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Thymectomy for myasthenia gravis in the young adult
J
THoRAc CARDIOVASC SURG
80:696-701, 1980
Thymectomy for myasthenia gravis in the young adult Long-term results An 8 year experience with a prospective treatment program for patients with myasthenia gravis is reviewed with particular focus on the results in patients less than 35 years of age. Twenty myasthenic young adults with an average age of 24 years and a duration of symptoms of 22 months, excluding two with the juvenile form, had thymectomy followed by short-term anticholinesterase and long-term prednisone therapy. All (J!" the 18 patients with a short duration of symptoms are in markedly improved condition and 61 % of them are in remission after a mean postoperative period of 32 months. The longest follow-up period is 7.3 years. Two patients have mild improvement. There was no correlation between thymic disease and clinical result. Complete en bloc extirpation of all thymic and adjacent tissue through a median sternotomy is advocated. The patients were treated postoperatively with prednisone, 100 mg lday, a regimen which gradually is changed to every other day medication and finally a gradual reduction of dosage. There have been no operative or late deaths and no serious complications of therapy. The effects have been long lasting, with not a single instance of significant recurrence of symptoms of myasthenia gravis 6 months after thymectomy.
Richard E. Clark, M.D., John P. Marbarger, M.D. (by invitation), Phillip N. West, M.D. (by invitation), John A. Spratt, M.D. (by invitation), Julaine M. Florence (by invitation), Charles L. Roper, M.D., Thomas B. Ferguson, M.D., and Clarence S. Weldon, M.D., St. Louis, Mo.
More than forty years ago, Alfred Blalock and colleagues I reviewed the literature concerning maladies of the thymus gland associated with myasthenia gravis. Adding to the cases collected by Bell- and Norris," they reported a total of 54 cases of thymic disease associated with myasthenia gravis in 1939. The only four cases of surgical removal of the thymus in patients with myasthenia gravis were summarized, and Blalock added a case of his own in which a cystic thymic tumor was removed through a median sternotomy in 1936. Marked improvement resulted and in two years the patient was totally asymptomatic. Since that report, many case reports, collected surgical series, and reviews have established a strong role for thymectomy in the management of myasthenia gravis.":" From the Division of Cardiothoracic Surgery, Washington University School of Medicine, St. Louis, Mo. Read at the Sixtieth Annual Meeting of The American Association of Thoracic Surgeons, San Francisco, Calif., April 28 to 30, 1980. Address for reprints: Richard E. Clark, M.D., Suite 3108 Queeny Tower, 4989 Barnes Hospital Plaza, SI. Louis, Mo. 63110.
696
Both Blalock and Keynes noted that the availability of a specific drug, neostigmine (Prostigmin), was of significance in the successful treatment of their surgical patients. Pharmacologic treatment prior to and after operation with anticholinesterase, corticotropins, and steroid compounds has been advocated over the past two decades. Johns," Mann.!" and associates, by advocating long-term use of corticosteroids for weeks to years prior to operation, placed thymectomy last in the sequence of therapy, a position not now deserved in the contemporary management of patients with myasthenia gravis. Eight years ago, a group of neurologists specializing in muscle disorders at the Washington University Medical Center reviewed their prior experience with myasthenia gravis and thymectomy and established a protocol of using thymectomy as the initial major therapeutic step followed by short-term anticholinesterase treatment and long-term prednisone management. This report describes our experience with reversal of the usual sequence of treatment events, with particular attention to
0022-5223/80/110696+06$00.6010 © 1980 The C. V. Mosby Co.
Volume
eo Thymectomy for myasthenia gravis
Number 5
697
November, 1980
those patients with myasthenia gravis who underwent thymectomy prior to the age of 35 years. Methods and patients Record review. All surgical, hospital, and outpatient records were reviewed for the period Jan. I, 1972, to Jan. I, 1980, for patients with myasthenia gravis and thymectomy. Details of the status and medications of each patient, the preoperative pulmonary function test data, muscle biopsy findings, nerve conduction studies, electromyographic data, chest roentgenograms, hematologic status, and more recently the findings by computerized axial tomography (CT scan) were extracted. The Osserman!' classification is based on the clinical evaluation prior to elective operation and has six categories: asymptomatic, I-ocular, IIA-generalized mild, lIB-generalized moderately severe, IIIacute fulminating, IV-late severe. Postoperative management with particular attention to the pulmonary complications and need for ventilatory support was catalogued. The pathological aspects of all thymus glands were tabulated in the manner of Papatestas and associates." The course of pharmacologic management was obtained from the outpatient records. Thymectomy. All patients had a median sternotomy and wide excision of the thymus gland. Depending on the asymmetry of the organ, dissection was begun inferiorly or laterally, and the thymus and all attached soft tissue was taken as far as the pleuropericardial reflection and generally to the phrenic nerves. Great attention was given to complete dissection around the innominate vein and near the innominate and carotid arteries. Cephalic tails of thymus extending high into the neck were carefully removed en bloc with the gland. Complete extirpation of all thymic and immediately adjacent soft tissue without fragmentation of the specimen was performed in each case. Postoperative management. All patients were returned to an intensive care unit with an endotracheal tube securely in place. Each was mechanically ventilated and tested with the endotracheal tube in place until a sustained forced vital capacity of 1.0 to 1.5 L was achieved, voluntary minute ventilation exceeded 8 Llmin, and there was no hypercarbia over a 2 to 8 hour interval with voluntary ventilation. Neostigmine in 10 mg intramuscular doses was begun when the patient was fully alert and ready for physiological testing. Oral pyridostigmine (Mestinon) was begun and neostigmine discontinued as soon as the endotracheal and nasogastric tubes were removed. In most patients, the pyridostigmine requirement was 180 to 360 mg/24 hr. Predni-
