NEUROMUSCULAR COUNCIL CONSENSUS STATEMENT

1. NEUROMUSCULAR COUNCIL CONSENSUS STATEMENT THYMECTOMY FOR NONTHYMOMATOUS AUTOIMMUNE MYASTHENIA GRAVIS PATIENTS

2. Introduction

3. Through the years many neurologists have favored the use of thymectomy in the management of patients with nonthymomatous autoimmune myasthenia gravis (MG). This wide acceptance is based largely upon case series and retrospective studies which have suggested that thymectomy may be beneficial. However, many of these studies have shown variable results. Moreover, the absence of controlled, prospective trials casts some doubt regarding effectiveness of the procedure in this group of patients. Thus, until the results of an ongoing international, prospective, single blind randomized trial controlling for medical therapy become available, the use of thymectomy in this situation remains controversial.

4. In the local medical centers where thymectomy is being performed, no standard guidelines in the selection of patients and the pre- and post-operative management have been created. This necessitates the formulation of such guidelines.

5. Objectives

6. General Objective The Neuromuscular Council of the Philippine Neurological Association aims to improve outcomes for MG patients by providing the initial framework for decision-making for neurologists with regard to the patient diagnosed with nonthymomatous autoimmune MG who is a candidate for thymectomy.

7. Specific Objective To develop a combined evidence- and consensus-based practice parameter to guide neurologists in managing patients diagnosed with nonthymomatous autoimmune myasthenia gravis who can be candidates for thymectomy.

8. Methodology

9. Group Composition The working group is composed of the members of the Neuromuscular Council of the PNA. Dr. Lina Renales Dr. Rosalia Teleg Dr. Valmarie Estrada Dr. Darwin Dasig Dr. Emmanuel Eduardo Dr. Alejandro Diaz Dr. Raymond Rosales Dr. Jose Paciano Reyes Dr. Ludwig Damian Dr. Marita Dantes

10. Consensus Process The initial draft of the consensus statement was a synthesis of the survey, identification of the key clinical issues, output of literature search using Medline and the local registry and academic deliberation by the working group over the identified key issues. Deliberation included appraisal of the literature in terms of validity and applicability, preparation of evidence-based summaries and development of judgments by consensus. This is to be followed by presentation of the statements in a public forum composed of the PNA fellows.

11. Disclaimer: The assessment and recommendations provided herein represent the best professional judgment of the working group at this time, based on research data gathered and on expertise currently available. The conclusions and recommendations will be regularly assessed as new information becomes available. The consensus statement is intended to be an educational guideline and is therefore neither rigidly prescriptive nor restrictive.

12. Key Clinical Issues Addressed

13. Should thymectomy for nonthymomatous myasthenia gravis be recommended? • What is the clinical profile of nonthymomatous autoimmune MG patients likely to benefit from thymectomy? • When is the ideal time to perform thymectomy?

14. What is the preferred thymectomy technique to use? • What is the recommended pre-operative management? • What is the recommended post-operative management?

15. Consensus Proper

16. QUESTION 1: Should thymectomy for nonthymomatous autoimmune myasthenia gravis be recommended?

17. A. Consensus Statement Practice Recommendation For patients with nonthymomatous autoimmune MG, thymectomy is recommended as an option to increase the probability of remission or improvement (Level 2 evidence). Research Recommendation There is a need to conduct a well-designed, prospective, controlled study to evaluate clinical effectiveness of thymectomy in nonthymomatous, autoimmune myasthenia gravis patients that utilize comparison with standardized medical therapy and well-defined evaluation standards.

18. B. Summary of Evidence To address the uncertainty of the usefulness of thymectomy in nonthymomatous autoimmune MG because of the lack of prospective and controlled studies, the working group utilized the systematic review done by the American Academy of Neurology.1 Their review of 28 articles (Class II evidence 2) published from 1953 to 1998 describing outcome in 21 MG cohorts revealed the following observations:

19. Positive associations in most studies between thymectomy and MG remission and improvement with median rates of 2.1 for medication-free remission, 1.6 for asymptomatic group and 1.7 for improvement; • Confounding differences in baseline characteristics of prognostic importance between thymectomy and nonthymectomy groups in all studies;

20. Persistent positive associations between thymectomy and improved outcomes after controlling for single confounding variables such as age, gender and severity of MG; • Conflicting associations between thymectomy and improved MG outcomes in studies controlling for multiple confounding variables simultaneously.

