Volume 95.
Number 5
May 1988
THORACIC AND CARDIOVASCULAR SURGERY TheJournalof
J
THORAC CARDIOVASC SLRG
1988;95:747-57
Original Communications
"Maximal" thymectomy for myasthenia gravis Results Thymectomy has been shown to be effective in the treatment of myasthenia gravis. The logical goal of operation has been complete removal of the thymus, but there has been controversy about the surgical techniqueand its relation to results. Surgical-anatomic studies have shown gross and microscopic thymus widely distributed in the neck and mediastinum. We believe that an en bloc transcervical-transstemal "maximal" thymectomy is required to remove aU thymic tissue predictably. Ninety-five patients with generalized myasthenia gravis underwent "maximal" thymectomy consecutively between 1977 and 1985 and were evaluated 6 months to 89 months after operation. In Group A (N = 72), myasthenia gravis without thymoma, the uncorrected data revealed that 96% (69) had benefited from operation: 79% (57) had no symptoms; 46 % (33) were in remission; 33 % (24) were symptom free when receiving minimal doses of pyridostigmine; and none were worse. Life table analysis yielded a remission rate of 81 % at 89 months. In group B (N = 8), myasthenia gravis without thymoma for which patients underwent reexploration for incapacitating weakness after earlier transcervical or transsternal operations, residual thymus was found in all, One patient was in remission, two were symptom free when receiving medication, one was unchanged, and none were worse. In group C (N 15), myasthenia gravis and thymoma, two patients were in remission and nine were symptom free when receiving medication. Two patients in this group died 2 and 4 years postoperatively in crisis. Response to thymectomy in group A was greater in patients with mild myasthenia gravis and may have been better in patients who had symptoms for less than 60 months preoperatively, but the response did not depend on age, sex, presence or absence of thymic hyperplasia or involution, or titers of acetylcholine receptor antibodies. The response to thymectomy in
Alfred Jaretzki Ill, MD, Audrey S. Penn, MD (by invitation), David S. Younger, MD (by invitation), Marianne Wolff, MD (by invitation), Marcelo R. Olarte, MD (by invitation), Robert E. Lovelace, MD (by invitation), and Lewis P. Rowland, MD (by invitation), New York, N. Y.
From the Departments of Surgery, Neurology, and Pathology, Columbia-Presbyterian Medical Center, New York, N.Y.
Read at the Sixty-seventh Annual Meeting of The American Association for Thoracic Surgery, Chicago, 11I., April 6-8, 1987.
Supported by grants from the Muscular Dystrophy Association and the National Institutes of Health (N.S. 17904).
Address for reprints: Alfred Jaretzki III, MD, Columbia-Presbyterian Medical Center, 161 Fort Washington Ave.. New York. NY 10032.
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group B was striking but slower than in group A, perhaps because symptoms were more severe and of longer duration. The response in group C was also less good than in group A and proportionately fewer benefited. These results support the recommendation for thymectomy in the treatment of patients with generalized myasthenia gravis and indicate the desirability of a maximal procedure. For persistent or recurrent severe symptoms after previous transcervical or submaximal traossternal resections, reoperation by this technique is also recommended.
Myasthenia gravis (MG) is an autoimmune disease in which the thymus gland is thought to playa central role in the pathogenesis.' Weakness results from a reduction in acetylcholine receptors (AchR) at the neuromuscular junction.' MG is still a potentially debilitating and life-threatening illness despite advances in therapy. Thymectomy is now standard therapy, and improvements in surgical techniques, anesthesia, and respiratory care and the use of plasmapheresis have drastically reduced the operative morbidity. The mortality is close to nil regardless of the surgical approach. There is, however, controversy about the surgical technique and its relation to results. In 1977, preliminary surgical-anatomic studies indicated that thymic tissue was widely distributed in the neck and anterior mediastinum.' As a result of that experience, and because of reports of microscopic foci of thymus in pericapsular mediastinal fat," we5 developed a combined transcervical-transsternal en bloc resection that, we believe, comes as close to complete removal of thymic tissue as is surgically possible. The term maximal rather than total thymectomy has been used because microscopic foci or distant ectopic tissue may remam. Patients and methods Patient selection. Between June 1977 and Jan. I, 1985, we performed 124 consecutive "maximal" thymectomies. No selection was made for age or sex or for duration or severity of symptoms. Of the 124 patients, 95 were evaluated 6 to 89 months after operation. Primary operations were done in 72 patients for MG without thymoma (group A), and these patients were divided for analysis into series I (the first 41 patients) and series 2 (the second 31 patients). Reoperations for MG without thymoma were done in eight patients who had incapacitating weakness after earlier transcervical or transsternal operations (group B). Fifteen patients had MG and thymoma (group C). Patient characteristics. The diagnosis of MG was made on clinical grounds (fluctuating weakness of ocular muscles and varying combinations of weakness of facial, oropharyngeal, neck, limb, and respiratory muscles), with unequivocal response to edrophonium or neostigmine. A decremental response to repetitive nerve stimulation and abnormal titers of AChR antibodies were confirmatory," but not required for diagnosis. There were 27 men and 45 women in group A, two
