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Studies in myasthenia gravis: Early thymectomy
Studies in Myasthenia Gravis: Early Thymectomy Electrophysiologic
and Pathologic Correlations
GABRIEL GENKINS, M.D. ANGELOS E. PAPATESTAS,
M.D.
STEVEN H. HOROWITZ, M.D. PETER KORNFELD, M.D. New York, New York
From the Myasthenia Gravis Clinic and Research Laboratory, the Department of Medicine, the Department of Surgery and the Departments of Neurology, Mount Sinai Hospital and School of Medicine of the City University of New York, New York, New York 10020. This study was supported in part by a grant from HoffNew Jersey mann-LaRoche, Inc., Nutley, 07110. Requests for reprints should be addressed to Dr. Gabriel Genkins, 30 East 60th Street, New York, New York 10022. Manuscript accepted May 20. 1974.
Indications for thymectomy in myasthenia gravis have been recently expanded to include all cases with extraocular symptoms as a result of the minimal morbidlty and negligible mortality of the transcervical approach. As increasing numbers of patients with myasthenia gravis, covering the entire spectrum of generalized disease, have been added to the thymectomy population, a more accurate evaluation of the effects of the operation is possible. Our experience with 353 patients who have undergone thymectomy indicates that early thymectomy, particularly in patlents who do not have thymic germinal centers, is followed by early remission of the disease. Delayed remission after thymectomy is related to the duration and severity of the disease, and to presence of thymic germinal centers. Germinal centers were found more frequently in patients with long duration of the disease and in patients in whom the disease had progressed to respiratory involvement. Marked improvement in electromyographic findings immediately after thymectomy was observed in the majority of patients who had had the disease for 1 year or less and where germinal centers were absent. The percentage of malignant thymomas was higher in patients who underwent thymectomy 1 year or more afler the onset of symptoms of myasthenia gravis. These data indicate the importance of early thymectomy while the disease is still in the mild stages. Transcervical thymectomy is the treatment of choice as it is followed by a higher percentage of remissions and by less morbidity than other forms of treatment. Early empirical observations on thymectomy for myasthenia gravis indicated that best results were obtained in young women with a short duration of disease [l-3]. Since thymectomy through transthoracic approaches (transternal, intercostal incisions) was followed by a considerable morbidity related to myasthenia gravis, and since only a small percentage of patients had an immediate response to the operation, thymectomy was reserved for a selected group of patients with myasthenia gravis, essentially those with severe disease who had become unresponsive to medication. In a previous analysis of the results obtained on 111 such patients with nonthymomatous myasthenia gravis [4], it was shown that the effects of thymectomy are delayed and that the delay in the onset of remissions after thymectomy is related to the pres-
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MYASTHENIA
TABLE
I
GRAVIS-GENKINS
ET AL.
1,452 Patients with Myasthenia
Gravis Followed at Mount Sinai Hospital
No Thymectomy
Myasthenia
.___
___
Thymectomy
Totals
Men
Women
Total
Men
Women
Total
Men
Women
Total
491 16
559 33
1,050 49
63 43
192 55
255 98 ___-
554 59
751 88
1,306 146
507
592
1,099
106
247
353
613
839
1,452
Gravis
Without thymoma With thymoma Totals
ence of thymic germinal centers. This was noted both in patients with a short history and those with a long history of myasthenic symptoms prior to thymectomy. The pattern of delayed remissions was later confirmed in a cooperative study on 267 patients of the Massachusetts General Hospital and the Mount Sinai Hospital, New York 151. Since 1967, thymectomy via the transcervical approach [6-8] has been the procedure of choice at the Mount Sinai Hospital; it has been performed in 160 patients.. As a result of the reduced morbidity and negligible postoperative mortality of the procedure, indications for thymectomy were expanded to include patients with milder cases and a shorter history of disease. As most of these patients did not have respiratory symptoms related to myasthenia gravis, routine tracheostomy at the time of thymectomy was abandoned. Even in patients with postoperative respiratory distress, endotrachael intubation with a soft cuff tube is the procedure of choice, and
Thymic
TABLE II
Germinal
Centers
at Thymectomy
tracheostomy is used only as the last resort. The length of hospitalization at present is less than a week. These features have led to an extension of the indications for thymectomy to all cases of generalized myasthenia gravis (classes IIA, IIB, Ill and IV-Osserman’s clinical classification [9]), preferably earlier in the course of the disease. Thus, a more representative sample of the entire spectrum of generalized myasthenia gravis has been added to the thymectomy population permitting a more accurate evaluation of the effects of the procedure on the disease. We have evaluated the prognostic significance of the preoperative duration of the disease and of thymic pathology by studying the possible correlation between these two factors and the clinical response after thymectomy, in terms of delay and onset of remission, and by investigating possible correlations of these factors with observed changes between preand postoperative electromyographic findings.
in Patients
with Nonthymomatous
to Age and Sex
Germinal
o-9
Gravis
According
Men (no.)
Age (yr) at Onset of Disease
Myasthenia
Absent (0) or Rare (l+)
Women (no.)
Centers
Germinal Frequent (3+) or Prominent (4+)
Present (2-t)
Absent (0) or Rare (l+)
Centers Frequent (3+) or Prominent (4+)
Present (2+)
2
2
1
4
3
0
10-19 20-29 30-39 40-49 50-59 60-69 70-79
7 11 0 4 4 9 1
5 2 0 0 0 0 0
4 4 3 0 1 0 0
19 15 10 4 2 1 ...
21 16 6 1 0 0 ...
21 15 3 2 1 0 ...
No.
38
9 -
55
47
Per cent
63
All
Under No.
13
37
38
62
42
40
Per cent
518
I
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20
9
49
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12 51
Volume 58
48 36
46 -
39 64
MYASTHENIA
TABLE
III
Thymic Germinal
Centers
According
to Duration
of Symptoms
Before Thymectomy
Germinal Centers 0, 1+ 2+ 3+, 4+ All NOTE:
Numbers
MATERIALS
Symptoms
Present
ET AL.
-----
Men (no.)
Women (no.) Symptoms
GRAVIS-GENKINS
-
Present
--
-~
> 1 Year <5 Years
> 5 Years
1 Year or Less
>l Year <5 Years
25 (8) 14 (6) 15 (14)
13 (5) 21 (5) 21(8)
17 (2) 12 (2) 6
19 (9) 2 (1) 8 (2)
12 (3) 5 3 (1)
7 2 2
54 (28)
55 (18)
35 (4)
29 (12)
20 (4)
1.1
1 Year or Less
> 5 Years
in parentheses indicate number of patients in class III.
