Wan I, Law CY, Chang C, Garzon JC, Yim AP. Video-assisted thoracic surgery thymectomy for nonthymomatous myas- thenia gravis. Chest 2005;128:3454–3460.
24. Novellino L, Longoni M, Spinelli L, Andretta M, Cozzi M, Faillace G. Extended thymectomy without sternotomy performed by cervicotomy and thoracoscopic technique in the treatment of myasthenia gravis. Int Surg 1994;79:1378–1381.
25. Mantegazza R, Fulvio B, Bernasconi P, et al. Video- assisted thoracoscopic extended thymectomy and extended transsternal thymectomy (T-3b) in non- thymomatous myasthenia gravis patients: remis- sion after 6 years of follow-up. J Neurol Sci 2003;
212:31–36.
26. Henze A, Biderfeld P, Chrisensson B, Matell G, Pirsanen R. Failing transcervical thymectomy in myasthenis gravis. An evaluation of transternal re-exploration. Scand J Thorac Cardiovasc Surg 1984;18:235–238.
27. Masaoka A, Monden Y, Seike Y, Tanioka T, Kago- tani K. Reoperation after transcervical thymec- tomy for myasthenias gravis. Neurology 1982;32:
83–85.
28. Miller RG, Filler-Katz A, Kiprov D, Roan R. Repeat thymectomy in chronic refractory myasthenia gravis. Neurology 1991;41:923–924.
29. Rosenberg M, Jauregui WO, De Vewga M, Herrera MR, Roncoroni AJ. Recurrence of thymic hyper- plasia after thymectomy in myasthenia gravis. Its importance as a cause of failure of surgical treat- ment. Am J Med 1983;74:78–82.