sone was begun for most patients at a dose of 100 mg/ day on the seventh postoperati ve day. During the ensuing 2 to 4 weeks, the dosage of pyridostigmine was gradually decreased. Prednisone therapy was maintained. During the hospital postoperative course, the vital capacity and muscle strength were assessed daily. Regular and frequent outpatient visits to a neurologist were made by all patients. Late follow-up. All patients were interviewed by a neurologist and explicit details of exercise tolerance, employment, symptoms, and current medications were noted. A classification of each patient was made following the last interview and examination. These classifications were remission with no medication, remission with steroids only, marked improvement with any combination of drug treatment, moderate-to-slight improvement, or no improvement. Results Total series characteristics. Twenty-eight patients had thymectomy for myasthenia gravis in the time period reviewed. These operations were distributed biannually as follows: 1972 to 1973, two operations; 1974 to 1975, two operations; 1976 to 1977, seven operations; 1978 to 1979, 17 operations. There were 15 females and six black patients. Age at operation ranged from 10 to 61 years with a mean age of 30 years. Twenty patients were 35 years of age or less at the time of operation. The age distribution is shown in Fig. I. Although the average duration of symptoms was 5.3 years for the entire series, this average was greatly increased by five patients aged 44,28,21,43, and 39 years, in whom the duration of symptoms was 14, 28, 21,24, and 23 years, respectively. Two of these patients had a juvenile form of myasthenia gravis. When these five are excluded, the average duration of symptoms for the majority of patients prior to operation was 1.4 years. The young adult patient. The 20 patients who were 35 years of age or less were of special interest because these patients as a group have had dramatic results with the sequence of no preoperative medication or shortterm pharmacologic treatment, thymectomy, and steroid treatment in the postoperative phase. In the young adult group of 20 patients, there were II females and six black patients. The average age was 24 years and the average duration of symptoms in 18 patients without the juvenile form of myasthenia gravis was 22 months. All had bulbar and extremity signs of myasthenia and all but two had ocular signs. Preoperative classification in terms of severity of myasthenia gravis was as follows: seven-IIA, seven-lIB, five-III,
The Journal of
698
Thoracic and Cardiovascular Surgery
Clark et al.
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AGE AT OPERATION Fig. 1. Distribution of patients by age at operation in 5 year intervals. Patients older than 35 years (shaded bars) were excluded from detailed analysis. and one-IV. Prior to operation, 12 patients were taking anticholinesterase only, one was taking prednisone only, four were taking both medications, and three were receiving no medication. The average pyridostigmine requirement was 300 mg/day for the group. The preoperative vital capacity was 2.98 Lor 68% of the predicted value. Electromyographic and nerve conduction studies were performed preoperatively in 85% and 90% of the patients, respectively. Five patients (25%) had a CT scan, although this modality was used in 63% of the patients older than 35 years. A skeletal muscle biopsy was performed prior to operation in seven and in an equal number at the time of operation. The preoperative white blood cell count was 7,276 ± 816 cells/rnrn". Postoperative course. Seven patients were extubated on the day of operation. Thirteen patients required an average of 5 days on a ventilator (I to 15 days), and the first patient in our series received the only tracheostomy. At discharge the average vital capacity was 2.43 L or 54% of the predicted value. The white blood cell count was 8,994 ± 973 cells/rnm", There were no serious pulmonary, urinary tract, or infectious complications. All patients survived. Pathology. Seven or 35% of the 20 surgical specimens were normal. Germinal centers were present in 12 with a spectrum of hyperplasia ranging from slight in two, to moderate in seven, to marked in three. One patient had a malignant thymoma and received postoperative irradiation.
Late clinical results. All patients in the entire series were last seen in 1980, and all but two are in significantly improved condition or are in remission. The two patients who have had mild improvement had the juvenile form of myasthenia gravis and underwent thymectomy after having had symptoms for 21 and 28 years. The remainder of the young «35 years) patients have had marked improvement. Six patients are in remission with no medication, and an additional five are in remission taking an average dose of prednisone of 69 mg every other day. Seven patients have had marked improvement but have symptoms which in most cases were associated with an upper respiratory tract infection or unusual physical stress. Three of these patients used an average of 180 mg of pyridostigmine daily, significantly less than prior to operation. Two are receiving prednisone at an average dose of 75 mg every other day. Two children, aged 10 and 13 at operation, require both steroids and anticholinesterase medication. The duration of follow-up ranged from 5 to 88 months, with an average duration of 30 months for the entire series and 32 months for the young adult group. The rapid improvement in symptoms, the decreased medication requirement, and the durability of response to treatment in all but one patient has been significant. This patient, extremely ill prior to operation, required plasmapheresis in the first few months after thymectomy but now is in markedly improved condition with
Volume 80 Number 5 November, 1980
continued steroid treatment 7 months after operation. Thus the rate of long-term marked improvement in the 18 patients without the juvenile form of myasthenia gravis is 100%, with 55% totally asymptomatic nearly 3 years after operation.