AND
METHODS
In the period 1951 to 1973, 1,452 patients with myasthen-
ia gravis have been registered at the Myasthenia Gravis Clinic and Research Laboratory. Of these, 353 patients have undergone thymectomy. The distribution of these patients, according to sex and the presence or absence of thymoma, is shown in Table I. The clinical course following thymectomy was studied in the 255 patients with nonthymomatous myasthenia gravis (Table I). In 51 of these patients, not operated upon at Mount Sinai Hospital, pathology reports were not available, therefore clinical-pathologic correlative studies were carried in the remaining 204 patients. Routine electromyographic studies before and after thymectomy were carried out on all patients referred for thymectomy since January 1973. Repetitive supramaximal percutaneous peripheral nerve stimulation at different frequencies with regional curare testing when necessary, as described by Horowitz et al. [lo]. Information on electrophysiologic findings was available on 48 patients. The following correlative studies were carried out: Cllnlcal-Pathologic Correlations. Available pathology reports on 204 patients were reviewed and the presence, absence and frequency of germinal centers were recorded. Patients were separated into the following three groups according to thymic pathology. The previously reported [ 1 I] modification of Burnet’s scale was used: (1) absent germinal centers (0), or rare, or occasional germinal centers (1 i-); (2) germinal centers present, but neither frequent nor prominent (2-F); and (3) frequent (3-I), numerous (4-k) or prominent (4+) germinal centers. Table II shows the distribution of patients in the three groups according to sex and age at onset of disease. The duration of disease before thymectomy was taken into consideration in order to investigate whether the duration of symptoms prior to surgery is associated with thymic pathology. Patients were separated into three categories (Table Ill): (A) duration of disease 1 year or less; (B) duration of disease of more than 1 year and less than 5 years; (c) duration of disease of more than 5 years. These intervals were selected in order to evaluate whether the arbitrary restricted indications for thymectomy, previously used, i.e., young women, duration of disease less than 5 years and failure of response to medication, have had an influence on the clinical prognosis. As
young women in clinical class Ill have been shown to have a high percentage of germinal centers [ 111, the clinical classification was also taken into consideration. Correlations with duration of disease and clinical classification are shown in Table Ill. The pattern of remissions following thymectomy was then evaluated separately in patients with absent or rare germinal centers (0) (1 -I), and those with many prominent germinal centers (3+) (4-t), taking into consideration the duration of disease prior to removal of the thymus (Table IV). In patients with thymomatous myasthenia gravis, possible correlations between the percentage of benign and malignant tumors and intervals from qlrset of disease to thymectomy were evaluated. Tumors were considered to be malignant if at surgery dense adhesions, fixation to or invasions into adjacent structures were present, or if evidence of metastatic disease was detected. The influence of sex and age was evaluated by separating patients into appropriate groups (Table V). Patients in whom the appearance of thymoma preceded the onset of myasthenia gravis were tabulated separately.
TABLE IV
Results of Thymectomy-Percentage Remissions According to Thymic and Duration of Disease Patients with No Germinal Centers (%)
Year Follow-up After Thymectomy
April 1975
Duration
1
17
2 3 4 5 6 7 8 9 10
20 24 27 45 55 50 50 50 50
Patients with Many Germinal Centers (%)
of Disease >l Year (49 patients)
of Disease
Duration
11 15 16 35 40 43 53 54 44 44
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of Disease > 1 Year (32 patients)
0 0 0 20 33 66 66 ... ... ...
Volume 58
0 0 5 6 15 18 18 33 43 ...
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MYASTHENIA
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Frequency of Malignant Thymomas in Patients with Thymomatous Myasthenia Gravis and Interval in Years Between Onset of Symptoms and Thymectomy
TABLE V
Women
Men
Age (yr) at Onset of Disease
Malignant
Benign
o-39 40-79 Totals No. Per cent Thymoma preceding onset of myasthenia gravis (no.)
__-
>l Benign
.__
____
Benign
Malignant
4 18
4 7
3 6
2 8
10 53
9 47
7 41
10 59
22 67
11 33
‘9 47
10 53
2
4
...
1
2
1
...
...
gist’s report on germinal centers, and the latter was not aware of the electromyographic findings. RESULTS Clinical-Pathologic Correlations. In patients with nonthymomatous myasthenia gravis unequivocal germinal center formation (1 -k to 4-k) was present in 65 per cent of all patients. The percentage in women
(68 per cent) was higher than that in men (58 per cent). An association with the age of the patient at onset of disease was also discernible. In patients with onset of disease after the age of 40 years, germinal centers were unequivocally present only in 20 per cent. Table II shows the distribution of patients according to age and thymic pathology.
(EMG) Following Thymectomy
No. of Patients
1 year or less
17
A B C
8 2 8
1 to 5 years
11
A c D
2 2 4 2
A C D
2 3 2
B
7
Malignant
3 7
EMG Changes*
or
Benign
Year
3 4
No. of Patients
5 years more
Malignant
>l
Year
4 5
Changes in Electromyogram and Thymic Disease
Duration of Symptoms
3 7
Clinical, Pathologic and Electrophysiologic Correlations. Electromyography before and/or after thymectomy was evaluated in 40 patients who underwent thymectomy since January 1973. The tests were performed as described by Horowitz et al. [lo]. In 37 patients the tests were carried out both before and after the operation. Criteria for evaluation of repetitive supramaximal stimulation responses after thymectomy were characterized as follows: Decrements of the second through sixth evoked responses: (A) 50 per cent less than the decrements before thymectomy, definite improvement; (B) 25 to 50 per cent less than decrements before thymectomy, probable improvement; (C) change of decrement of less than 25 per cent in any direction, no change; and (D) increase in decrement of 25 per cent or more, worsening. These electromyographic changes are shown in Table VI. The neurologist performing the electromyogram was not aware of the patholo-
TABLE VI
Year
According
to Preoperative
Per Cent of A+
Bt
i 56
40 i 29
Totals Per cent
of
Duration
of Symptoms
Thymic Disease and Germinal Centers ~_____ Absent Present Prominent 5 1 3
1 ... 3
... ... 3
2 2 1
...
..I
2 1 1
... ...
...
1
...
16 50
10 50
9 33
2 1 2
... ... ... 2 2
A+B * A = marked improvement, B = probable improvement, C = no change, D = worsening. t Per cent of A + B in patients with duration of symptoms of 1 year or less and absent those with a duration of 1 year or more and prominent germinal centers is 0 per cent.
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germinal
centers
is 60 per cent
and in
h4YnSTHENlAC~RAVIS---GENKINS ET AL.
