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Anti-acetylcholine receptor antibody titer with extended thymectomy in myasthenia gravis
J THoRAc
CARDIOVASC SURG
90:7-12, 1985
Original Communications
Anti-acetylcholine receptor antibody titer with extended thymectomy in myasthenia gravis Twenty-four patients with myasthenia gravis of Osserman's generalized type underwent extended thymectomy through a sternal-sptitting approach. Their clinical responses to thymectomy and postoperative changes in anti-acetylc~oline receptor antibody titers were evaluated. The follow-up time ranged from 1 month to 7 years and 7 months (average, 36 months). Six patients (25 %) had remissions and 17 patients (71 %) were improved after operation. The preoperative anti-acetylcholine receptor antibody titers dropped significantly after operation (p < 0.001). The postoperative reduction in these titers correlated with the time course after operation (p < 0.05). Their postoperative reduction was significantly greater in the six patients having remissions than in the 15 having marked (p < 0.02) and the six having moderate improvement (p < 0.0(5). This study has revealed that anti-acetylcholine receptor antibody titer in plasma declines progressively after thymectomy, and the postoperative reduction of this titer correlates with the clinical effect of thymectomy.
K. Kagotani, M.D., Y. Monden, M.D., K. Nakahara, M.D., Y. Fujii, M.D., Y. Seike, M.D.,
S. Kitamura, M.D., * A. Masaoka, M.D., ** and Y. Kawashima, M.D., Osaka, Japan
hymectomy has resulted in a favorable course for myasthenia gravis (MG) since the first report by Blalock and associates' in 1939. Buckingham and celleagues,' using computer-matched testing, showed that surgical therapy was more satisfactory than medical therapy in treating MG. Recently, emphasis has been placed on early thymectomy as being more effective than late operation." The anti-acetylcholine receptor (AChR) antibody, considered to be the cause of MG, is found in the sera of The First Department of Surgery, Osaka University Medical School, Fukushima-ku, Osaka 553, Japan. Received for publication June 22, 1984_ Accepted for publication Sept. 10, 1984. Address for reprints: K. Kagotani, The First Department of Surgery, Osaka University Medical School, Fukushima-ku, Osaka 553, Japan. 'Department of Surgery, Division of Thoracic and Cardiovascular Surgery, Nara Medical College, 840 Shijo-cho, Kashihara, Nara 634, Japan. "The Second Department of Surgery, Nagoya City University Medical School.
80% to 90% of MG patients."? The correlation between the AChR antibody titer and the clinical state of MG, however, remains uncertain. It has been shown that plasmapheresis and steroid therapy induce both clinical improvement and reduction in AChR antibody titer. 10·12 On the other hand, the change in AChR antibody titer after thymectomy remains obscure, despite the obvious clinical effects of thymectomy. We measured AChR antibody titers serially in the plasma of thymectomized MG patients and assessed the titers in relation to prognoses and time courses after operation. In this report we also discuss the role of the thymus in the pathogenesis of MG. Patients and methods Fifty-nine patients with generalized MG (types IIA and lIB) according to Osserman's" classification underwent extended thymectomy through a sternal-splitting approach, that is, en bloc excision of the thymus together with adjacent adipose tissue", between 1973 and 1980. AChR antibodies were detected preoperatively in the plasma of 50 (85%) of the patients. Postoper7
The Journal of
8
Kagotani et al.
Thoracic and Cardiovascular Surgery
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ty was counted on a gamma counter. The AChR antibody titer was expressed as moles of the precipitable alpha-bungarotoxin binding to AChR antibody complex per liter of plasma. A level greater than 0.33 nmoljL in 26 healthy control subjects was taken as positive. All samples were measured in duplicate, the individual serial samples being measured at the same time. The AChR antibody titers before and after thymectomy were analyzed statistically by a paired t test. The correlation between postoperative changes in AChR antibody titers and clinical responses to thymectomy was analyzed by the Mann-Whitney test. The percent values were transformed by Fisher's arcsin transformation. Results
1.0 0.5 0.33
T
Preoperation
Postoperation
Fig. 1. Comparisons of anti-acetylcholine receptor antibody (AChR Ab) titers before and after thymectomy. The postoperative AChR Ab titers were reduced in 21 patients and elevated in three. The AChR Ab titers declined significantly after operation according to a paired t test (p < 0.001).
