Scand J Thor Cardiovasc Surg 10: 183-188, 1976
THYMECTOMY FOR MYASTHENIA GRAVIS Severi Mattila, Ritva Pirskanen and Jussi Heinonen
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From the Departments of Thoracic Surgery and Neurology, Universit). Central Hospital, Helsinki, Finland
(Submitted for publication September 25, 1974)
Abstract. Thymectomy was performed on 3 I patients with myasthenia gravis. Four of them had thymoma, 17 hyperplasia and 9 had normal thymic histology on microscopy. Discontinuation of anticholinergic medication together with tracheostomy, artificial ventilation and intensive observation were essential in the postoperative management. All the patients survived operation and were discharged from hospital. Sixty-eight per cent of the patients were in remission or improved after an average follow-up of 2.5 years. If the patients with thymoma were excluded, 7 4 % were improved and, if only the patients with thymic hyperplasia were included in the series, 89 % were improved after thymectomy.The seventy of disease and duration of symptoms pre-operatively seemed to be of minor importance for the results of operation, since good results were obtained also in patients with a long history and in clinical classes 111 and IV. Two patients developed tracheal stenosis as a complication of intubation with a tracheostomy tube. Tracheal resection was performed in one of them and endobronchial removal of granulation tissue producing the stenosis in the other. Both recovered uneventfully. One patient, who was asymptomatic and without medication for myasthenia, died suddenly of acute cerebral bleeding 3 years after thymectomy.
The first observation that thymectomy influenced the course of myasthenia gravis was made by Sauerbruch, who in 191 1 performed thymectomy on a 20-year-old girl with hyperthyroidism and myasthenia gravis (Schumacher & Roth, 1913). In 1936 Blalock removed a cystic thymic tumour from a 19-year-old girl, which resulted in a dramatic improvement of her myasthenia gravis. His report published in 1939 had a truly catalytic effect on the operative treatment of myasthenia gravis (Blalock et al., 1939). The procedure then became established in the ’forties by Keynes’ large series, in which improvement of the disease was noted in approximately two-thirds of the cases after thymec-
tomy (Keynes, 1954). He also noticed that the results were better in patients without thymoma. Some criticism and cold water were poured on the enthusiasm by Eaton & Clagett (1955) from Mayo Clinic, and Grob (1953) from Johns Hopkins Hospital in the ’fifties. They found spontaneous remissions or improvement of myasthenia gravis in 30% of the non-operated myasthenic patients compared with an improvement or remission rate of 50 to 60 % of thymectomized patients. In 1959 Smithers advanced the hypothesis that myasthenia gravis was an auto-immune disease. The germinal centres of the thymus in myasthenia gravis resembled those observed in Hashimoto’s thyroiditis (Smithers, 1959). In 1959 Nastuk et al. found in the sera of myasthenic patients antibodies against the striated muscle cells, myocardial and thymic cells not reacting with the endplate of the nerves (Nastuk et al., 1959; Strauss et al., 1960). In 1968 Goldstein separated from the calf thymus a substance (thymine) which produced a myasthenic disease in guinea pig (Goldstein, 1968). These new immunological findings, which supported the view that thymus was involved in the pathogenesis of myasthenia, and the accumulated clinical evidence from various centres (Perlo et a]., 1966; Papatestas et al., 1971; Mulder et al., 1972; Levasseur et al., 1972) encouraged us to test thymectomy in the treatment of myasthenia gravis. Eighty-two thymectomies have been performed for myasthenia gravis in Finland since 1958. Thirty-one of them were carried out at the Department of Thoracic Surgery, University Central Hospital, Helsinki. The experience obtained from these 31 patients is described in the present paper. Scand J Thor Cardiovasr Surg I0
184
S . Muttila r t a / .
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Table I . Thymrctomyfbr myasthenia gravis. Clinical dutu of the patients
Pat.
Sex
Age
Year
R. H . M. K . R. T. M. K . M. V. T. M. M. L. E. N. M. K. S. K. K. H. E. S. T. H. A. H. T. U . E. S. H. H. R. H. V. K. T. M. 0. J . A. K. A. L. V. J. u. P. M. S . G. S . L. P. u. G . R. M. P. A .