Relation between duration of disease and germinal centers was also examined (Table 111). Absent or rare germinal centers were recorded in 33 per cent of the women with a history of symptoms of more than 1 year and in 46 per cent of those with duration of disease of 1 year or less. The corresponding numbers in men were 61 and 66 per cent, respectively. In women a long duration of disease appears to be associated with a higher percentage of germinal centers. This is more obvious when the clinical classification is taken into consideration. As shown in Table Ill, only 8 of the 28 women (29 per cent) with duration of disease of 1 year or less and an acute fulminating onset (class Ill) had absent or rare germinal centers, whereas in the remaining 26 women with milder disease and similar duration of symptoms, 17 (65 per cent) had absent or rare germinal centers. Fourteen of the 15 women with history of symptoms of 1 year or less who had prominent germinal centers were in class Ill. Duration of disease and pathology appeared to influence prognosis after thymectomy. The shortest interval between thymectomy and complete remission of myasthenic symptoms occurred in patients with no germinal centers and short preoperative duration of disease, whereas the longest delay prior to remission occurred in the group with many germinal centers and long duration of disease. In all groups, however, the percentage of remissions in patients with longterm follow-up (Table IV) reached a level between 40 and 60 per cent. The presence of germinal centers appears to be a more important prognostic factor than the preoperative duration of disease, as this is often difficult to determine precisely. In most patients with thymomatous myasthenia gravis there was an association between the interval from onset of symptoms to the time of thymectomy and the presence of malignant characteristics of the thymus tumor (Table V). Thus, in patients who were operated on within 1 year from the onset of symptoms, the percentage of benign tumors was higher than in patients with longer duration of symptoms prior to surgery (Table V). In a few patients, roentgenologic evidence of thymoma was present at the time the diagnosis of myasthenia gravis was made. Six of the 10 thymomas in this category were found to be malighant at the time of surgery. Electromyographic changes after thymectomy showed marked improvement in 37 per cent of the patients and over-all improvement in 43 per cent of the patients. The duration of the disease prior to the operation and the presence of germinal centers seemed to play a significant role, as the group of patients with highest percentages in category A and B (marked improvement and probable electromyogra-
phic improvement) had short duration of disease and absent germinal centers (Table VI). COMMENTS The critical role of the thymus in immunosurveillance, autoimmune diseases, and neuromuscular transmission has been clearly demonstrated in recent years [12-141. Experimental thymectomy in adults was thought to have no immediate effect on immunologic responses [ 151, but a delayed effect was described In 1965 [ 16-181. The effects become more obvious as the interval between thymectomy and time of evaluation increases. A similar pattern of delayed responses after thymectomy for myasthenia gravis was described in a review of the results of thymectomy in 111 patients with nonthymomatous myasthenia gravis [4]. A correlation between delay of remissions after thymectomy and presence of thymic germinal centers has abo been observed [4]. Based on these observations, the delay in appearance of remission after thymectomy was attributed to the existing pool of abnormal immunocompetent lymphocytes [4]. Namba et al. [ 191, demonstrated that lymphocytes from patients with myasthenia gravis produced a more severe systemic graft versus host reaction in mice than normal human lymphocytes. Kawanami and Mori [20] reported a waning phenomenon on electromyography, in mice immunized with thymic extracts, and also passive transfer of this phenomenon with lymph node cells. The incidence of this phenomenon was less frequent in mice that had thymectomies prior to immunization. A correlation between absolute peripheral lymphocyte counts and clinical status of patients with myasthenia gravis has also been observed. Progressive fall in the number of lymphocytes was noted in nonthymectomized patients with progression of disease, whereas after thymectomy lymphocyte counts progressively increased [ 2 11. Patients with many germinal centers had lower absolute peripheral lymphocyte counts than those without germinal centers [ 211. Similarly, a decrease in peripheral lymphocytes has been observed in NZB mice in which thymic germinal centers develop spontaneously [ 221. This study further clarifies the relationship between thymic pathology, clinical status and electromyographic findings. Variations in the percentages of germinal centers in different age groups suggests a possible relationship between age at onset of disease and thymic pathology (Table II). It would seem that patients with myasthenia gravis of early onset are more prone to the development of germinal centers. The recent re-
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MYASTHENIA
GRAVIS-GENKINS
ET AL.
ports on HL-A types in such patients suggest a correlation between thymic pathology and HL-A antigens [23]. The relation observed between sex and age at onset of disease and HL-A types [23,24] may explain the variations observed in germinal centers between patients with myasthenia gravis of different ages (Table II). Burnet and Holmes [25] observed a higher percentage of germinal centers in NZB mice with
progressive
age.
This
discrepancy
with
the
myasthenic population may partly be due to the fact the interval between the onset of disease and time of thymectomy was not taken into consideration (Table II). A temporal relation is obvious from Table Ill in which patients who were operated upon early in the course of disease had lower percentages of germinal centers than those with long duration of symptoms. There appears to be an association between the severity of the disease and thymic pathology. As previously reported [ 111, women in class Ill have the higher percentage of germinal centers. This was again noticeable (Table Ill) in this study as the percentage of germinal centers was higher in women in class Ill (70 per cent) than in the other groups. Furthermore, although only 1 of the 26 women (4 per cent) with milder forms of the disease operated upon in the first year of disease had prominent germinal centers, the corresponding percentage of women in class Ill was 50 per cent. The practical implications of these associations are obvious when the reported delay in remissions observed in patients with nonthymomatous myasthenia gravis and many germinal centers [4] is taken into consideration. Although the trend of delayed remissions is present in all groups, and eventually the percentage of patients in remission is high in all categories (Table IV), the advantage of early thymectomy before the disease progresses, in terms of clinical course in the first few years after thymectomy, should benefit the patient. It would seem that early thymectomy, particularly in young patients who appear to be more predisposed to the formation of germinal centers, would give an opportunity for an earlier remission. In addition, since thymectomy arrests progress of disease, and improvement prior to remission occurs in the large majority of patients [4], progression to the more severe categories should occur in a smaller percentage of patients. Our preliminary data indicate a decreasing percentage of patients who advance to class IV of the disease. The association between malignant characteristics of thymoma and delay of the operation (Table V) suggests that a long-standing thymoma may undergo malignant degeneration. This association further indi-
