- Email: [email protected]
Thymectomy for elderly myasthenia gravis patients
Ann Thorac Surg 2000;69:311–20
which should allow to decrease the dosage of NO inhibitors to the minimum necessary. Tadaomi Alfonso Miyamoto, MD Research Department Kokura Memorial Hospital 1-1 Kifunecho, Kokura-Kitaku Kitakyushu-shi 802, Japan Koho-Julio Miyamoto, MD, PhD II Department of Physiology University of the Ryukius School of Medicine Okinawa, Japan
References 1. Tseng EE, Block MV, Lange MS, et al. Nitric oxide mediates neurologic injury after hypothermic circulatory arrest. Ann Thorac Surg 1999;67:65–71. 2. Tseng EE, Brock MV, Kwon CC, et al. Increased intracerebral excitatory amino acids and nitric oxide after hypothermic circulatory arrest. Ann Thorac Surg 1999;67:371– 6. 3. Du Plessis AJ, Jonas RA, Wypij, D et al. Perioperative effects of alpha-stat versus pH-stat strategies for deep hypothermic cardiopulmonary bypass in infants. J Thorac Cardiovasc Surg 1997;114:991–1001. 4. Giffard RG, Monyer H, Christine CW, Choi DW. Acidosis reduces NMDA receptor activation, glutamate neurotoxicity, and oxygen-glucose deprivation neuronal injury in cortical cultures. Brain Res 1990;506:339– 42. 5. Miyano H, Inagaki M, Hashimoto N, et al. Regional cerebral blood flow during rewarming of cardiopulmonary bypass correlates with post hypothermic regional glucose use. J Thorac Cardiovasc Surg 1998;116:503–10. 6. Tombaugh GC, Sapolsky RM. Mild acidosis protects hippocampal neurons from injury induced by oxygen and glucose deprivation. Brain Res 1990;506:343–5. 7. Schwiening CJ, Thomas RC. pH consequences of calcium regulation. In: Kaila K, Ransom BR, eds. pH and brain function. New York: Wiley-Liss,1998:277– 88. 8. Giffard RG, Weiss JH, Choi DW. Extracellular alkalinity exacerbates injury of cultured cortical neurons. Stroke 1992; 23:1817–21. 9. Lascola CD, Kraig RP. Astroglial pH during and after global ischemia. In: Kaila K, Ransom BR, eds. pH and brain function. New York: Wiley-Liss, 1998:583– 603. 10. Lutz PL, Nilsson GE. Mechanisms of brain anoxia tolerance. In: Lutz PL, Nilsson GE, eds. The brain without oxygen. Austin, TX: Landes Bioscence and Chapman & Hall, 1997: 103– 64.
Reply To the Editor: We appreciate very much the comments of Drs Tadaomi-A. Miyamoto and Koho-J Miyamoto from Kokura Memorial Hospital and the University of the Ryukius, respectively. They have raised a very interesting point to our experiments involving hypothermic circulatory arrest. Their letter and support of evidence would suggest that pH-stat management during hypothermic circulatory arrest would enhance cerebral recovery in this canine model. We agree with them that there are certainly many factors that contribute to neurologic injury after both routine cardiopulmo© 2000 by The Society of Thoracic Surgeons Published by Elsevier Science Inc
CORRESPONDENCE
313
nary bypass as well as adjunctive hypothermic circulatory arrest. These include acidosis, hemoglobin changes, and reduced glucose. For these reasons, all of our experimental studies (both control and interventional) are conducted so that hemoglobin, glucose, and pH are maintained at similar levels throughout the experiments. We very much appreciate their comments and in the future will address the issue of pH-stat management and its effect on cerebral function after hypothermic circulatory arrest. As they point out, we have a very stable model that can be used to further elucidate the mechanism of neurologic injury and those interventions that may be beneficial to overall cerebral recovery.
William A. Baumgartner, MD Elaine E. Tseng, MD Division of Cardiac Surgery The Johns Hopkins Hospital Baltimore, MD 21287 e-mail: [email protected].