Discussion The young adult with myasthenia gravis is most likely to be female and to have a non-tumor bearing thymus gland. This likelihood was borne out in our series, for 5% of the patients had thymoma and 55% were female, although the latter percentage usually is greater in reported series.v " 11-15 As experience has accumulated, surgical extirpation of all recognized thymic tissue early in the course of the disease has been found more beneficial, over the long term, than withholding operation for many years, regardless of preoperative medical regimens.v "- 12. 15 Many have emphasized the need for a careful and complete dissection of the gland. In our view, the operation should be performed as if it were an en bloc dissection for a malignant tumor. The reports of recurrent myasthenia gravis with concurrent findings of remaining thymic tissue at reoperation or autopsy support this approach.!" Second, consideration of the embryonic origins and studies of the translocated thymic rests'? in fat further suggest that wide surgical exposure and removal of all attached and adjacent tissue will yield superior long-term results. Finally, careful surgical descriptions of the location of aberrant thymic tissue found at operation and verified histologically" emphasize the need for wide en bloc dissection. Careful dissection of the tails of the thymus into the neck is required in every case. These thymic tails were found to some extent in every case in this series. Thymic extensions may be the remnants of the descent of the third branchial pouch into the mediastinum."? Papatestas;" Alpert.!" and their associates have repeatedly reported the correlation of the intensity of lymphoid hyperplastic response and numbers of germinal centers to the late clinical results. Germinal centers are not found in the normal thymus gland of the young adult. 19 Papatestas and colleagues" noted a strong positive relationship between the absence or sparse presence of germinal centers to a rapid and significant improvement in symptoms of patients with myasthenia gravis following thymectomy. No such correlation could be made in this series or in others. 20 Of the 11 patients in remission, four patients had normal glands, one had 1+ hyperplasia, four had 2+ hyperplasia, and two had 3+ hyperplasia. Conversely, of seven of the patients with normal thymus glands, four are in remission, two have mild
Thymectomy for myasthenia gravis
6 99
improvement only, and one has had a good clinical result but continues to take pyridostigmine and steroids. Strong support for the use of prednisone in the preoperative period is found in the reports of Johns and co-workers" and Bolooki and Schwartzman." The former group used steroids for the long term whereas the latter advocated high doses (1,000 mg) starting on the day of operation. In our study, prednisone was given intraoperatively only to those patients receiving the drug prior to operation. There was no statistically significant correlation between the preoperative and intraoperative use of prednisone and the days on the ventilator, as has been reported. 21 The long-term emphasis on high doses of steroids deserves special mention. No other report found in the literature search has specifically detailed such a prospective postoperative plan. We were unable to determine the relative influences of patient age, short duration of symptoms prior to operation, and the use of high doses of prednisone in the postoperative phase on the rapid and consistent postsurgical improvement of symptoms of myasthenia gravis and decreased requirement for anticholinesterase drugs. Others have reported the exacerbations associated with the initial period of high-dose steroids in nonsurgical myasthenic patients. 9, 10 Postoperatively, most patients experienced a 7 to 10 day period of increased weakness prior to objective improvement in skeletal muscle strength. The decreased vital capacities at discharge may be evidence for this, although median sternotomy could result in a similar small depression. The late postoperative complications of high-dose steroids have been minimal. The incidence of upper respiratory tract infection has not been increased and there have been no known septic episodes. No other unexpected disease states have appeared in any patient; specifically, no malignant tumors have developed. The following case history illustrates the management of drug therapy.
Case report A 35-year-old white woman had symptoms of myasthenia gravis for 5 years. The diagnosis of myasthenia gravis was made 6 months prior to operation. Despite treatment with pyridostigmine she had a gradual increase in symptoms. Fourteen months ago she underwent thymectomy. She was discharged on postoperative day 20 on a regimen of prednisone, 100 mg/day, and no pyridostigmine. Seven months after operation, the prednisone dosage was reduced 5 mg on alternate days. The reduction of prednisone continues at a rate of 5 mg every 2 weeks. This patient is presently at her preoperative weight and is totally asymptomatic. She is working full time and totally manages her household.
The lasting effect of this course of treatment, as evidenced by the two patients now 6.8 and 7.3 years after
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Surgery
operation and the remainder of this series of young adults with similar but shorter courses, continues to be gratifying. Especially noteworthy is the fact that, over the long term, this sequence of therapy has not failed in any patient to date. Although our medical colleagues have long recognized surgery as the initial treatment of choice in many illnesses, thymectomy on an elective basis early in the course of myasthenia has not gained such acceptance, if duration of symptoms in many series is considered. If the recurrence rate of significant symptoms under nonoperative medical therapy and the durability of the results of early operation, coupled with postoperative high-dose steroid management, are considered, the latter appears to offer significant advantages to the young patient with myasthenia gravis. We wish to acknowledge the follow-up and advice of Drs. Michael H. Brooke and Jack B. Shumate. The use of patient information from Drs. Leonard Berg, Joseph T. Black, Douglas J. Dove, Owen S. Kantor, Arthur L, Prensky, and Herbert E. Rosenbaum was appreciated. The secretarial talents of Mrs. Frances L. Grubbs are gratefully acknowledged.
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REFERENCES
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Blalock A, Mason MF, Morgan HJ, Riven SS: Myasthenia gravis and tumors of the thymic region. Report of a case in which tumor was removed. Ann Surg 110:544561, 1939 Bell ET: Tumors of the thymus in myasthenia gravis. J Nerv Ment Dis 45:130-133,1917 Norris EH: Thymoma and thymic hyperplasia in myasthenia gravis with observations on general pathology. Am J Cancer 27:421-433, 1936 Keynes G: The results of thymectomy in myasthenia gravis. Br Med J 2:611-616,1949 Papatestas AE, Alpert LI, Osserman KE, Osserman RS, Kark AE: Studies in myasthenia gravis. Effects of thymectomy results on 185 patients with non thymomatous and thymomatous myasthenia gravis, 1941-1969. Am J Med 50:465-474, 1971 Cohn HE, Solit RW, Schatz NJ, Schlezinger N: Surgical treatment in myasthenia gravis. A 27 year experience. J THoRAc CARDIOVASC SURG 68:876-885, 1974 Faulkner SL, Ehyai A, Fisher RD, Fenichel GM, Bender HW Jr: Contemporary management of myasthenia gravis. The clinical role of thymectomy Ann Thorac Surg 23:348-352, 1977 Jaretzki A, Bethea M, Wolff M, Olarte MR, Lovelace RE, Penn AS, Rowland L: A rational approach to total thymectomy in the treatment of myasthenia gravis. Ann Thorac Surg 24: 120-130, 1977 Johns TR, Mann JD, Joseph as, Campa JF: Long term administration of corticosteroids in myasthenia gravis. Neurology 22:400, 1972 Mann JD, Campa JF, Muller WH: Long-term prednisone