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cates that monitoring patients by periodic roentgenograms for the development of thymoma [23] instead of early excision of the thymus could be detrimental to the patient, as x-ray evidence of a thymoma and/ or the finding of invasive characteristics at surgery have been associated with poor prognosis [3,26]. Further small thymomas may be undetected, and tumors have been found at surgery when preoperative x-rays films were negative. In our previous report on the effects of thymectomy, 40 per cent of the patients operated on were found to have thymic tumors, whereas the corresponding percentage in the present study is 28 per cent. Although this may reflect the change in the indications for thymectomy, a decrease of thymomas, because of early removal of the gland, is possible. The importance of early thymectomy is also obvious from preliminary data collected in 1973 from patients who had electromyography before and after thymectomy. An immediate electromyographic improvement was present in 60 per cent of the patients with no germinal centers and short duration of disease, whereas no immediate improvement was demonstrable in patients with many germinal centers and long duration of disease. Advanced age of the patient at the time of thymectomy does not appear to be a contraindication as both electromyographic and clinical improvement was noted even in patients who were over the age of 50 at the time of thymectomy. Indeed, as germinal centers at that age do not seem to be as frequent, earlier improvement is noted. Thus, in four of the seven patients over the age of 50 immediate electromyographic improvement was evident. The oldest patient was 67 years of age. The thymus gland persists as a definite anatomic entity in patients of all ages [27,28], and older patients with myasthenia gravis seem to tolerate the procedure well. These data indicate the advantage of early thymectomy. As the transcervical approach has a low morbidity and a negligible mortality, it should be recommended as the treatment of choice for generalized myasthenia gravis. Its advantages are evident, particularly when compared with other therapeutic modalities. The long-term use of steroids [29-311 is followed in general by considerable morbidity, and there are no reports on long-term effects comparable to the high percentage of remissions without medication after thymectomy. Our own experience with 38 patients, using various modalities of steroid administration, has been disappointing. With daily, alternate daily and, as recently suggested [31], incremental schedule, we have observed only two or three fair results with an average time of administration of 3
MYASTHENIA GRAVIS-GENKINS
l/2 months and a range of 6 weeks to 11 months. As corticosteroid treatment has been found effective in patients who have undergone thymectomy [31], any trial of steroid administration should follow rather than precede thymectomy in an attempt to shorten the interval between thymectomy and remission. The report of increased risk of extrathymic neoplasms in nonthymectomized patients with myasthenia gravis and decreased risk after thymectomy [32] seem to indicate a potential hazard in the use of immunosuppressive drugs in patients with myasthenia gravis [33] prior to thymectomy, because of the reported association of neoplasms in patients receiving immunosuppressive drugs [34,35]. As may be the case with steroids, immunosuppressive treatment may have a place after thymectomy; this is supported by the report of Pirofsky et al. [33] who noted a good response to immunosuppressive drugs in three of eight patients with myasthenia gravis, all of whom had had a prior thymectomy. Recognizing that in a significant percentage (30 to 40 per cent) of patients in whom symptoms are limited to ocular muscles, myasthenia gravis progresses to generalized disease within 2 years, we have sought to identify such patients prior to the clinical appearance of generalized disease. Repetitive supra-
ET AL.
maximal percutaneous peripheral nerve stimulation and regional curare testing are employed for such identification. We have classified these patients with electromyographic testing, but no clinical evidence of generalized myasthenia gravis as group IA in modification of Osserman’s classification [9]. Results of thymectomy in three such patients have been excellent. We have no experience with surgery in purely ocular myasthenia gravis. As increasing numbers of patients with myasthenia gravis are now referred for thymectomy (approximately 100 in the last 3 years and over 50 in the last 12 month period), a better understanding of the role of the thymus in the disease has been made possible. The observed association between extrathymic neoplasms in general [32] and breast cancer in particular [36] in nonthymectomized patients myasthenia gravis and the decrease of neoplasms after thymectomy [32] may be an additional indication for early thymectomy. ADDENDUM Since this paper was prepared 118 more thymectomies have been performed. Evaluation of results as presented has remained entirely the same in the total series.
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13. Miller JFAP: The function of the thymus in immunity. The Scientific Basis of Surgery (Irving WT, ed), London, Churchill, 1967. p 468. 14. Goldstein F: The thymus and neuromuscular function. A substance in thymus which causes myositis and myasthenic neuromuscular block in guinea pigs. Lancet 2:119, 1968. 15. Fichtelius KE, Laurel1 G, Philipsson L: The influence of thymectomy on antibody formation. Acta Path Microbial Stand 51:81. 1961. 16. Miller JFAP: Effect of thymectomy in adult mice on immunological responsiveness. Nature (Lond) 208:1337, 1965. 17. Metcalf D: Delayed effect of thymectomy in adult life on immunological competence. Nature (Lond) 208: 1336, 1965. 18. Taylor RB: Decay of immunological responsiveness after thymectomy in adult life. Nature (Lond) 208:1334, 1965. 19. Namba T, Arimor S, Grob D: Lymphocytes of patients with myasthenia gravis. Neurology 19: 173. 1969. 20. Kawanami S. Mori R: Experimental myasthenia in mice. The role of the thymus and lymphoid cells. Clin Exp lmmunol 121447, 1972. 21. Papatestas AE, Kark AE: The rationale of thymectomy and its effects on oncogenesis (abstract). Program of the New York Surgical Society Meeting, March 17, 1973. 22. Stutman 0: Lymphocyte subpopulation in NZB mice: deficit of thymusdependent lymphocytes. J lmmunol 109:602, 1972. 23. Fritze D, Herman C Jr, Naeim F, Smith G, Walford R: HL-A antigens in myasthenia gravis. Lancet 1:240, 1974. 24. Feltkamp TEW, Van Den Herg-Loonen PM, Nizenhuis LE, Engelfriet GP, Van Rossum AL, Van Loghen JJ, Oosterhuis HJGN: Myasthenia gravis, autoantibodies and HL-A antigens. Br Med J 1:131, 1974.
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Burnet FM. Holmes MC: Thymic changes in the mouse strain NZB in relation to autoimmune state. J Pathol 88:229, 1964. Wilkins EW. Edmunds LH Jr, Castleman B: Cases of thymoma at the Massachusetts General Hospital. J Thorac Cardiovasc Surg 52:322, 1966. Young M. Turnbull HM: An analysis of the data collected by the status lymphoma investigation committee. J Pathol 34~213, 1931. Labreque G, Soudjian JV, Titus JL: Etude morphologique quantative du thymus humain dans une serie d’autopsies. Union Med Can 101:691, 1972. Kjaer M: Myasthenia gravis and myasthenic syndromes treated with prednisone. Acta Neurol Stand 47:464, 1971. Flacke W: Treatment of myasthenia gravis. N Engl J Med 288~27, 1973.
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31. Seybold ME, Drachman DB: Gradually increasing doses of prednisone in myasthenia gravis. Reducing the hazards of treatment. N Engl J Med 209:8 1, 1974. 32. Papatestas AE, Osserman KE, Kark AE: The relationship between thymus and oncogenesis. Br J Cancer 25:635, 1971. 33. Pirofsky B, Reis RH, Bardana EJ, Bayrakci C: Antithymocyte antisera therapy in nonsurgical immunologic disease. Transplant Proc 3:769, 197 1. 34. Starjl TE, Halgrimson CG: lmmunosuppression and malignant neoplasms. N Engl J Med 283:934, 1970. 35. Editorial: lmmunosuppression and malignancy. Br Med J 3: 713,1972. 38. Papatestas AE, Osserman KE, Kark AE: 17-ketosteroid excretion, myasthenia gravis and breast cancer. Lancet 1: 691, 1972.
and Pathologic Correlations
GABRIEL GENKINS, M.D. ANGELOS E. PAPATESTAS,
M.D.