atively, these antibodies could be evaluated retrospectively in 24 patients. Table I shows the clinical characteristics of the patients. Postoperative follow-up times ranged from I month to 7 years and 7 months (average, 36 months). The clinical response to thymectomy was judged according to the criteria of Papatestas' group. IS The patients postoperatively receivingimmunosuppressants were excluded from this study to permit analysis of the influence of thymectomy on the AChR antibody titer. The AChR antibody plasma titers were measured before and after operation in 65 samples from the 24 patients. In 11 patients measurements were made several times during their postoperative courses. The plasma samples were stored at -20 C for measurement. We employed the radioimmunoassay method of Appel, Almon, and Levy," utilizing 125I-alpha-bungarotoxin-bound AChR from the denervated leg muscles of rats as the antigen." Ten microliters of plasma was employed for this assay. The anti-human immunoglobulin G antiserum of rabbits was used to precipitate the toxin-AChR antibody complex. Precipitate radioactivi0
Table II shows individual clinical characteristics and preoperative and postoperative AChR antibody titers. Six patients (25%) had remissions, 17 (71%) were improved, and one (4%) evidenced no change at the latest follow-up examination. Comparisons of AChR antibody titers before and after thymectomy (Fig. I). The latest titers of postoperative AChR antibody were reduced in 21 patients (87.5%) and elevated in three (12.5%). The preoperative AChR antibody titers ranged from 0.76 to 173.68 nmol/L, and postoperatively they ranged from 0.30 to 159.16 nmoljL. The titers decreased significantly after operation as determined by a paired t test (p < 0.001). Changes in AChR antibody titers in regard to the time course after thymectomy (Fig. 2). The postoperative AChR antibody titers were measured in 41 samples from the 24 patients. The postoperative followup averaged 36 months. We determined the postoperative rate of change in the titers as follows: Postop. AChR antibody titer - preop. titer
-------------- X
Preop. titer
100%
The titer change rates ranged from +60% to -95%, being most variable within 2 years after operation. After 2 years postoperatively, however, all samples except one showed a reduction in titers. A significant correlation was found between the titer change rate (y%) and the postoperative time course (x months) (y = -0.464x -15.400, r = 0.316, P < 0.05). Thus, the postoperative titers declined gradually and progressively after thymectomy. Comparison of the postoperative change rate of AChR antibody titers and the clinical response to thymectomy (Fig. 3). The titer change rates ranged from -58% to -94% (average, -75%) in the six
Volume 90
Myasthenia gravis 9
Number 1 July, 1985
100
-100
- 0.464X - 15.400 r=0.316 (n=41)
P/O.05
• • •• • -50
y=
•
50
••
• • • • •• • • •• • •
• • •
•
2
•
3
•
4
•
5
8 years
7
6
Time course after thymectomy
Fig. 2. Changes in anti-acetylcholine receptor antibody (AChR Ab) titers in regard to the time course after thymectomy. A significant correlation was found between the titer change rate and the postoperative time course in 41 samples from the 24 patients (p < 0.05).
Table I. Clinical characteristics of patients with myasthenia gravis Osserman's classification
Age (yr)
Sex M
I
F
<20
o
IIA II B
4
5
I 14
Total
9
15
I
I
20-29
I
30-39
Thymoma
I
40-49
I
50~
No
I
Yes
4
2 4
6
I 4
9
2 10
5
6
7
5
12
12
1
patients having remissions. The titers declined remarkably after operation. On the other hand, the change rates ranged from +65% to -95% (average, -28%) in the 15 markedly improved patients and from + 11% to - 31% (average, -11 %) in the six moderately improved patients. The rates were +33%, +32%, and -70% in the three patients whose status was unchanged and +25% in the patient whose condition worsened. A significant difference was observed in the titer change rates between the patients having remissions and those having marked (p < 0.02) or moderate improvement (p < 0.005). Thus, it may be concluded that the more effective thymectomy was against MG clinically, the greater the reduction in postoperative AChR antibody titers.
Discussion Clinical effects of thymectomy have been reported frequently in the literature, but investigation concerning the changes in AChR antibody titer in MG after thymectomy are still lacking. Seybold," Tindall," and their co-workers have reported that AChR antibody titers in MG patients showed variable changes after
I
3
thymectomy. The follow-up time averaged 17.6 weeks in Seybold's series and ranged from 4 to 18 months in Tindall's. The study by Bartoccioni and associates" revealed that most AChR antibody titers declined after thymectomy, but the decline was not significant statistically in the 3 to 21 month follow-up period. The follow-up times in these reports appear to be too short to permit discussion of the change in AChR antibody titers after thymectomy. Scadding and co-workers'? reported that AChR antibody titers in MG patients thymectomized more than 10 years previously were significantly lower than those in nonthymectomized MG patients. However, this investigation was not performed on the same individual patients. 0lanow's group's" prospective study of extended thymectomy combined with plasmapheresis revealed that all patients were improved and AChR antibody titers declined gradually for an average 25.5 months after operation. Plasmapheresis itself reduced AChR antibody titer in the plasma of MG patients. 10. 22 However, this investigation did not discuss the relationship between the postoperative change in AChR antibody titers and thymectomy. Our long-term follow-up study revealed that extended
The Journal of Thoracic and Cardiovascular Surgery
Kagotani et al.