20
21
followed by thymectomy in myasthenia gravis. Ann NY Acad Sci 274:608-622, 1976 Osserman KE: Myasthenia Gravis. New York, 1958, Grune & Stratton, Inc. Papatestas AE, Genkins G, Horowitz SH, Kornfeld P: Thymectomy in myasthenia gravis. Pathologic, clinical and electrophysiologic correlations. Ann NY Acad Sci 274:555-573, 1976 Blalock A: Thymectomy in the treatment of myasthenia gravis. J THoRAc CARDIOVASC SURG 13:316-339, 1944 Keynes G: Surgery of the thymus gland, second (and third) thoughts. Lancet 266:1197-1202, 1954 Genkins G, Papatestas AE, Horowitz SH, Kornfeld P: Studies in myasthenia gravis. Early thymectomy. Am J Med 58:517-524, 1975 Joseph BS, Johns TR: Recurrence of non neoplasmic thymus after thymectomy for myasthenia gravis. Neurology 23:109-116, 1973 Masaoka A, Nagaoka Y, Kotake Y: Distribution of thymic tissue at the anterior mediastinum. Current procedures in thymectomy. J THoRAc CARDIOVASC SURG 70:747-754, 1975 Alpert LI, Papatestas AE, Kark AE: A histologic reappraisal of the thymus in myasthenia gravis. A correlative study of thymic pathology and response to thymectomy. Arch PathoI91:55-61, 1961-19 Castleman B, Norris EH: The pathology of the thymus in myasthenia gravis. A study of 35 cases. Medicine 28:27-58, 1949 Reinglass JL, Brickel ACJ: The prognostic significance of thymic germinal center proliferation in myasthenia gravis. Neurology 23:69-72, 1973 Bolooki H, Schwartzman RJ: High-dose steroids for perioperative management of patients with myasthenia gravis. A preliminary report. J THoRAc CARDIOVASC SURG 75:754-757, 1978
Discussion DR. ALFRED JARETZKI III New York, N. Y.
We of the surgical faith are convinced that thymectomy is indicated in almost all patients with myasthenia gravis. If we are to prove this, we must design mutually agreed upon, reproducible preoperative and follow-up classifications and must stratify all studies for severity of disease and extent of thymectomy, as well as for age, sex, duration of disease, and presence of thymoma. In the authors' series, after 2 years, one third of the patients were in complete remission and another one third were symptom free while taking prednisone (this second group cannot be considered in remission). Although early thymectomy may be a significant factor in obtaining these results, as suggested by the authors, almost 40% had mild myasthenia gravis, which in itselffavorably influences the outcome. Thus a comparative analysis of patients with mild and severe myasthenia gravis subjected to this therapeutic regimen is still needed.
Volume 80 Number 5
Thymectomy for myasthenia gravis
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November, 1980
The authors also stressed the importance of removing all thymic tissue. In this we concur, and we believe their operative procedure significantly contributed to the success. Our studies suggest that there probably is a direct relationship between the extent of thymectomy and the speed and rate of remission. One can subdivide the surgical approaches to thymectomy by estimated extent of resection. We believe we are doing the "maximum" possible resection. The authors' procedure probably lies between the "classical" transstemal procedure and our extended "maximum" operation. The "extended" transcervical resection, which some are doing now, certainly removes less thymus than either of the others. The transcervical intracapsulary thymectomy, which has been and is being used by some, has been demonstrated to be no more than a 50% resection in most instances. A composite drawing of our last 40 specimens depicts the commonest anatomic findings. All tissue from diaphragm to thyroid and from hilum to hilum is routinely removed en bloc, including both mediastinal pleural envelopes. To date, we have reoperated upon only two patients using this surgical approach (the original operations done elsewhere were cervical alone in one and sternal alone in the other), and we found 25 gm of residual thymic tissue in one and II gm in the other. I congratulate the authors on the results of their series, give caution concerning interpretation, urge analysis of comparable patient groups, and stress the importance of complete removal of the gland. DR. DAVID M. LONG, JR. LaMesa. Calif.
Dr. Clark and his colleagues are to be congratulated for their excellent results in treating these patients with myasthenia gravis. Myasthenia gravis is a rare disease, but we know more about it than any other autoimmune disease. Thymectomy early in the course is specific therapy in that it prevents formation of antireceptor antibodies. The authors appear to emphasize the treatment of the young patient. I would like to inquire about the application of thymectomy in the other patient with myasthenia gravis. In this regard, Dr. Fred Baughman, our neurologist, and I have
treated an 82-year-old patient with recent onset of myasthenia gravis who was unable to walk or even eat while receiving full medical therapy. She had a prompt and sustained improvement following thymectomy. The patient also had symptomatic idiopathic hypertrophic subaortic stenosis. We performed the thymectomy through the transcervical approach developed by Dr. Paul Kirschner. The Mount Sinai group has had excellent clinical results with this surgical technique in patients of all age groups. It seems to be particularly appropriate and well tolerated in the older, high-risk patients with significant associated diseases. DR. C LA R K (Closing) I would like to thank Dr. Jaretzki and Dr. Long for their comments. I quite agree that consolidated, stratified, and multi-institutional studies are needed to compare similar patients and the long-term effects of thymectomy in myasthenia. The series in the literature are the recordings, sometimes a bit anecdotal, of various surgeons experiences. No long-term randomized trial has been performed. The initial patients were very ill with myasthenia gravis. As the results became longer term and lasting, the neurologists were willing to refer patients with milder forms of the disease from the general community, not just within our hospital itself. With a small series of only 20 patients, we are unable to distinguish the influence of the duration of the disease from the age of the patient or the severity of the symptoms, or to determine how these three variables may have influenced the outcome. We can only say that in the young, early complete thymectomy and treatment with high-dose prednisone has been very effective in this series. Dr. Long, I think your achievement in your older patient may be a record. The results in your patient were quite dramatic, and we have seen similar results both in the young and in older patients. In the older group, however, we tend to have less dramatic results, with only approximately 50% improving and with the other half requiring medication, many of them remaining somewhat symptomatic. In all series, the young patient with a short duration of symptoms has achieved the best results. This is the case with our series.