0 d
17 37 34 38 20 26 27 22 24 40 23 30 26 20 27 35 20 24 53 20 23 63 47 45 38 53 20 20 38 44 17
1958 I962 1969 I969 1969 1969 1970 I970 1970 1970 1971 1971 1971 1971 1971 1971 I972 1972 I972 1972 I972 I972 1972 I973 1973 I973 1973 1973 1974 1974 1974
P 6 d
0
P 0
P 0
P 0
0 0
P 0
P 0 d P d
P d d
6 d
P P P
9 d
Duration of symptoms Pre-op. (years) class 2.0 6.0 I .o 13.5 1.5 3.5 2.0 1.5 2.0 1 .o
6.0 I .5 14.0 I .o 2.0 3.5 4.Q 1.5 I .5 4.0 4.0 1.o
0.5 4.0 4.0 12.0 1.5 4.0 7.0 0.5 0.5
I11 I11 111
IV I1 B 11B 111 I1 B IV 111 I1 B I1B IV I1 B 11B 111 I1 B IIB I1 B I1 B I1 B I1 A 11A I1 B 1v
I1 A IV I1B I1 B I1 A 111
MATERIAL A N D M E T H O D S During the years 1958-74, thymectomy was performed on 31 patients (10 men and 21 women) with myasthenia gravis at the Department of Thoracic Surgery, University Hospital, Helsinki. The clinical data of the patients are compiled in Table I. The average age at the time of thymectomy was 32 years (range 17-63 years) and the duration of symptoms before the thyrnectomy was 4.2 years (range 0.5-14.0 years). The follow-up time after thymectomy averaged 2.5 years (range 0.5-12.0 years). Selection of patients
Thyrnectomy was recommended for patients with generalized myasthenia, in whom increasing dosages of medication failed to give control of the disease (Table 11). The exception to this criterion was radiographic demonstration of a thymic tumour in 4 cases. Thymectorny was performed on them for the tumour itself, regardless of the status of myasthenia. Patients with focal myasthenia, which essentially involved only the extraocular muscles, were not recommended for thymectomy. Many of the patients were young people with a short duration of symptoms (less than 5 years), but advanced age or longer duration of symptoms were not considered as contraindications for operation if the patient's condition was Scand J Thor Curdiovusc Surg 10
Histology
Result
Normal H yperplasia H yperplasia H yperplasia H yperplasia Hyperplasia
A A A A
-
H yperplasia Normal H yperplasia Hyperplasia H y perplasia Normal H yperplasia Normal H yperplasia H yperplasia H yperplasia Normal Hyperplasia Normal Thymoma Thymoma Thymoma Normal Normal H y perplasia Hyperplasia Normal Thymoma H yperplasia
B D C B B B B B C A
C C B
B B B B C D B C C B B B C B
FOIIOW-UP (years) 2.0 14.0 3.0 4.5 4.5 4.5 4.0 4.0 4.0 1.5 2.0 3.5 3.5 3.0 I .5 2.5 2.5 2.0 2.0 1.5 1.5 2.5 2.5 1.0 1.5 1.5 0.5 0.5 0.5 0.5 0.5
deteriorating rapidly and did not respond to medical treatment. The average dosage of Mestinon" was 425 rng pro die (range 80-900 mg) before thymectomy. Preoperative assessment
A meticulous physical and neurological evaluation was carried out on every patient on repeated visits. Tensilona test was used in both diagnosis and evaluation of optimal anticholinesterase dosage. Complete neurological examination, including analysis of cerebrospinal fluid and electrophysiological studies, was made on every patient. Spirometry was used for evaluation of respiratory capacity. The vital capacity and forced expiratory volume were usually normal, but the maximal voluntary ventilation in 40 sec was reduced in most cases: it averaged 65% of normal values (range 36-104%). It was a useful guide when evaluating the need of tracheostomy. Operative and postoperative management
Anticholinesterase drugs were withheld in the morning of the day of surgery. Pethidine 40-60 mg and atropine 0.4-0.6 mg were given for premedication. For induction of anesthesia, a sleeping dose of thiopental was administered ' halothane in and the patient was allowed to breathe 1-3 2 oxygen. When necessary, ventilation was assisted or
Thymectorny f o r myasthenia gruvis Table 11. The pre-operative distribution qf patients in clinicul cutegories
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No. of patients I. Ocular I I A . Generalized mild I1 B. Generalized moderately severe 111. Acute fulminating IV. Late severe
0 4" I5 7 5
Total
31
a
Three patients with thymoma included.
controlled before intubation. Anaesthesia was maintained with nitrous oxide (60-70%), halothane (0.5-1 %) and, if necessary, with small doses of intravenous pethidine. No muscle relaxants were given. Ventilation was controlled with an Engstrom respirator. A median sternotomy incision was used in all cases. The entire thymus gland with the surrounding mediastinal fat tissue was removed. Tracheostomy was made primarily in 27 patients; it was required in one additional patient on the first postoperative day and in another on the fifth postoperative day. Postoperatively, the patients were treated in the Intensive Care Unit, where ventilation was controlled with a volume pre-set Engstrom respirator until they could maintain a vital capacity of a minimum of one litre. The mean duration of the respirator treatment was 4 days (range 1 to 12 days). Anticholinesterase medication was withheld during the postoperative period to avoid cholinergic crisis with increased bronchial secretions. In most of the patients, the tracheostomy tube could be removed before anticholinesterase drugs were given to those requiring them. Diazepam, streptomycin, neomycin, kanamycin and gentamycin were not allowed because of their inhibitory action on neuromuscular transmission.
RESULTS
185
an aneurysm in arteria cerebri media, verified at autopsy. Two of the thymectomized patients developed tracheal stenosis at the site of the tracheostomy tube cuff. Tracheal resection and end-to-end anastomosis were carried out in one of them and endoscopic removal of excessive granulation tissue producing the stenosis was performed on the other. Both recovered uneventfully. Effect of histology on the results The influence of thymic histology on the results is presented in Table 111. Four patients with thymoma had the less favourable outcome: only one of them improved, two of them were unchanged and one deteriorated after thymectomy. The patients with thymic hyperplasia had the best results: 15 of these 17 patients were either in remission or improved after thymectomy, i.e. 89% of them were improved. Effect of pre-operative severity of myusthenia gruvis on the results The relationship between the pre-operative severity of myasthenia and the results is presented in Fig. 1. Thirteen of the 21 patients, who were improved after thymectomy, were pre-operatively in class I1 B (generalized moderately severe myasthenia) and 8 of them were pre-operatively either in class I11 (acute fulminating myasthenia) or in class IV (late severe myasthenia). Thus, the good results seemed to favour the class I1 B patients, but also the class I11 and IV patients appeared to benefit from thymectomy as eight of the total 12 belonging to these classes were improved after operation. The results were worst in class I1 A patients (generalized mild myasthenia), as none of them improved. Three of these patients had thymoma, which probably influenced the results unfavourably ; one of them had a histologically normal thymus and continued to have unchanged mild myasthenia after thymectomy.
