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Effect of thymectomy in patients with myasthenia gravis
Effect of Thymectomy in Patients with Myasthenia Gravis A Sixteen Year Experience
Donald G, Mulder, MD, Los Angeles, California Christian H e r r m a n n , M D , * Los Angeles, California Gerald D. B u c k b e r g , M D , * Los Angeles, California
T h e cause of m y a s t h e n i a gravis r e m a i n s obscure, as does the precise relationship of th e t h y m u s to this disorder. T h y m e c t o m y has b e e n a d v o c a t e d in selected p a t i e n t s because of the o b s e r v a t i o n t h a t in m a n y cases it m a y f a v o r a b l y alter t h e course of the disease |1-4]. However, the s p o n t a n e o u s f l u c t u a t i o n in severity of s y m p t o m s in p a t i e n t s with m y a s t h e n i a is well recognized, and only o b s e r v a t i o n s over an extended period of t i m e will afford an a c c u r a t e a p p r a i s a l of the influence of a n y medical or surgical intervention. In an effort to provide such i n f o r m a t i o n we are r e p o r t i n g our experience in 100 consecutive patients who have u n d e r g o n e t h y m e c t o m y a n d who h a v e h a d careful follow-up s t u d y up to sixteen years. Material and Methods
Clinical Data. Of 443 patients with confirmed myasthenia gravis seen at the UCLA Medical Center during the past sixteen years, 100 underwent thymectomy. Twenty-four were males and seventy-six were females; their ages ranged from two and a half to seventytwo years. (Figure 1.) Twenty-one patients were twenty years of age or younger, and fifteen were older than fifty years. From the Departments of Surgery and Neurology, UCLA Medical Center. Los Angeles, California, This work was supported in part by grants from the California Chapter of the MyastheniaGravis Foundation,Inc., and the Blalock Foundation. Reprint requests shouldbe addressed to Dr Donald G. Mulder, Department of Surgery (Thoracic), UCLA Medical Center, Los Angeles, Califor-
nia 90024.
Presented at the Forty-Fifth Annual Meeting of the Pacific Coast Surgical Association,Kaanapali,Maul, Hawaii, February 17-21. 1974.
* By invitation.
202
Seven patients had mild generalized myasthenia, including ocular involvement (class I); forty-one had moderately severe generalized disease, including some bulbar involvement (class II); thirty-five had acute, severe generalized and bulbar impairment (class III); seventeen had the later stages of the disease with marked generalized and bulbar involvement (class IV). Thymoma was found in twenty-seven patients. Eight of the eighteen tumors found in females were invasive, as were three of the nine found in males. Thymic hyperplasia was present in forty-seven patients and in eight involutional changes were noted. The thymus was interpreted as being normal in the remaining eighteen patients. Follow-up information obtained within the past year is available for ninety patients. The ten who could not be located had been followed up two months to ten years (average, four years). Their condition when last seen is included in the evaluation data. Surgical Considerations. Thymectomy was performed as an elective procedure and never during an acute relapse or myasthenic crisis. Patients were selected for operation if satisfactory medical control of the symptoms could not be achieved. Those with mild symptoms that were readily controlled by anticholinesterase drugs were not considered operative candidates unless chest roentgenograms (including laminograms) suggested the presence of mediastinal tumor. Patients with long-standing end stage myasthenia, especially in the older age group, also did not have surgical treatment. A median sternotomy was used to provide optimal exposure of the anterior mediastinum. This lessens the possibility of injury to the phrenic nerves or serious bleeding that may result when visibility in the operative field is compromised, as in the transcervical technic [5,6]. Additional disadvantages of the transcervical approach are that it cannot be used in the presence of
The American Journalof Surgery
Thymectomy for Myasthenia Gravis
tumor and that removal of the gland may be incomplete, which must be considered if response of the myasthenia is unsatisfactory after operation. Concomitant tracheostomy was performed in the presence of one or more of the following indications: (1) oropharyngeal weakness (bulbar), (2) previous respiratory complications, (3) previous myasthenic crisis, (4) a vital capacity of less than 2,000 cc. In patients in whom tracheostomy was not anticipated, a nasotracheal tube was inserted and usually left in place twelve to fortyeight hours. Thymic tumor was excised widely along with generous segments of contiguous pericardium and pleura. In one instance the invaded superior vena cava and the tumor were removed en bloc, and venous continuity was restored with a pericardial tube graft. Although the usual dose of anticholinesterase drug was given the morning of operation, no such medication was administered postoperatively because of the known increased sensitivity of these patients at this time. Furthermore, it is sometimes difficult to differentiate the symptoms of insufficient doses of medication from those of toxic doses; with control of the airway there is no necessity, except for patient comfort, to reinstitute theraPy. Results
The current status of the patients was evaluated in most instances by one of us (CH), but in some cases it was necessary to rely on information obtained by another physician or by telephone contact with the patient. Remission indicates minimal or no symptoms and no need for anticholinesterase drugs. Improvement implies a substantial decrease in preoperative symptoms and a sustained reduction in drug requirements. Of the seventy-three patients without tumor (Table I), fifty-two of the fifty-eight females (89 per cent) benefited from operation, as did ten of the fifteen males (66 per cent). The condition was not made worse by operation in any patient, but in six patients it was unchanged; five patients died. The response of the myasthenia to thymectomy could not be predicted on the basis of the histologic features of the nontumorous gland. Although thymic hyperplasia was the most common finding (in 64 per cent of the seventy-three specimens), the chance of a favorable result was no greater than that in the normal (25 per cent) or involuted (11 per cent) glands. Of the twenty-seven patients with thymic tumor (Table II), twelve of the sixteen females (75 per cent) benefited from operation, as did five of the eleven males (45 per cent). There was no change in the condition in two patients, but in one it was worse after operation; seven patients died.
