Video-assisted thymectomy for myasthenia gravis: an update of a single institution experience q

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1 European Journal of Cardio-thoracic Surgery 22 (2002) Abstract Video-assisted thymectomy for myasthenia gravis: an update of a single institution experience q Michal Savcenko, Gretchen K. Wendt, Syma L. Prince, Michael J. Mack* Cardiopulmonary Research Science and Technology Institute (CRSTI), 7777 Forest Lane, Suite A323, Dallas, TX 75230, USA Received 18 September 2001; received in revised form 27 August 2002; accepted 13 September 2002 Objective: Video-assisted thymectomy was introduced in 1992 as a minimally invasive alternative for the treatment of myasthenia gravis. As experience with this technique is limited and follow-up short, we present this expanded and updated experience for purposes of validation of the technique. Methods: Thirty-eight video-assisted thymectomies for myasthenia gravis were performed in our institution between March 1992 and March Two patients were lost to follow-up. We analyzed clinical results of 36 patients (14 males and 22 females) with a mean age of 41.2 years. Preoperative clinical staging was assessed by the newly recommended Myasthenia Gravis Foundation of America Clinical Classification. Clinical status at follow-up was assessed by the Myasthenia Gravis Foundation of America Postintervention Status classification. Results: There was no perioperative mortality or long-term morbidity. One of 38 (2.6%) patients required conversion to limited thoracotomy for bleeding. The mean length of hospital stay was 1.64 days (range 0 8 days) with a median stay of 1 day. The mean length of follow-up is months (range months). Overall clinical improvement at follow-up was observed in 30 of 36 (83.0%) patients, with five of 36 (14.0%) patients in complete stable remission. Conclusions: Video-assisted thymectomy for myasthenia gravis provides acceptable clinical long-term results by a minimally invasive approach comparable to standard surgical approaches to the disease. The presented data is reported in accordance with the new guidelines by Myasthenia Gravis Foundation of America Task Force for valid comparison with future studies. q 2002 Elsevier Science B.V. All rights reserved. Keywords: Video-assisted thymectomy; Thymectomy; Myasthenia gravis; Thoracoscopic thymectomy 1. Introduction Video assisted thymectomy was introduced in 1992 as a minimally invasive alternative for thymectomy in patients with myasthenia gravis. It was hoped that the less invasive thoracoscopic approach would be associated with less morbidity and greater patient acceptance leading to earlier thymectomy in more patients with the disease. We presented our initial experience of 13 patients as part of a multicenter experience in 1996 [1]. We updated our own center s experience in 1998 [2]. Appropriately, concern was raised in the literature regarding the ability to perform a complete thymectomy by a minimally invasive approach, therefore, leading to a potential compromise of the therapeutic result [3]. The purpose of this report is to provide the results in a larger group of patients with longer-term follow-up so that a q Presented at the joint 15th Annual Meeting of the European Association for Cardio-thoracic Surgery and the 9th Annual Meeting of the European Society of Thoracic Surgeons, Lisbon, Portugal, September 16 19, * Corresponding author. Tel.: ; fax: address: mjmack@earthlink.net (M.J. Mack). more firm assessment of the approach can be made. Because of the heterogeneity of the disease and variable course, comparison of the results of different approaches is difficult, if not impossible. In an attempt to rectify this problem, the Task Force of the Myasthenia Gravis Foundation of America (MGFA) has published new classifications for clinical status, therapy status, and postintervention status [4]. Accordingly, we have classified our current patients and reclassified our earlier patients according to these guidelines to serve as a benchmark for comparison by future studies. 2. Materials and methods A retrospective review was performed of 38 consecutive patients who underwent video-assisted thymectomy for myasthenia gravis (MG) by a single surgeon over a 10- year period between March 1992 and March Two patients are lost to follow-up. We therefore analyzed clinical outcomes of VATS thymectomy in the 36 evaluable patients. The data were collected and analyzed using medical records and telephone interviews /02/$ - see front matter q 2002 Elsevier Science B.V. All rights reserved. PII: S (02)