and six in group B, and seven and eight in group C. The ages ranged from 9 to 66 years (68';7, younger than 35) in group A. from 16 to 54 in group B, and from 25 to 73 years (40';7, older than 60) in group C. Severity of symptoms, duration of disease, preoperative AChR titers, and therapy before operation are recorded in Table I. Timing of operation and perioperative care. The timing of operation and selection of drugs before operation were not uniform. Attempts were made to have all patients free of aspiration or respiratory symptoms at the time of operation. but a few who failed to respond to plasmapheresis or other therapy were operated on while still supported by a respirator or with the expectation of requiring a tracheostomy early postoperatively. Immunosuppressive drugs (corticosteroids or azathioprine) were given preoperatively by the referring physician in some instances and by us to patients who failed to respond adequately to anticholinesterase drugs or plasmapheresis. Starting in 1982, we gave four to five plasma exchanges preoperatively to patients who had symptomatic dysphagia. dysarthria, or respiratory weakness (assessed by standardized pulmonary function studies'). Postoperatively, the patients were cared for in the surgical-anesthesia intensive care unit. Patients who were not extubated in the operating room were considered for extubation when they met criteria described previously. ' Classification (severity and results). Preoperatively severity of symptoms was determined by the patient's maximum symptoms at any time before operation and classified as follows: class I (ocular)---ocular signs without generalization: class II (mild)-mild generalized weakness without oropharyngeal symptoms; class III (moderate)-moderate generalized weakness with nonincapacitating oropharyngeal or respiratory symptoms; class IV (severe)-severe generalized weakness and/or incapacitating oropharyngeal or respiratory symptoms; and class V (crisis)-need for intubation and mechanical ventilation. Postoperative results were classified as follows: remissionno signs or symptoms of MG and no medication: asymptomatic (A I)-may have minimal ptosis but otherwise clinically normal, receiving 60 to 240 mg pyridostigmine daily; asymptomatic (A 2)----clinica lly normal when receiving immunosuppressive drugs; improved-better than preoperatively when receiving medication but not A, or A,: unchanged; worse;died of MG. Thymic pathologic classification. Hyperplasia was defined by the presence of lymphoid follicles not ordinarily seen in the normal adult thymus; involution by the degree of fatty replacement of thymic tissue. In cases of complete involution, epithelial thymic remnants were the only indication that the tissue did represent thymus.' Method of analysis. The data were analyzed uncorrected
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Table I. Patient characteristics Group A (n = 72) Maximum severity class (No. of patients) I. Ocular II. Mild III. Moderate IV. Severe V. Crisis Mean duration of symptoms in years (range) Mean preop. AChR titers (range) Therapy before operation (No. of patients) None Cholinergic agents Plasmapheresis Steroids
Group B (n =
o 13 37
(18%) (51.5%)
I~}
(30.5%)
2.8 (01-20) 73 (0.6-2000)
Group C (n = 15)
8)
o o
o o
I
5
~}
~} (60'!r)
(87%)
1.7 ( 1-8) 62 (5-174)
14.1 (1-25) 59 (4-150)
o
o
o
65 30 21
8 5
15
and corrected for length of follow-up. To assess the effect of length of follow-up and the significance of the variables, we performed multivariate analysis by the Cox proportional hazard model.' Life table analysis was performed by the Kaplan-Meier method.' As a result of these analyses, some of the current interpretations differ from an earlier report."
Results
Clinical response. Evaluation was performed at least 1 year after operation. However, of the 72 patients in group A, six who were not in remission were lost to follow-up within the first 11 months. The mean duration of follow-up was 40 months (6 to 89 months). The uncorrected results at 6 to 89 months after thymectomy for groups A, B, and C are recorded in Table II. Life table analyses for group A are shown in Figs. 1 and 2. In Group A. the uncorrected results for the 72 patients at 6 to 89 months revealed that 96% (69) had benefited from operation; 79% (57) had no symptoms, 46% (33) were in remission, and 33% (24) were asymptomatic (AI)' Fifty-five percent of those in remission and 67% of those asymptomatic (AI) had achieved that status within 2 years; 60% and 79% by 4 years. Life table analysis for the 72 patients gave a remission rate of 81% at 89 months. Comparison of patients in series 1 (N = 41) with those in series 2 (N = 31) indicated that remission rates were significantly higher (p = 0.02) for those operated on after June 1982 (series 2), Patients in class II or III had a better response (p = 0.04) than those in class IV or V. Multivariate analysis failed to show significant differences for age, sex, preoperative duration of symptoms, thymic hyperplasia and involution, or use of steroids or plasmapheresis preoperatively. Four of five patients
7 9
4
Table II. Results of thymectomy (uncorrected)
Remission Asymptomatic (AI) Asymptomatic (AJ Improved Unchanged Worse Died (MG)
Group A
Group B
(n = 72)
tn = 8)
Group C in = 15)
%
No.
%
No.
%
No.
46 33
33 24
12.5 25
I 2
13 6.5
2
11
8
25
2
46.5
7
6 4
4 3 0 0
25 12.5
2 I 0 0
20
3 0 0 2
13
older than 60 years and comparable percentages of men (55%) and women (54%) were in remission. By Cox regression analysis, a significant difference could not be shown for duration of symptoms before operation, although 51% of patients (30/59) with symptoms of less than 60 months' duration were in remission compared with 23% (3/13) with symptoms for 60 months or more. The presence or absence of thymic hyperplasia (most in patients less than 36 years of age) or involution did not have a predictive influence. Preoperative AChR antibody titers were not related to outcome or thymic lesions: Postoperatively, antibody titers fell 25% or more in 35 of 70 patients so studied; 18 of these 35 were in remission or asymptomatic (AI)' The outcome was also excellent in the 17 of the 72 patients whose test results showed seronegativity (eight were in remission and three asymptomatic [AI])' although the number was too small to demonstrate statistical significance.