10
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that the thymus is not a main producer of AChR antibody, but a supply source of the lymphocytes contributing to the production of AChR antibody. The postoperative AChR antibody titers remain above the normal range for a long time. For this reason, it is speculated that the foregoing lymphocytes are long-lived or divide in the peripheral lymphatic tissue, and the reduction in these lymphocytes will possibly induce the decline in AChR antibody titers in the plasma of MG patients. The decline of postoperative titers was significantly greater in patients experiencing remissions than in those noting improvement. Clinical responses to thymectomy correlated with the postoperative decline of AChR antibody titers in our individual patients. However, preoperative AChR antibody titers of MG patients did not correlate well with the severity of symptoms in the majority of patients, whereas the postoperative titer changes did correlate with clinical responses to th~ec tomy. Thus, AChR antibody titers in plasma can be an objective indicator for judging the efficacy of treatments for MG, including thymectomy.
• • marked
moderate
improvement
improvement
nochange
worse
Clinical response to thymectomy
Fig. 3. Comparison of the postoperative change rate of anti-acetylcholine receptor antibody (AChR Ab) titers and the clinicalresponse to thymectomy. The AChR Ab titers declined remarkably in the six patients having remissions after operation. The change in AChR Ab titers was variable in the markedly improved patients. The AChR Ab titers declined slightly after operation in the six moderately improved patients. A significant difference was observed in the change rate between patients having remissions and those having marked (p < 0.02) and moderate improvement (p < 0.005). thymectomy progressively reduced the AChR antibody titer in the plasma of MG patients. This result has suggested that the thymus of MG patients contributes to the production of AChR antibody. Scadding and co-workers" reported in 1981 that AChR antibody was detected in a culture medium of the thymocytes of MG patients. Fujii and colleagues" also showed the production of AChR antibody by lymphocytes from the thymus and from thymoma in MG patients. However, it is not likely that the thymus or thymoma alone produces AChR antibody, because the decline in AChR antibody titers rarely appears early after operation in most patients, although the half-life of immunoglobulin G (AChR antibody) is about 3 weeks. Thus, it appears
2
3
4 5
6
7 8
9
REFERENCES BlalockA, Mason MF, Morgan HJ, Riven SS: Myasthenia gravisand tumors of thymic region. Report of a case in which tumor was removed. Ann Surg 110:544-561, 1939 Buckingham J, Howard FM, Bernatz PE, Payne WS, Harrison EG Jr, O'Brien PC, Weiland LH: The value of thymectomy in myasthenia gravis. A computer-assisted matched study. Ann Surg 184:453-458, 1976 Genkins G, Papatestas AE, Horowitz SH, Kornfeld P: Studies in myasthenia gravis: Early thymectomy. Electrophysiologic and pathologic correlation. Am J Med 58:517524, 1975 Emerky B, Strugalska MH: Evaluation of results of thymectomy in myasthenia gravis. J NeuroI211:155-168, 1976 Monden Y, Masaoka A, Maeda M, Nakahara K, Ohshirna S, Tani Y, Seike Y, Nakaoka K, Kagotani K, Nanjoh S: Relationships between preoperative duration of symptom and prognosis or immunological findings in myasthenia gravis. J Jpn Assoc Thorac Surg 28:68-74, 1980 Mittag T, Kornfeld P, Tormay A, Woo C: Detection of anti-acetylcholine receptor factors in serum and thymus from patients with myasthenia gravis. N Engl J Med 294:691-694, 1976 Lindstrom JM, Seybold ME, Lennon VA, Whittingham S, Daunne DD: Antibody to acetylcholine receptor in myasthenia gravis. Neurology 26:1054-1059, 1976 Monnier VM, Fulpius BW: A radioimmunoassay for the quantitative evaluation of antihuman acetylcholine receptor antibodies in myasthenia gravis. Clin Exp Immunol 29:16-22, 1977 Nishitani H, Nakao K, Ohta M, Noguchi S, Hayashi K:
Volume 90
Myasthenia gravis
Number 1
11
July, 1985
Table Il, Clinical presentation and anti-acetylcholine receptor antibody titer AChR Ab titer (nmoljL) Case
Age (yr)
Sex
Type
Thymoma
I 2
39 43
F M
IIA IIA
No No
2.45
3
24
M
IIA
No
8.41
4
60
M
IIA
Yes
0.76
34
M
IIA
Yes
2.45
26 18
M
F
lIB lIB
No No
1.49 1.99
50
F
lIB
No
3.00
9
56
F
lIB
No
3.48
10
34
F
lIB
No
4.45
11 12
37 24 34 32 45 69 25
F F
lIB lIB lIB lIB
No No No No
lIB
Yes Yes Yes
6.01 9.95 11.96 173.68 0.76 2.29 4.85
6 7
13 14 15 16 17
45 48 26 43
18 19 20
21
M
F F F F
M M
F F
lIB lIB
lIB lIB lIB IIB
Yes Yes Yes Yes
23
43 41
M F
lIB lIB
Yes Yes
24
53
F
lIB
Yes
22
1.70
5.37 7.46 8.13 8.35
9.62 12.84 29.56 13.38
Mean value 'Change:
Preop.