THoRAc CARDIOVASC SURG
80:696-701, 1980
Thymectomy for myasthenia gravis in the young adult Long-term results An 8 year experience with a prospective treatment program for patients with myasthenia gravis is reviewed with particular focus on the results in patients less than 35 years of age. Twenty myasthenic young adults with an average age of 24 years and a duration of symptoms of 22 months, excluding two with the juvenile form, had thymectomy followed by short-term anticholinesterase and long-term prednisone therapy. All (J!" the 18 patients with a short duration of symptoms are in markedly improved condition and 61 % of them are in remission after a mean postoperative period of 32 months. The longest follow-up period is 7.3 years. Two patients have mild improvement. There was no correlation between thymic disease and clinical result. Complete en bloc extirpation of all thymic and adjacent tissue through a median sternotomy is advocated. The patients were treated postoperatively with prednisone, 100 mg lday, a regimen which gradually is changed to every other day medication and finally a gradual reduction of dosage. There have been no operative or late deaths and no serious complications of therapy. The effects have been long lasting, with not a single instance of significant recurrence of symptoms of myasthenia gravis 6 months after thymectomy.
Richard E. Clark, M.D., John P. Marbarger, M.D. (by invitation), Phillip N. West, M.D. (by invitation), John A. Spratt, M.D. (by invitation), Julaine M. Florence (by invitation), Charles L. Roper, M.D., Thomas B. Ferguson, M.D., and Clarence S. Weldon, M.D., St. Louis, Mo.
More than forty years ago, Alfred Blalock and colleagues I reviewed the literature concerning maladies of the thymus gland associated with myasthenia gravis. Adding to the cases collected by Bell- and Norris," they reported a total of 54 cases of thymic disease associated with myasthenia gravis in 1939. The only four cases of surgical removal of the thymus in patients with myasthenia gravis were summarized, and Blalock added a case of his own in which a cystic thymic tumor was removed through a median sternotomy in 1936. Marked improvement resulted and in two years the patient was totally asymptomatic. Since that report, many case reports, collected surgical series, and reviews have established a strong role for thymectomy in the management of myasthenia gravis.":" From the Division of Cardiothoracic Surgery, Washington University School of Medicine, St. Louis, Mo. Read at the Sixtieth Annual Meeting of The American Association of Thoracic Surgeons, San Francisco, Calif., April 28 to 30, 1980. Address for reprints: Richard E. Clark, M.D., Suite 3108 Queeny Tower, 4989 Barnes Hospital Plaza, SI. Louis, Mo. 63110.
696
Both Blalock and Keynes noted that the availability of a specific drug, neostigmine (Prostigmin), was of significance in the successful treatment of their surgical patients. Pharmacologic treatment prior to and after operation with anticholinesterase, corticotropins, and steroid compounds has been advocated over the past two decades. Johns," Mann.!" and associates, by advocating long-term use of corticosteroids for weeks to years prior to operation, placed thymectomy last in the sequence of therapy, a position not now deserved in the contemporary management of patients with myasthenia gravis. Eight years ago, a group of neurologists specializing in muscle disorders at the Washington University Medical Center reviewed their prior experience with myasthenia gravis and thymectomy and established a protocol of using thymectomy as the initial major therapeutic step followed by short-term anticholinesterase treatment and long-term prednisone management. This report describes our experience with reversal of the usual sequence of treatment events, with particular attention to
0022-5223/80/110696+06$00.6010 © 1980 The C. V. Mosby Co.
Volume
eo Thymectomy for myasthenia gravis
Number 5
697
November, 1980
those patients with myasthenia gravis who underwent thymectomy prior to the age of 35 years. Methods and patients Record review. All surgical, hospital, and outpatient records were reviewed for the period Jan. I, 1972, to Jan. I, 1980, for patients with myasthenia gravis and thymectomy. Details of the status and medications of each patient, the preoperative pulmonary function test data, muscle biopsy findings, nerve conduction studies, electromyographic data, chest roentgenograms, hematologic status, and more recently the findings by computerized axial tomography (CT scan) were extracted. The Osserman!' classification is based on the clinical evaluation prior to elective operation and has six categories: asymptomatic, I-ocular, IIA-generalized mild, lIB-generalized moderately severe, IIIacute fulminating, IV-late severe. Postoperative management with particular attention to the pulmonary complications and need for ventilatory support was catalogued. The pathological aspects of all thymus glands were tabulated in the manner of Papatestas and associates." The course of pharmacologic management was obtained from the outpatient records. Thymectomy. All patients had a median sternotomy and wide excision of the thymus gland. Depending on the asymmetry of the organ, dissection was begun inferiorly or laterally, and the thymus and all attached soft tissue was taken as far as the pleuropericardial reflection and generally to the phrenic nerves. Great attention was given to complete dissection around the innominate vein and near the innominate and carotid arteries. Cephalic tails of thymus extending high into the neck were carefully removed en bloc with the gland. Complete extirpation of all thymic and immediately adjacent soft tissue without fragmentation of the specimen was performed in each case. Postoperative management. All patients were returned to an intensive care unit with an endotracheal tube securely in place. Each was mechanically ventilated and tested with the endotracheal tube in place until a sustained forced vital capacity of 1.0 to 1.5 L was achieved, voluntary minute ventilation exceeded 8 Llmin, and there was no hypercarbia over a 2 to 8 hour interval with voluntary ventilation. Neostigmine in 10 mg intramuscular doses was begun when the patient was fully alert and ready for physiological testing. Oral pyridostigmine (Mestinon) was begun and neostigmine discontinued as soon as the endotracheal and nasogastric tubes were removed. In most patients, the pyridostigmine requirement was 180 to 360 mg/24 hr. Predni-