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Jaretzki et al.
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100 90 80 70
"
c
0
60 50
'00
40
'E
30
a:
20
(JJ
10]
..
_
Ql
• 10
20
-.--
----
30
40
GroupA
(n~ 72)
Series # 1 (n=41)
Series #2
50
60
70
80
(n~31)
90
Follow-up (months)
Fig. 1. Remission rates for MG with no thymoma (life table analysis). Remission rates are shown for all patients in group A and for the subgroups series I and series 2. There was a statistically significant difference between series 1 and series 2 (p = 0.02).
There were two relapses: One was minor, occurred after 2 years of remission, and lasted I day; the patient required no therapy and subsequently has been in remission for 3 years. The other relapse occurred 2 years after the onset of remission; the patient was treated by the reinstitution of steroids and 3 years later had become asymptomatic (A 2) (the patient is not recorded as being in remission). In group B, residual thymus was found in all surgical specimens (2 to 23 gm) regardless of the original surgical approach, although most computed tomographic scans were deemed normal or inconclusive. In the four patients who had previous transcervical procedures (all were performed elsewhere), thymus was found in the neck in one of two patients undergoing reexploration and in the mediastinum in all four; in the four patients who had previous transsternal procedures (two at Columbia-Presbyterian Medical Center before 1973), thymus was found in the neck in all four and in the mediastinum in three. Reoperation was followed by considerable improvement in all but one patient, who remained unchanged (followed up for only I year). Of the patients in group C, MG with thymona (all stage I), 64% were symptom free; two died 2 and 4 years postoperatively in crisis (at other institutions). Pathologic study. Thymus was found in all specimens regardless of the patient's age. In group A, 26 patients had hyperplasia, 28 involution, 17 both, and I neither. In groups B and C the numbers, respectively, were 1, 4, 3, and 0 and 3, 6, 5, and 1. The thymoma cell type was predominantly lymphoid in two patients, predominantly epithelial in five, with mixed lymphoid and epithelial elements in eight; no spindle cell thymo-
mas were seen. The tumors were mostly solid; some were cystic and one had a totally calcified shell. All IS were Bergh classification stage I," without pericapsular invasion, invasion of adjacent organs, or pleural or diaphragmatic implants. In one patient, there were two distinct thymomas of different cell types in separate mediastinal thymic lobes. Thyroid specimens were submitted from 25 patients; there was thyroiditis in seven (one Hashimoto's type), nontoxic nodular goiter in five, and 12 were normal. One specimen showed an area of C-cell hyperplasia 12; test results after subsequent thyroidectomy were negative for thyroid carcinoma. Complications. There were no operative or hospital deaths, phrenic or recurrent nerve injuries, or hypoparathyroidism in this series or in the 157 patients operated on since 1973. There were seven major postoperative complications: bilateral staphylococcal empyema in a diabetic patient who had been taking corticosteroids and had presternal folliculitis at the time of operation-the empyema responded to antibiotic therapy alone; a deep sternal wound infection in a patient who had a functioning tracheostomy at the time of thymectomy and was receiving corticosteroids-the sternal infection responded to debridement with myocutaneous closure; postpericardiotomy syndrome in two patients-both responded promptly to indomethacin therapy; bilateral chylothorax in a patient who had had an earlier transcervical thymectomy-the chylothorax responded to chest tube drainage; sternal wound dehiscence in a 64-year-old patient with thymoma who was receiving steroids-after reclosure, with parasternal vertical wire reinforcement, the sternum healed without complications; and a pulmonary embolism in a 63-year-old
Volume 95
"Maximal" thymectomy
Number 5 May 1988
75 1
100 90 80 70 -:§2.
60
C/l
50
e; c
a
'00
40
E
30
C/l
Q)
a:
_e - -
Group A (n=72)
Class II-Ill (n=50)
20
.-------.-
10
10
20
30
40
Class IV-V (n=22)
50
60
70
80
90
Follow-up (months)
Fig. 2. Remission rates for MG with no thymoma (life table analysis). Remission rates are shown for all patients in group A and for the subgroups class II or III and class IV or V. There was a statistically significant difference between the two subgroups (p = 0.04).