Thymectomy for Elderly Myasthenia Gravis Patients To the Editor: The back-to-back articles by Tsuchida and associates [1] and Nieto and associates [2] fail to emphasize the heterogeneous nature of myasthenia gravis as related to pathologic, demographic, and immunobiological findings, although some references to this are deeply embedded in the two papers. I believe it is essential to differentiate thymomatous myasthenia gravis from the nonthymomatous variety for the following reasons: (1) Osserman classification: This is a clinical classification but thymomas are mentioned to have the highest incidence in groups III and IV, the most severe cases [4]. (2) Demographics: A preponderance of thymomas is noted in older males, while most nonthymomatous myasthenia occurs in younger females [3]. (3) Immunology: Different HLA antigen and other immunological patterns occur in thymomas vs nonthymomas [3]. (4) Emergence of myasthenia gravis after thymectomy: This, to my knowledge, only occurs in thymoma patients [5]. A subheading of this is exacerbation of myasthenia after thymomectomy [6]. There is no comparable phenomenon in nonthymomatous myasthenia. Parenthetically, Somnier [7] has shown that the titer of acetylcholine receptor antibodies rises after thymomectomy as compared with a fall with nonthymomatous thymectomy. (5) Extent of resection: “Extended” or “maximal” thymectomy in nonthymomatous myasthenia refers to wide excision of extrathymic fatty tissue, which may contain islands of ectopic thymus [8], while in thymomas, it usually refers to en bloc or otherwise wide excision of invasive thymomas [9]. (6) Pathology of the thymus: The term “thymoma” is not further defined, except in the paper by Nieto and associates [2], in which they list an astounding 9.8% incidence of thymolipoma. In practically all other reports, thymolipoma is rarely if ever associated with myasthenia. It deserves further comment. Also, no mention is made in either paper of the new classifications of thymomas including the cortical, medullary, and well-differentiated thymic carcinoma. 0003-4975/00/$20.00
314
CORRESPONDENCE
Stricter adherence to these distinctions would further our knowledge of this vexing group of diseases, the myasthenias. Paul A. Kirschner, MD Department of Cardiothoracic Surgery Mount Sinai Medical Center One Gustave L. Levy Place Box 1028 New York, NY 10029
References 1. Tsuchida M, Yamato Y, Souma T, et al. Efficacy and safety of extended thymectomy for elderly patients with myasthenia gravis. Ann Thorac Surg 1999;67:1563–7. 2. Nieto IP, Robledo JPP, Pajuelo MC, et al. Prognostic factors for myasthenia gravis treated by thymectomy: review of 61 cases. Ann Thorac Surg 1999;67:1568–71. 3. Compston DAS, Vincent A, Newsom-Davis J, et al. Clinical, pathological, HLA antigen and immunological evidence for disease heterogeneity in myasthenia gravis. Brain 1980;103: 579 – 601. 4. Osserman KE, Genkins G. Studies in myasthenia gravis: review of a twenty-year experience in over 1200 patients. Mt Sinai J Med 1971;38:497–537. 5. Namba T, Brunner NG, Grob D. Myasthenia gravis in patients with thymoma with particular reference to onset after thymectomy. Medicine 1978;57:411–33. 6. Kuroda Y, Oda K, Neshige R, et al. Exacerbation of myasthenia gravis after removal of a thymoma having a membrane phenotype of suppressor T-cells. Ann Neurol 1984;15:400–2. 7. Somnier FE. Exacerbation of myasthenia gravis after removal of thymomas. Acta Neurol Scand 1994;90:56– 66. 8. Jaretzki A III, Penn AS, Younger DS, et al. “Maximal” thymectomy for myasthenia gravis results. J Thorac Cardiovasc Surg 1988;95:747–57. 9. Kirschner PA. Reoperation for thymoma: report of 23 cases. Ann Thorac Surg 1990;49:550–5.