All the 31 patients with myasthenia gravis, who underwent thymectomy, survived operation and were discharged from hospital. They were carefully followed-up and the status of the myasthenia was repeatedly assessed. After an average follow-up of 2.5 years (range 0.5-14.0 years), 16% of the patients were in full remission and an additional 52 per Table 111. The results after thymectomy (average cent were improved, 26% had no change in their follow-up 2.5 years) disease and 6 % had deteriorated (Table 111). Thus No. of Per 68% of the patients benefited from operation. One Result after thymectomy patients cent patient died during the follow-up period. She was a 34-year-old female with a class I11 myasthenia and A. Remission 5 16 16 52 was in full remission 6 months after the B. Improvement 8 26 thymectomy and was still without any symptoms of C . Nochange D. Deterioration 2 6 myasthenia and without any medication 3 years Total 31 I00 after surgery, when she suddenly died of rupture of
Scand J Thor Curdiovusc Surg 10
S . Mattilci rt a / .
186 Result
. ... . .... .... .. .. ....
A
B
No of pls Improved t t> = thymomd
20.
A = rems$1on 15
C
.th
D
-
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LA
I
. 113
10
Z
!I
.
/
~ r o clinical o ~ class
Fig. 1 . Relationship between pre-operative severity of myasthenia gravis (HA-IV as in Table 11) and result (A-D) after thymectomy. Good results (A and B, remis-
sion and improvement are seen to favour pre-op. class IIB, but are also found in patients with severe and late myasthenia gravis (classes I11 and IV).
Effect ofpre-operative duration of myasthenia gravis on the results
l m o 6rno
Iyr
2yrs
3
4
5yr5
time after thyrnectom)
Fig. 3 . Cumulative number of patients who improved after thymectomy plotted against time after thymectomy. Onethird (7 of 21) of the patients who improved did so within I month and 2/3 ( I S of 21) within 6 months after thymectomy, and the remainder within 6 months to S
years.
The duration of symptoms before operation seemed to be of minor importance, since remissions and improvement after thymectomy were also noted in patients with long duration of symptoms (up to 13.5 years) pre-operatively (Fig. 2). However, most of the patients selected in the series had histories of less than 5 years’ duration. Therefore it was difficult to interpret the results in this respect. Effect of sex on the results
Effect of age on the results The mean age of the patients was 32 years. The majority were therefore young people and it was impossible to divide them in age groups large enough to permit any conclusions to b e drawn. The 4 patients with thymoma belonged to the older age groups (mean age 50 years), which made it more complicated to interpret the results on the basis of age.
The female/male ratio in the total material was
21 : 10. Of the 5 patients with remission after thymectomy, 3 were women and 2 men. Of the 16 additional patients who were improved after thymectomy, 11 were females and 5 males. Thus, the improvement after thymectomy did not depend on the sex of the patient.
D
lh. year5 Durdtion 01 symptomi
Fig. 2. Influence of pre-operative duration of symptoms on the result after thyrnectomy. Most of the good results (A and B) are seen in patients with myasthenia gravis of less than 5 years’ duration, but even patients with longer
duration of symptoms benefit from thymectomy. Scand J Thor Cardiovusc Surg 10
Interval between thyrnectomy and remission or improvement Three patients had remission in less than 6 months after thymectomy. One patient experienced rernission 3 years and another patient 5 years after thymectomy. Six of the 16 additional patients who improved after thymectomy did so within one month, 6 patients in 6 months and 4 patients in 1-3 years. Fig. 3 presents the cumulative number of patients who benefited from surgery plotted against time after thymectomy. It is seen that most of the patients who benefited from thymectomy did so within one year, but not necessarily immediately after operation. Some patients, however, improved o r experienced full remission some years after operation. Two of the patients gave birth during myasthenia before thymectomy . Neonatal myasthenic disease was noted in 3 of the 4 babies delivered. Two other patients gave birth after thymectomy. A probable transient neonatal myasthenia was observed in one
of the babies, but no myasthenic disease could be noted in the other baby delivered after thymectomy. Both of these patients were in excellent condition during both pregnancy and childbirth.