Volume 128, August 1974
20
[ ] MALES (24) I
FEMALES (76)
15
~o
0-10
1%20 21-50 31~40 41-50 51-60 61-70 71-80 AGE,yr
Figure 1. The age and sex distribution of 100 patients undergoing thymectomy for myasthenia gravis.
The preoperative classification was a factor in predicting the surgical result in both sexes; those with less severe forms of the disease (classes I and II) had a better response than did those with more severe involvement (classes III and IV). (Table III.) Complete remission occurred in six of seven patients in class I (85 per cent), in fifteen of fortyone in class I1 (36 per cent), in seven of thirty-five in class III (20 per cent), and in two of seventeen in class IV (12 per cent). The over-all remission rate for the entire group of 100 patients was 30 per cent. Tracheostomy had been performed preoperatively or was performed concomitantly in fifty patients. Based on the indications stated previously, it was anticipated that none of the remaining fifty patients would require it. However, in six patients it was necessary to perform tracheostomy (over the endotracheal tube) within forty-eight hours after operation, a reflection of inaccurate preoperative assessment in these patients. Despite this, fortyfour patients were spared tracheostomy, a procedure some investigators have recommended routinely but which carries significant morbidity. Although the hospital stay was protracted because of the severity of disease in some patients, no serious complications were encountered in seventy-three patients. As would be anticipated, the majority of the postoperative problems were pulmonary, with significant atelectasis in seventeen patients and pneumonitis in four; miscellaneous problems, such as thrombophlebitis and urinary tract infection, occurred in six patients. Twelve patients died; two of these were operative deaths. An elderly diabetic patient died from gram-negative septicemia seven days postoperatively, and the second operative death was caused by massive hemorrhage during re-exploration for recurrent invasive thymoma.
203
Mulder, Herrmann, and Buckber9
TABLEI
Results of Thymectomy in Seventy-Three Myasthenic Patients without Tumor
Postoperative Status
Males
Females
Remission Improvement No change Deterioration Death Total
51 5~ 66% 3 0 2 15
21 31[ 89% 3 0 3 58
TABLE II
Results of Thymectomy in Twenty-Seven Myasthenic Patients with Tumor
Postoperative Status
Males
Females
Remission Improvement No change Deterioration Death Total
1'[ 4/45% 1 0 5 11
3'[ 9,/ 75% 1 1 2
TABLE III
Preoperative Classification i
I, Ill IV
16
Incidence of Complete Remission after Thymectomy Correlated with Sex and Preoperative Classification
Sex and Number of Patients M
3
F M F M F M
4 8 33 9 26 4 13
F
Postoperative Remission
27_85% 4_1 4-1_36% 1tJ -30% 17_20o/o 6J 0"]
2J
Eight patients died two and a half months to six years after thymectomy from relapse of the myasthenia with pulmonary complications. The remaining two patients died of unrelated causes, one from coronary thrombosis at two years and the other from congestive heart failure at seven years. Of interest is the fact that thymic tumor had been excised in seven of the twelve patients who died. Comments
Despite our lack of knowledge concerning the pathophysiology of myasthenia gravis, it is clear that thymectomy favorably alters the course of the disease in many cases. Because of this, we have liberalized our indications somewhat and tend to operate earlier in the course of the disease if the response to medical treatment is unsatisfactory.