patient on postoperative day 8-this was treated with anticoagulant therapy without further complications. There were five late deaths. In group A, myocardial infarction occurred at 3 years in a patient whose MG had improved, and carcinoma of the lung occurred in a patient in remission at 5 years. In group B, a patient whose condition had improved died in a motorcycle accident 2 years after reoperation. In group C, two patients died in crisis at other institutions at 2 and 4 years postoperatively without evidence of recurrent thymoma. Discussion With McQuillen,13 we believe the most reliable measur" of response to thymectomy is complete and sustained remission. The results of patients who are in worse condition, have recurrent symptoms, require reoperation, or die in crisis must also be recorded because they represent failure of therapy. In this series of 72 patients with MG without thymoma, 30% of whom were in class IV or V, the uncorrected remission rate at 6 to 89 months was 46%; it would have been 57.5% if six patients had been excluded (lost to follow-up before I year and not in remission) and if five patients had been included (known to have gone into remission after the study was completed). The remission rate by life table analysis was 81 % at 7 years. None were in worse condition, required reoperation, or died in crisis. One patient had a relapse after a remission lasting 2 years, subsequently remained asymptomatic on steroids (A 2) , and has not been recorded as in remission. As in other series, age, sex, and cell type of the thymus (exclusive of thymoma) did not influence out-
come.":" As we" previously reported, the absolute AChR antibody titer or even the absence of detectable antibodies (seronegativity) did not predict outcome.'? We have operated on patients as young as eight years (others have done so on patients as young as 2 V2 years") and as old as 75 years. We believe that age per se is not a contraindication to operation, operation frequently being preferable to severe MG or corticosteroids at both extremes of age. Older patients invariably have residual thymic epithelium (all in our series and all in an autopsy study of accident victims 60 to 90 years of age"), and although at higher risk they tolerate the maximum procedure and respond as well as younger individuals. Others have found that the milder or shorter the duration of symptoms and the longer the postoperative follow-up, the more favorable the results. 14. IS. 18-20 In this series, the milder cases had a more favorable outcome, and the longer the follow-up, the better the results. However, we did not find a statistical difference for preoperative duration of symptoms, although the uncorrected remission rates were much higher for duration of symptoms less than 60 months. Accordingly, in the evaluation of the results of different surgical techniques, allowance must be made for the severity of the symptoms, the length of follow-up, and perhaps preoperative duration of symptoms. The life table remission rate was better in patients operated on after June 1982. This finding remains unexplained. Although the patients in series 2 had *O'Toole C. Pushparaj N. Studies of aging. 1987. Unpublished data.
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Jaretzki et al.
Surgery
60 50
~ e; UJ
c 0
'eUJn
'E
40
D Low mI Mean
•
High
30 20
OJ
a:
10 0
Cervical
Sternal
Extended
Maximal
(6)
(6)
(2)
(4)
Type of Thymectomy
Fig. 3. Comparative remission rates for MG with no thymoma (uncorrected). Collated from 18 reports (six transcervical, six classic transsternaJ. two extended, and four maximal thymectomies: see text for references). The difference between the maximal and cervical procedures is highly significant (p = 0.0001).
milder symptoms (15% were in class IV or V compared with 25% in series 1) and although many more received plasmapheresis preoperatively (84% compared with 29% in series 1), multivariate analysis failed to show that these or other parameters analyzed were statistically significant. However, the combination of operating on patients with milder symptoms and a more aggressive exploration of the neck (when the importance of neck exploration became apparent}' may account, in part, for these improved results. The results of maximal thymectomy are better than those reported for classic transsternal or transcervical procedures (Fig. 3) and imply that the less residual thymus, the better the outcome. The reported uncorrected remission rates for transcervical thymectomy have been 6% to 24% (mean 15.7%)21.26 and for the classic transsternal procedure, 23% to 37% (mean 35%),18.19.22.27.29 whereas those for the maximal procedure are 46% to 58% (mean 51.4%).J5 30. 31 The difference between the uncorrected remission rates for maximal thymectomy and transcervical thymectomy is statistically significant (p = 0.0001), if these individual studies can be compared. Even though, to date, the uncorrected results of "extended" procedures'<" approximate those of maximal resection, we prefer the maximal type of operation because our anatomic study' indicates that it should leave less thymus in the neck and the mediastinum, and life table analysis of comparable patients corrected for length of follow-up should demonstrate a clear superiority of the maximal procedure. We believe reoperation, with maximal thymectomy,
is indicated if a patient with severe MG fails to respond to one of the more limited resections (or responds and then deteriorates). The decision is based on clinical assessment and evaluation of the extent of the original procedure. In our 15 reoperations (eight in group Band seven after this series), 10 of the patients had had previous transcervical and five transsternal thymectomy; all had residual thymus, even though preoperative computed tomographic scan had been normal or inconclusive in most. Although the mean duration of symptoms at reoperation was 14.6 years and all but one patient had disabling symptoms at the time of operation, all are markedly improved at this time, including the patient (Table II) whose condition at I year was unchanged. The slower response is presumably related to the severity and duration of the symptoms in this group compared with those who had a maximal type of operation initially. These reoperations show that thymus can be overlooked both in the neck and mediastinum regardless of the initial approach unless a maximal type procedure is used, and the findings imply that as little as 2 gm of residual thymus can be responsible for severe symptoms, because subsequent removal has resulted in marked improvement. Although we did not reexplore the neck in four of the patients who had previous transcervical operations, we now believe the reoperative procedure should also be maximal in extent in the neck and the mediastinum regardless of which site had been previously explored. "The Case Against Transcervical Thymectomy?" no
Volume 95 Number 5 May 1988
longer seems to be a matter of speculation. In our opinion, now shared by Kirschner* (one of the original transcervical proponents) and expressed by Henze and associates" and Fischer and, associates," transcervical thymectomy should be abandoned in the treatment of MG without thymoma. In addition, we believe it is contraindicated in the treatment of thymoma with or without MG. The remission rates have been significantlylower, 27% and 32% of the patients in two series have required reoperations.F" residual thymus has been found in all patients, 16.34-37 and there has been subsequent clinical improvement in most." Papatestas and associates," with life table analysis for the transcervical operations they personally performed, reported remission rates at 10 years of 40% for all patients and of 64% for those with mild symptoms and symptoms of short duration. These figures compare unfavorably with ours. These authors state that their results were equal to transsternal thymectomy; however, they compared transcervical thymectomy with outdated extra pleural transsternal procedures that were also incomplete including "median sternotomy (partial or complete), lateral thoracotomy, or parasternal mediastinotomy.'?" Also, they have not indicated how many of the patients who were not in remission (40% to 60% of the total) did not improve, were worse, or required reoperation. The transcervical technique recently described by Cooper.31 which reportedly gives better exposure for more extensive thymic excision, gave an uncorrected remission rate of 52% at follow-up (mean 3.5 years) and suggests he may be removing significantly more thymus through the neck than is accomplished by others. However, the anatomy of the gland precludes complete removal predictably through the neck regardless of the exposure. Since his patients were not consecutive and had predominantly mild MG (two of 65 ocular alone, 15% no medication before operation, and twice as many as we had with mild symptoms), they formed a more favorable cohort and would thereby be expected to surpass our results if the resections were equivalent. In contrast, he reported 44% worsening postoperatively and one death in crisis. The occasional mediastinal thymoma that develops after a transcervical thymectomy," the discovery of thymomas at transcervical operations" with possible spreading of the tumor by incomplete resection.v" and the finding of two distinct thymomas of different cell "Kirschner PA. Discussion of Papatestas AE et al. Effects of thymectomy in myasthenia gravis. New York Surgical Society meeting, Jan. 8, 1986. Unpublished data.