Reply To the Editor: We appreciate the opportunity to reply to the comments by Dr Kirschner concerning our article [1]. As pointed out by Dr Kirschner, myasthenia gravis (MG) patients comprise a wide and heterogeneous population, even with respect to the pathology of thymus. Thus, the patients’ background should be considered when comparing the efficacy of treatment. When we compared the young and elderly groups in our series, there were no statistically significant differences with respect to several parameters, including gender, Osserman classification, and pathology of the thymus. Furthermore, according to gender, 6 of the 10 males (60%) and 4 of the 15 females (27%) in the elderly group had thymoma, which is comparable with the young group, in which thymoma was present in 10 of the 18 males (56%) and 12 of the 51 females (24%). Thus, we did not encounter the same demographic distribution of thymomatous and nonthymomatous MG patients as reported by Compston and associates [2]. Recent reports have also indicated an increase in late-onset MG with no evidence of a relationship between thymoma and age [3, 4]. However, we did note gender differences with respect to Osserman classification between nonthymoma and thymoma elderly patients, such that there were more women who tended to have a lower Osserman classification (IIA) among nonthymomatous patients. On the other hand, thymomatous patients tended to comprise more
Ann Thorac Surg 2000;69:311–20
men, with a more severe Osserman classification (IIB). It is also of note that the surgical results did not differ remarkably between nonthymomatous and thymomatous patients; 14 improved (including 2 delayed deaths) and 1 worsened among the 15 nonthymomatous patients. Among the 10 thymomatous patients, 2 went into remission and 6 showed improvement. Extended thymectomy in thymomatous patients refers to excision of the entire anterior mediastinal fatty tissue including the thymus and thymoma. In our series, thymoma is defined as a tumor composed of neoplastic epithelial cells and lymphocytes, and does not include thymic carcinoma, thymic carcinoid, or thymolipoma. In addition, we did not observe a rise in the titers of acetylcholine receptor antibodies after extended thymectomy for thymomatous myasthenia gravis. In summary, we reexamined our results from a different point of view based on Kirschner’s comments by dividing elderly patients into thymomatous and nonthymomatous myasthenia gravis patients. Despite these modifications, we still came to the conclusion that surgery is indicated for both nonthymomatous and thymomatous elderly patients. We thank Dr Kirschner for his comments. Masanori Tsuchida, MD Yasushi Yamato, MD Jun-ichi Hayashi, MD Department of Thoracic and Cardiovascular Surgery Niigata University School of Medicine 1-757 Asahimachi-dori, Niigata City 951-8510, Japan e-mail: [email protected].
References 1. Tsuchida M, Yamato Y, Souma T, et al. Efficacy and safety of extended thymectomy for elderly patients with myasthenia gravis. Ann Thorac Surg 1999;67:1563–7. 2. Compston DAS, Vincent A, Newsom-Davis J, et al. Clinical, pathological, HLA antigen and immunological evidence for disease heterogeneity in myasthenia gravis. Brain 1980;103: 579 – 601. 3. Aarli JA. Late-onset myasthenia gravis: a changing scene. Arch Neurol 1999;56:25–7. 4. Phillips LD 2nd. The epidemiology of myasthenia gravis. Neurol Clin 1994;12:263–71.