204
Although approximately 35 to 40 per cent of patients have periods of spontaneous improvement, this cannot compare with the prognosis after thymectomy, especially in females. Successful management of these patients, however, requires close cooperation between the neurologist, surgeon, and anesthetist, as well as intensive postoperative care by capable nurses and physiotherapists. It is very important that all who participate in the care of patients with myasthenia be aware of the responses that are unique to these patients: (1) marked sensitivity to curare-like drugs, (2) rapid fatigability of striated muscle even when the disease is controlled, (3) inability to convey anxiety due to hypoxia in those with impaired facial muscle strength, (4) susceptibility to the myasthenic weakness potentiated by certain "-mycin" type antibiotics, (5) enhanced sensitivity to anticholinesterase drugs immediately after operation, which is further complicated by the difficulty in differentiating crisis due to drug toxicity from that due to insufficient medication. Anticipation and prompt recognition and treatment of impending problems will influence significiantly the outcome in many of these seriously ill patients. Since myasthenia gravis is often considered an autoimmune disorder, ACTH and adrenal corticosteroids should be tried in an effort to suppress immunologic responsiveness. In our limited experience with twenty-five patients (ten of whom are included in this series), all seemed to derive some benefit from the administration of steroids, although the action appeared to be suppressive rather than curative since no remission persisted when prednisone was discontinued after six months. In addition, significant complications are associated with the use of steroids; therefore, we now reserve alternate-day prednisone therapy for those patients with generalized incapacitating myasthenia who do not respond satisfactorily to anticholinesterase treatment, thymectomy, or both. At the present time we are looking at the effect thymectomy may have on the immune response in myasthenic patients by testing them with the nonspecific chemical antigen dinitrocholorobenzene (DNCB) [7] before and at intervals after operation. It is hoped that this assessment of changes in immunologic responsiveness may be of value in predicting the end result after operation and may have therapeutic implications in the use of other drugs. All patients with thymic tumor are considered candidates for thymectomy, even if the myasthenia is mild and would otherwise not warrant opera-
The AmericanJournalof Surgery
Thymectomy for MyastheniaGravis
tion. This is justified not only because of the freq u e n t l y favorable effect on the myasthenia, b u t more i m p o r t a n t l y because of the very real danger of later t u m o r involvement of mediastinal structures such as the superior vena cava and innominate vein. Since even " m a l i g n a n t " t u m o r s are usually locally invasive, wide en bloc resection is usually curative. If only incomplete resection of the t u m o r is possible, postoperative irradiation should be given. We have also had two patients with invasive t h y m o m a who a p p e a r e d to benefit from a combination of a l t e r n a t e - d a y prednisone and cyclophosphamide. One additional p a t i e n t with chronic lymphocytic leukemia also showed mild i m p r o v e m e n t in the m y a s t h e n i a after cyclophosphamide treatment. T h e s e newer agents for use in patients with nonresectable t h y m i c t u m o r w a r r a n t f u r t h e r trial. T h e results after t h y m e c t o m y as r e p o r t e d in this p r e s e n t series confirm our previous experience [8]. We are convinced t h a t when patients are selected for operation carefully and are managed properly, objective i m p r o v e m e n t in the m y a s t h e n i a will occur in the majority of cases.
Summary T h y m e c t o m y was p e r f o r m e d in 100 patients with m y a s t h e n i a gravis who were selected for operation because of poor medical control of the disease or the presence of t h y m i c tumor. Significant i m p r o v e m e n t occurred in fifty-two of the fiftyeight females who did not have t h y m o m a (89 per cent) and in ten of the fifteen males in the same category (66 per cent). Of the twenty-seven patients who had t h y m i c tumor, twelve of the sixteen females were improved (75 per cent), as were five of the eleven males (45 per cent). T h e r e were two operative and ten late deaths during a follow-up period of sixteen years. It is concluded t h a t in selected patients with m y a s t h e n i a gravis, thymect o m y favorably influences the course of the disease in most cases.
References 1. Keynes G: Surgery of the thymus gland. Lancet 2: 1197, 1954. 2. Schwab RS, Wilkins EW, Head JM, Pontoppidan H, Viets HR: Thymectomy in myasthenia gravis. JAMA 187: 850, 1964. 3. Perlo VP, Poskanzer DC, Schwab RS, Viets HR, Osserman KE, Genkins G: Myasthenia gravis: evaluation of treatment in 1355 patients. Neurology 16: 431, 1966. 4. Buckberg GD, Herrmann C, Dillon JB, Mulder DG: A further evaluation of thymectomy for myasthenia gravis. J Thorac Cardiovasc Surg 53: 401, 1967. 5. Kirschner PA, Osserman KE, Kark AE: Studies in myasthenia
Volume 128, August 1974
gravis, transcervical total thymectomy. JAMA 209: 906, 1969. 6. Crile G Jr: Thymectomy through the neck. Surgery 59: 213, !966. 7. Eilber FR, Morton DL: Impaired immunologic reactivity and recurrence following cancer surgery. Cancer 25: 362, 1970. 8. Mulder DG, Braitman H, Li Wei-i: Surgical management in myasthenJa gravJs. J Thorac Cardiovasc Surg 63: 105, 1972.