Postop. AChR Ab titer-Preop. ACh R Ab titer Preop. AChR Ab titer
I
Postop. 1.48 2.73 1.89 1.05 2.66 1.85 0.42 0.39 0.28 0.37 2.08 0.66 0.46 2.61 2.35 1.29 1.11 1.27 4.58 5.75
5.92 5.29 1.09 2.90 0.60 159.16 1.15 2.10 2.82 2.75 0.95 0.30 3.12 1.37 8.39 10.43 5.82
4.72 10.12 6.08 10.66 9.15:1:
After operation Change* (%) -13 +11 -23 -57 -69 -78 -45 -49 -63 -52 -15 -74 -70 +31 +18 -35 -63 -58 +32 +60 +33 +18 -82 -71 -95 -8 +51 - 8 -42 -44 -80 -94 -58 -83 00 +25 -31 -51 -21 -53 -64 -39:1:
I
Effectf
B BBB A A B B B B BAC
B B B B B C
B
C
B AAB BB B B B B A A B BD
BB BB B
Time (mo) 34 II 35 51 6 24 5 12 38 75 4 33 4 2 6 25 16 74 18 49 1 16 14 12 11 30 I 15
1 31 60
72 20 8 4 12 21 91 62 79 46 36:1:
X 100 (%)
tfffect: Clinical effect according to Papatestas' criteria. jMean value of the individual latest figures.
Anti-acetylcholine receptor antibody and myasthenia gravis. Igakunoayumi 102:335-340, 1977 10 Dau PC, Lindstrom JM, Cassel CK, Denys EH, Shev EE, Spitler LE: Plasmapheresis and immunosuppressive drug therapy in myasthenia gravis. N Engl J Med 297: 11341140, 1977 II Newsom-Davis J, Pinching AJ, Vincent A, Wilson SG:
Long term effects of repeated plasma exchange in myasthenia gravis. Lancet 3:464-468, 1979 12 Tindall RS: Humoral immunity in myasthenia gravis. Effect of steroids and thymectomy. Neurology 30:554557, 1980 13 Osserman KE: Myasthenia Gravis, New York, 1958, Grune & Stratton, Inc.
The Journal of Thoracic and Cardiovascular Surgery
1 2 Kagotani et al.
14 Masaoka A, Nagaoka Y, Kotake Y: Distribution of thymic tissue at the anterior mediastinum. Current procedure in thymectomy. J THORAC CARDIOVASC SURG 70:747-754, 1975 15 Papatestas AE, Alpert LI, Osserman KE, Osserman RS, Kark AE: Studies in myasthenia gravis: Effect of Thymectomy. Result on 185 patients with nonthymomatous and thymomatous myasthenia gravis, 1941-1969. Am J Med 50:465-474, 1971 16 Appel SH, Almon RR, Levy N: Acetylcholine receptor antibodies in myasthenia gravis. N Engl J Med 293:760761, 1975 17 Kagotani K, Monden Y, Nakahara K, Seike Y, Fujii Y, Kitamura S, Masaoka A, Kawashima Y: Anti-acetylcholine receptor antibody in myasthenia gravis: Study on the clinical features and the thymus. Clin Immunol 16:336346, 1984 18 Seybold ME, Baergen RN, Lindstrom JM; Anti-acetylcholine receptor antibody concentrations after thymectomy in patients with myasthenia gravis. Br Med J 14:10511053, 1978 19 Bartoccioni E, Scuderi F, Scoppetta C, Evoli A, Tonali P,
20
21
22
23
24
Guidi L, Bartoloni C, Terranova T: Myasthenia gravis, thymectomy, and acetylcholine receptor antibody. J Neurol 224:9-15, 1980 Scadding GK, Webster ADB, Ross M, Tomas HC, Havard CWH: Humoral immunity before and after thymectomy in myasthenia gravis. Neurology (Minn) 29:502-506, 1979 Olanow CW, Wechsler AS, Roses AD: A prospective study of thymectomy and serum acetylcholine receptor antibodies in myasthenia gravis. Ann Surg 196: 113-121, 1982 Newsom-Davis J, Pinching AJ, Vincent A, Wilson SG: Function of circulating antibody to acetylcholine receptor in myasthenia gravis: investigation by plasma exchange. Neurology (Minn) 28:266"272, 1978 Scadding GK, Vincent A, Newsom-Davis J, Henry K: Acetylcholine receptor antibody synthesis by thymic lymphocytes. Correlation with thymic histology. Neurology 31:935-943, 1981 Fujii Y, Monden Y, Nakahara K, Hashimoto J, Kawashima Y: Antibody to acetylcholine receptor in myasthenia gravis. Neurology 34: 1182-1186, 1984
Bound volumes available to subscribers Bound volumes of THE JOURNAL OFTHORACIC AND CARDIOVASCULAR SURGERY are available to subscribers (only) for the 1985 issues from the Publisher, at a cost of $61.45 ($77.10 international) for Vol. 89 (January-June) and Vol. 90 (July-December). Shipping charges are included. Each bound volume contains a subject and author index and all advertising is removed. Copies are shipped within 30 days after publication of the last issue of the volume. The binding is durable buckram with the JOURNAL name, volume number. and year stamped in gold on the spine. Payment must accompany all orders. Contaet The C. V. Mosby Company, Circulation Department, 11830 Westline Industrial Drive, St. Louis, Missouri 63146, USA; phone (800) 325-4177, ext. 351. Subscriptions must be in force to qualify. Bound volumes are not available in place of a regular JOURNAL subscription.