Reply To the Editor: First things first, I would like to thank Dr Kirschner for the chance he gives us to clear up some issues in our paper entitled “Prognostic Factors for Myasthenia Gravis Treated by Thymectomy: Review of 61 Cases” (Ann Thorac Surg 1999;67:1568 –71), as well as to congratulate him for his shrewd criticism to the aforementioned article. To begin on one’s subject, we in no way state in our paper that thymomas present the highest incidence in Osserman classification III and IV groups, which are, no doubt, the most severe cases. We state rather that these patients present a lower rate of clinical remission (18.1%) as well as higher morbility rate, as compared with patients with other postthymectomy histologic findings. However, this difference did not reach statistical significance, presumably due to the small size of our subsample of patients with thymoma (n ⫽ 11) and the fact that we did not consider histologic type as a dychotomous (thymomatous myasthenia gravis [MG], nonthymomatous MG) independent variable, so we can just hypothesize that thymoma patients were more likely to be classified in the highest Osserman groups, a
which should allow to decrease the dosage of NO inhibitors to the minimum necessary. Tadaomi Alfonso Miyamoto, MD Research Department Kokura Memorial Hospital 1-1 Kifunecho, Kokura-Kitaku Kitakyushu-shi 802, Japan Koho-Julio Miyamoto, MD, PhD II Department of Physiology University of the Ryukius School of Medicine Okinawa, Japan
References 1. Tseng EE, Block MV, Lange MS, et al. Nitric oxide mediates neurologic injury after hypothermic circulatory arrest. Ann Thorac Surg 1999;67:65–71. 2. Tseng EE, Brock MV, Kwon CC, et al. Increased intracerebral excitatory amino acids and nitric oxide after hypothermic circulatory arrest. Ann Thorac Surg 1999;67:371– 6. 3. Du Plessis AJ, Jonas RA, Wypij, D et al. Perioperative effects of alpha-stat versus pH-stat strategies for deep hypothermic cardiopulmonary bypass in infants. J Thorac Cardiovasc Surg 1997;114:991–1001. 4. Giffard RG, Monyer H, Christine CW, Choi DW. Acidosis reduces NMDA receptor activation, glutamate neurotoxicity, and oxygen-glucose deprivation neuronal injury in cortical cultures. Brain Res 1990;506:339– 42. 5. Miyano H, Inagaki M, Hashimoto N, et al. Regional cerebral blood flow during rewarming of cardiopulmonary bypass correlates with post hypothermic regional glucose use. J Thorac Cardiovasc Surg 1998;116:503–10. 6. Tombaugh GC, Sapolsky RM. Mild acidosis protects hippocampal neurons from injury induced by oxygen and glucose deprivation. Brain Res 1990;506:343–5. 7. Schwiening CJ, Thomas RC. pH consequences of calcium regulation. In: Kaila K, Ransom BR, eds. pH and brain function. New York: Wiley-Liss,1998:277– 88. 8. Giffard RG, Weiss JH, Choi DW. Extracellular alkalinity exacerbates injury of cultured cortical neurons. Stroke 1992; 23:1817–21. 9. Lascola CD, Kraig RP. Astroglial pH during and after global ischemia. In: Kaila K, Ransom BR, eds. pH and brain function. New York: Wiley-Liss, 1998:583– 603. 10. Lutz PL, Nilsson GE. Mechanisms of brain anoxia tolerance. In: Lutz PL, Nilsson GE, eds. The brain without oxygen. Austin, TX: Landes Bioscence and Chapman & Hall, 1997: 103– 64.
Reply To the Editor: We appreciate very much the comments of Drs Tadaomi-A. Miyamoto and Koho-J Miyamoto from Kokura Memorial Hospital and the University of the Ryukius, respectively. They have raised a very interesting point to our experiments involving hypothermic circulatory arrest. Their letter and support of evidence would suggest that pH-stat management during hypothermic circulatory arrest would enhance cerebral recovery in this canine model. We agree with them that there are certainly many factors that contribute to neurologic injury after both routine cardiopulmo© 2000 by The Society of Thoracic Surgeons Published by Elsevier Science Inc
CORRESPONDENCE
313
nary bypass as well as adjunctive hypothermic circulatory arrest. These include acidosis, hemoglobin changes, and reduced glucose. For these reasons, all of our experimental studies (both control and interventional) are conducted so that hemoglobin, glucose, and pH are maintained at similar levels throughout the experiments. We very much appreciate their comments and in the future will address the issue of pH-stat management and its effect on cerebral function after hypothermic circulatory arrest. As they point out, we have a very stable model that can be used to further elucidate the mechanism of neurologic injury and those interventions that may be beneficial to overall cerebral recovery.
William A. Baumgartner, MD Elaine E. Tseng, MD Division of Cardiac Surgery The Johns Hopkins Hospital Baltimore, MD 21287 e-mail: [email protected].