21. They concluded that it cannot be determined from available studies whether the observed association between thymectomy and improved MG outcome was a result of thymectomy benefit or was merely a result of multiple differences in baseline characteristics. Thus, the benefit of thymectomy in nonthymomatous autoimmune MG has not been established conclusively.

22. QUESTION 2: What is the clinical profile of nonthymomatous autoimmune MG patients most likely to benefit from thymectomy?

23. A. Consensus Statement Practice Recommendation The candidate most likely to benefit is the patient with all of the following attributes (Level 2 evidence): • generalized MG • age between puberty and 60 years and • positive titers for anti-Acetylcholine Receptor Antibody (anti-AChR Ab) when applicable • female gender

24. Research Recommendation There is a need to conduct a well-designed prospective, controlled study to evaluate clinical outcome after thymectomy with respect to the disease variables (e.g. grade or severity of the illness, age of the patient, gender, duration of the disease, etc.), treating these variables singly or in combination.

25. B. Summary of Evidence • Gender Women have been reported to have a better outcome than men after thymectomy • Age • There is general consensus that patients with generalized MG between puberty and 60 years will benefit from thymectomy. • Most MG experts advocate cutoff ages ranging between 50 to 70 years with median at 60 years. • Thymectomy has been performed with favorable results in childhood. Procedure, however, remains controversial in younger children with ages ranging from 1 year to puberty.

26. Clinical Severity • Patient subgroup analysis in one studyindicated that only those patients with MG with moderate weakness or greater (Osserman 2B3 / MGFNA4 ) showed significant improvement after thymectomy compared with control subjects. Results, however, were confounded by baseline patient differences across groups. • The studies reviewed did not include patients with pure ocular MG. • Severe patients who underwent thymectomy had better prognosis compared with severe patients who did not.

27. Duration of Disease No data have been gathered as yet regarding measurement of outcome after controlling for single confounding variable like duration of disease (whether within 1-2 years from onset or beyond 2 years from onset). No conclusive data likewise are available associating improved MG outcome with thymectomy after controlling for multiple confounding variables.

28. QUESTION 3: When is the ideal time to perform thymectomy?

29. A. Consensus Statement Practice Recommendation Thymectomy is best performed within 1 to 2 years from the time of diagnosis provided that the patient has achieved: • optimal muscle strength and • optimal medical condition • adequate cardio-pulmonary functions (Level 2 evidence)

30. Research Recommendation There is a need to conduct a well-designed prospective, controlled study to evaluate clinical outcome after thymectomy with respect to the timing of surgery.

31. B. Summary of Evidence Some authors suggested that benefits from thymectomy were achieved more readily the earlier the surgery was done, with larger remission rates per unit time (Class III evidence). However, it has been postulated that this may be solely due to non-linear rate at which MG patients achieve remission after diagnosis. This means that for a given duration of time, MG patients are more likely to remit earlier than later.

32. QUESTION 4: What is the preferred thymectomy technique to use?

33. A. Consensus Statement Practice Recommendation Properly performed total thymectomy using the Extended Transsternal Approach may provide the greatest resection with low morbidity and less risk for recurrent laryngeal nerve injury (Level 2 evidence). Research Recommendation There is a need to conduct a well-designed prospective, controlled study to evaluate clinical outcome after thymectomy with respect to the different thymectomy technique.

34. B. Summary of Evidence The report of the Quality Standards Committee of the American Academy of Neurology1 concluded that the outcome comparisons between uncontrolled studies do not provide conclusive evidence of the superiority of one technique over another. This was due to the numerous confounding differences in patients’ baseline characteristics and new confounders (institutional, geographic and historical differences).

35. Likewise, controlled trials reviewed failed to provide convincing evidences that one technique was superior, again due to the confounding differences and inconsistent results. Moreover, operative techniques employed were either not identified or limited to standard transsternal and basic transcervical thymectomy.

36. The review of the retrospective studies3 that waspublished after the AAN Guidelines publication concluded that the studies had conflicting results and had many confounding variables such as patient population, accompanying therapy, details of evaluation, extreme variability and unpredictability of MG, variability of selection of patients for thymectomy and immunesuppressives drugs after surgery. The need for properly designed prospective trials or a non-randomized prospective study of two or more techniques remains.