2 M. Savcenko et al. / European Journal of Cardio-thoracic Surgery 22 (2002) Our surgical technique has been well described elsewhere [1,2]. Although some evolution of the technique has occurred over the years, the principles have remained the same. We now routinely use the right-sided approach with four thoracoscopic ports (2 10 mm and 2 5 mm) with carbon dioxide insufflation, a complete resection of all anterior mediastinal tissue, extubation in the operating room, and no intensive care unit utilization. We have also extended our patient selection criteria to patients not traditionally candidates including elderly patients $ 55 years, with long-standing, refractory disease. Preoperative clinical staging was assessed by the newly recommended MGFA clinical classification (Table 1). Treatment mortality and morbidity was analyzed by the MGFA morbidity and mortality criteria (Table 2). Clinical status at follow-up was assessed by the MGFA postintervention status classification (Table 3). All patients who were assessed and operated upon before the new staging system, were restaged. 3. Results The study population consisted of 22 females (61.1%) and 14 males (38.9%). The mean age was 41.2 ^ years (range years). Initially 15 procedures were performed through a left thoracoscopic approach, while the subsequent 21 procedures were performed through a right thoracoscopic approach. There was no perioperative mortality or long-term morbidity. One patient (2.6%) required conversion to a limited right thoracotomy for Table 1 MGFA clinical classification Class Class I Class II IIa IIb Class III IIIa IIIb Class IV IVa IVb Class V Description bleeding, although transfusion was not required. All patients were extubated in the operating room. Two patients (5.2%), one patient with marked obesity and one patient in preoperative MGFA clinical classification V, required reintubation and respiratory support in the intensive care unit (ICU) for 24 and 72 h, respectively. Routine observation in the ICU was stopped after the initial five patients. The mean length of hospital stay was 1.64 ^ 1.86 days (median 1 day, range 0 8 days). Nineteen patients were discharged from the hospital on the day after surgery and one procedure was performed in an outpatient setting. The mean length of follow-up was ^ months (range months). Complete morbidity and mortality according to the MGFA classification is in Table 4. By preoperative staging by the MGFA clinical classification, one (3%) patient was in class I, nine (25%) patients in class IIa, four (11%) patients in class IIb, four (11%) patients in class IIIa, 12 (33%) patients in class IIIb, one patient in class IVa (3%), two patients in class IVb and three patients in class V. Overall, clinical improvement at followup was observed in 83.3% (30/36) of patients with five (14%) patients unchanged and 1 (3%) patient worse (Table 5). The changes in MGFA postintervention status classification at follow-up in relationship to preoperative MGFA clinical class are depicted in Table Discussion We now have a 10-year experience with video-assisted thymectomy. The technique remains controversial with Any ocular muscle weakness May have weakness of eye closure All other muscle strength is normal Mild weakness affecting other than ocular muscles May also have ocular muscle weakness of any severity Predominantly affecting limb, axial muscles, or both May also have lesser involvement of oropharyngeal muscles Predominantly affecting oropharyngeal, respiratory muscles, or both May also have lesser or equal involvement of limb, axial muscles, or both Moderate weakness affecting other than ocular muscles May also have ocular muscle weakness of any severity Predominantly affecting limb, axial muscles, or both May also have lesser involvement of oropharyngeal muscles Predominantly affecting oropharyngeal, respiratory muscles, or both May also have lesser or equal involvement of limb, axial muscles, or both Severe weakness affecting other than ocular muscles May also have ocular muscle weakness of any severity Predominantly affecting limb and/or axial muscles May also have lesser involvement of oropharyngeal muscles Predominantly affecting oropharyngeal, respiratory muscles, or both May also have lesser or equal involvement of limb, axial muscles, or both Defined by intubation, with or without mechanical ventilation, except when employed during routine postoperative management. The use of a feeding tube without intubation places the patient in class IVb

3 980 M. Savcenko et al. / European Journal of Cardio-thoracic Surgery 22 (2002) Table 2 MGFA morbidity and mortality Hospitalizations Number per year (average since onset Rx and no. in the last year) Days per year (average onset Rx & no. in the last year) Intensive care stays Number per year (average since onset of Rx & no. in the last year) Days per year (average since onset of Rx & no. in the last year) Ventilatory support Pre-Rx or during Rx Duration in place (days) Tracheostomy Pre-Rx or During Rx Duration in place (days) Infections Pulmonary Line Other Therapy-specific complication (name of drug and complication) Death (list cause, relation to therapy, and indicate whether therapy related. Include all deaths occurring during a hospitalization) Operative/postoperative Length of surgery (hours/minutes) Intraoperative complications Hospital stay (days) Intensive care stay (days) Ventilatory support (days) Infection (location, type, and severity) Transfusions (number) Nerve injury (phrenic/recurrent/intercostal-temporary/permanent) Persistent