Thymectomy for Elderly Myasthenia Gravis Patients To the Editor: The back-to-back articles by Tsuchida and associates [1] and Nieto and associates [2] fail to emphasize the heterogeneous nature of myasthenia gravis as related to pathologic, demographic, and immunobiological findings, although some references to this are deeply embedded in the two papers. I believe it is essential to differentiate thymomatous myasthenia gravis from the nonthymomatous variety for the following reasons: (1) Osserman classification: This is a clinical classification but thymomas are mentioned to have the highest incidence in groups III and IV, the most severe cases [4]. (2) Demographics: A preponderance of thymomas is noted in older males, while most nonthymomatous myasthenia occurs in younger females [3]. (3) Immunology: Different HLA antigen and other immunological patterns occur in thymomas vs nonthymomas [3]. (4) Emergence of myasthenia gravis after thymectomy: This, to my knowledge, only occurs in thymoma patients [5]. A subheading of this is exacerbation of myasthenia after thymomectomy [6]. There is no comparable phenomenon in nonthymomatous myasthenia. Parenthetically, Somnier [7] has shown that the titer of acetylcholine receptor antibodies rises after thymomectomy as compared with a fall with nonthymomatous thymectomy. (5) Extent of resection: “Extended” or “maximal” thymectomy in nonthymomatous myasthenia refers to wide excision of extrathymic fatty tissue, which may contain islands of ectopic thymus [8], while in thymomas, it usually refers to en bloc or otherwise wide excision of invasive thymomas [9]. (6) Pathology of the thymus: The term “thymoma” is not further defined, except in the paper by Nieto and associates [2], in which they list an astounding 9.8% incidence of thymolipoma. In practically all other reports, thymolipoma is rarely if ever associated with myasthenia. It deserves further comment. Also, no mention is made in either paper of the new classifications of thymomas including the cortical, medullary, and well-differentiated thymic carcinoma. 0003-4975/00/$20.00
314
CORRESPONDENCE
Stricter adherence to these distinctions would further our knowledge of this vexing group of diseases, the myasthenias. Paul A. Kirschner, MD Department of Cardiothoracic Surgery Mount Sinai Medical Center One Gustave L. Levy Place Box 1028 New York, NY 10029
References 1. Tsuchida M, Yamato Y, Souma T, et al. Efficacy and safety of extended thymectomy for elderly patients with myasthenia gravis. Ann Thorac Surg 1999;67:1563–7. 2. Nieto IP, Robledo JPP, Pajuelo MC, et al. Prognostic factors for myasthenia gravis treated by thymectomy: review of 61 cases. Ann Thorac Surg 1999;67:1568–71. 3. Compston DAS, Vincent A, Newsom-Davis J, et al. Clinical, pathological, HLA antigen and immunological evidence for disease heterogeneity in myasthenia gravis. Brain 1980;103: 579 – 601. 4. Osserman KE, Genkins G. Studies in myasthenia gravis: review of a twenty-year experience in over 1200 patients. Mt Sinai J Med 1971;38:497–537. 5. Namba T, Brunner NG, Grob D. Myasthenia gravis in patients with thymoma with particular reference to onset after thymectomy. Medicine 1978;57:411–33. 6. Kuroda Y, Oda K, Neshige R, et al. Exacerbation of myasthenia gravis after removal of a thymoma having a membrane phenotype of suppressor T-cells. Ann Neurol 1984;15:400–2. 7. Somnier FE. Exacerbation of myasthenia gravis after removal of thymomas. Acta Neurol Scand 1994;90:56– 66. 8. Jaretzki A III, Penn AS, Younger DS, et al. “Maximal” thymectomy for myasthenia gravis results. J Thorac Cardiovasc Surg 1988;95:747–57. 9. Kirschner PA. Reoperation for thymoma: report of 23 cases. Ann Thorac Surg 1990;49:550–5.