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DISCUSSION The influence of thymectomy on myasthenia gravis in 31 patients is described. After an average follow-up of 2.5 years, 68% of the patients were improved. This figure is in agreement with the results reported in the literature: Keynes (1954): 65.8%; Perlo et al. (1966): 8 9 % for females; Papatestas et al. (1971): 7 6 % for patients without thymoma; Buckberg & Mulder (1967): 63 %; Levasseur e t al. (1972): 67 lo. It is evident that several factors affect the results. The patients with thymoma had the worst prognosis of myasthenia gravis after thymectomy: only one of the 4 patients improved. The same trend is to be noted in the previous literature (Buckberg & Mulder, 1967; Alpert et al., 1971; Keynes, 1954; Levasseur e t al., 1972). The patients with thymic hyperplasia had the best results: 89% of them benefited from thymectomy. This suggests that hyperplasia (lymphocytic infiltration, numerous germinal centres) of the thymus gland is associated with the pathogenesis of myasthenia gravis and supports the hypothesis that a substance or cells released by the thymus interfere with the neuromuscular transmission, as removal of actively functioning gland resulted in improvement of such a great proportion of the patients. It should be noted that removal of the thymus resulted in improvement or remission as late as 5 years after operation. Thymocytes are long-lived cells and it may take some years before they all disappear from the circulation. This explains why remission may occur several years after thymectomy, as was also observed in the present study. Therefore, when evaluating the results after thymectomy, it is of primary importance to followup the patients carefully for some months or even years before drawing final conclusions about the effectiveness of thymectomy on the course of myasthenia gravis. If the hypothesis that myasthenia gravis is produced by a thymic agent, which interferes with the neuromuscular transmission, is correct, thymectomy should be performed before the agent
causes irreversible changes. The pre-operative duration of symptoms and pre-operative severity of disease should therefore be helpful guides in this respect. The evaluation cannot, however, be based on these two parameters alone, as overlapping occurred: good results were obtained in both patients with short duration of symptoms and mild or moderately severe disease and in patients with long duration of symptoms and with severe disease. Myasthenia is a fluctuating disease in its clinical course and it is difficult to predict its reversibility on the basis of clinical symptoms and signs. The amount and rate of elimination of long-lived thymocytes from the circulation may also vary from case to case and affect the immunological status of the host after thymectomy, thus causing overlapping in the results in different clinical categories. It was interesting to note that in three newborn babies delivered by myasthenic mothers before thymectomy, a transient myasthenic disease could be observed and that one baby of another myasthenic mother after thymectomy did not show any such symptoms. This suggests that the myasthenic agent was transferred from the mother to the chiid via placenta and that no such a transferable agent existed after thymectomy, probably because thymectomy had eliminated it. There was, however, one exception to this: one baby delivered by a myasthenic mother did show a mild neonatal myasthenic disease. This could be explained by long-lived thymocytes still existing in the maternal circulation after thymectomy and being responsible for the transferable agent. It would be of great value if more clinical data could be obtained about the effects of thymectomy on the incidence of neonatal myasthenia. Thymectomy is a simple and safe procedure from the surgical point of view, but teamwork between surgeon, anaesthesiologist and neurologist is required in the pre-, per- and postoperative phases. We prefer median sternotomy and evacuation of all adipose tissue in the anterior mediastinum in order to remove also possible ectopic thymus tissue. Tracheostomy was performed primarily on almost all the patients to facilitate the postoperative care when anticholinergic drugs were withheld and controlled ventilation was used. When more experience is accumulated, we feel that it may be possible to reduce the number of primary tracheostomies, particularly in patients with minor bulbar involvement. Scand J Thor Curdiovusc Surg 10
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188
S. Mattila et al.
In conclusion, we consider that thymectomy is indicated in myasthenia gravis if medical therapy fails to give control of the disease and the patient’s condition is deteriorating rapidly. Long duration of symptoms and severe disease pre-operatively are not necessarily contra-indications for thyrnectomy. For final results, the patients must be carefully followed-up f o r some years before conclusions are drawn about the effects of operation on the course of the disease.
REFERENCES Alpert, L . I., Papatestas, A., Kark, A., Osserman, R. S. & Osserman, K. 1971. A histologic reappraisal of the thymus in myasthenia gravis. Arch Purh 91, 5 5 . Blalock, A . , Mason, M. F., Morgan, H. J. & Riven, S . S. 1939. Myasthenia gravis and tumors of the thymic region. Ann Surg 110, 544. Buckberg, G. D. & Mulder, D. G. 1967. Thymectomy for myasthenia gravis: principles of surgical management. Amer Surg 33, 797. Eaton, L . M. & Clagett, 0. T. 1955. Present status of thymectomy in treatment of myasthenia gravis. Am J Med 19, 703. Goldstein, G. 1968. The thymus and neuromuscular function. A substance in thymus which causes myositis and myasthenic neuromuscular block in guinea-pigs. Lancet 11, 119. Grob, D. 1953. Course and management of myasthenia gravis. JAMA 153, 529.
Scund J Thor Cardiovasc Surg 10
Keynes, G . 1954. Surgery of the thymus gland. Second (and third) thoughts. Lancer I , 1197. Levasseur, P., Noviant, Y., Miranda, A. R., Merlier, M. & LeBrigand, H . 1972. Thyrnectomy for myasthenia gravis. Long-term results in 74 cases. J Thor Cardiovusc Surg 64, 1. Mulder, D. G . , Braitman, H., Li, W. & Herrrnann, C. 1972. Surgical management in myasthenia gravis. J . Thor Cardiovasc Surg 63, 105. Nastuk, W. L., Strauss, A. J. L. & Osserman, K. E. 1959. Search for a neuromuscular blocking agent in the blood of patients with myasthenia gravis. Am J Med 26, 394. Papatestas, A. E., Alpert, L . I., Osserrnan, K. E . , Osserman, R. S. & Kark, A. E. 1971. Studies in myasthenia gravis: effects of thymectomy. Results on 185 patients with nonthyrnomatous and thymornatous myasthenia gravis. Am J Med 50, 465. Perlo, V. P., Poskanzer, D. C., Schwab, R. S . , Viets, H . R., Osserman, K. E. & Genkins, G . 1966. Myasthenia gravis: evaluation of treatment in L 355 patients. Neurology 16, 43 1. Schuhmacher & Roth. 1913. Thymektomie bei einem Fall von Morbus Basedowi mit Myasthenie. MiffGrenzgeb Med Chir 25, 746. Smithers, D. W. 1959. Tumours of the thyroid gland in relation to some general concepts of neoplasia. J Fac Radio! 10, 3. Strauss, A. J . L., Seegal, B. C., Hsu, K. C., Burkholder, P. M., Nastuk, W. L. & Osserman, K . E. 1960. Immunofluorescence demonstration of a muscle binding, complement-fixing serum globulin fraction in myasthenia gravis. Proc Soc Exp B i d Med 105, 184.