CARDIOVASC SURG
90:7-12, 1985
Original Communications
Anti-acetylcholine receptor antibody titer with extended thymectomy in myasthenia gravis Twenty-four patients with myasthenia gravis of Osserman's generalized type underwent extended thymectomy through a sternal-sptitting approach. Their clinical responses to thymectomy and postoperative changes in anti-acetylc~oline receptor antibody titers were evaluated. The follow-up time ranged from 1 month to 7 years and 7 months (average, 36 months). Six patients (25 %) had remissions and 17 patients (71 %) were improved after operation. The preoperative anti-acetylcholine receptor antibody titers dropped significantly after operation (p < 0.001). The postoperative reduction in these titers correlated with the time course after operation (p < 0.05). Their postoperative reduction was significantly greater in the six patients having remissions than in the 15 having marked (p < 0.02) and the six having moderate improvement (p < 0.0(5). This study has revealed that anti-acetylcholine receptor antibody titer in plasma declines progressively after thymectomy, and the postoperative reduction of this titer correlates with the clinical effect of thymectomy.
K. Kagotani, M.D., Y. Monden, M.D., K. Nakahara, M.D., Y. Fujii, M.D., Y. Seike, M.D.,
S. Kitamura, M.D., * A. Masaoka, M.D., ** and Y. Kawashima, M.D., Osaka, Japan
hymectomy has resulted in a favorable course for myasthenia gravis (MG) since the first report by Blalock and associates' in 1939. Buckingham and celleagues,' using computer-matched testing, showed that surgical therapy was more satisfactory than medical therapy in treating MG. Recently, emphasis has been placed on early thymectomy as being more effective than late operation." The anti-acetylcholine receptor (AChR) antibody, considered to be the cause of MG, is found in the sera of The First Department of Surgery, Osaka University Medical School, Fukushima-ku, Osaka 553, Japan. Received for publication June 22, 1984_ Accepted for publication Sept. 10, 1984. Address for reprints: K. Kagotani, The First Department of Surgery, Osaka University Medical School, Fukushima-ku, Osaka 553, Japan. 'Department of Surgery, Division of Thoracic and Cardiovascular Surgery, Nara Medical College, 840 Shijo-cho, Kashihara, Nara 634, Japan. "The Second Department of Surgery, Nagoya City University Medical School.
80% to 90% of MG patients."? The correlation between the AChR antibody titer and the clinical state of MG, however, remains uncertain. It has been shown that plasmapheresis and steroid therapy induce both clinical improvement and reduction in AChR antibody titer. 10·12 On the other hand, the change in AChR antibody titer after thymectomy remains obscure, despite the obvious clinical effects of thymectomy. We measured AChR antibody titers serially in the plasma of thymectomized MG patients and assessed the titers in relation to prognoses and time courses after operation. In this report we also discuss the role of the thymus in the pathogenesis of MG. Patients and methods Fifty-nine patients with generalized MG (types IIA and lIB) according to Osserman's" classification underwent extended thymectomy through a sternal-splitting approach, that is, en bloc excision of the thymus together with adjacent adipose tissue", between 1973 and 1980. AChR antibodies were detected preoperatively in the plasma of 50 (85%) of the patients. Postoper7
The Journal of
8
Kagotani et al.
Thoracic and Cardiovascular Surgery
t
6a 173. 159.16
-"'"
P
30.0
0
20.0 15.0
s::::
10.0
(]) ..-
5.0
E
-...
~
.0
«
c:::
.:
U
«
ty was counted on a gamma counter. The AChR antibody titer was expressed as moles of the precipitable alpha-bungarotoxin binding to AChR antibody complex per liter of plasma. A level greater than 0.33 nmoljL in 26 healthy control subjects was taken as positive. All samples were measured in duplicate, the individual serial samples being measured at the same time. The AChR antibody titers before and after thymectomy were analyzed statistically by a paired t test. The correlation between postoperative changes in AChR antibody titers and clinical responses to thymectomy was analyzed by the Mann-Whitney test. The percent values were transformed by Fisher's arcsin transformation. Results
1.0 0.5 0.33
T
Preoperation
Postoperation
Fig. 1. Comparisons of anti-acetylcholine receptor antibody (AChR Ab) titers before and after thymectomy. The postoperative AChR Ab titers were reduced in 21 patients and elevated in three. The AChR Ab titers declined significantly after operation according to a paired t test (p < 0.001).