Reply To the Editor: We appreciate the opportunity to reply to the comments by Dr Kirschner concerning our article [1]. As pointed out by Dr Kirschner, myasthenia gravis (MG) patients comprise a wide and heterogeneous population, even with respect to the pathology of thymus. Thus, the patients’ background should be considered when comparing the efficacy of treatment. When we compared the young and elderly groups in our series, there were no statistically significant differences with respect to several parameters, including gender, Osserman classification, and pathology of the thymus. Furthermore, according to gender, 6 of the 10 males (60%) and 4 of the 15 females (27%) in the elderly group had thymoma, which is comparable with the young group, in which thymoma was present in 10 of the 18 males (56%) and 12 of the 51 females (24%). Thus, we did not encounter the same demographic distribution of thymomatous and nonthymomatous MG patients as reported by Compston and associates [2]. Recent reports have also indicated an increase in late-onset MG with no evidence of a relationship between thymoma and age [3, 4]. However, we did note gender differences with respect to Osserman classification between nonthymoma and thymoma elderly patients, such that there were more women who tended to have a lower Osserman classification (IIA) among nonthymomatous patients. On the other hand, thymomatous patients tended to comprise more
Ann Thorac Surg 2000;69:311–20
men, with a more severe Osserman classification (IIB). It is also of note that the surgical results did not differ remarkably between nonthymomatous and thymomatous patients; 14 improved (including 2 delayed deaths) and 1 worsened among the 15 nonthymomatous patients. Among the 10 thymomatous patients, 2 went into remission and 6 showed improvement. Extended thymectomy in thymomatous patients refers to excision of the entire anterior mediastinal fatty tissue including the thymus and thymoma. In our series, thymoma is defined as a tumor composed of neoplastic epithelial cells and lymphocytes, and does not include thymic carcinoma, thymic carcinoid, or thymolipoma. In addition, we did not observe a rise in the titers of acetylcholine receptor antibodies after extended thymectomy for thymomatous myasthenia gravis. In summary, we reexamined our results from a different point of view based on Kirschner’s comments by dividing elderly patients into thymomatous and nonthymomatous myasthenia gravis patients. Despite these modifications, we still came to the conclusion that surgery is indicated for both nonthymomatous and thymomatous elderly patients. We thank Dr Kirschner for his comments. Masanori Tsuchida, MD Yasushi Yamato, MD Jun-ichi Hayashi, MD Department of Thoracic and Cardiovascular Surgery Niigata University School of Medicine 1-757 Asahimachi-dori, Niigata City 951-8510, Japan e-mail: [email protected].
References 1. Tsuchida M, Yamato Y, Souma T, et al. Efficacy and safety of extended thymectomy for elderly patients with myasthenia gravis. Ann Thorac Surg 1999;67:1563–7. 2. Compston DAS, Vincent A, Newsom-Davis J, et al. Clinical, pathological, HLA antigen and immunological evidence for disease heterogeneity in myasthenia gravis. Brain 1980;103: 579 – 601. 3. Aarli JA. Late-onset myasthenia gravis: a changing scene. Arch Neurol 1999;56:25–7. 4. Phillips LD 2nd. The epidemiology of myasthenia gravis. Neurol Clin 1994;12:263–71.
Reply To the Editor: First things first, I would like to thank Dr Kirschner for the chance he gives us to clear up some issues in our paper entitled “Prognostic Factors for Myasthenia Gravis Treated by Thymectomy: Review of 61 Cases” (Ann Thorac Surg 1999;67:1568 –71), as well as to congratulate him for his shrewd criticism to the aforementioned article. To begin on one’s subject, we in no way state in our paper that thymomas present the highest incidence in Osserman classification III and IV groups, which are, no doubt, the most severe cases. We state rather that these patients present a lower rate of clinical remission (18.1%) as well as higher morbility rate, as compared with patients with other postthymectomy histologic findings. However, this difference did not reach statistical significance, presumably due to the small size of our subsample of patients with thymoma (n ⫽ 11) and the fact that we did not consider histologic type as a dychotomous (thymomatous myasthenia gravis [MG], nonthymomatous MG) independent variable, so we can just hypothesize that thymoma patients were more likely to be classified in the highest Osserman groups, a