pain (severity, duration, and therapy) Chylotharax (severity, duration, and therapy) Death (occurring within 30 days of surgery, even if the patient has been discharged, and occurring after 30 days when clearly related to the surgical procedure. Deaths within 90 days of surgery should also be recorded) some misconceptions persisting. Many surgeons still do not accept it as equivalent to conventional approaches [3,4]. A minimally invasive approach does not necessarily mean minimal exposure. VATS thymectomy, despite the minimal access approach, provides excellent exposure and visualization of all anterior mediastinal and cervical tissue because of the magnification and lighting associated with the video technique. We continue to feel confident that the resection of anterior mediastinal tissue can be as complete by thoracoscopic approach as by open techniques. In our experience there is less postoperative pain, less intensive care unit utilization, better cosmesis, and shorter hospital stay using this approach. Experience with the video-assisted approach for thymectomy in myasthenia gravis is still limited with only relatively small experience from a few centers published. Mineo et al. have reported a 96% improvement rate at 48 months in 31 patients by a left-sided approach [5]. The same group has also described the same approach for a completion thymectomy in eight patients after a previous transternal or transcervical approach [6]. More recently Gramone et al. have reported an infra-mammary video-assisted approach in 71 patients with an 80% clinical remission rate at 12 months [7]. A technique by Takeo et al. for video-assisted extended thymectomy has also been recently reported [8]. We presented our early experience by a predominately left thoracoscopic approach in 1996 as part of a multi-center experience. In our 33 patients (13 of our own) we reported an 18% remission rate and an 88% improvement rate at a mean follow-up of 23 months. We further updated our experience of 20 patients at a mean of 20 months followup with an 85% improvement rate in 1998 [2]. We now present our complete experience over a 10-year period. In 38 patients at a mean follow-up of 41 months, our complete remission rate is 14% and clinical improvement rate 83%. We have previously published a meta-analysis of outcomes by various techniques [2]. At follow-up periods ranging from a mean of months, complete remission rates range from 17 to 52% and clinical improvement from 57 to 97%. Although overall improvement rate in myasthenia symptoms after VATS thymectomy in our series seems to be equivalent to the more invasive approaches, we are aware that the complete stable remission (CSR) still seems to be somewhat lower. There can be a number of explanations for this, including the more strict and precise classification of CSR status by the new classification and inclusion of more elderly patients with more advanced disease. Further validation of this approach for thymectomy, however, awaits longterm follow-up and accurate comparison to outcomes of the more traditional approaches using new assessment guidelines. However, the complexity of myasthenia gravis in pathologic findings, clinical presentation, course of the disease and response to treatment makes objective assessment difficult. There was a need for universally accepted classifications and methods of analysis for patients undergoing therapy for MG in order to achieve more uniformity and objectivity in outcome analysis. The Task Force of the MGFA developed new guidelines for clinical research standards [3]. The MGFA clinical classification (Table 1) in combination with Quantitative MG Score for Disease Severity provides a more objective and quantitative assessment of the disease. The MGFA postintervention status classification (Table 3) provides precise and detailed assessment of treatment outcomes. We feel that strict adherence to the newly recommended MGFA classification should accomplish more precise reporting of posttreatment outcomes in myasthenia patients, and thus increase the accuracy of statistical comparisons between the studies. Based on our experience we have eliminated the need for an intensive care unit for postoperative care and have begun

4 Table 3 MGFA postintervention status classification M. Savcenko et al. / European Journal of Cardio-thoracic Surgery 22 (2002) Status Description Complete stable remission (CSR) Pharmacologic remission (PR) Minimal manifestations (MM) MM-0 MM-1 MM-2 MM-3 Improved (I) Unchanged (U) Worse (W) Exacerbation (E) Died of MG (D of MG) to perform the procedure in an outpatient setting. In addition, because of the minimal morbidity associated with the procedure, we have begun to offer thymectomy to patients not traditionally considered candidates for thymectomy due to advanced age, long-standing disease, and without detectable thymic tissue by preoperative scanning. We have experienced the ability to improve the clinical status and Table 4 MGFA operative morbidity and mortality The patient has had no