Sohaila Mohsin Ali ( Department of Surgery, The Aga Khan University Hospital, Karachi. )
Farhat Abbas ( Department of Surgery, The Aga Khan University Hospital, Karachi. )
Aziz Sona walla ( Departments of Medicine (Neurology), The Aga Khan University Hospital, Karachi. )
Irfan Altafullah ( Departments of Medicine (Neurology), The Aga Khan University Hospital, Karachi. )
Hizbullah Sheikh ( Departments of Pathology, The Aga Khan University Hospital, Karachi. )
Thirteen patients with myasthenia gravis underwent total thymectomy between January, 1988 and December, 1991. The duration of symptoms prior to surgery varied from 2 months to 20 years. In a follow-up ranging from 2 months to 4 years, 11 patients showed a significant improvement with either complete discontinuation of medication of a marked reduction in doses. One patient with a small benign thymoma showed some improvement but subsequently required stepping up of anticholinesterase medication and addition of steroids and immune suppressants; another patient with atrophic thymic tissue had complete remission after thymectomy but developed myasthenic symptoms six months later requiring medication again. Thymectomy is recommended for all patients with generalised myasthenia gravis with or without thymoma regardless of the duration of disease unless the patient is a very high risk candidate for surgery. It is not recommended for isolated ocular myasthenia gravis. (JPMA 42:107, 1992).
Although the symptoms of myasthenia gravis were described in 16721, prior to the introduction of anticholinesterase drugs the disease was only recognized because of severe weakness and was fatal within a short period of time. The association of myasthenia gravis and thymic tumours was first made by Weigert in 19012. Thymectomy for the treatment of thymomas and of myasthenia gravis was first introduced by Blalock and associates in 1939 and 19413,4. This report describes our experience of surgical management of myasthenia gravis.
PATIENTS AND METHODS
From January, 1988 to December, 1991 thirteen patients underwent thymectomy for myasthenia gravis. Ages ranged from 15 to 50 years with a mean age of 30.5 years. Myasthenia gravis had been present for 2 months to 20 years with a mean duration of 4.5 years. Six were males and seven females (Table I).
All patients had moderate to severe generalised myasthenia gravis (Osserman classification Class II and III)5 and were moderately incapacitated in daily living and work. All patients were given anticholiriesterase medication pre-operatively and 6 were taking steroids prior to surgery. Three patients also had plasmapharesis on several occasions. The preoperative medications were determined by the referring physicians and were not changed prior to surgery (Table II)
No attempt was made to add steroids if the patient was not already taking them. In the first 8 patients all medications were continued at the same dose immediately post-operatively and were gradually tapered off during the follow-up period using clinical improvement as an indicator. In the last 5 patients anticholinesterase drugs were begun at half the preoperative dose at least 12 hours after thymectomy and were then adjusted according to the clinical response of the patient. Three patients had proved thymomas, 6 had lymphoid hyperplasia and 5 had involuted thymic tissue. In 5 of these patients lymphoid aggregates were found in the extrathymic anterior mediastinal fat. In one of the patients with a thyrnoma no other thymic tissue was evident (Table III).
A complete median sternotomy was used through a midline vertical skin incision as the primary approach in all patients. The first patient had a simple thymectomy but 21 months later was re- explored and a clean out of the anterior mediastinal and anterior cervical fat was carried out. In the other 12 patients following wide exposure of the mediastinum not only all the thymic tissue, but also all suspected thymic tissue and anterior mediastinal fat were excised. The dissection was routinely carried laterally to the phrenic nerves or beyond and inferiorly to the diaphragm. Occasionally thin sheets of thymic tissue were initially misinterpreted as being normal pleura, and almost always while peeling mediastinal fat from the pleura and phrenic nerves, one or both pleural cavities
were entered. Mediastinal and pleural chest tubes were used routinely. Great care was taken to prevent injury to the phrenic nerves and none of the patients demonstrated diaphragmatic paralysis following thymectomy. The transcervical approach was avoided because of the possibility of phrenic nerve injury, of significant bleeding in the depth of the mediastinum in areas of compromised visibility and because a clean out of the entire anterior mediastinal fat is technically difficult through this approach. The importance of the latter to prevent leaving behind islands of thymic tissue has been demonstrated by Jaretzki and associates6. Extubation was achieved in 11 patients after thymectomy; of these two patients required reintubation and ventilatory support but were weaned successfully 6 days and 7 days later respectively from the ventilator. Two other patients were electively ventilated for 1 and 3 days respectively. Tracheostomy was not needed in any patient in this series.