THYMECTOMY FOR MYASTHENIA GRAVIS Severi Mattila, Ritva Pirskanen and Jussi Heinonen
Scand Cardiovasc J Downloaded from informahealthcare.com by Flinders University of South Australia on 01/18/15 For personal use only.
From the Departments of Thoracic Surgery and Neurology, Universit). Central Hospital, Helsinki, Finland
(Submitted for publication September 25, 1974)
Abstract. Thymectomy was performed on 3 I patients with myasthenia gravis. Four of them had thymoma, 17 hyperplasia and 9 had normal thymic histology on microscopy. Discontinuation of anticholinergic medication together with tracheostomy, artificial ventilation and intensive observation were essential in the postoperative management. All the patients survived operation and were discharged from hospital. Sixty-eight per cent of the patients were in remission or improved after an average follow-up of 2.5 years. If the patients with thymoma were excluded, 7 4 % were improved and, if only the patients with thymic hyperplasia were included in the series, 89 % were improved after thymectomy.The seventy of disease and duration of symptoms pre-operatively seemed to be of minor importance for the results of operation, since good results were obtained also in patients with a long history and in clinical classes 111 and IV. Two patients developed tracheal stenosis as a complication of intubation with a tracheostomy tube. Tracheal resection was performed in one of them and endobronchial removal of granulation tissue producing the stenosis in the other. Both recovered uneventfully. One patient, who was asymptomatic and without medication for myasthenia, died suddenly of acute cerebral bleeding 3 years after thymectomy.
The first observation that thymectomy influenced the course of myasthenia gravis was made by Sauerbruch, who in 191 1 performed thymectomy on a 20-year-old girl with hyperthyroidism and myasthenia gravis (Schumacher & Roth, 1913). In 1936 Blalock removed a cystic thymic tumour from a 19-year-old girl, which resulted in a dramatic improvement of her myasthenia gravis. His report published in 1939 had a truly catalytic effect on the operative treatment of myasthenia gravis (Blalock et al., 1939). The procedure then became established in the ’forties by Keynes’ large series, in which improvement of the disease was noted in approximately two-thirds of the cases after thymec-
tomy (Keynes, 1954). He also noticed that the results were better in patients without thymoma. Some criticism and cold water were poured on the enthusiasm by Eaton & Clagett (1955) from Mayo Clinic, and Grob (1953) from Johns Hopkins Hospital in the ’fifties. They found spontaneous remissions or improvement of myasthenia gravis in 30% of the non-operated myasthenic patients compared with an improvement or remission rate of 50 to 60 % of thymectomized patients. In 1959 Smithers advanced the hypothesis that myasthenia gravis was an auto-immune disease. The germinal centres of the thymus in myasthenia gravis resembled those observed in Hashimoto’s thyroiditis (Smithers, 1959). In 1959 Nastuk et al. found in the sera of myasthenic patients antibodies against the striated muscle cells, myocardial and thymic cells not reacting with the endplate of the nerves (Nastuk et al., 1959; Strauss et al., 1960). In 1968 Goldstein separated from the calf thymus a substance (thymine) which produced a myasthenic disease in guinea pig (Goldstein, 1968). These new immunological findings, which supported the view that thymus was involved in the pathogenesis of myasthenia, and the accumulated clinical evidence from various centres (Perlo et a]., 1966; Papatestas et al., 1971; Mulder et al., 1972; Levasseur et al., 1972) encouraged us to test thymectomy in the treatment of myasthenia gravis. Eighty-two thymectomies have been performed for myasthenia gravis in Finland since 1958. Thirty-one of them were carried out at the Department of Thoracic Surgery, University Central Hospital, Helsinki. The experience obtained from these 31 patients is described in the present paper. Scand J Thor Cardiovasr Surg I0
184
S . Muttila r t a / .
Scand Cardiovasc J Downloaded from informahealthcare.com by Flinders University of South Australia on 01/18/15 For personal use only.
Table I . Thymrctomyfbr myasthenia gravis. Clinical dutu of the patients
Pat.
Sex
Age
Year
R. H . M. K . R. T. M. K . M. V. T. M. M. L. E. N. M. K. S. K. K. H. E. S. T. H. A. H. T. U . E. S. H. H. R. H. V. K. T. M. 0. J . A. K. A. L. V. J. u. P. M. S . G. S . L. P. u. G . R. M. P. A .