STEVEN H. HOROWITZ, M.D. PETER KORNFELD, M.D. New York, New York
From the Myasthenia Gravis Clinic and Research Laboratory, the Department of Medicine, the Department of Surgery and the Departments of Neurology, Mount Sinai Hospital and School of Medicine of the City University of New York, New York, New York 10020. This study was supported in part by a grant from HoffNew Jersey mann-LaRoche, Inc., Nutley, 07110. Requests for reprints should be addressed to Dr. Gabriel Genkins, 30 East 60th Street, New York, New York 10022. Manuscript accepted May 20. 1974.
Indications for thymectomy in myasthenia gravis have been recently expanded to include all cases with extraocular symptoms as a result of the minimal morbidlty and negligible mortality of the transcervical approach. As increasing numbers of patients with myasthenia gravis, covering the entire spectrum of generalized disease, have been added to the thymectomy population, a more accurate evaluation of the effects of the operation is possible. Our experience with 353 patients who have undergone thymectomy indicates that early thymectomy, particularly in patlents who do not have thymic germinal centers, is followed by early remission of the disease. Delayed remission after thymectomy is related to the duration and severity of the disease, and to presence of thymic germinal centers. Germinal centers were found more frequently in patients with long duration of the disease and in patients in whom the disease had progressed to respiratory involvement. Marked improvement in electromyographic findings immediately after thymectomy was observed in the majority of patients who had had the disease for 1 year or less and where germinal centers were absent. The percentage of malignant thymomas was higher in patients who underwent thymectomy 1 year or more afler the onset of symptoms of myasthenia gravis. These data indicate the importance of early thymectomy while the disease is still in the mild stages. Transcervical thymectomy is the treatment of choice as it is followed by a higher percentage of remissions and by less morbidity than other forms of treatment. Early empirical observations on thymectomy for myasthenia gravis indicated that best results were obtained in young women with a short duration of disease [l-3]. Since thymectomy through transthoracic approaches (transternal, intercostal incisions) was followed by a considerable morbidity related to myasthenia gravis, and since only a small percentage of patients had an immediate response to the operation, thymectomy was reserved for a selected group of patients with myasthenia gravis, essentially those with severe disease who had become unresponsive to medication. In a previous analysis of the results obtained on 111 such patients with nonthymomatous myasthenia gravis [4], it was shown that the effects of thymectomy are delayed and that the delay in the onset of remissions after thymectomy is related to the pres-
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MYASTHENIA
TABLE
I
GRAVIS-GENKINS
ET AL.
1,452 Patients with Myasthenia
Gravis Followed at Mount Sinai Hospital
No Thymectomy
Myasthenia
.___
___
Thymectomy
Totals
Men
Women
Total
Men
Women
Total
Men
Women
Total
491 16
559 33
1,050 49
63 43
192 55
255 98 ___-
554 59
751 88
1,306 146
507
592
1,099
106
247
353
613
839
1,452
Gravis
Without thymoma With thymoma Totals
ence of thymic germinal centers. This was noted both in patients with a short history and those with a long history of myasthenic symptoms prior to thymectomy. The pattern of delayed remissions was later confirmed in a cooperative study on 267 patients of the Massachusetts General Hospital and the Mount Sinai Hospital, New York 151. Since 1967, thymectomy via the transcervical approach [6-8] has been the procedure of choice at the Mount Sinai Hospital; it has been performed in 160 patients.. As a result of the reduced morbidity and negligible postoperative mortality of the procedure, indications for thymectomy were expanded to include patients with milder cases and a shorter history of disease. As most of these patients did not have respiratory symptoms related to myasthenia gravis, routine tracheostomy at the time of thymectomy was abandoned. Even in patients with postoperative respiratory distress, endotrachael intubation with a soft cuff tube is the procedure of choice, and
Thymic
TABLE II
Germinal
Centers
at Thymectomy
tracheostomy is used only as the last resort. The length of hospitalization at present is less than a week. These features have led to an extension of the indications for thymectomy to all cases of generalized myasthenia gravis (classes IIA, IIB, Ill and IV-Osserman’s clinical classification [9]), preferably earlier in the course of the disease. Thus, a more representative sample of the entire spectrum of generalized myasthenia gravis has been added to the thymectomy population permitting a more accurate evaluation of the effects of the procedure on the disease. We have evaluated the prognostic significance of the preoperative duration of the disease and of thymic pathology by studying the possible correlation between these two factors and the clinical response after thymectomy, in terms of delay and onset of remission, and by investigating possible correlations of these factors with observed changes between preand postoperative electromyographic findings.
in Patients
with Nonthymomatous
to Age and Sex
Germinal
o-9
Gravis
According
Men (no.)
Age (yr) at Onset of Disease
Myasthenia
Absent (0) or Rare (l+)
Women (no.)
Centers
Germinal Frequent (3+) or Prominent (4+)
Present (2-t)
Absent (0) or Rare (l+)
Centers Frequent (3+) or Prominent (4+)
Present (2+)
2
2
1
4
3
0
10-19 20-29 30-39 40-49 50-59 60-69 70-79
7 11 0 4 4 9 1
5 2 0 0 0 0 0
4 4 3 0 1 0 0
19 15 10 4 2 1 ...
21 16 6 1 0 0 ...
21 15 3 2 1 0 ...
No.
38
9 -
55
47
Per cent
63
All
Under No.
13
37
38
62
42
40
Per cent
518
I
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20
9
49
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12 51
Volume 58
48 36
46 -
39 64
MYASTHENIA
TABLE
III
Thymic Germinal
Centers
According
to Duration
of Symptoms
Before Thymectomy
Germinal Centers 0, 1+ 2+ 3+, 4+ All NOTE:
Numbers
MATERIALS
Symptoms
Present
ET AL.
-----
Men (no.)
Women (no.) Symptoms
GRAVIS-GENKINS
-
Present
--
-~
> 1 Year <5 Years
> 5 Years
1 Year or Less
>l Year <5 Years
25 (8) 14 (6) 15 (14)
13 (5) 21 (5) 21(8)
17 (2) 12 (2) 6
19 (9) 2 (1) 8 (2)
12 (3) 5 3 (1)
7 2 2
54 (28)
55 (18)
35 (4)
29 (12)
20 (4)
1.1
1 Year or Less
> 5 Years
in parentheses indicate number of patients in class III.