"Maximal" thymectomy
75 3
type in separate mediastinal lobes* are additional reasons for abandoning the transcervical approach. The morbidity and mortality of the transsternal procedures are no longer deterrents and the cosmetic benefit of the cervical incision is offset by the lower rates of remission or asymptomatic (AI) status after partial thymectomy and by the patients who continue to have disabling symptoms. Although some believe that the transcervical procedure should be done first and that extensive procedures should be reserved for patients whose conditions fail to improve after the transcervical procedure, that policy would condemn many patients to persistent symptoms, some severe. The incidence of thymoma in this series was 16% and all cases were nonmalignant (stage I). In our overall experience of 154 consecutive thymectomies, the incidence of thymoma was 17%. Of the 154 patients, 2.3% had invasive thymoma and the likelihood of a thymoma being present increased with age (3% for 20 years and younger; 12% for 21 to 45 years; and 35% for 46 and older t). Although many patients with thymoma respond symptomatically to thymectomy, and thymectomy is indicated, it has long been recognized that the response is less favorable than in patients without thymoma.20.41.43.44 In our patients with thymoma, the outcome was less favorable than in those without thymoma, and the delayed mortality from MG was 13% (2/15) without tumor recurrence. Even so, almost two thirds did become symptom free. Although we use postoperative radiation for stage II and III thymoma, we have not used it for stage I, contrary to the recommendations of Mondon and colleagues." Complete removal of coexisting thymus gland (maximal thymectomy) is also indicated in the presence of thymoma with or without MG. This recommendation is supported by the presence of hyperplasia with variable degrees of involution in the thymus in association with the thymoma in all but one in this series and the occasional late onset of MG (6% to 10%) after removal of an asymptomatic thymoma without removal of the coexisting thymus." We are indebted to Robert R. Sciacca, EngScD, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, for the statistical analysis.
"Wolff M, Lovelace RE. Jaretzki A III. Two histologically dissimilar thymomas in a patient with myasthenia gravis. Unpublished data. tEllis K, Austin JHM, Jaretzki A III. Radiologic detection of thymoma in patients with myasthenia gravis. Unpublished data.
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REFERENCES I. Wekerle H, Muller-Herrnelink HK. The thymus in myasthenia gravis. Curr Top Pathol 1986;75: 179-206. 2. Engel AG. Myasthenia gravis and myasthenic syndrome. Ann Neurol 1984;16:519-34. 3. Jaretzki A III, Bethea M, Wolff M, Olarte MR, Penn AS, Rowland LP. A rational approach to total thymectomy in the treatment of myasthenia gravis. Ann Thorac Surg 1977;24: 120-30. 4. Masaoka A, Nagaoka Y, Kotake Y. Distribution of thymic tissue in the anterior mediastinum: current procedures in thymectomy. J THoRAc CARDIOVASC SURG 1975; 70:747-54. 5. Jaretzki A III, Wolff M. "Maximal" thymectomy for myasthenia gravis: surgical anatomy and operative technique. J THoRAc CARDIOVASC SURG (In press). 6. Penn AS, Schotland DL, Lamme S. Antimuscle and antiacetylcholine receptor antibodies in myasthenia gravis. Muscle Nerve 1986;9:407-15. 7. Younger DS, Braun NMT, Jaretzki A III, Penn AS, Lovelace RE. Myasthenia gravis: determinants for independent ventilation after transsternal thymectomy. Neurology 1984;34:336-40. 8. Penn AS, Jaretzki A III, Wolff M, Chang HW, Tennyson V. Thymic abnormalities: antigen or antibody? Response to thymectomy in myasthenia gravis. Ann NY Acad Sci 1981;377:789-91. 9. Lawless JF. Statistical models and methods for life table data. New York: John Wiley & Sons, Inc., 1982. 10. Younger DS, Jaretzki A III, Penn AS, et a!. Maximum thymectomy for myasthenia gravis. Ann NY Acad Sci 1987;505:832-5. 11. Bergh NP, Gatzinsky P, Larrsons S, et a!. Tumors of the thymus and thymus region. I. Clinicopathological studies on thymomas. Ann Thorac Surg 1978;25:91-8. 12. LiVolsi VA. Calcitonin: the hormone and its significance. In: Fenoglio CM, Wolff M, eds. Progress in Surgical Pathology; vol 1. New York: Masson Pub!. USA Inc., 1980:88-9. 13. McQuillen MP. Symposium on therapeutic controversies: myasthenia gravis-thymectomy. Trans Am Neurol Assoc 1978; I03:283-6. 14. Mulder DG, Hermann C Jr, Keesey J, Edwards H. Thymectomy for myasthenia gravis. Am J Surg 1983; 146:61-6. 15. Olanow CW, Wechsler AS, Roses AD. A prospective study of thymectomy and serum acetylcholine receptor antibodies in myasthenia gravis. Ann Surg 1982; 196:11321. 16. Stump WJ, Adornato BT, Engel WK, McIntosh CL, Castleman BJ. Thymectomy in myasthenia gravis. Neurology 1978;28:372-3. 17. Soliven BC, Lange DJ, Penn AS, Younger D, Jaretzki A III, Rowland LP. Seronegative myasthenia gravis. Neurology (In press).