atively, these antibodies could be evaluated retrospectively in 24 patients. Table I shows the clinical characteristics of the patients. Postoperative follow-up times ranged from I month to 7 years and 7 months (average, 36 months). The clinical response to thymectomy was judged according to the criteria of Papatestas' group. IS The patients postoperatively receivingimmunosuppressants were excluded from this study to permit analysis of the influence of thymectomy on the AChR antibody titer. The AChR antibody plasma titers were measured before and after operation in 65 samples from the 24 patients. In 11 patients measurements were made several times during their postoperative courses. The plasma samples were stored at -20 C for measurement. We employed the radioimmunoassay method of Appel, Almon, and Levy," utilizing 125I-alpha-bungarotoxin-bound AChR from the denervated leg muscles of rats as the antigen." Ten microliters of plasma was employed for this assay. The anti-human immunoglobulin G antiserum of rabbits was used to precipitate the toxin-AChR antibody complex. Precipitate radioactivi0
Table II shows individual clinical characteristics and preoperative and postoperative AChR antibody titers. Six patients (25%) had remissions, 17 (71%) were improved, and one (4%) evidenced no change at the latest follow-up examination. Comparisons of AChR antibody titers before and after thymectomy (Fig. I). The latest titers of postoperative AChR antibody were reduced in 21 patients (87.5%) and elevated in three (12.5%). The preoperative AChR antibody titers ranged from 0.76 to 173.68 nmol/L, and postoperatively they ranged from 0.30 to 159.16 nmoljL. The titers decreased significantly after operation as determined by a paired t test (p < 0.001). Changes in AChR antibody titers in regard to the time course after thymectomy (Fig. 2). The postoperative AChR antibody titers were measured in 41 samples from the 24 patients. The postoperative followup averaged 36 months. We determined the postoperative rate of change in the titers as follows: Postop. AChR antibody titer - preop. titer
-------------- X
Preop. titer
100%
The titer change rates ranged from +60% to -95%, being most variable within 2 years after operation. After 2 years postoperatively, however, all samples except one showed a reduction in titers. A significant correlation was found between the titer change rate (y%) and the postoperative time course (x months) (y = -0.464x -15.400, r = 0.316, P < 0.05). Thus, the postoperative titers declined gradually and progressively after thymectomy. Comparison of the postoperative change rate of AChR antibody titers and the clinical response to thymectomy (Fig. 3). The titer change rates ranged from -58% to -94% (average, -75%) in the six
Volume 90
Myasthenia gravis 9
Number 1 July, 1985
100
-100
- 0.464X - 15.400 r=0.316 (n=41)
P/O.05
• • •• • -50
y=
•
50
••
• • • • •• • • •• • •
• • •
•
2
•
3
•
4
•
5
8 years
7
6
Time course after thymectomy
Fig. 2. Changes in anti-acetylcholine receptor antibody (AChR Ab) titers in regard to the time course after thymectomy. A significant correlation was found between the titer change rate and the postoperative time course in 41 samples from the 24 patients (p < 0.05).
Table I. Clinical characteristics of patients with myasthenia gravis Osserman's classification
Age (yr)
Sex M
I
F
<20
o
IIA II B
4
5
I 14
Total
9
15
I
I
20-29
I
30-39
Thymoma
I
40-49
I
50~
No
I
Yes
4
2 4
6
I 4
9
2 10
5
6
7
5
12
12
1
patients having remissions. The titers declined remarkably after operation. On the other hand, the change rates ranged from +65% to -95% (average, -28%) in the 15 markedly improved patients and from + 11% to - 31% (average, -11 %) in the six moderately improved patients. The rates were +33%, +32%, and -70% in the three patients whose status was unchanged and +25% in the patient whose condition worsened. A significant difference was observed in the titer change rates between the patients having remissions and those having marked (p < 0.02) or moderate improvement (p < 0.005). Thus, it may be concluded that the more effective thymectomy was against MG clinically, the greater the reduction in postoperative AChR antibody titers.
Discussion Clinical effects of thymectomy have been reported frequently in the literature, but investigation concerning the changes in AChR antibody titer in MG after thymectomy are still lacking. Seybold," Tindall," and their co-workers have reported that AChR antibody titers in MG patients showed variable changes after
I
3
thymectomy. The follow-up time averaged 17.6 weeks in Seybold's series and ranged from 4 to 18 months in Tindall's. The study by Bartoccioni and associates" revealed that most AChR antibody titers declined after thymectomy, but the decline was not significant statistically in the 3 to 21 month follow-up period. The follow-up times in these reports appear to be too short to permit discussion of the change in AChR antibody titers after thymectomy. Scadding and co-workers'? reported that AChR antibody titers in MG patients thymectomized more than 10 years previously were significantly lower than those in nonthymectomized MG patients. However, this investigation was not performed on the same individual patients. 0lanow's group's" prospective study of extended thymectomy combined with plasmapheresis revealed that all patients were improved and AChR antibody titers declined gradually for an average 25.5 months after operation. Plasmapheresis itself reduced AChR antibody titer in the plasma of MG patients. 10. 22 However, this investigation did not discuss the relationship between the postoperative change in AChR antibody titers and thymectomy. Our long-term follow-up study revealed that extended
The Journal of Thoracic and Cardiovascular Surgery
Kagotani et al.