AND
METHODS
In the period 1951 to 1973, 1,452 patients with myasthen-
ia gravis have been registered at the Myasthenia Gravis Clinic and Research Laboratory. Of these, 353 patients have undergone thymectomy. The distribution of these patients, according to sex and the presence or absence of thymoma, is shown in Table I. The clinical course following thymectomy was studied in the 255 patients with nonthymomatous myasthenia gravis (Table I). In 51 of these patients, not operated upon at Mount Sinai Hospital, pathology reports were not available, therefore clinical-pathologic correlative studies were carried in the remaining 204 patients. Routine electromyographic studies before and after thymectomy were carried out on all patients referred for thymectomy since January 1973. Repetitive supramaximal percutaneous peripheral nerve stimulation at different frequencies with regional curare testing when necessary, as described by Horowitz et al. [lo]. Information on electrophysiologic findings was available on 48 patients. The following correlative studies were carried out: Cllnlcal-Pathologic Correlations. Available pathology reports on 204 patients were reviewed and the presence, absence and frequency of germinal centers were recorded. Patients were separated into the following three groups according to thymic pathology. The previously reported [ 1 I] modification of Burnet’s scale was used: (1) absent germinal centers (0), or rare, or occasional germinal centers (1 i-); (2) germinal centers present, but neither frequent nor prominent (2-F); and (3) frequent (3-I), numerous (4-k) or prominent (4+) germinal centers. Table II shows the distribution of patients in the three groups according to sex and age at onset of disease. The duration of disease before thymectomy was taken into consideration in order to investigate whether the duration of symptoms prior to surgery is associated with thymic pathology. Patients were separated into three categories (Table Ill): (A) duration of disease 1 year or less; (B) duration of disease of more than 1 year and less than 5 years; (c) duration of disease of more than 5 years. These intervals were selected in order to evaluate whether the arbitrary restricted indications for thymectomy, previously used, i.e., young women, duration of disease less than 5 years and failure of response to medication, have had an influence on the clinical prognosis. As
young women in clinical class Ill have been shown to have a high percentage of germinal centers [ 111, the clinical classification was also taken into consideration. Correlations with duration of disease and clinical classification are shown in Table Ill. The pattern of remissions following thymectomy was then evaluated separately in patients with absent or rare germinal centers (0) (1 -I), and those with many prominent germinal centers (3+) (4-t), taking into consideration the duration of disease prior to removal of the thymus (Table IV). In patients with thymomatous myasthenia gravis, possible correlations between the percentage of benign and malignant tumors and intervals from qlrset of disease to thymectomy were evaluated. Tumors were considered to be malignant if at surgery dense adhesions, fixation to or invasions into adjacent structures were present, or if evidence of metastatic disease was detected. The influence of sex and age was evaluated by separating patients into appropriate groups (Table V). Patients in whom the appearance of thymoma preceded the onset of myasthenia gravis were tabulated separately.
TABLE IV
Results of Thymectomy-Percentage Remissions According to Thymic and Duration of Disease Patients with No Germinal Centers (%)
Year Follow-up After Thymectomy
April 1975
Duration
1
17
2 3 4 5 6 7 8 9 10
20 24 27 45 55 50 50 50 50
Patients with Many Germinal Centers (%)
of Disease >l Year (49 patients)
of Disease
Duration
11 15 16 35 40 43 53 54 44 44
The American Journal of Medicine
of Disease > 1 Year (32 patients)
0 0 0 20 33 66 66 ... ... ...
Volume 58
0 0 5 6 15 18 18 33 43 ...
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MYASTHENIA
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Frequency of Malignant Thymomas in Patients with Thymomatous Myasthenia Gravis and Interval in Years Between Onset of Symptoms and Thymectomy
TABLE V
Women
Men
Age (yr) at Onset of Disease
Malignant
Benign
o-39 40-79 Totals No. Per cent Thymoma preceding onset of myasthenia gravis (no.)
__-
>l Benign
.__
____
Benign
Malignant
4 18
4 7
3 6
2 8
10 53
9 47
7 41
10 59
22 67
11 33
‘9 47
10 53
2
4
...
1
2
1
...
...
gist’s report on germinal centers, and the latter was not aware of the electromyographic findings. RESULTS Clinical-Pathologic Correlations. In patients with nonthymomatous myasthenia gravis unequivocal germinal center formation (1 -k to 4-k) was present in 65 per cent of all patients. The percentage in women
(68 per cent) was higher than that in men (58 per cent). An association with the age of the patient at onset of disease was also discernible. In patients with onset of disease after the age of 40 years, germinal centers were unequivocally present only in 20 per cent. Table II shows the distribution of patients according to age and thymic pathology.
(EMG) Following Thymectomy
No. of Patients
1 year or less
17
A B C
8 2 8
1 to 5 years
11
A c D
2 2 4 2
A C D
2 3 2
B
7
Malignant
3 7
EMG Changes*
or
Benign
Year
3 4
No. of Patients
5 years more
Malignant
>l
Year
4 5
Changes in Electromyogram and Thymic Disease
Duration of Symptoms
3 7
Clinical, Pathologic and Electrophysiologic Correlations. Electromyography before and/or after thymectomy was evaluated in 40 patients who underwent thymectomy since January 1973. The tests were performed as described by Horowitz et al. [lo]. In 37 patients the tests were carried out both before and after the operation. Criteria for evaluation of repetitive supramaximal stimulation responses after thymectomy were characterized as follows: Decrements of the second through sixth evoked responses: (A) 50 per cent less than the decrements before thymectomy, definite improvement; (B) 25 to 50 per cent less than decrements before thymectomy, probable improvement; (C) change of decrement of less than 25 per cent in any direction, no change; and (D) increase in decrement of 25 per cent or more, worsening. These electromyographic changes are shown in Table VI. The neurologist performing the electromyogram was not aware of the patholo-
TABLE VI
Year
According
to Preoperative
Per Cent of A+
Bt
i 56
40 i 29
Totals Per cent
of
Duration
of Symptoms
Thymic Disease and Germinal Centers ~_____ Absent Present Prominent 5 1 3
1 ... 3
... ... 3
2 2 1
...
..I
2 1 1
... ...
...
1
...
16 50
10 50
9 33
2 1 2
... ... ... 2 2
A+B * A = marked improvement, B = probable improvement, C = no change, D = worsening. t Per cent of A + B in patients with duration of symptoms of 1 year or less and absent those with a duration of 1 year or more and prominent germinal centers is 0 per cent.
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germinal
centers
is 60 per cent
and in
h4YnSTHENlAC~RAVIS---GENKINS ET AL.