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18. Mulder DG, Herrmann C, Buckberg GD. Effect of thymectomy in patients with myasthenia gravis: a sixteen year experience. Am J Surg 1974; 128:202-5. 19. Emeryk B, Strugalska MH. Evaluation of results of thymectomy in myasthenia gravis. J Neurol 1976; 21 I :I 55-68. 20. Papatestas AE, Genkins G, Kornfeld P, et al. Effects of thymectomy in myasthenia gravis. Ann Surg 1987: 206:79-88. 21. Masaoka A, Monden Y. Comparison of the results of transsternal simple, transcervical simple and extended thymectomy. Ann NY Acad Sci 1981;377:755-65. 22. Matell G, Lebram G, Osterman PO, Pirskanen R. Follow up comparison of suprasternal vs transsternal method for thymectomy in myasthenia gravis. Ann NY Acad Sci 1981 ;377:844-5. 23. Donnelly RJ, Laquaglia MP, Fabri B, Hayward M, Florence AM. Cervical thymectomy in the treatment of myasthenia gravis. Ann R Coli Surg Engl 1984;66: 305-8. 24. Paletto AE Maggi G. Thymectomy in the treatment of myasthenia gravis: results in 320 patients. Int Surg 1982;67:13-6. 25. Papatestas AE, Genkins G, Kornfeld P. Comparison of the results of transcervical and transsternal thymectomy in myasthenia gravis. Ann NY Acad Sci 1981;377:76678. 26. Klingen G, Johansson L, Westerholm CJ, Sundstroom C. Transcervical thymectomy with the aid of mediastinoscopy for myasthenia gravis: eight years' experience. Ann Thorac Surg 1977;23:342-7. 27. Buckingham JM, Howard FM Jr, Bernatz PE, et al. The value of thymectomy in myasthenia gravis: a computer-assisted matched study. Ann Surg 1976; 184: 453-8. 28. Masaoka A, Maeda M, Monden Y, Nakahara K, Kotake Y. Clinical results following thymectomy in myasthenia gravis. Med J Osaka Univ 1976;26: 117-28. 29. Oosterhuis HJ. Observations of the natural history of myasthenia gravis and the effect of thymectomy. Ann NY Acad Sci 1981;377:678-90. 30. Rubin JW, Ellison RG, Moore HV, Pai GP. Factors affecting response to thymectomy for myasthenia gravis. J THORAC CARDIOVASC SURG 1981;82:720-8. 31. Fischer JE, Grinvalski HT, Nussbaum MS, et a!. Aggressive surgical approach for drug-free remission from myasthenia gravis. Ann Surg 1987;205:496-503. 32. Ferguson TB, Hankins JR, Mayer RF, Satterfield JR. Thymectomy for myasthenia gravis: 14 year experience. Am Surg 1985;201:618-25. 33. Jaretzki A III. Myasthenia gravis: the case against transcervical thymectomy. Trans Am Neurol Assoc 1978;103:288-91. 34. Henze A, Biberfeld P, Christensson B, Matell G, Pirskanen R. Failing transcervical thymectomy in myasthenia
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gravis: an evaluation of transsternal re-exploration. Scand J Thorac Cardiovasc Surg 1984; 18:235-8. 35. Masaoka A, Monden Y, Seike Y, Tanioka T, Kagotani K. Reoperation after transcervical thymectomy for myasthenia gravis. Neurology 1982;32:83-5. 36. Rosenberg M, Jauregui WO, DeVega ME, Herrera MR, Roncoroni AJ. Recurrence of thymic hyperplasia after thymectomy in myasthenia gravis: its importance as a cause of failure of surgical treatment. Am J Med 1983;74:78-82. 37. Rosenberg M, Jauregui WO, Herrera MR, Roncoroni AJ, Rojas OR, Olmedo GSM. Recurrence of thymic hyperplasia after transsternal thymectomy in myasthenia gravis. Chest 1986;89:888-9. 38. Pirskanen R, Matell G, Henze A. Results following transsternal thymectomy after failing transcervical "thymectomy." Ann NY Acad Sci (In press). 39. Cooper J. An improved technique for transcervical thymectomy in myasthenia gravis. Ann Thorac Surg (In press). 40. Austin EH, Olanow CW, Wechsler AS. Thymoma following transcervical thymectomy for myasthenia gravis. Ann Thorac Surg 1983;35:548-50. 41. Shamji F, Pearson FG, Todd TRJ, Ginsberg RJ, Ives R, Cooper JD. Results of surgical treatment of thymoma. J THORAC CARDIOVASC SURG 1984;87:43-7. 42. Kirscher PA. Discussion of Shamji and associates:" 43. Simpson JA. An evaluation of thymectomy in myasthenia gravis. Brain 1958;81: 112-45. 44. Perlo VP, Poskanzer DC, Schwab RS, Viets HR, Osserman KE, Genkins G. Myasthenia gravis: evaluation of treatment in 1355 patients. Neurol 1966;16:431-9. 45. Mondon Y, Nakahara K, Iioka S, et al. Recurrence of thymoma; clinicopathological features, therapy and prognosis. Ann Thorac Surg 1985;39:165-9. 46. Namba T, Brunner NG, Grob D. Myasthenia gravis in patients with thymoma, with particular referrence to onset after thymectomy. Medicine 1978;57:411-33.