Discussion Eric W. Fonkalsrud (Los Angeles, Calif): Doctor Mulder has provided us with a summary of a large clinical experience with thymectomy for myasthenia gravis. Since the serendipitous observation by Blalock thirtyfive years ago that thymectomy relieved the symptoms of a myasthenic patient, the literature has been replete with contradictory reports regarding the role of thymectomy in the treatment of this condition. The unpredictable course of myasthenia, including the not infrequent spontaneous remissions, has made evaluation even more confusing. However, Doctor Mulder's study clearly shows that the majority of patients with myasthenia who do not have tumor experience complete remission of symptoms or show considerable clinical improvement after ablation of the thymus, albeit the reason for the improvement is as mysterious as is the cause of myasthenia in the first place. It is of interest that myasthenia is twenty times more common in females under the age of twenty years than in males. Doctor Mulder, do you have any theories regarding the reason for this marked disparity, such as the possibility of a hormonal influence? I concur that median sternotomy provides the best surgical exposure. The pleura generally may be left intact. (Slide) A year ago we evaluated our experience with anterior mediastinal tumors in childhood and found that tumors of the lymph nodes and of the thymus had many similar radiologic and clinical features. (Slide) Biopsy of the lymph nodes and the Tensilon® test were among the most helpful diagnostic methods, since we attempt to avoid thoracotomy in patients with primary tumors of the lymph nodes. Many of the patients in the reported cases of malignant thymoma have also had a second primary malignant lesion, suggesting that there may be a decrease in immune resistance. The long-term prognosis for patients with malignant thymoma has been poor regardless of the therapy. Recent reports by Namba and associates have shown that lymphocytes from patients with myasthenia gravis produced changes in motor end plates when injected into rats, whereas lymphocytes from normal human subjects did not. It is quite possible that thymocytes in t h e circulation after thymectomy may account for the persistence of myasthenia symptoms for many days or weeks. Doctor Mulder, would you care to speculate on the possible role of horse antihuman thymocyte serum in the management of patients with myasthenia, since it has been shown quite clearly that horse antihuman lyre-
205
Mulder, Herrmann, and Buckberg
phocyte serum may have many effects on lymphocytes in other conditions? Perhaps this has already been tried. Thomas C. Moore (Torrance, Calif): I have enjoyed this paper relating to the removal of the thymus for symptomatic considerations; however, there are p o t e n tial problems involved with the surgical removal of large masses of lymphoid tissue, such as the spleen and the thymus. We recently have observed significant changes in the metabolism of vasoactive substances (histamine and prostaglandin E z) in the rat thymus in response to organ allografting and simple surgical stress, as well as changes in the progression of age-related involution of the thymus. A study of the metabolism of vasoactive substances in myasthenic patients might be of considerable interest and value. I would like to ask the authors if they have observed any long-term immunologic defects and difficulties in these patients after thymectomy. Ralph D. Cressman (Palo Alto, Calif): Doctor Fonkalsrud has referred to the first case of thymectomy for myasthenia gravis. Very seldom does one have any association with the first case of anything, but this first patient of Doctor Blalock's was named Jeddy Hill and I had the pleasure of seeing her in 1938 with Doctor Blalock. She had undergone operation the year before and was well at that time. Robert W. damplis (Palo Alto, Calif): In the late 1940's I had the privilege of assisting Doctor Jim Clagett in many of the early thymectomies he performed. In those days we were forced to use large doses of Prostigmin ® postoperatively, and many of the patients were in iron lungs. Two days ago I performed thymectomy in a woman with myasthenia who had a vital capacity of 750 cc; her Mestinon ® requirements went from fifteen tablets per day to none, and I just removed the intratracheal tube. Obviously, we have come a long way in the management of this disease, and I agree with everything Doctor Mulder has said about it. I was hoping to hear something about the hazards of hemorrhage, pneumothorax, and inadvertently cut nerves when the gland is removed through the neck. My neurologist friends are making me feel like a sissy because I still split the sternum rather than use the cervi-
206
cal route. I wonder if Doctor Mulder would elaborate on the surgical approach so I can return home feeling a little better about the old way. Donald G. Mulder (closing): Let me answer Doctor Cressman first. The interesting thing about Doctor Blalock's case was that his treatment should not have worked, since he excised a thymic cyst but did not remove any of the remaining thymus. This indicates how poorly we understand this disease and the role that the thymus plays. In regard to the question Doctor Fonkalsrud raised, it is not known why the incidence of myasthenia gravis is relatively high in children and more prevalent in females. Possible hormonal factors in addition to the status of the immunologic system are probably involved. It is known that in childhood the thymus is large and there are large numbers of thymocytes; with age there is a slow regression. Even after thymectomy there is a slow disappearance of the thymocytes, which possibly explains the delay of weeks to many months before improvement or remission occurs. Regarding the transcervical approach for thymectomy, I spoke with Doctor Paul Kirchner who has been one of the strong advocates of this technic. He believes it is the method of choice for the usual patient with myasthenia but considers it inappropriate when thymoma is present because of the limited exposure and access. On occasion it has been necessary to convert the transcervical approach into a median sternotomy because of fragmentation of the gland or uncontrollable mediastinal bleeding. Doctor Jamplis, I think you can reassure your colleagues that the sternotomy approach is the most widely used and probably the safest, although we certainly should be willing to look critically at other methods if the facts warrant. As far as the immunologic aspects of this disease are concerned, we are now beginning a prospective study testing patients with a nonspecific chemical antigen dinitrochlorobenzene (DNCB), before and after operation at intervals to see whether the autoimmune system is altered in any way by thymectomy. I think this may offer some clues prognostically as well as possibly therapeutically.