37. In a separate article4 ,Jaretzski had written that the more complete the thymic resection, the better the outcome. A retrospective trial comparing the late results of basic transsternal and extended transsternal thymectomies5revealed that complete remission rates were significantly higher in the extended group at 1, 2, 3 and 4 years follow-up (Level 2 evidence). Negative results (no improvement, deterioration or death from MG) were significantly lower in the extended thymectomy group. The difference was postulated to be due to the removal of ectopic foci of thymic tissue from the neck and mediastinum.

38. Mantegazza et.al. performed a prospective, uncontrolled trial comparing video-assisted thoracoscopic extended thymectomy (VATET) and T3-B operative techniques6and concluded that VATET seems to be effective in inducing complete stable remission similar to T-3B TS approach (Level _ evidence). VATET had the advantage of being easier to perform and having lower morbidity and negligible esthetic sequelae.

39. QUESTION 5: What is the recommended pre-operative management?

40. A. Consensus Statement The objective of a pre-operative management is to ensure that there will be careful selection of patients for thymectomy to optimize its long term benefits. The patients must be in optimum medical condition prior to surgery to avoid or minimize intraoperative and post-operative complications. Management in the peri-operative period requires a concerted effort among the neurologist, thoracic surgeon, pulmonologist and other internists, the anesthesiologist and the physiatrist.

41. Practice Recommendation 5.1 What are the steps to follow during pre-operative management? 1. Perform a thorough neurologic evaluation and clearance: Ensure that the patient has optimum muscle power. When appropriate, correct oropharyngeal, bulbar and respiratory muscle weakness using the following regimen: • anti-cholinesterase inhibitors (pyridostigmine, neostigmine) and/or any of the following: • corticosteroids (prednisone, prednisolone)

42. c) other immunosuppressants when these become necessary. Use of these, however, may require several weeks to a several months before optimum therapeutic benefit is obtained. d) plasmapheresis or intravenous immune-globulin, when applicable, in patients with moderate to severe bulbar and respiratory muscle weakness or in patients with a high titer of anti-Acetylcholine Receptor antibodies.

43. 5.1 2. Acquire adequate pulmonary evaluation and clearance to assure presence of patent airways, optimum respiratory muscle power, adequate clearing of secretions and absence of respiratory infection.The following pre-operative tests are recommended: a) chest x-ray b) arterial blood gases

44. c) pulmonary function test (including VC, FEV, MEF, flow-volume loop) and exercise testing (with 6-8 hours off anticholinesterase inhibitor e.g. Mestinon) d) sputum G/S, C/S when necessary e) chest CT scan when necessary f) perfusion studies when necessary

45. 5.1 • Perform cardiac evaluation as follows: a) basic tests: ECG, chest x-ray; b) complete cardiology evaluation and clearance if - the patient is 40 years old or above - if patient has history of ischemic heart disease or other cardiac problems or risks for developing cardiac problems.

46. c) 2D echocardiography when necessary d) stress test when necessary e) nuclear medical tests when necessary

47. 5.1 • Search for and adequately treat concomitant medical conditions: a) Infection b) Disorders associated with MG. Do the following tests: - ESR - thyroid function tests - blood sugar - ANA - rheumatoid factor c) Disturbance in nutrition, fluids and electrolytes

48. 5.1 5. Check CBC and bleeding parameters (CT, BT, PT, PTT). 6. Refer to Rehabilitation Medicine specialist to assure good pulmonary capacity and adequate muscle tone. 7. Consider drug effects and drug interactions. If the patient is on medications, ensure that there are no side effects of these drugs or adverse drug reactions that may interfere with or complicate the intra- and post-operative course of the patient (Refer to Table on Drug Effects and Interactions ).

49. Practice Recommendation 5.2 What is the recommended anesthetic management? 1. Anesthesiologists must consider the patient’s disease severity including: - voluntary and respiratory muscle strength - ability to protect and maintain patent airway post-operatively - the type of surgical procedure and the surgeons’ preferences - patient’s ongoing medication (e.g. Mestinon and steroids).

50. 5.2 2. For pre-operative medications: Generally, anxiolytics, sedatives and opioids are rarely given to patients with little respiratory reserve. Small dose benzodiazepines, when necessary, may be given to patients with good respiratory reserve.