0 d
17 37 34 38 20 26 27 22 24 40 23 30 26 20 27 35 20 24 53 20 23 63 47 45 38 53 20 20 38 44 17
1958 I962 1969 I969 1969 1969 1970 I970 1970 1970 1971 1971 1971 1971 1971 1971 I972 1972 I972 1972 I972 I972 1972 I973 1973 I973 1973 1973 1974 1974 1974
P 6 d
0
P 0
P 0
P 0
0 0
P 0
P 0 d P d
P d d
6 d
P P P
9 d
Duration of symptoms Pre-op. (years) class 2.0 6.0 I .o 13.5 1.5 3.5 2.0 1.5 2.0 1 .o
6.0 I .5 14.0 I .o 2.0 3.5 4.Q 1.5 I .5 4.0 4.0 1.o
0.5 4.0 4.0 12.0 1.5 4.0 7.0 0.5 0.5
I11 I11 111
IV I1 B 11B 111 I1 B IV 111 I1 B I1B IV I1 B 11B 111 I1 B IIB I1 B I1 B I1 B I1 A 11A I1 B 1v
I1 A IV I1B I1 B I1 A 111
MATERIAL A N D M E T H O D S During the years 1958-74, thymectomy was performed on 31 patients (10 men and 21 women) with myasthenia gravis at the Department of Thoracic Surgery, University Hospital, Helsinki. The clinical data of the patients are compiled in Table I. The average age at the time of thymectomy was 32 years (range 17-63 years) and the duration of symptoms before the thyrnectomy was 4.2 years (range 0.5-14.0 years). The follow-up time after thymectomy averaged 2.5 years (range 0.5-12.0 years). Selection of patients
Thyrnectomy was recommended for patients with generalized myasthenia, in whom increasing dosages of medication failed to give control of the disease (Table 11). The exception to this criterion was radiographic demonstration of a thymic tumour in 4 cases. Thymectorny was performed on them for the tumour itself, regardless of the status of myasthenia. Patients with focal myasthenia, which essentially involved only the extraocular muscles, were not recommended for thymectomy. Many of the patients were young people with a short duration of symptoms (less than 5 years), but advanced age or longer duration of symptoms were not considered as contraindications for operation if the patient's condition was Scand J Thor Curdiovusc Surg 10
Histology
Result
Normal H yperplasia H yperplasia H yperplasia H yperplasia Hyperplasia
A A A A
-
H yperplasia Normal H yperplasia Hyperplasia H y perplasia Normal H yperplasia Normal H yperplasia H yperplasia H yperplasia Normal Hyperplasia Normal Thymoma Thymoma Thymoma Normal Normal H y perplasia Hyperplasia Normal Thymoma H yperplasia
B D C B B B B B C A
C C B
B B B B C D B C C B B B C B
FOIIOW-UP (years) 2.0 14.0 3.0 4.5 4.5 4.5 4.0 4.0 4.0 1.5 2.0 3.5 3.5 3.0 I .5 2.5 2.5 2.0 2.0 1.5 1.5 2.5 2.5 1.0 1.5 1.5 0.5 0.5 0.5 0.5 0.5
deteriorating rapidly and did not respond to medical treatment. The average dosage of Mestinon" was 425 rng pro die (range 80-900 mg) before thymectomy. Preoperative assessment
A meticulous physical and neurological evaluation was carried out on every patient on repeated visits. Tensilona test was used in both diagnosis and evaluation of optimal anticholinesterase dosage. Complete neurological examination, including analysis of cerebrospinal fluid and electrophysiological studies, was made on every patient. Spirometry was used for evaluation of respiratory capacity. The vital capacity and forced expiratory volume were usually normal, but the maximal voluntary ventilation in 40 sec was reduced in most cases: it averaged 65% of normal values (range 36-104%). It was a useful guide when evaluating the need of tracheostomy. Operative and postoperative management
Anticholinesterase drugs were withheld in the morning of the day of surgery. Pethidine 40-60 mg and atropine 0.4-0.6 mg were given for premedication. For induction of anesthesia, a sleeping dose of thiopental was administered ' halothane in and the patient was allowed to breathe 1-3 2 oxygen. When necessary, ventilation was assisted or
Thymectorny f o r myasthenia gruvis Table 11. The pre-operative distribution qf patients in clinicul cutegories
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No. of patients I. Ocular I I A . Generalized mild I1 B. Generalized moderately severe 111. Acute fulminating IV. Late severe
0 4" I5 7 5
Total
31
a
Three patients with thymoma included.
controlled before intubation. Anaesthesia was maintained with nitrous oxide (60-70%), halothane (0.5-1 %) and, if necessary, with small doses of intravenous pethidine. No muscle relaxants were given. Ventilation was controlled with an Engstrom respirator. A median sternotomy incision was used in all cases. The entire thymus gland with the surrounding mediastinal fat tissue was removed. Tracheostomy was made primarily in 27 patients; it was required in one additional patient on the first postoperative day and in another on the fifth postoperative day. Postoperatively, the patients were treated in the Intensive Care Unit, where ventilation was controlled with a volume pre-set Engstrom respirator until they could maintain a vital capacity of a minimum of one litre. The mean duration of the respirator treatment was 4 days (range 1 to 12 days). Anticholinesterase medication was withheld during the postoperative period to avoid cholinergic crisis with increased bronchial secretions. In most of the patients, the tracheostomy tube could be removed before anticholinesterase drugs were given to those requiring them. Diazepam, streptomycin, neomycin, kanamycin and gentamycin were not allowed because of their inhibitory action on neuromuscular transmission.
RESULTS
185
an aneurysm in arteria cerebri media, verified at autopsy. Two of the thymectomized patients developed tracheal stenosis at the site of the tracheostomy tube cuff. Tracheal resection and end-to-end anastomosis were carried out in one of them and endoscopic removal of excessive granulation tissue producing the stenosis was performed on the other. Both recovered uneventfully. Effect of histology on the results The influence of thymic histology on the results is presented in Table 111. Four patients with thymoma had the less favourable outcome: only one of them improved, two of them were unchanged and one deteriorated after thymectomy. The patients with thymic hyperplasia had the best results: 15 of these 17 patients were either in remission or improved after thymectomy, i.e. 89% of them were improved. Effect of pre-operative severity of myusthenia gruvis on the results The relationship between the pre-operative severity of myasthenia and the results is presented in Fig. 1. Thirteen of the 21 patients, who were improved after thymectomy, were pre-operatively in class I1 B (generalized moderately severe myasthenia) and 8 of them were pre-operatively either in class I11 (acute fulminating myasthenia) or in class IV (late severe myasthenia). Thus, the good results seemed to favour the class I1 B patients, but also the class I11 and IV patients appeared to benefit from thymectomy as eight of the total 12 belonging to these classes were improved after operation. The results were worst in class I1 A patients (generalized mild myasthenia), as none of them improved. Three of these patients had thymoma, which probably influenced the results unfavourably ; one of them had a histologically normal thymus and continued to have unchanged mild myasthenia after thymectomy.