10
100
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that the thymus is not a main producer of AChR antibody, but a supply source of the lymphocytes contributing to the production of AChR antibody. The postoperative AChR antibody titers remain above the normal range for a long time. For this reason, it is speculated that the foregoing lymphocytes are long-lived or divide in the peripheral lymphatic tissue, and the reduction in these lymphocytes will possibly induce the decline in AChR antibody titers in the plasma of MG patients. The decline of postoperative titers was significantly greater in patients experiencing remissions than in those noting improvement. Clinical responses to thymectomy correlated with the postoperative decline of AChR antibody titers in our individual patients. However, preoperative AChR antibody titers of MG patients did not correlate well with the severity of symptoms in the majority of patients, whereas the postoperative titer changes did correlate with clinical responses to th~ec tomy. Thus, AChR antibody titers in plasma can be an objective indicator for judging the efficacy of treatments for MG, including thymectomy.
• • marked
moderate
improvement
improvement
nochange
worse
Clinical response to thymectomy
Fig. 3. Comparison of the postoperative change rate of anti-acetylcholine receptor antibody (AChR Ab) titers and the clinicalresponse to thymectomy. The AChR Ab titers declined remarkably in the six patients having remissions after operation. The change in AChR Ab titers was variable in the markedly improved patients. The AChR Ab titers declined slightly after operation in the six moderately improved patients. A significant difference was observed in the change rate between patients having remissions and those having marked (p < 0.02) and moderate improvement (p < 0.005). thymectomy progressively reduced the AChR antibody titer in the plasma of MG patients. This result has suggested that the thymus of MG patients contributes to the production of AChR antibody. Scadding and co-workers" reported in 1981 that AChR antibody was detected in a culture medium of the thymocytes of MG patients. Fujii and colleagues" also showed the production of AChR antibody by lymphocytes from the thymus and from thymoma in MG patients. However, it is not likely that the thymus or thymoma alone produces AChR antibody, because the decline in AChR antibody titers rarely appears early after operation in most patients, although the half-life of immunoglobulin G (AChR antibody) is about 3 weeks. Thus, it appears
2
3
4 5
6
7 8
9
REFERENCES BlalockA, Mason MF, Morgan HJ, Riven SS: Myasthenia gravisand tumors of thymic region. Report of a case in which tumor was removed. Ann Surg 110:544-561, 1939 Buckingham J, Howard FM, Bernatz PE, Payne WS, Harrison EG Jr, O'Brien PC, Weiland LH: The value of thymectomy in myasthenia gravis. A computer-assisted matched study. Ann Surg 184:453-458, 1976 Genkins G, Papatestas AE, Horowitz SH, Kornfeld P: Studies in myasthenia gravis: Early thymectomy. Electrophysiologic and pathologic correlation. Am J Med 58:517524, 1975 Emerky B, Strugalska MH: Evaluation of results of thymectomy in myasthenia gravis. J NeuroI211:155-168, 1976 Monden Y, Masaoka A, Maeda M, Nakahara K, Ohshirna S, Tani Y, Seike Y, Nakaoka K, Kagotani K, Nanjoh S: Relationships between preoperative duration of symptom and prognosis or immunological findings in myasthenia gravis. J Jpn Assoc Thorac Surg 28:68-74, 1980 Mittag T, Kornfeld P, Tormay A, Woo C: Detection of anti-acetylcholine receptor factors in serum and thymus from patients with myasthenia gravis. N Engl J Med 294:691-694, 1976 Lindstrom JM, Seybold ME, Lennon VA, Whittingham S, Daunne DD: Antibody to acetylcholine receptor in myasthenia gravis. Neurology 26:1054-1059, 1976 Monnier VM, Fulpius BW: A radioimmunoassay for the quantitative evaluation of antihuman acetylcholine receptor antibodies in myasthenia gravis. Clin Exp Immunol 29:16-22, 1977 Nishitani H, Nakao K, Ohta M, Noguchi S, Hayashi K:
Volume 90
Myasthenia gravis
Number 1
11
July, 1985
Table Il, Clinical presentation and anti-acetylcholine receptor antibody titer AChR Ab titer (nmoljL) Case
Age (yr)
Sex
Type
Thymoma
I 2
39 43
F M
IIA IIA
No No
2.45
3
24
M
IIA
No
8.41
4
60
M
IIA
Yes
0.76
34
M
IIA
Yes
2.45
26 18
M
F
lIB lIB
No No
1.49 1.99
50
F
lIB
No
3.00
9
56
F
lIB
No
3.48
10
34
F
lIB
No
4.45
11 12
37 24 34 32 45 69 25
F F
lIB lIB lIB lIB
No No No No
lIB
Yes Yes Yes
6.01 9.95 11.96 173.68 0.76 2.29 4.85
6 7
13 14 15 16 17
45 48 26 43
18 19 20
21
M
F F F F
M M
F F
lIB lIB
lIB lIB lIB IIB
Yes Yes Yes Yes
23
43 41
M F
lIB lIB
Yes Yes
24
53
F
lIB
Yes
22
1.70
5.37 7.46 8.13 8.35
9.62 12.84 29.56 13.38
Mean value 'Change:
Preop.