Subsequent to a thymectomy the patients can be categorized as follows: remission - no symptoms and no medication; improved - less medication and better control of symptoms; same - equivocal improvement; worse - more medication, and symptoms unchanged increased 9. Using these criteria 3 patients went into remission, 1 patient went into remission for the first 5 months but subsequently developed fluctuating weakness requiring medication, and was therefore reassigned to the equivocal group, 8 patients were improved and 1 patient became worse. Benefit from the operation was thusachievedin 11 out of 13 patients (84.6%) (Table IV).
Thymomas were present in 3 patients in this group (Figures 1 & 2).
One patient (QMH) had a large invasive thymoma at the time of original thymectomy in January, 1988. The thymectomy was followed by a severe exacerbation of the myasthenia. Twenty-one months later a second exploration of the neck and mediastinum was done to completely remove all anterior mediastinal and cervical fat to eliminate any residual islands of thymic tissue as suggested by Jaretzki et al6. Although no recurrence of the thymoma was found, and no thymic tissue was identified on random histopathological sampling of the rather extensive amount of mediastinal and cervical fat removed, in view of the patient’s significant improvement over 25 months of follow-up it is highly probable that microscopic islands of thymic tissue have indeed been eliminated. Lymphoid aggregates were identified in the mediastinal fat in this patient and may well have been responsible for perpetuation and worsen. ing of his myasthenia following the initial thymectomy. He has now gone into complete remission and requires no medication. The second patient (SMA) was found to have asmall thymomaand a small involuted thymus. After an initial mild improvement the course of myasthenia in this patient was exacerbated, leading to the addition of steroids and azathioprine (Imuran) and to a higher dose of pyridostigmine (Mestinon) to keep her moderately symptom free over a 24 month follow-up period. The third patient (AAHK) had a mixed lympho- epithelial thymoma but has shown significant improvement in 16 months of follow- up. In 6 patients where lymphoid hyperplasia of the thymus was the primary pathology (Figure 3),
thymectomy uniformly led to improvement in the symptoms of myasthenia gravis and to a decrease in medication requirements. Five patients were found to have an involuted thymus on histopathology (Figure 4).
One of these went into remission initially, became symptomatic again 5 months later and is now symptomatically almost the same as prior to surgery (Table V).
Other 4 patients have shown significant improvement with decreased anticholinesterase requirements. Five patients had lymphocytic aggregates in the extrathymic mediastinal fat (Figure 5).
No Hassel’s corpuscles were present in the aggregates and their exact significance with respect to myasthenia remains ill defined. One patient was found to have tuberculosis as an incidental finding in the anterior mediastinal lymph nodes removed at thymectomy and has required initiation of antituberculous treatment. The presence of tuberculosis did not appear to have an adverse effect on the myasthenic state of this patient or on her recovery following thymectomy. One patient developed a staphylococcal wound infection at the operative site which cleared on drainage and antibiotic therapy. No other complications occurred in this series.