sone was begun for most patients at a dose of 100 mg/ day on the seventh postoperati ve day. During the ensuing 2 to 4 weeks, the dosage of pyridostigmine was gradually decreased. Prednisone therapy was maintained. During the hospital postoperative course, the vital capacity and muscle strength were assessed daily. Regular and frequent outpatient visits to a neurologist were made by all patients. Late follow-up. All patients were interviewed by a neurologist and explicit details of exercise tolerance, employment, symptoms, and current medications were noted. A classification of each patient was made following the last interview and examination. These classifications were remission with no medication, remission with steroids only, marked improvement with any combination of drug treatment, moderate-to-slight improvement, or no improvement. Results Total series characteristics. Twenty-eight patients had thymectomy for myasthenia gravis in the time period reviewed. These operations were distributed biannually as follows: 1972 to 1973, two operations; 1974 to 1975, two operations; 1976 to 1977, seven operations; 1978 to 1979, 17 operations. There were 15 females and six black patients. Age at operation ranged from 10 to 61 years with a mean age of 30 years. Twenty patients were 35 years of age or less at the time of operation. The age distribution is shown in Fig. I. Although the average duration of symptoms was 5.3 years for the entire series, this average was greatly increased by five patients aged 44,28,21,43, and 39 years, in whom the duration of symptoms was 14, 28, 21,24, and 23 years, respectively. Two of these patients had a juvenile form of myasthenia gravis. When these five are excluded, the average duration of symptoms for the majority of patients prior to operation was 1.4 years. The young adult patient. The 20 patients who were 35 years of age or less were of special interest because these patients as a group have had dramatic results with the sequence of no preoperative medication or shortterm pharmacologic treatment, thymectomy, and steroid treatment in the postoperative phase. In the young adult group of 20 patients, there were II females and six black patients. The average age was 24 years and the average duration of symptoms in 18 patients without the juvenile form of myasthenia gravis was 22 months. All had bulbar and extremity signs of myasthenia and all but two had ocular signs. Preoperative classification in terms of severity of myasthenia gravis was as follows: seven-IIA, seven-lIB, five-III,
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AGE AT OPERATION Fig. 1. Distribution of patients by age at operation in 5 year intervals. Patients older than 35 years (shaded bars) were excluded from detailed analysis. and one-IV. Prior to operation, 12 patients were taking anticholinesterase only, one was taking prednisone only, four were taking both medications, and three were receiving no medication. The average pyridostigmine requirement was 300 mg/day for the group. The preoperative vital capacity was 2.98 Lor 68% of the predicted value. Electromyographic and nerve conduction studies were performed preoperatively in 85% and 90% of the patients, respectively. Five patients (25%) had a CT scan, although this modality was used in 63% of the patients older than 35 years. A skeletal muscle biopsy was performed prior to operation in seven and in an equal number at the time of operation. The preoperative white blood cell count was 7,276 ± 816 cells/rnrn". Postoperative course. Seven patients were extubated on the day of operation. Thirteen patients required an average of 5 days on a ventilator (I to 15 days), and the first patient in our series received the only tracheostomy. At discharge the average vital capacity was 2.43 L or 54% of the predicted value. The white blood cell count was 8,994 ± 973 cells/rnm", There were no serious pulmonary, urinary tract, or infectious complications. All patients survived. Pathology. Seven or 35% of the 20 surgical specimens were normal. Germinal centers were present in 12 with a spectrum of hyperplasia ranging from slight in two, to moderate in seven, to marked in three. One patient had a malignant thymoma and received postoperative irradiation.
Late clinical results. All patients in the entire series were last seen in 1980, and all but two are in significantly improved condition or are in remission. The two patients who have had mild improvement had the juvenile form of myasthenia gravis and underwent thymectomy after having had symptoms for 21 and 28 years. The remainder of the young «35 years) patients have had marked improvement. Six patients are in remission with no medication, and an additional five are in remission taking an average dose of prednisone of 69 mg every other day. Seven patients have had marked improvement but have symptoms which in most cases were associated with an upper respiratory tract infection or unusual physical stress. Three of these patients used an average of 180 mg of pyridostigmine daily, significantly less than prior to operation. Two are receiving prednisone at an average dose of 75 mg every other day. Two children, aged 10 and 13 at operation, require both steroids and anticholinesterase medication. The duration of follow-up ranged from 5 to 88 months, with an average duration of 30 months for the entire series and 32 months for the young adult group. The rapid improvement in symptoms, the decreased medication requirement, and the durability of response to treatment in all but one patient has been significant. This patient, extremely ill prior to operation, required plasmapheresis in the first few months after thymectomy but now is in markedly improved condition with
Volume 80 Number 5 November, 1980
continued steroid treatment 7 months after operation. Thus the rate of long-term marked improvement in the 18 patients without the juvenile form of myasthenia gravis is 100%, with 55% totally asymptomatic nearly 3 years after operation.