Relation between duration of disease and germinal centers was also examined (Table 111). Absent or rare germinal centers were recorded in 33 per cent of the women with a history of symptoms of more than 1 year and in 46 per cent of those with duration of disease of 1 year or less. The corresponding numbers in men were 61 and 66 per cent, respectively. In women a long duration of disease appears to be associated with a higher percentage of germinal centers. This is more obvious when the clinical classification is taken into consideration. As shown in Table Ill, only 8 of the 28 women (29 per cent) with duration of disease of 1 year or less and an acute fulminating onset (class Ill) had absent or rare germinal centers, whereas in the remaining 26 women with milder disease and similar duration of symptoms, 17 (65 per cent) had absent or rare germinal centers. Fourteen of the 15 women with history of symptoms of 1 year or less who had prominent germinal centers were in class Ill. Duration of disease and pathology appeared to influence prognosis after thymectomy. The shortest interval between thymectomy and complete remission of myasthenic symptoms occurred in patients with no germinal centers and short preoperative duration of disease, whereas the longest delay prior to remission occurred in the group with many germinal centers and long duration of disease. In all groups, however, the percentage of remissions in patients with longterm follow-up (Table IV) reached a level between 40 and 60 per cent. The presence of germinal centers appears to be a more important prognostic factor than the preoperative duration of disease, as this is often difficult to determine precisely. In most patients with thymomatous myasthenia gravis there was an association between the interval from onset of symptoms to the time of thymectomy and the presence of malignant characteristics of the thymus tumor (Table V). Thus, in patients who were operated on within 1 year from the onset of symptoms, the percentage of benign tumors was higher than in patients with longer duration of symptoms prior to surgery (Table V). In a few patients, roentgenologic evidence of thymoma was present at the time the diagnosis of myasthenia gravis was made. Six of the 10 thymomas in this category were found to be malighant at the time of surgery. Electromyographic changes after thymectomy showed marked improvement in 37 per cent of the patients and over-all improvement in 43 per cent of the patients. The duration of the disease prior to the operation and the presence of germinal centers seemed to play a significant role, as the group of patients with highest percentages in category A and B (marked improvement and probable electromyogra-
phic improvement) had short duration of disease and absent germinal centers (Table VI). COMMENTS The critical role of the thymus in immunosurveillance, autoimmune diseases, and neuromuscular transmission has been clearly demonstrated in recent years [12-141. Experimental thymectomy in adults was thought to have no immediate effect on immunologic responses [ 151, but a delayed effect was described In 1965 [ 16-181. The effects become more obvious as the interval between thymectomy and time of evaluation increases. A similar pattern of delayed responses after thymectomy for myasthenia gravis was described in a review of the results of thymectomy in 111 patients with nonthymomatous myasthenia gravis [4]. A correlation between delay of remissions after thymectomy and presence of thymic germinal centers has abo been observed [4]. Based on these observations, the delay in appearance of remission after thymectomy was attributed to the existing pool of abnormal immunocompetent lymphocytes [4]. Namba et al. [ 191, demonstrated that lymphocytes from patients with myasthenia gravis produced a more severe systemic graft versus host reaction in mice than normal human lymphocytes. Kawanami and Mori [20] reported a waning phenomenon on electromyography, in mice immunized with thymic extracts, and also passive transfer of this phenomenon with lymph node cells. The incidence of this phenomenon was less frequent in mice that had thymectomies prior to immunization. A correlation between absolute peripheral lymphocyte counts and clinical status of patients with myasthenia gravis has also been observed. Progressive fall in the number of lymphocytes was noted in nonthymectomized patients with progression of disease, whereas after thymectomy lymphocyte counts progressively increased [ 2 11. Patients with many germinal centers had lower absolute peripheral lymphocyte counts than those without germinal centers [ 211. Similarly, a decrease in peripheral lymphocytes has been observed in NZB mice in which thymic germinal centers develop spontaneously [ 221. This study further clarifies the relationship between thymic pathology, clinical status and electromyographic findings. Variations in the percentages of germinal centers in different age groups suggests a possible relationship between age at onset of disease and thymic pathology (Table II). It would seem that patients with myasthenia gravis of early onset are more prone to the development of germinal centers. The recent re-
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MYASTHENIA
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ET AL.
ports on HL-A types in such patients suggest a correlation between thymic pathology and HL-A antigens [23]. The relation observed between sex and age at onset of disease and HL-A types [23,24] may explain the variations observed in germinal centers between patients with myasthenia gravis of different ages (Table II). Burnet and Holmes [25] observed a higher percentage of germinal centers in NZB mice with
progressive
age.
This
discrepancy
with
the
myasthenic population may partly be due to the fact the interval between the onset of disease and time of thymectomy was not taken into consideration (Table II). A temporal relation is obvious from Table Ill in which patients who were operated upon early in the course of disease had lower percentages of germinal centers than those with long duration of symptoms. There appears to be an association between the severity of the disease and thymic pathology. As previously reported [ 111, women in class Ill have the higher percentage of germinal centers. This was again noticeable (Table Ill) in this study as the percentage of germinal centers was higher in women in class Ill (70 per cent) than in the other groups. Furthermore, although only 1 of the 26 women (4 per cent) with milder forms of the disease operated upon in the first year of disease had prominent germinal centers, the corresponding percentage of women in class Ill was 50 per cent. The practical implications of these associations are obvious when the reported delay in remissions observed in patients with nonthymomatous myasthenia gravis and many germinal centers [4] is taken into consideration. Although the trend of delayed remissions is present in all groups, and eventually the percentage of patients in remission is high in all categories (Table IV), the advantage of early thymectomy before the disease progresses, in terms of clinical course in the first few years after thymectomy, should benefit the patient. It would seem that early thymectomy, particularly in young patients who appear to be more predisposed to the formation of germinal centers, would give an opportunity for an earlier remission. In addition, since thymectomy arrests progress of disease, and improvement prior to remission occurs in the large majority of patients [4], progression to the more severe categories should occur in a smaller percentage of patients. Our preliminary data indicate a decreasing percentage of patients who advance to class IV of the disease. The association between malignant characteristics of thymoma and delay of the operation (Table V) suggests that a long-standing thymoma may undergo malignant degeneration. This association further indi-