The American Journal of Surgery
Donald G, Mulder, MD, Los Angeles, California Christian H e r r m a n n , M D , * Los Angeles, California Gerald D. B u c k b e r g , M D , * Los Angeles, California
T h e cause of m y a s t h e n i a gravis r e m a i n s obscure, as does the precise relationship of th e t h y m u s to this disorder. T h y m e c t o m y has b e e n a d v o c a t e d in selected p a t i e n t s because of the o b s e r v a t i o n t h a t in m a n y cases it m a y f a v o r a b l y alter t h e course of the disease |1-4]. However, the s p o n t a n e o u s f l u c t u a t i o n in severity of s y m p t o m s in p a t i e n t s with m y a s t h e n i a is well recognized, and only o b s e r v a t i o n s over an extended period of t i m e will afford an a c c u r a t e a p p r a i s a l of the influence of a n y medical or surgical intervention. In an effort to provide such i n f o r m a t i o n we are r e p o r t i n g our experience in 100 consecutive patients who have u n d e r g o n e t h y m e c t o m y a n d who h a v e h a d careful follow-up s t u d y up to sixteen years. Material and Methods
Clinical Data. Of 443 patients with confirmed myasthenia gravis seen at the UCLA Medical Center during the past sixteen years, 100 underwent thymectomy. Twenty-four were males and seventy-six were females; their ages ranged from two and a half to seventytwo years. (Figure 1.) Twenty-one patients were twenty years of age or younger, and fifteen were older than fifty years. From the Departments of Surgery and Neurology, UCLA Medical Center. Los Angeles, California, This work was supported in part by grants from the California Chapter of the MyastheniaGravis Foundation,Inc., and the Blalock Foundation. Reprint requests shouldbe addressed to Dr Donald G. Mulder, Department of Surgery (Thoracic), UCLA Medical Center, Los Angeles, Califor-
nia 90024.
Presented at the Forty-Fifth Annual Meeting of the Pacific Coast Surgical Association,Kaanapali,Maul, Hawaii, February 17-21. 1974.
* By invitation.
202
Seven patients had mild generalized myasthenia, including ocular involvement (class I); forty-one had moderately severe generalized disease, including some bulbar involvement (class II); thirty-five had acute, severe generalized and bulbar impairment (class III); seventeen had the later stages of the disease with marked generalized and bulbar involvement (class IV). Thymoma was found in twenty-seven patients. Eight of the eighteen tumors found in females were invasive, as were three of the nine found in males. Thymic hyperplasia was present in forty-seven patients and in eight involutional changes were noted. The thymus was interpreted as being normal in the remaining eighteen patients. Follow-up information obtained within the past year is available for ninety patients. The ten who could not be located had been followed up two months to ten years (average, four years). Their condition when last seen is included in the evaluation data. Surgical Considerations. Thymectomy was performed as an elective procedure and never during an acute relapse or myasthenic crisis. Patients were selected for operation if satisfactory medical control of the symptoms could not be achieved. Those with mild symptoms that were readily controlled by anticholinesterase drugs were not considered operative candidates unless chest roentgenograms (including laminograms) suggested the presence of mediastinal tumor. Patients with long-standing end stage myasthenia, especially in the older age group, also did not have surgical treatment. A median sternotomy was used to provide optimal exposure of the anterior mediastinum. This lessens the possibility of injury to the phrenic nerves or serious bleeding that may result when visibility in the operative field is compromised, as in the transcervical technic [5,6]. Additional disadvantages of the transcervical approach are that it cannot be used in the presence of
The American Journalof Surgery
Thymectomy for Myasthenia Gravis
tumor and that removal of the gland may be incomplete, which must be considered if response of the myasthenia is unsatisfactory after operation. Concomitant tracheostomy was performed in the presence of one or more of the following indications: (1) oropharyngeal weakness (bulbar), (2) previous respiratory complications, (3) previous myasthenic crisis, (4) a vital capacity of less than 2,000 cc. In patients in whom tracheostomy was not anticipated, a nasotracheal tube was inserted and usually left in place twelve to fortyeight hours. Thymic tumor was excised widely along with generous segments of contiguous pericardium and pleura. In one instance the invaded superior vena cava and the tumor were removed en bloc, and venous continuity was restored with a pericardial tube graft. Although the usual dose of anticholinesterase drug was given the morning of operation, no such medication was administered postoperatively because of the known increased sensitivity of these patients at this time. Furthermore, it is sometimes difficult to differentiate the symptoms of insufficient doses of medication from those of toxic doses; with control of the airway there is no necessity, except for patient comfort, to reinstitute theraPy. Results