It is well recognized that myasthenia gravis is an autoimmune disease, in the pathogenesis of which the thyrnus gland seems to play a central role, although the details of this role are not yet completely defined7. Weakness results from a reduction in acetylcholine receptors at the neuromuscular junction8. Despite significant advances in therapy myasthenia remains a potentially debilitating and life threatening disease. Currently 4 methods of treatment are available for patients with myasthenia: anticholinesterase drugs (Mestinon, Prostigmin) to enhance neuromuscular transmission; immune suppression (Prednisone, azathioprine) to decrease the immune response; plasmapharesis to remove some of the circulating autoantibodies; and thymectomy to remove a major source of antibody production9. For this complex autoimmune disorder while all or any of the above modes of therapy may be necessary, it is now generally accepted that removal of the thymus gland is distinctly beneficial in the majority of patients with generalised myasthenia gravis9,10. It has also become gradually clear that for remission of myasthenia to occur the thymectomy must be :complete:, in that not only the thymus gland itself but all possible islands of thymic tissue should also be removed. In a series of elegantly carried out dissections, Jaretzki et al demonstrated that accessory thymic tissue occurs in unusual position in the neck and large amounts may be found in the anterior mediastinal fat away from the thymic lobes10. They have therefore, recommended a :maximal: thymecout through a mid-sternotomy and a separate transcervical incision. Recently Fukai et al from Japan have demonstrated the presence of accessory thymic tissue in the retrocarinal fat in 2 of 27 autopsy subjects although none was found in the fat anterior to the descending thoracic aorta11. The retrocarinal area is not accessible through a median sternotomy. This tissue therefore cannot be removed at the time of the initial thymectomy but should be explored in cases of recurrent myasthenia where a complete anterior mediastinal clean out has been previously performed and no evidence of thymoma can be seen on re-evaluation with a CT scan. Some of the factors which have been known to favourably affect the results ofthymectomy have been the presence of acetyicholine receptor antibody9, the presence of hyperplasia in the thymus removed,the absence of a thymoma and a shorter duration of disease with milder symptoms12. A younger age group (second and third decades) and the female sex, previously considered favourable predictors, now appear not to affect the incidence of remission following thymectomy12,13. However, none of these factors are absolute indicators of the response to thymectomy in an individual patient. This is corroborated by the results of our series where age, sex, and the presence of thymic hyperplasia or involution did not effect the response to thymectomy. A study by Papatestas et al clearly demonstrates that thymectomy significantly influences the clinical course in patients with myasthenia gravis; compared with nonsurgical treatment thymectomy is followed by an earlier onset of remissions, a lower mortality, a delay in the appearance of extrathymic neoplasms and also appears to avert the progression of the disease12. Buchingham et al in a computer assisted matched study to assess the value of thymectomy in myasthenia gravis showed the distinct benefits of thymectomy as compared to medical treatment alone in a lower early mortality, a higher five year survival rate and in the induction of complete remissions13. Others14 have also underscored the benefits of thymectomy in patients with myasthenia gravis. We have therefore adopted rather liberal criteria for selecting patients for thymectomy All patients with generalised myasthenia gravis are offered the operation unless the patient is medically unfit for surgery or the symptoms are minimal and the patient asymptomatic on small doses of anticholinesterase drugs. In patients with ocular myasthenia alone, thymectomy is not recommended because long term follow-up in these group IA patients (Osserman classification’) has shown this to be an essentially benign condition which, except in rare instances, remains confined to the lids or ocular muscles15,16. In patients over the age of 55years thymectomy was previously discouraged because of the frequent observation of an atrophic involuted gland. In fact, the presence of atrophic involuted thymus may not preclude immunological activity since Dalakas et al18 reported significant staining for thymosin alpha - 1 hormone in grossly atrophic thymic tissue, and Haynes et al19 found altered T-cell subsets following removal of atrophic thymus. Although some controversy still exists regarding the performance of thymectomy through a median sternotomy versus a transcervical incision, the former has been exclusively used as the primary approach in this series since it allows a complete resection to be performed easily and safely. In the first 8 patients the anticholinesterase medication as well as steroids were started at pre-operative doses immediately after thymectomy. It was found however, that the 2 patients who required reintubation and ventilation were in cholinergic crisis. It has been shown that following thymectomy most patients develop increased sensitivity to the medication9,17. Our protocol therefore has now been modified to resume medication no sooner than 12 hours postoperatively and to initially give only one half of the preoperative dose. This is then increased according to the individual requirement of each patient. The steroids however are continued at preoperative doses and then tapered over 4 to 6 months. Plasmapharesis prior to surgery is recommended in patients with very severe and rapidly progressive symptoms9. Three to six exchanges over a one to four weeks period allow for a much safer peri-operative course. Only two of the patients in this series had plasmapharesis although 2 others could also have benefited from it. In Pakistan at this time the inconsistency in the availability and the high cost of the plasmapharesis kits necessary for the procedure make it difficult to use this modality in our patients. In conclusion the distinct benefits of thymectomy as demonstrated by the experience of others and corroborated by our results make it a highly desirable therapeutic measure in the management of patients with myasthenia gravis.
Our thanks to Dr. Mushtaq Ahmed for allowing the inclusion of one of his patients in this series and to other consultants at the Aga Khan University Hospital and elsewhere in Karachi for referring their patients to us for thymectomy. The secretarial assistance of Mr. Muradali Bana has been invaluable in the preparation of this paper and is greatly appreciated.