Discussion Dr. Donald G. Mulder (Los Angeles. Calif). Dr. Jaretzki has made a point I think we would support completely, that a median sternotomy is the appropriate approach for removing the thymus. I would have some reservations, however, about seeing this extended procedure, the maximal thymectomy, recommended as the accepted operation in these patients. I say that for two reasons. First, the increased mobidity associated with dissecting high in the anterior and lateral mediastinum and neck with regard to phrenic nerve and even recurrent nerve injury is, I think, substantial. This is a catastrophic injury in a sick myasthetic patient who often already has respiratory compromise. Second, I am not sure the good results presented are due to the extension of the more standard operation. I would like to review briefly our previously reported experience' over the past 27 years with such patients (Am J Surg 1983;146:61-6),
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because I think our results are comparable to those presented today. There were a total of 781 patients in this group of which 249 underwent thymectomy. Approximately 20% had thymoma, which is similar to the experience of Dr. Jaretzki. The patients were categorized according to the severity of disease and only a small number, nine, were in the ocular stage or class I, whereas the majority were in the same category as the patients of Dr. Jaretzki, namely classes II and III, which are the more severely ill. Thymectomy was done through a median sternotomy in every instance, and the entire thymus including the cervical pedicles was removed. The pleural spaces were entered whenever the gland extended laterally to ensure careful dissection near the phrenic nerves. The patients were followed up continually, often yearly, with an average follow-up of 7'/2 years. The remission rate (defined as no medication and no symptoms) was 51%. Improvement (less medication with better control of the symptoms) was found in an additional 36%, so that the overall benefit from operation was 87%. The 51 patients with thymoma did not fare quite as well. Even so, the remission rate was 37% with an improvement noted in 31% for an overall benefit of 68%. By contrast, in the 198 patients without thymoma, a remission rate of 54% was noted along with an improvement of 37% for an overall benefit from operation of 91%. We do believe that the severity of illness preoperatively made a difference in the result, because the rate of remission dropped from 67% in class I to 25% in class IV. These were the patients with longstanding myasthenia who often had invasive tumor, and they did not do well. On the basis of this experience, then, I have reservations about recommending this extended procedure with its increased risk as being either necessary or even advisable. However, I would like to thank Dr. Jaretzki and his group for continuing to look for better solutions to this difficult problem. Dr. Yasunaru Kawashima (Osaka. Japan). I would like to congratulate Dr. Jaretzki and his co-workers for the excellent results obtained by the maximal thymectomy procedure. I also definitely recommend this kind of thymectomy in the treatment of MG. We have performed thymectomy in 297 patients with MG at Osaka University Hospital. In the early days, we also performed transsternal simple thymectomy and transcervical thymectomy. However, we have done the extended thymectomy procedure exclusively since Masaoka, one of my coworkers, found histologically in more than 70% of patients that extracapsular thymic tissue existed among the fat surrounding the thymus. Since April 1973, 173 of our patients without thymoma and 63 patients with thymoma underwent extended thymectomy. In this procedure, the adipose tissue in the vicinity of the thymus is resected as much as possible until the major blood vessels of the anterior mediastinum, pericardium, pleural surface, and phrenic nerve are almost completely exposed. The remission rate of the patients undergoing extended thymectomy increased with passage of time after operation, but there were no statistically significant differences between the remission rates of extended thymectomy and of other
7 5 6 Jaretzki et al.