The current status of the patients was evaluated in most instances by one of us (CH), but in some cases it was necessary to rely on information obtained by another physician or by telephone contact with the patient. Remission indicates minimal or no symptoms and no need for anticholinesterase drugs. Improvement implies a substantial decrease in preoperative symptoms and a sustained reduction in drug requirements. Of the seventy-three patients without tumor (Table I), fifty-two of the fifty-eight females (89 per cent) benefited from operation, as did ten of the fifteen males (66 per cent). The condition was not made worse by operation in any patient, but in six patients it was unchanged; five patients died. The response of the myasthenia to thymectomy could not be predicted on the basis of the histologic features of the nontumorous gland. Although thymic hyperplasia was the most common finding (in 64 per cent of the seventy-three specimens), the chance of a favorable result was no greater than that in the normal (25 per cent) or involuted (11 per cent) glands. Of the twenty-seven patients with thymic tumor (Table II), twelve of the sixteen females (75 per cent) benefited from operation, as did five of the eleven males (45 per cent). There was no change in the condition in two patients, but in one it was worse after operation; seven patients died.
Volume 128, August 1974
20
[ ] MALES (24) I
FEMALES (76)
15
~o
0-10
1%20 21-50 31~40 41-50 51-60 61-70 71-80 AGE,yr
Figure 1. The age and sex distribution of 100 patients undergoing thymectomy for myasthenia gravis.
The preoperative classification was a factor in predicting the surgical result in both sexes; those with less severe forms of the disease (classes I and II) had a better response than did those with more severe involvement (classes III and IV). (Table III.) Complete remission occurred in six of seven patients in class I (85 per cent), in fifteen of fortyone in class I1 (36 per cent), in seven of thirty-five in class III (20 per cent), and in two of seventeen in class IV (12 per cent). The over-all remission rate for the entire group of 100 patients was 30 per cent. Tracheostomy had been performed preoperatively or was performed concomitantly in fifty patients. Based on the indications stated previously, it was anticipated that none of the remaining fifty patients would require it. However, in six patients it was necessary to perform tracheostomy (over the endotracheal tube) within forty-eight hours after operation, a reflection of inaccurate preoperative assessment in these patients. Despite this, fortyfour patients were spared tracheostomy, a procedure some investigators have recommended routinely but which carries significant morbidity. Although the hospital stay was protracted because of the severity of disease in some patients, no serious complications were encountered in seventy-three patients. As would be anticipated, the majority of the postoperative problems were pulmonary, with significant atelectasis in seventeen patients and pneumonitis in four; miscellaneous problems, such as thrombophlebitis and urinary tract infection, occurred in six patients. Twelve patients died; two of these were operative deaths. An elderly diabetic patient died from gram-negative septicemia seven days postoperatively, and the second operative death was caused by massive hemorrhage during re-exploration for recurrent invasive thymoma.
203
Mulder, Herrmann, and Buckber9
TABLEI
Results of Thymectomy in Seventy-Three Myasthenic Patients without Tumor
Postoperative Status
Males
Females
Remission Improvement No change Deterioration Death Total
51 5~ 66% 3 0 2 15
21 31[ 89% 3 0 3 58
TABLE II
Results of Thymectomy in Twenty-Seven Myasthenic Patients with Tumor
Postoperative Status
Males
Females
Remission Improvement No change Deterioration Death Total
1'[ 4/45% 1 0 5 11
3'[ 9,/ 75% 1 1 2
TABLE III
Preoperative Classification i
I, Ill IV
16
Incidence of Complete Remission after Thymectomy Correlated with Sex and Preoperative Classification
Sex and Number of Patients M
3
F M F M F M
4 8 33 9 26 4 13
F
Postoperative Remission
27_85% 4_1 4-1_36% 1tJ -30% 17_20o/o 6J 0"]
2J
Eight patients died two and a half months to six years after thymectomy from relapse of the myasthenia with pulmonary complications. The remaining two patients died of unrelated causes, one from coronary thrombosis at two years and the other from congestive heart failure at seven years. Of interest is the fact that thymic tumor had been excised in seven of the twelve patients who died. Comments
Despite our lack of knowledge concerning the pathophysiology of myasthenia gravis, it is clear that thymectomy favorably alters the course of the disease in many cases. Because of this, we have liberalized our indications somewhat and tend to operate earlier in the course of the disease if the response to medical treatment is unsatisfactory.