1. Willis. T. De Anima Brutorum. Oxford.Teatro Sheldiano. 1672, pp. 404-5.
2. Weigert, C. Pathogisch - anatomischer Beirtrag Zur Erbvchen Krankheit (Myasthenia Gravis). Neurol. Central., 1901; 20:597.&
3. Blalock. A., Mason, M.F., Morgan, Hi. and Riven. S.S. Myasthenia gravisand tumours of the thymic region. Ann. Surg., 1939; 110:544-60:
4. Blalock, A., McGehee, H.A. and Ford, Fit The treatment of myasthenia gravis by removal of the thymus gland. JAMA., 1941:117:1529-34.
5. Osserman, K.E. Myasthenia Gravis. New York, Grune and Stratton. 1958; pp. 79-81.
6. Daretzki, A. 3rd, Penn, A.S., Younger, D.S., Wolff M., Olarte, M.R., Lovelace, R.E, and Rowland, LP. Maximal thymectomy for myasthenia gravis. Results. J. Thorac. Cardiovase Surg., 1988:95:747-57.
7. Wekerle, H. and Muller-Herinelink, H.K. The thymus in myasthenia gravis. Curr.Top. PathoL 1986; 75:179-83.
8. Engel, A.G. Myasthenia gravis and myasthenic syndromes. Ann. NeuroL, 1984; 16:519-34.
9. Mulder. D.G., Graves, M. and Hermann. C. Thymectomy formyasthenia gravis: Recent observationsand comparisonswith pastexperience. Ann. Thorac. Surg., 1989; 48:551-5.
10. Jsretzki, A., Bcthea, M., Wolff. M., Olarte, MR., L.ovelace, R.E., Penn, AS. and Rowland. LA rational approach to total thymectomy in the treatment of myasthenia gravis. Ann.Thorac. Surg., 1977; 24:120-30.
11. Fukai, LFunato, Y., Mizuno,T., Hashimoto, T. and Masoaka, A. Distribution of thymic tissue in the mediastinal aduposetissue. J. Thorac. Cardiovasc. Surg., 1991; 101:1099-102.
12. Papatestas. A.E.. Genkins. G., Kornfeld, P.. Eisenkraft, J.B.. Fagerstrom, R.P., Pozner, J. and Aufses. A.H. Jr. Effects of thymectomy in myasthenia gravis. Ann. Surg., 1987; 206:79-88.
13. Buckingbam, J.M., Howard, F.M., Bernatz, P.E., Payne, W.S., Harrison, E.G., O’Brien, P.C. and Weiland, LH. The value of thymectomy in myasthenia gravis: A computer assisted matched study. Ann. Sur&, 1976; 184:453-8.
14. Cohn, H.&, Solit, R.W., Schatz, N.J. and Schlezinger, N. Surgical treatment in myasthenia gravis.). Thorac. Cardiovasc. Surg., 1974; 68:876-85.
15. Perlo, V.P., Poskanzer, D.C., Schwab, R.S., Viets, HR., Osserman, K.E. and Genkins, G. Myasthenia gravis: Evaluation of treatment in 1,355 patients. Neurology, 1966; 16: 431-9.
16. Grob, D., Brunner, N.G. and Namba, T. The natural course of myasthenia gravis and effect of therapeutic measures. Ann. N.Y. Acad. ScL, 1981; 377:652-69.
17. Simpson. A. and Thomaides, T. Treatment of myasthenia gravis: an audiL QJ. Med., 1987; 244:693-704.
18. Dalakas, MC., Engel, W.K., McClure, J.E., Goldstein, A.L., and Askanas, V. Immunocytochemical localization of thymosin-alpha-1 in thymic epithelial cells of normal and myasthenia gravis. Patients and in thymic cultures.). Neurol. Sci,, 1981; 50239-47.
19. Haynes. B.F.. Harden. E.A., Olanow. C.W.. Eisenbarth, G.S., Wechsler, A.S., Hensley, LL and Roses. A.D. Effect of thymectomy on peripheral lymphocyte subsets in myasthenia gravis: Selective effect on T-cells in patients with thymic atrophy. J. Immunol., 1983; 131:773-7.