All the 31 patients with myasthenia gravis, who underwent thymectomy, survived operation and were discharged from hospital. They were carefully followed-up and the status of the myasthenia was repeatedly assessed. After an average follow-up of 2.5 years (range 0.5-14.0 years), 16% of the patients were in full remission and an additional 52 per Table 111. The results after thymectomy (average cent were improved, 26% had no change in their follow-up 2.5 years) disease and 6 % had deteriorated (Table 111). Thus No. of Per 68% of the patients benefited from operation. One Result after thymectomy patients cent patient died during the follow-up period. She was a 34-year-old female with a class I11 myasthenia and A. Remission 5 16 16 52 was in full remission 6 months after the B. Improvement 8 26 thymectomy and was still without any symptoms of C . Nochange D. Deterioration 2 6 myasthenia and without any medication 3 years Total 31 I00 after surgery, when she suddenly died of rupture of
Scand J Thor Curdiovusc Surg 10
S . Mattilci rt a / .
186 Result
. ... . .... .... .. .. ....
A
B
No of pls Improved t t> = thymomd
20.
A = rems$1on 15
C
.th
D
-
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LA
I
. 113
10
Z
!I
.
/
~ r o clinical o ~ class
Fig. 1 . Relationship between pre-operative severity of myasthenia gravis (HA-IV as in Table 11) and result (A-D) after thymectomy. Good results (A and B, remis-
sion and improvement are seen to favour pre-op. class IIB, but are also found in patients with severe and late myasthenia gravis (classes I11 and IV).
Effect ofpre-operative duration of myasthenia gravis on the results
l m o 6rno
Iyr
2yrs
3
4
5yr5
time after thyrnectom)
Fig. 3 . Cumulative number of patients who improved after thymectomy plotted against time after thymectomy. Onethird (7 of 21) of the patients who improved did so within I month and 2/3 ( I S of 21) within 6 months after thymectomy, and the remainder within 6 months to S
years.
The duration of symptoms before operation seemed to be of minor importance, since remissions and improvement after thymectomy were also noted in patients with long duration of symptoms (up to 13.5 years) pre-operatively (Fig. 2). However, most of the patients selected in the series had histories of less than 5 years’ duration. Therefore it was difficult to interpret the results in this respect. Effect of sex on the results
Effect of age on the results The mean age of the patients was 32 years. The majority were therefore young people and it was impossible to divide them in age groups large enough to permit any conclusions to b e drawn. The 4 patients with thymoma belonged to the older age groups (mean age 50 years), which made it more complicated to interpret the results on the basis of age.
The female/male ratio in the total material was
21 : 10. Of the 5 patients with remission after thymectomy, 3 were women and 2 men. Of the 16 additional patients who were improved after thymectomy, 11 were females and 5 males. Thus, the improvement after thymectomy did not depend on the sex of the patient.
D
lh. year5 Durdtion 01 symptomi
Fig. 2. Influence of pre-operative duration of symptoms on the result after thyrnectomy. Most of the good results (A and B) are seen in patients with myasthenia gravis of less than 5 years’ duration, but even patients with longer
duration of symptoms benefit from thymectomy. Scand J Thor Cardiovusc Surg 10
Interval between thyrnectomy and remission or improvement Three patients had remission in less than 6 months after thymectomy. One patient experienced rernission 3 years and another patient 5 years after thymectomy. Six of the 16 additional patients who improved after thymectomy did so within one month, 6 patients in 6 months and 4 patients in 1-3 years. Fig. 3 presents the cumulative number of patients who benefited from surgery plotted against time after thymectomy. It is seen that most of the patients who benefited from thymectomy did so within one year, but not necessarily immediately after operation. Some patients, however, improved o r experienced full remission some years after operation. Two of the patients gave birth during myasthenia before thymectomy . Neonatal myasthenic disease was noted in 3 of the 4 babies delivered. Two other patients gave birth after thymectomy. A probable transient neonatal myasthenia was observed in one
of the babies, but no myasthenic disease could be noted in the other baby delivered after thymectomy. Both of these patients were in excellent condition during both pregnancy and childbirth.