Postop. AChR Ab titer-Preop. ACh R Ab titer Preop. AChR Ab titer
I
Postop. 1.48 2.73 1.89 1.05 2.66 1.85 0.42 0.39 0.28 0.37 2.08 0.66 0.46 2.61 2.35 1.29 1.11 1.27 4.58 5.75
5.92 5.29 1.09 2.90 0.60 159.16 1.15 2.10 2.82 2.75 0.95 0.30 3.12 1.37 8.39 10.43 5.82
4.72 10.12 6.08 10.66 9.15:1:
After operation Change* (%) -13 +11 -23 -57 -69 -78 -45 -49 -63 -52 -15 -74 -70 +31 +18 -35 -63 -58 +32 +60 +33 +18 -82 -71 -95 -8 +51 - 8 -42 -44 -80 -94 -58 -83 00 +25 -31 -51 -21 -53 -64 -39:1:
I
Effectf
B BBB A A B B B B BAC
B B B B B C
B
C
B AAB BB B B B B A A B BD
BB BB B
Time (mo) 34 II 35 51 6 24 5 12 38 75 4 33 4 2 6 25 16 74 18 49 1 16 14 12 11 30 I 15
1 31 60
72 20 8 4 12 21 91 62 79 46 36:1:
X 100 (%)
tfffect: Clinical effect according to Papatestas' criteria. jMean value of the individual latest figures.
Anti-acetylcholine receptor antibody and myasthenia gravis. Igakunoayumi 102:335-340, 1977 10 Dau PC, Lindstrom JM, Cassel CK, Denys EH, Shev EE, Spitler LE: Plasmapheresis and immunosuppressive drug therapy in myasthenia gravis. N Engl J Med 297: 11341140, 1977 II Newsom-Davis J, Pinching AJ, Vincent A, Wilson SG:
Long term effects of repeated plasma exchange in myasthenia gravis. Lancet 3:464-468, 1979 12 Tindall RS: Humoral immunity in myasthenia gravis. Effect of steroids and thymectomy. Neurology 30:554557, 1980 13 Osserman KE: Myasthenia Gravis, New York, 1958, Grune & Stratton, Inc.
The Journal of Thoracic and Cardiovascular Surgery
1 2 Kagotani et al.
14 Masaoka A, Nagaoka Y, Kotake Y: Distribution of thymic tissue at the anterior mediastinum. Current procedure in thymectomy. J THORAC CARDIOVASC SURG 70:747-754, 1975 15 Papatestas AE, Alpert LI, Osserman KE, Osserman RS, Kark AE: Studies in myasthenia gravis: Effect of Thymectomy. Result on 185 patients with nonthymomatous and thymomatous myasthenia gravis, 1941-1969. Am J Med 50:465-474, 1971 16 Appel SH, Almon RR, Levy N: Acetylcholine receptor antibodies in myasthenia gravis. N Engl J Med 293:760761, 1975 17 Kagotani K, Monden Y, Nakahara K, Seike Y, Fujii Y, Kitamura S, Masaoka A, Kawashima Y: Anti-acetylcholine receptor antibody in myasthenia gravis: Study on the clinical features and the thymus. Clin Immunol 16:336346, 1984 18 Seybold ME, Baergen RN, Lindstrom JM; Anti-acetylcholine receptor antibody concentrations after thymectomy in patients with myasthenia gravis. Br Med J 14:10511053, 1978 19 Bartoccioni E, Scuderi F, Scoppetta C, Evoli A, Tonali P,
20
21
22
23
24
Guidi L, Bartoloni C, Terranova T: Myasthenia gravis, thymectomy, and acetylcholine receptor antibody. J Neurol 224:9-15, 1980 Scadding GK, Webster ADB, Ross M, Tomas HC, Havard CWH: Humoral immunity before and after thymectomy in myasthenia gravis. Neurology (Minn) 29:502-506, 1979 Olanow CW, Wechsler AS, Roses AD: A prospective study of thymectomy and serum acetylcholine receptor antibodies in myasthenia gravis. Ann Surg 196: 113-121, 1982 Newsom-Davis J, Pinching AJ, Vincent A, Wilson SG: Function of circulating antibody to acetylcholine receptor in myasthenia gravis: investigation by plasma exchange. Neurology (Minn) 28:266"272, 1978 Scadding GK, Vincent A, Newsom-Davis J, Henry K: Acetylcholine receptor antibody synthesis by thymic lymphocytes. Correlation with thymic histology. Neurology 31:935-943, 1981 Fujii Y, Monden Y, Nakahara K, Hashimoto J, Kawashima Y: Antibody to acetylcholine receptor in myasthenia gravis. Neurology 34: 1182-1186, 1984
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