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Although approximately 35 to 40 per cent of patients have periods of spontaneous improvement, this cannot compare with the prognosis after thymectomy, especially in females. Successful management of these patients, however, requires close cooperation between the neurologist, surgeon, and anesthetist, as well as intensive postoperative care by capable nurses and physiotherapists. It is very important that all who participate in the care of patients with myasthenia be aware of the responses that are unique to these patients: (1) marked sensitivity to curare-like drugs, (2) rapid fatigability of striated muscle even when the disease is controlled, (3) inability to convey anxiety due to hypoxia in those with impaired facial muscle strength, (4) susceptibility to the myasthenic weakness potentiated by certain "-mycin" type antibiotics, (5) enhanced sensitivity to anticholinesterase drugs immediately after operation, which is further complicated by the difficulty in differentiating crisis due to drug toxicity from that due to insufficient medication. Anticipation and prompt recognition and treatment of impending problems will influence significiantly the outcome in many of these seriously ill patients. Since myasthenia gravis is often considered an autoimmune disorder, ACTH and adrenal corticosteroids should be tried in an effort to suppress immunologic responsiveness. In our limited experience with twenty-five patients (ten of whom are included in this series), all seemed to derive some benefit from the administration of steroids, although the action appeared to be suppressive rather than curative since no remission persisted when prednisone was discontinued after six months. In addition, significant complications are associated with the use of steroids; therefore, we now reserve alternate-day prednisone therapy for those patients with generalized incapacitating myasthenia who do not respond satisfactorily to anticholinesterase treatment, thymectomy, or both. At the present time we are looking at the effect thymectomy may have on the immune response in myasthenic patients by testing them with the nonspecific chemical antigen dinitrocholorobenzene (DNCB) [7] before and at intervals after operation. It is hoped that this assessment of changes in immunologic responsiveness may be of value in predicting the end result after operation and may have therapeutic implications in the use of other drugs. All patients with thymic tumor are considered candidates for thymectomy, even if the myasthenia is mild and would otherwise not warrant opera-
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Thymectomy for MyastheniaGravis
tion. This is justified not only because of the freq u e n t l y favorable effect on the myasthenia, b u t more i m p o r t a n t l y because of the very real danger of later t u m o r involvement of mediastinal structures such as the superior vena cava and innominate vein. Since even " m a l i g n a n t " t u m o r s are usually locally invasive, wide en bloc resection is usually curative. If only incomplete resection of the t u m o r is possible, postoperative irradiation should be given. We have also had two patients with invasive t h y m o m a who a p p e a r e d to benefit from a combination of a l t e r n a t e - d a y prednisone and cyclophosphamide. One additional p a t i e n t with chronic lymphocytic leukemia also showed mild i m p r o v e m e n t in the m y a s t h e n i a after cyclophosphamide treatment. T h e s e newer agents for use in patients with nonresectable t h y m i c t u m o r w a r r a n t f u r t h e r trial. T h e results after t h y m e c t o m y as r e p o r t e d in this p r e s e n t series confirm our previous experience [8]. We are convinced t h a t when patients are selected for operation carefully and are managed properly, objective i m p r o v e m e n t in the m y a s t h e n i a will occur in the majority of cases.
Summary T h y m e c t o m y was p e r f o r m e d in 100 patients with m y a s t h e n i a gravis who were selected for operation because of poor medical control of the disease or the presence of t h y m i c tumor. Significant i m p r o v e m e n t occurred in fifty-two of the fiftyeight females who did not have t h y m o m a (89 per cent) and in ten of the fifteen males in the same category (66 per cent). Of the twenty-seven patients who had t h y m i c tumor, twelve of the sixteen females were improved (75 per cent), as were five of the eleven males (45 per cent). T h e r e were two operative and ten late deaths during a follow-up period of sixteen years. It is concluded t h a t in selected patients with m y a s t h e n i a gravis, thymect o m y favorably influences the course of the disease in most cases.
References 1. Keynes G: Surgery of the thymus gland. Lancet 2: 1197, 1954. 2. Schwab RS, Wilkins EW, Head JM, Pontoppidan H, Viets HR: Thymectomy in myasthenia gravis. JAMA 187: 850, 1964. 3. Perlo VP, Poskanzer DC, Schwab RS, Viets HR, Osserman KE, Genkins G: Myasthenia gravis: evaluation of treatment in 1355 patients. Neurology 16: 431, 1966. 4. Buckberg GD, Herrmann C, Dillon JB, Mulder DG: A further evaluation of thymectomy for myasthenia gravis. J Thorac Cardiovasc Surg 53: 401, 1967. 5. Kirschner PA, Osserman KE, Kark AE: Studies in myasthenia
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gravis, transcervical total thymectomy. JAMA 209: 906, 1969. 6. Crile G Jr: Thymectomy through the neck. Surgery 59: 213, !966. 7. Eilber FR, Morton DL: Impaired immunologic reactivity and recurrence following cancer surgery. Cancer 25: 362, 1970. 8. Mulder DG, Braitman H, Li Wei-i: Surgical management in myasthenJa gravJs. J Thorac Cardiovasc Surg 63: 105, 1972.