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DISCUSSION The influence of thymectomy on myasthenia gravis in 31 patients is described. After an average follow-up of 2.5 years, 68% of the patients were improved. This figure is in agreement with the results reported in the literature: Keynes (1954): 65.8%; Perlo et al. (1966): 8 9 % for females; Papatestas et al. (1971): 7 6 % for patients without thymoma; Buckberg & Mulder (1967): 63 %; Levasseur e t al. (1972): 67 lo. It is evident that several factors affect the results. The patients with thymoma had the worst prognosis of myasthenia gravis after thymectomy: only one of the 4 patients improved. The same trend is to be noted in the previous literature (Buckberg & Mulder, 1967; Alpert et al., 1971; Keynes, 1954; Levasseur e t al., 1972). The patients with thymic hyperplasia had the best results: 89% of them benefited from thymectomy. This suggests that hyperplasia (lymphocytic infiltration, numerous germinal centres) of the thymus gland is associated with the pathogenesis of myasthenia gravis and supports the hypothesis that a substance or cells released by the thymus interfere with the neuromuscular transmission, as removal of actively functioning gland resulted in improvement of such a great proportion of the patients. It should be noted that removal of the thymus resulted in improvement or remission as late as 5 years after operation. Thymocytes are long-lived cells and it may take some years before they all disappear from the circulation. This explains why remission may occur several years after thymectomy, as was also observed in the present study. Therefore, when evaluating the results after thymectomy, it is of primary importance to followup the patients carefully for some months or even years before drawing final conclusions about the effectiveness of thymectomy on the course of myasthenia gravis. If the hypothesis that myasthenia gravis is produced by a thymic agent, which interferes with the neuromuscular transmission, is correct, thymectomy should be performed before the agent
causes irreversible changes. The pre-operative duration of symptoms and pre-operative severity of disease should therefore be helpful guides in this respect. The evaluation cannot, however, be based on these two parameters alone, as overlapping occurred: good results were obtained in both patients with short duration of symptoms and mild or moderately severe disease and in patients with long duration of symptoms and with severe disease. Myasthenia is a fluctuating disease in its clinical course and it is difficult to predict its reversibility on the basis of clinical symptoms and signs. The amount and rate of elimination of long-lived thymocytes from the circulation may also vary from case to case and affect the immunological status of the host after thymectomy, thus causing overlapping in the results in different clinical categories. It was interesting to note that in three newborn babies delivered by myasthenic mothers before thymectomy, a transient myasthenic disease could be observed and that one baby of another myasthenic mother after thymectomy did not show any such symptoms. This suggests that the myasthenic agent was transferred from the mother to the chiid via placenta and that no such a transferable agent existed after thymectomy, probably because thymectomy had eliminated it. There was, however, one exception to this: one baby delivered by a myasthenic mother did show a mild neonatal myasthenic disease. This could be explained by long-lived thymocytes still existing in the maternal circulation after thymectomy and being responsible for the transferable agent. It would be of great value if more clinical data could be obtained about the effects of thymectomy on the incidence of neonatal myasthenia. Thymectomy is a simple and safe procedure from the surgical point of view, but teamwork between surgeon, anaesthesiologist and neurologist is required in the pre-, per- and postoperative phases. We prefer median sternotomy and evacuation of all adipose tissue in the anterior mediastinum in order to remove also possible ectopic thymus tissue. Tracheostomy was performed primarily on almost all the patients to facilitate the postoperative care when anticholinergic drugs were withheld and controlled ventilation was used. When more experience is accumulated, we feel that it may be possible to reduce the number of primary tracheostomies, particularly in patients with minor bulbar involvement. Scand J Thor Curdiovusc Surg 10
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S. Mattila et al.
In conclusion, we consider that thymectomy is indicated in myasthenia gravis if medical therapy fails to give control of the disease and the patient’s condition is deteriorating rapidly. Long duration of symptoms and severe disease pre-operatively are not necessarily contra-indications for thyrnectomy. For final results, the patients must be carefully followed-up f o r some years before conclusions are drawn about the effects of operation on the course of the disease.
REFERENCES Alpert, L . I., Papatestas, A., Kark, A., Osserman, R. S. & Osserman, K. 1971. A histologic reappraisal of the thymus in myasthenia gravis. Arch Purh 91, 5 5 . Blalock, A . , Mason, M. F., Morgan, H. J. & Riven, S . S. 1939. Myasthenia gravis and tumors of the thymic region. Ann Surg 110, 544. Buckberg, G. D. & Mulder, D. G. 1967. Thymectomy for myasthenia gravis: principles of surgical management. Amer Surg 33, 797. Eaton, L . M. & Clagett, 0. T. 1955. Present status of thymectomy in treatment of myasthenia gravis. Am J Med 19, 703. Goldstein, G. 1968. The thymus and neuromuscular function. A substance in thymus which causes myositis and myasthenic neuromuscular block in guinea-pigs. Lancet 11, 119. Grob, D. 1953. Course and management of myasthenia gravis. JAMA 153, 529.
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Keynes, G . 1954. Surgery of the thymus gland. Second (and third) thoughts. Lancer I , 1197. Levasseur, P., Noviant, Y., Miranda, A. R., Merlier, M. & LeBrigand, H . 1972. Thyrnectomy for myasthenia gravis. Long-term results in 74 cases. J Thor Cardiovusc Surg 64, 1. Mulder, D. G . , Braitman, H., Li, W. & Herrrnann, C. 1972. Surgical management in myasthenia gravis. J . Thor Cardiovasc Surg 63, 105. Nastuk, W. L., Strauss, A. J. L. & Osserman, K. E. 1959. Search for a neuromuscular blocking agent in the blood of patients with myasthenia gravis. Am J Med 26, 394. Papatestas, A. E., Alpert, L . I., Osserrnan, K. E . , Osserman, R. S. & Kark, A. E. 1971. Studies in myasthenia gravis: effects of thymectomy. Results on 185 patients with nonthyrnomatous and thymornatous myasthenia gravis. Am J Med 50, 465. Perlo, V. P., Poskanzer, D. C., Schwab, R. S . , Viets, H . R., Osserman, K. E. & Genkins, G . 1966. Myasthenia gravis: evaluation of treatment in L 355 patients. Neurology 16, 43 1. Schuhmacher & Roth. 1913. Thymektomie bei einem Fall von Morbus Basedowi mit Myasthenie. MiffGrenzgeb Med Chir 25, 746. Smithers, D. W. 1959. Tumours of the thyroid gland in relation to some general concepts of neoplasia. J Fac Radio! 10, 3. Strauss, A. J . L., Seegal, B. C., Hsu, K. C., Burkholder, P. M., Nastuk, W. L. & Osserman, K . E. 1960. Immunofluorescence demonstration of a muscle binding, complement-fixing serum globulin fraction in myasthenia gravis. Proc Soc Exp B i d Med 105, 184.