Discussion The young adult with myasthenia gravis is most likely to be female and to have a non-tumor bearing thymus gland. This likelihood was borne out in our series, for 5% of the patients had thymoma and 55% were female, although the latter percentage usually is greater in reported series.v " 11-15 As experience has accumulated, surgical extirpation of all recognized thymic tissue early in the course of the disease has been found more beneficial, over the long term, than withholding operation for many years, regardless of preoperative medical regimens.v "- 12. 15 Many have emphasized the need for a careful and complete dissection of the gland. In our view, the operation should be performed as if it were an en bloc dissection for a malignant tumor. The reports of recurrent myasthenia gravis with concurrent findings of remaining thymic tissue at reoperation or autopsy support this approach.!" Second, consideration of the embryonic origins and studies of the translocated thymic rests'? in fat further suggest that wide surgical exposure and removal of all attached and adjacent tissue will yield superior long-term results. Finally, careful surgical descriptions of the location of aberrant thymic tissue found at operation and verified histologically" emphasize the need for wide en bloc dissection. Careful dissection of the tails of the thymus into the neck is required in every case. These thymic tails were found to some extent in every case in this series. Thymic extensions may be the remnants of the descent of the third branchial pouch into the mediastinum."? Papatestas;" Alpert.!" and their associates have repeatedly reported the correlation of the intensity of lymphoid hyperplastic response and numbers of germinal centers to the late clinical results. Germinal centers are not found in the normal thymus gland of the young adult. 19 Papatestas and colleagues" noted a strong positive relationship between the absence or sparse presence of germinal centers to a rapid and significant improvement in symptoms of patients with myasthenia gravis following thymectomy. No such correlation could be made in this series or in others. 20 Of the 11 patients in remission, four patients had normal glands, one had 1+ hyperplasia, four had 2+ hyperplasia, and two had 3+ hyperplasia. Conversely, of seven of the patients with normal thymus glands, four are in remission, two have mild
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improvement only, and one has had a good clinical result but continues to take pyridostigmine and steroids. Strong support for the use of prednisone in the preoperative period is found in the reports of Johns and co-workers" and Bolooki and Schwartzman." The former group used steroids for the long term whereas the latter advocated high doses (1,000 mg) starting on the day of operation. In our study, prednisone was given intraoperatively only to those patients receiving the drug prior to operation. There was no statistically significant correlation between the preoperative and intraoperative use of prednisone and the days on the ventilator, as has been reported. 21 The long-term emphasis on high doses of steroids deserves special mention. No other report found in the literature search has specifically detailed such a prospective postoperative plan. We were unable to determine the relative influences of patient age, short duration of symptoms prior to operation, and the use of high doses of prednisone in the postoperative phase on the rapid and consistent postsurgical improvement of symptoms of myasthenia gravis and decreased requirement for anticholinesterase drugs. Others have reported the exacerbations associated with the initial period of high-dose steroids in nonsurgical myasthenic patients. 9, 10 Postoperatively, most patients experienced a 7 to 10 day period of increased weakness prior to objective improvement in skeletal muscle strength. The decreased vital capacities at discharge may be evidence for this, although median sternotomy could result in a similar small depression. The late postoperative complications of high-dose steroids have been minimal. The incidence of upper respiratory tract infection has not been increased and there have been no known septic episodes. No other unexpected disease states have appeared in any patient; specifically, no malignant tumors have developed. The following case history illustrates the management of drug therapy.
Case report A 35-year-old white woman had symptoms of myasthenia gravis for 5 years. The diagnosis of myasthenia gravis was made 6 months prior to operation. Despite treatment with pyridostigmine she had a gradual increase in symptoms. Fourteen months ago she underwent thymectomy. She was discharged on postoperative day 20 on a regimen of prednisone, 100 mg/day, and no pyridostigmine. Seven months after operation, the prednisone dosage was reduced 5 mg on alternate days. The reduction of prednisone continues at a rate of 5 mg every 2 weeks. This patient is presently at her preoperative weight and is totally asymptomatic. She is working full time and totally manages her household.
The lasting effect of this course of treatment, as evidenced by the two patients now 6.8 and 7.3 years after
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operation and the remainder of this series of young adults with similar but shorter courses, continues to be gratifying. Especially noteworthy is the fact that, over the long term, this sequence of therapy has not failed in any patient to date. Although our medical colleagues have long recognized surgery as the initial treatment of choice in many illnesses, thymectomy on an elective basis early in the course of myasthenia has not gained such acceptance, if duration of symptoms in many series is considered. If the recurrence rate of significant symptoms under nonoperative medical therapy and the durability of the results of early operation, coupled with postoperative high-dose steroid management, are considered, the latter appears to offer significant advantages to the young patient with myasthenia gravis. We wish to acknowledge the follow-up and advice of Drs. Michael H. Brooke and Jack B. Shumate. The use of patient information from Drs. Leonard Berg, Joseph T. Black, Douglas J. Dove, Owen S. Kantor, Arthur L, Prensky, and Herbert E. Rosenbaum was appreciated. The secretarial talents of Mrs. Frances L. Grubbs are gratefully acknowledged.
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REFERENCES
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Blalock A, Mason MF, Morgan HJ, Riven SS: Myasthenia gravis and tumors of the thymic region. Report of a case in which tumor was removed. Ann Surg 110:544561, 1939 Bell ET: Tumors of the thymus in myasthenia gravis. J Nerv Ment Dis 45:130-133,1917 Norris EH: Thymoma and thymic hyperplasia in myasthenia gravis with observations on general pathology. Am J Cancer 27:421-433, 1936 Keynes G: The results of thymectomy in myasthenia gravis. Br Med J 2:611-616,1949 Papatestas AE, Alpert LI, Osserman KE, Osserman RS, Kark AE: Studies in myasthenia gravis. Effects of thymectomy results on 185 patients with non thymomatous and thymomatous myasthenia gravis, 1941-1969. Am J Med 50:465-474, 1971 Cohn HE, Solit RW, Schatz NJ, Schlezinger N: Surgical treatment in myasthenia gravis. A 27 year experience. J THoRAc CARDIOVASC SURG 68:876-885, 1974 Faulkner SL, Ehyai A, Fisher RD, Fenichel GM, Bender HW Jr: Contemporary management of myasthenia gravis. The clinical role of thymectomy Ann Thorac Surg 23:348-352, 1977 Jaretzki A, Bethea M, Wolff M, Olarte MR, Lovelace RE, Penn AS, Rowland L: A rational approach to total thymectomy in the treatment of myasthenia gravis. Ann Thorac Surg 24: 120-130, 1977 Johns TR, Mann JD, Joseph as, Campa JF: Long term administration of corticosteroids in myasthenia gravis. Neurology 22:400, 1972 Mann JD, Campa JF, Muller WH: Long-term prednisone