methods of thymectomy. These rates were 40% to 45% 10 years after operation. However, the palliation rate, which I presume to be equivalent to the asymptomatic and remission rates reported by Dr. Jaretzki, was much higher, particularly in patients who underwent extended thymectomy. The palliation rate increased with passage of time after operation regardless of the method of thymectomy. There were statistically significant differences between palliation rates in patients who underwent extended thymectomy and in patients who underwent simple or cervical thymectomy. There was a limited difference in the palliation rates of extended thymectomy between the patients with and without thymoma. However, the remission rate in patients with thymoma remained low for a long time after operation and was statistically significantly different from that in patients without thymoma. We have been recommending extended thymectomy for the treatment of MG for many years and so far have been satisfied with the result. We can obtain an excellent surgical view through a median sternotomy up to the thyroid gland. I would like to ask Dr. Jaretzki whether he has found any thymic tissue in cervical fat that was not accessible through the median sternotomy. I am wondering whether or not we should increase our extended thymectomy to maximal thymectomy. Dr. Joel D. Cooper (Toronto. Ontario. Canada). I too support the concept of maximal thymectomy, but would disagree with Dr. Jaretzki on the type of surgical approach required to produce it. We do a form of transcervical thymectomy. It uses a small incision, but it is a big operation. It involves removing the thymus gland, pericardium, and pleura when necessary, and the pleural fat-all under direct vision through a small neck incision. We have a series of 53 consecutive patients with longest follow-up only to 5 years; of course with time, as everyone has pointed out, the results would improve. These patients had a rather severe form of illness beforehand: Forty-four percent were receiving prednisone and pyridostigmine (Mestinon). The mean follow-up grade has been 0.5 (zero is asymptomatic, I is ocular symptoms only, 2 is mild generalized weakness, and 3 is moderate generalized weakness). There was improvement of one or more grades in 95% of the patients and of two or more grades in 81%; 6% showed no improvement. The complete remission rate, given the duration of follow-up, was equivalent to what Dr. Jaretzki has shown on his time curve. Dr. Jaretzki's anatomic drawings have been important in permitting a complete thymectomy to be (done with) this particular approach. I would also point out that if complete remission were an indication of complete thymectomy, we would have a right to expect a complete remission in every patient in which Dr. Jaretzki's operation is done., but unfortunately the nature of the disease is different from that. I think we must rather be able to compare results in patients with similar stages of disease and followed up for a similar period of time. Finally, thymectomy through the transcervical incision is a specialty that you have to work at if you want to accomplish it. I really only wanted to make the point that equivalent results can be obtained by performing complete thymectomy through a variety of different approaches. Although I do not currently practice in the United States, I have heard about something here called diagnosis related groups (DRGs), and I frankly
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would have thought that the opportunity of achieving equivalent results with a procedure that allows the patient to go home the next day might have some attraction at centers in the United States. Dr. Jaretzki (Closing). I appreciate the discussers' comments. Dr. Mulder's warning concerning the risks of the thymic dissection that we have described is appropriate; the maximal operation as we perform it is time-consuming and has potential for harm. There must be no injury to the phrenic or recurrent nerves; this could be catastrophic, especially to a patient with MG. The wide mediastinal exposure we obtain by opening both pleural spaces not only ensures complete thymus removal but helps safeguard the phrenic nerves. The same applies to the neck. We have demonstrated that this operation can be done with safety comparable with that of the standard transsternal procedure; the morbidity has been low, there has been no mortality, there have been no phrenic or recurrent nerve injuries, and the results justify the increased operative time. If the thoracic surgeon has had only limited experience doing this type of neck operation, he should seek assistance for this part of the procedure, initially at least. It is true that Dr. Mulder's overall uncorrected remission rates appear to equal those of the maximal procedure, even though his neck and mediastinal dissections are less complete. However, the two series are not comparable, and life table analysis should confirm this. His patients should do better since milder symptoms and longer follow-up favor a higher remission rate; 59% of his patients had mild MG (compared to our 20%) and his mean follow-up time is 7.5 years (compared to our 3.4 years). Of note, since our data were tabulated. our uncorrected remission rate has risen to 54% and we anticipate a continued rise with time. I appreciate Dr. Kawashima's comments as well. We are indebted to his group for the demonstration of microscopic foci of thymus in mediastinal fat outside the capsule of the gland. We believe that a combination of their observations reported in 1975 (J THoRAc CARDIOVASC SLRG 1975;70:747-54) and ours reported in 1977 (Ann Thorac Surg 1977;24:120-30) have led to a better understanding of the anatomy of the thymus and have led to more extensive resections with improved results. It is not clear to me, however. why in their hands the extended procedure has not yielded improved remission rates, because in all other series we have analyzed there appears to be a direct relationship between the remission rate and the extent of resection. In answer to Dr. Kawashima's question regarding the presence of thymus in the neck, in 40% of our dissections some thymic tissue was found outside the confines of the classic cervical lobes. Although I respect Dr. Cooper's surgical skill and am indebted to him for his suggestion that I describe our mediastinal dissection with the term "anterior mediastinal exenteration," I am in total disagreement with his conclusions. First, the anatomy of the thymus in the mediastinum (especially the presence of significant amounts of thymus in the aortopulmonary window, under the phrenic nerves, and in the distal mediastinal fat) precludes complete removal through the neck in the majority of patients, no matter how skilled the surgeon. Second, the need for as complete removal of thymus as possible is supported by the following: (1) the prevention of experimental autoimmune MG in rabbits after neonatal complete thymectomy, whereas it is not prevented by partial thymectomy; (2) the demonstration that the thymus has both
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antibody- and antigen-bearing cells; (3) the patients who did not benefit from incomplete thymectomy responded to reoperation with more complete resections; (4) the demonstration that as little as 2 to 3 gm of residual thymus can be severely symptomatic and its removal therapeutic; and (5) the superior remission rates of comparable patients with comparable follow-up evaluation after maximal thymectomy as compared with the transcervical or other less extensive procedures. Finally, although Dr. Cooper reports a 50% uncorrected remission rate, he has a more favorable patient cohort and he also has a 44% incidence of progression of symptoms after thymectomy. In our series, in addition to the considerably higher remission rates, we have virtually eliminated the devastating and life-threatening symptoms that persist indefinitely in many patients with lesser resections.
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In reference to Dr. Cooper's comments regarding DRGs in MG, I believe two comments are appropriate. First, we in the medical profession must take care not to compromise our care whatever the pressures. Second, the higher remission rates and marked decrease in the protracted illness in our patients should reduce the cost of their medical care and greatly offset the few extra days in the hospital necessitated by a thoracic as compared with a cervical procedure. Clearly, much remains unexplained. We can hope that successful treatment of MG will eventually not require an operation. However, at this time, analysis of the available data supports the thesis that the more comprehensive the thymic resection, the better the results and that a comprehensive resection cannot be achieved through the neck alone or even via a limited transsternal procedure.