symptoms or signs of MG for at least 1 year and has received no therapy for MG during that time. There is no weakness of any muscle on careful examination by someone skilled in the evaluation of neuromuscular disease. Isolated weakness of eyelid closure is accepted The same criteria as for CSR except that the patient continues to take some form of therapy for MG. Patients taking cholinesterase inhibitors are excluded from this category because their use suggests the presence of weakness The patient has no symptoms of functional limitations from MG but has some weakness on examination of some muscles. This class recognizes that some patients who otherwise meet the definition of CSR or PR do have weakness that is only detectable by careful examination The patient has received no MG treatment for at least 1 year The patient continues to receive some form of immunosuppression but no cholinesterase inhibitors or other symptomatic therapy The patient has received only low-dose cholinesterase inhibitors (,120 mg pyridostigmine/day) for at least 1 year The patient has received cholinesterase inhibitors or other symptomatic therapy and some form of immunosuppression during the past year A substantial decrease in pretreatment clinical manifestations or a sustained substantial reduction in MG medications as defined in the protocol. In prospective studies, this should be defined as a specific decrease in QMG score No substantial decrease in pretreatment clinical manifestations or a sustained substantial reduction in MG medications as defined in the protocol. In prospective studies, this should be defined in terms of a maximum change in QMG score A substantial increase in pretreatment clinical manifestations or a sustained substantial reduction in MG medications as defined in the protocol. In prospective studies, this should be defined as a specific increase in QMG score Patients who have fulfilled criteria of CSR, PR, or MM but subsequently developed clinical findings greater than permitted by these criteria Patients who died of MG, of complications of MG therapy, or within 30 days after thymectomy reduce the steroid regimen in a few of these refractory patients. Comparison of results of different therapeutic approaches is only possible with standardized classification and reporting. As such, we have classified the preoperative clinical status of all our patients, the operative mortality and morbidity, and the postintervention status by the MGFA task force guidelines. When the results of experience in other centers are reported by the same standardized criteria with the various surgical approaches, we may be better able to determine the efficacy of the various surgical approaches. Length of surgery Intraoperative complications Hospital stay Intensive care days Ventilatory support Infection 0 Transfusions 0 Nerve injury 0 Persistent pain 0 Chylothorax 0 Death 0 1 h 42 min (45 min to 3 h 10 min) 1: Conversion to thoracotomy for bleeding 1.64 days (0 8 days) 0.23 days (0 4 days) 0.15 days (0 3 days) Table 5 MGFA postintervention status results Status No. of patients (%) Complete stable remission (CSR) 5 (14%) Pharmacologic remission (PR) 3 (8%) Minimal manifestations (MM) 14 (39%) Improved (I) 8 (22%) Unchanged (U) 5 (14%) Worse (W) 1 (3%)

5 982 M. Savcenko et al. / European Journal of Cardio-thoracic Surgery 22 (2002) Table 6 MGFA postintervention status in relationship to preoperative MGFA clinical class MGFA class n Complete stable remission (CSR) Pharmacologic remission (PR) Minimal manifestation (MM) Improved (I) Unchanged (U) Worse (W) % I IIa IIb IIIa IIIb IVa IVb V Total % References [1] Mack MJ, Landreneau RJ, Yim AP, Hazelrigg SR, Scruggs GR:. Results of VATS thymectomy in patients with myasthenia gravis. J Thorac Cardiovasc Surg 1996;112:1352. [2] Mack MJ, Scruggs G. VATS thymectomy for myasthenia gravis. Chest Surg Clin North Am 1998;8:809. [3] Jaretzki III A. Thymectomy for myasthenia gravis: analysis of the controversies regarding technique and results. Neurology 1997;48:S52 S63. [4] Jaretzki III A, Barohn RJ, Ernstoff RM, Kaminski HJ, Keesey JC, Penn AS, Sanders DB:. Myasthenia gravis: recommendation for clinical research standards. Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America. Ann Thorac Surg 2000;70(1): [5] Mineo TC, Pompeo E, Lerut TE, Bernardi G, Coosemans W, Nofroni I. Thoracoscopic thymectomy in autoimmune myasthenia: results of leftsided approach. Ann Thorac Surg 2000;69: [6] Pompeo E, Nofroni I, Iavicoli N, Mineo TC. Thoracoscopic completion thymectomy in refractory nonthymomatous myasthenia. Ann Thorac Surg 2000;70: [7] Granone P, Margaritora S, Cesario A, Galetta D. Thymectomy in myasthenia gravis via video-assisted infra-mammary cosmetic incision. Eur J Cardiothorac Surg 1999;15: [8] Takeo S, Sakada T, Yano T. Video-assisted extended thymectomy in patients with thymoma by lifting the sternum. Ann Thorac Surg 2001;71: Appendix A. Conference discussion Mr J. Thorpe (Leeds, UK): VATS obviously lends itself well to thymectomy. Neither of the papers has talked about the