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followed by thymectomy in myasthenia gravis. Ann NY Acad Sci 274:608-622, 1976 Osserman KE: Myasthenia Gravis. New York, 1958, Grune & Stratton, Inc. Papatestas AE, Genkins G, Horowitz SH, Kornfeld P: Thymectomy in myasthenia gravis. Pathologic, clinical and electrophysiologic correlations. Ann NY Acad Sci 274:555-573, 1976 Blalock A: Thymectomy in the treatment of myasthenia gravis. J THoRAc CARDIOVASC SURG 13:316-339, 1944 Keynes G: Surgery of the thymus gland, second (and third) thoughts. Lancet 266:1197-1202, 1954 Genkins G, Papatestas AE, Horowitz SH, Kornfeld P: Studies in myasthenia gravis. Early thymectomy. Am J Med 58:517-524, 1975 Joseph BS, Johns TR: Recurrence of non neoplasmic thymus after thymectomy for myasthenia gravis. Neurology 23:109-116, 1973 Masaoka A, Nagaoka Y, Kotake Y: Distribution of thymic tissue at the anterior mediastinum. Current procedures in thymectomy. J THoRAc CARDIOVASC SURG 70:747-754, 1975 Alpert LI, Papatestas AE, Kark AE: A histologic reappraisal of the thymus in myasthenia gravis. A correlative study of thymic pathology and response to thymectomy. Arch PathoI91:55-61, 1961-19 Castleman B, Norris EH: The pathology of the thymus in myasthenia gravis. A study of 35 cases. Medicine 28:27-58, 1949 Reinglass JL, Brickel ACJ: The prognostic significance of thymic germinal center proliferation in myasthenia gravis. Neurology 23:69-72, 1973 Bolooki H, Schwartzman RJ: High-dose steroids for perioperative management of patients with myasthenia gravis. A preliminary report. J THoRAc CARDIOVASC SURG 75:754-757, 1978
Discussion DR. ALFRED JARETZKI III New York, N. Y.
We of the surgical faith are convinced that thymectomy is indicated in almost all patients with myasthenia gravis. If we are to prove this, we must design mutually agreed upon, reproducible preoperative and follow-up classifications and must stratify all studies for severity of disease and extent of thymectomy, as well as for age, sex, duration of disease, and presence of thymoma. In the authors' series, after 2 years, one third of the patients were in complete remission and another one third were symptom free while taking prednisone (this second group cannot be considered in remission). Although early thymectomy may be a significant factor in obtaining these results, as suggested by the authors, almost 40% had mild myasthenia gravis, which in itselffavorably influences the outcome. Thus a comparative analysis of patients with mild and severe myasthenia gravis subjected to this therapeutic regimen is still needed.
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The authors also stressed the importance of removing all thymic tissue. In this we concur, and we believe their operative procedure significantly contributed to the success. Our studies suggest that there probably is a direct relationship between the extent of thymectomy and the speed and rate of remission. One can subdivide the surgical approaches to thymectomy by estimated extent of resection. We believe we are doing the "maximum" possible resection. The authors' procedure probably lies between the "classical" transstemal procedure and our extended "maximum" operation. The "extended" transcervical resection, which some are doing now, certainly removes less thymus than either of the others. The transcervical intracapsulary thymectomy, which has been and is being used by some, has been demonstrated to be no more than a 50% resection in most instances. A composite drawing of our last 40 specimens depicts the commonest anatomic findings. All tissue from diaphragm to thyroid and from hilum to hilum is routinely removed en bloc, including both mediastinal pleural envelopes. To date, we have reoperated upon only two patients using this surgical approach (the original operations done elsewhere were cervical alone in one and sternal alone in the other), and we found 25 gm of residual thymic tissue in one and II gm in the other. I congratulate the authors on the results of their series, give caution concerning interpretation, urge analysis of comparable patient groups, and stress the importance of complete removal of the gland. DR. DAVID M. LONG, JR. LaMesa. Calif.
Dr. Clark and his colleagues are to be congratulated for their excellent results in treating these patients with myasthenia gravis. Myasthenia gravis is a rare disease, but we know more about it than any other autoimmune disease. Thymectomy early in the course is specific therapy in that it prevents formation of antireceptor antibodies. The authors appear to emphasize the treatment of the young patient. I would like to inquire about the application of thymectomy in the other patient with myasthenia gravis. In this regard, Dr. Fred Baughman, our neurologist, and I have
treated an 82-year-old patient with recent onset of myasthenia gravis who was unable to walk or even eat while receiving full medical therapy. She had a prompt and sustained improvement following thymectomy. The patient also had symptomatic idiopathic hypertrophic subaortic stenosis. We performed the thymectomy through the transcervical approach developed by Dr. Paul Kirschner. The Mount Sinai group has had excellent clinical results with this surgical technique in patients of all age groups. It seems to be particularly appropriate and well tolerated in the older, high-risk patients with significant associated diseases. DR. C LA R K (Closing) I would like to thank Dr. Jaretzki and Dr. Long for their comments. I quite agree that consolidated, stratified, and multi-institutional studies are needed to compare similar patients and the long-term effects of thymectomy in myasthenia. The series in the literature are the recordings, sometimes a bit anecdotal, of various surgeons experiences. No long-term randomized trial has been performed. The initial patients were very ill with myasthenia gravis. As the results became longer term and lasting, the neurologists were willing to refer patients with milder forms of the disease from the general community, not just within our hospital itself. With a small series of only 20 patients, we are unable to distinguish the influence of the duration of the disease from the age of the patient or the severity of the symptoms, or to determine how these three variables may have influenced the outcome. We can only say that in the young, early complete thymectomy and treatment with high-dose prednisone has been very effective in this series. Dr. Long, I think your achievement in your older patient may be a record. The results in your patient were quite dramatic, and we have seen similar results both in the young and in older patients. In the older group, however, we tend to have less dramatic results, with only approximately 50% improving and with the other half requiring medication, many of them remaining somewhat symptomatic. In all series, the young patient with a short duration of symptoms has achieved the best results. This is the case with our series.