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cates that monitoring patients by periodic roentgenograms for the development of thymoma [23] instead of early excision of the thymus could be detrimental to the patient, as x-ray evidence of a thymoma and/ or the finding of invasive characteristics at surgery have been associated with poor prognosis [3,26]. Further small thymomas may be undetected, and tumors have been found at surgery when preoperative x-rays films were negative. In our previous report on the effects of thymectomy, 40 per cent of the patients operated on were found to have thymic tumors, whereas the corresponding percentage in the present study is 28 per cent. Although this may reflect the change in the indications for thymectomy, a decrease of thymomas, because of early removal of the gland, is possible. The importance of early thymectomy is also obvious from preliminary data collected in 1973 from patients who had electromyography before and after thymectomy. An immediate electromyographic improvement was present in 60 per cent of the patients with no germinal centers and short duration of disease, whereas no immediate improvement was demonstrable in patients with many germinal centers and long duration of disease. Advanced age of the patient at the time of thymectomy does not appear to be a contraindication as both electromyographic and clinical improvement was noted even in patients who were over the age of 50 at the time of thymectomy. Indeed, as germinal centers at that age do not seem to be as frequent, earlier improvement is noted. Thus, in four of the seven patients over the age of 50 immediate electromyographic improvement was evident. The oldest patient was 67 years of age. The thymus gland persists as a definite anatomic entity in patients of all ages [27,28], and older patients with myasthenia gravis seem to tolerate the procedure well. These data indicate the advantage of early thymectomy. As the transcervical approach has a low morbidity and a negligible mortality, it should be recommended as the treatment of choice for generalized myasthenia gravis. Its advantages are evident, particularly when compared with other therapeutic modalities. The long-term use of steroids [29-311 is followed in general by considerable morbidity, and there are no reports on long-term effects comparable to the high percentage of remissions without medication after thymectomy. Our own experience with 38 patients, using various modalities of steroid administration, has been disappointing. With daily, alternate daily and, as recently suggested [31], incremental schedule, we have observed only two or three fair results with an average time of administration of 3
MYASTHENIA GRAVIS-GENKINS
l/2 months and a range of 6 weeks to 11 months. As corticosteroid treatment has been found effective in patients who have undergone thymectomy [31], any trial of steroid administration should follow rather than precede thymectomy in an attempt to shorten the interval between thymectomy and remission. The report of increased risk of extrathymic neoplasms in nonthymectomized patients with myasthenia gravis and decreased risk after thymectomy [32] seem to indicate a potential hazard in the use of immunosuppressive drugs in patients with myasthenia gravis [33] prior to thymectomy, because of the reported association of neoplasms in patients receiving immunosuppressive drugs [34,35]. As may be the case with steroids, immunosuppressive treatment may have a place after thymectomy; this is supported by the report of Pirofsky et al. [33] who noted a good response to immunosuppressive drugs in three of eight patients with myasthenia gravis, all of whom had had a prior thymectomy. Recognizing that in a significant percentage (30 to 40 per cent) of patients in whom symptoms are limited to ocular muscles, myasthenia gravis progresses to generalized disease within 2 years, we have sought to identify such patients prior to the clinical appearance of generalized disease. Repetitive supra-
ET AL.
maximal percutaneous peripheral nerve stimulation and regional curare testing are employed for such identification. We have classified these patients with electromyographic testing, but no clinical evidence of generalized myasthenia gravis as group IA in modification of Osserman’s classification [9]. Results of thymectomy in three such patients have been excellent. We have no experience with surgery in purely ocular myasthenia gravis. As increasing numbers of patients with myasthenia gravis are now referred for thymectomy (approximately 100 in the last 3 years and over 50 in the last 12 month period), a better understanding of the role of the thymus in the disease has been made possible. The observed association between extrathymic neoplasms in general [32] and breast cancer in particular [36] in nonthymectomized patients myasthenia gravis and the decrease of neoplasms after thymectomy [32] may be an additional indication for early thymectomy. ADDENDUM Since this paper was prepared 118 more thymectomies have been performed. Evaluation of results as presented has remained entirely the same in the total series.
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13. Miller JFAP: The function of the thymus in immunity. The Scientific Basis of Surgery (Irving WT, ed), London, Churchill, 1967. p 468. 14. Goldstein F: The thymus and neuromuscular function. A substance in thymus which causes myositis and myasthenic neuromuscular block in guinea pigs. Lancet 2:119, 1968. 15. Fichtelius KE, Laurel1 G, Philipsson L: The influence of thymectomy on antibody formation. Acta Path Microbial Stand 51:81. 1961. 16. Miller JFAP: Effect of thymectomy in adult mice on immunological responsiveness. Nature (Lond) 208:1337, 1965. 17. Metcalf D: Delayed effect of thymectomy in adult life on immunological competence. Nature (Lond) 208: 1336, 1965. 18. Taylor RB: Decay of immunological responsiveness after thymectomy in adult life. Nature (Lond) 208:1334, 1965. 19. Namba T, Arimor S, Grob D: Lymphocytes of patients with myasthenia gravis. Neurology 19: 173. 1969. 20. Kawanami S. Mori R: Experimental myasthenia in mice. The role of the thymus and lymphoid cells. Clin Exp lmmunol 121447, 1972. 21. Papatestas AE, Kark AE: The rationale of thymectomy and its effects on oncogenesis (abstract). Program of the New York Surgical Society Meeting, March 17, 1973. 22. Stutman 0: Lymphocyte subpopulation in NZB mice: deficit of thymusdependent lymphocytes. J lmmunol 109:602, 1972. 23. Fritze D, Herman C Jr, Naeim F, Smith G, Walford R: HL-A antigens in myasthenia gravis. Lancet 1:240, 1974. 24. Feltkamp TEW, Van Den Herg-Loonen PM, Nizenhuis LE, Engelfriet GP, Van Rossum AL, Van Loghen JJ, Oosterhuis HJGN: Myasthenia gravis, autoantibodies and HL-A antigens. Br Med J 1:131, 1974.
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Burnet FM. Holmes MC: Thymic changes in the mouse strain NZB in relation to autoimmune state. J Pathol 88:229, 1964. Wilkins EW. Edmunds LH Jr, Castleman B: Cases of thymoma at the Massachusetts General Hospital. J Thorac Cardiovasc Surg 52:322, 1966. Young M. Turnbull HM: An analysis of the data collected by the status lymphoma investigation committee. J Pathol 34~213, 1931. Labreque G, Soudjian JV, Titus JL: Etude morphologique quantative du thymus humain dans une serie d’autopsies. Union Med Can 101:691, 1972. Kjaer M: Myasthenia gravis and myasthenic syndromes treated with prednisone. Acta Neurol Stand 47:464, 1971. Flacke W: Treatment of myasthenia gravis. N Engl J Med 288~27, 1973.
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31. Seybold ME, Drachman DB: Gradually increasing doses of prednisone in myasthenia gravis. Reducing the hazards of treatment. N Engl J Med 209:8 1, 1974. 32. Papatestas AE, Osserman KE, Kark AE: The relationship between thymus and oncogenesis. Br J Cancer 25:635, 1971. 33. Pirofsky B, Reis RH, Bardana EJ, Bayrakci C: Antithymocyte antisera therapy in nonsurgical immunologic disease. Transplant Proc 3:769, 197 1. 34. Starjl TE, Halgrimson CG: lmmunosuppression and malignant neoplasms. N Engl J Med 283:934, 1970. 35. Editorial: lmmunosuppression and malignancy. Br Med J 3: 713,1972. 38. Papatestas AE, Osserman KE, Kark AE: 17-ketosteroid excretion, myasthenia gravis and breast cancer. Lancet 1: 691, 1972.