pathological results and the correlation between the symptoms and the pathology, which I think is important, and one of the basic rules of the operation is to have complete clearance of all thymic tissue, maybe ectopic thymic tissue, in the mediastinum. How confident are you that this operation is as good as an open operation in terms of complete pathological clearance? Dr Savcenko: We had six thymomas in the whole series. In the first 20 patients there were six enlarged, 13 patients who didn t have any. Preoperatively all patients are evaluated by CT scan the same as for any open procedure before surgery as far as you can say staging of thymoma is concerned. They were all encapsulated, very small stage I thymomas by Masaoka s classification. Of course, until you take it out and have evaluated the specimen by gross and histologic examination can one determine how extensive is the resection, we can evaluate it just the same as with an open thymectomy from the time back when you evaluate it after you remove the thymus and all anterior mediastinal tissue and from the specimen, what you get out. So evaluation is actually the same. So we are very confident that we are getting it all. You never know, even in open procedure, if you get all extra-anatomic microscopic thymic tissue, the same way you will never know in the VATS procedure. But the same principle applies for both approaches: do complete thymectomy and do maximal exenteration of all anterior mediastinal tissue. Dr T. Grodzki (Szczecin, Poland): It was a very nice presentation and good advertising of a new classification, but I couldn t see any specific advantages of this new classification over the old ones. You didn t compare them. Could you comment on that? Dr Savcenko: Absolutely. There is not enough time to go through this whole comprehensive booklet of this new classification. Most importantly, the authors hope that this classification would become more uniformly used as opposed to presently not so uniformly used various different preoperative classifications like the Osserman classification, modified Osserman and Genkins classification or Oosterhuis classification. Secondly, I did not have the slide on this because there is not enough time. Very important is the quantitative evaluation. Quantitative scoring would supplement those main categories I showed you. In order to put patients in class I, class II, class III, you have to not only evaluate just which muscle group is involved, but there is precise, very precise indication about the severity of muscle weakness. So this would give you a quantitative evaluation. Those are the most important points. Dr R. Schmid (Bern, Switzerland): We are also very interested in this new approach and we performed it. On the other side we carefully looked at our old data with 13 years of follow-up. Two questions: 20 or 25% of complete remission is not the same as the 30 40% which were achieved with the open approach. It is not proven at all that the results are the same in respect to complete remission, and complete remission I think is the main issue we have to look at. An improvement of 80% is okay and comparable to the old data, but we observed that the results in almost all studies in the literature deteriorate over time, and we therefore have to look at long-term outcome. I think we should avoid a premature conclusion. Thoracoscopy is an excellent approach, cosmetically good, and more patients might accept the operation, but we cannot say at the moment that the results of the thoracoscopic approach are the equal of the open technique. Dr Savcenko: Absolutely not, and unfortunately we cannot do a randomized study. There are not enough patients so that you could randomize them for either approach. In the old classification we would probably have up to a 35% incomplete state of remission, but by this new classification it is much lower because it is much more strict. But I agree with you. As I showed in the last slide, time alone will tell. There are still only 41 months of follow-up. Five years and more would be really necessary to have some real conclusions for that. Professor A. Yim (Shatin, Hong Kong): I rise to congratulate the Dallas group to be among one of the first to use this new MGFA Clinical Classification. This is a very detailed classification system meant to be used prospectively. Did you encounter much difficulty trying to apply this retrospectively on your patients who already had surgery?

6 M. Savcenko et al. / European Journal of Cardio-thoracic Surgery 22 (2002) Dr Savcenko: Absolutely. That is an excellent question. It doesn t make any sense to have a strict classification and not have enough information about it. In those retrospective studies like this and when we go back, from now on it will be much easier because everything will be routed in this classification. It took us a lot of time through the neurologists, patients, of course, and medical records to go back and precisely detail what was done 8 years ago. From now on it will be much easier. But that is an excellent question.