Discussion Eric W. Fonkalsrud (Los Angeles, Calif): Doctor Mulder has provided us with a summary of a large clinical experience with thymectomy for myasthenia gravis. Since the serendipitous observation by Blalock thirtyfive years ago that thymectomy relieved the symptoms of a myasthenic patient, the literature has been replete with contradictory reports regarding the role of thymectomy in the treatment of this condition. The unpredictable course of myasthenia, including the not infrequent spontaneous remissions, has made evaluation even more confusing. However, Doctor Mulder's study clearly shows that the majority of patients with myasthenia who do not have tumor experience complete remission of symptoms or show considerable clinical improvement after ablation of the thymus, albeit the reason for the improvement is as mysterious as is the cause of myasthenia in the first place. It is of interest that myasthenia is twenty times more common in females under the age of twenty years than in males. Doctor Mulder, do you have any theories regarding the reason for this marked disparity, such as the possibility of a hormonal influence? I concur that median sternotomy provides the best surgical exposure. The pleura generally may be left intact. (Slide) A year ago we evaluated our experience with anterior mediastinal tumors in childhood and found that tumors of the lymph nodes and of the thymus had many similar radiologic and clinical features. (Slide) Biopsy of the lymph nodes and the Tensilon® test were among the most helpful diagnostic methods, since we attempt to avoid thoracotomy in patients with primary tumors of the lymph nodes. Many of the patients in the reported cases of malignant thymoma have also had a second primary malignant lesion, suggesting that there may be a decrease in immune resistance. The long-term prognosis for patients with malignant thymoma has been poor regardless of the therapy. Recent reports by Namba and associates have shown that lymphocytes from patients with myasthenia gravis produced changes in motor end plates when injected into rats, whereas lymphocytes from normal human subjects did not. It is quite possible that thymocytes in t h e circulation after thymectomy may account for the persistence of myasthenia symptoms for many days or weeks. Doctor Mulder, would you care to speculate on the possible role of horse antihuman thymocyte serum in the management of patients with myasthenia, since it has been shown quite clearly that horse antihuman lyre-
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phocyte serum may have many effects on lymphocytes in other conditions? Perhaps this has already been tried. Thomas C. Moore (Torrance, Calif): I have enjoyed this paper relating to the removal of the thymus for symptomatic considerations; however, there are p o t e n tial problems involved with the surgical removal of large masses of lymphoid tissue, such as the spleen and the thymus. We recently have observed significant changes in the metabolism of vasoactive substances (histamine and prostaglandin E z) in the rat thymus in response to organ allografting and simple surgical stress, as well as changes in the progression of age-related involution of the thymus. A study of the metabolism of vasoactive substances in myasthenic patients might be of considerable interest and value. I would like to ask the authors if they have observed any long-term immunologic defects and difficulties in these patients after thymectomy. Ralph D. Cressman (Palo Alto, Calif): Doctor Fonkalsrud has referred to the first case of thymectomy for myasthenia gravis. Very seldom does one have any association with the first case of anything, but this first patient of Doctor Blalock's was named Jeddy Hill and I had the pleasure of seeing her in 1938 with Doctor Blalock. She had undergone operation the year before and was well at that time. Robert W. damplis (Palo Alto, Calif): In the late 1940's I had the privilege of assisting Doctor Jim Clagett in many of the early thymectomies he performed. In those days we were forced to use large doses of Prostigmin ® postoperatively, and many of the patients were in iron lungs. Two days ago I performed thymectomy in a woman with myasthenia who had a vital capacity of 750 cc; her Mestinon ® requirements went from fifteen tablets per day to none, and I just removed the intratracheal tube. Obviously, we have come a long way in the management of this disease, and I agree with everything Doctor Mulder has said about it. I was hoping to hear something about the hazards of hemorrhage, pneumothorax, and inadvertently cut nerves when the gland is removed through the neck. My neurologist friends are making me feel like a sissy because I still split the sternum rather than use the cervi-
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cal route. I wonder if Doctor Mulder would elaborate on the surgical approach so I can return home feeling a little better about the old way. Donald G. Mulder (closing): Let me answer Doctor Cressman first. The interesting thing about Doctor Blalock's case was that his treatment should not have worked, since he excised a thymic cyst but did not remove any of the remaining thymus. This indicates how poorly we understand this disease and the role that the thymus plays. In regard to the question Doctor Fonkalsrud raised, it is not known why the incidence of myasthenia gravis is relatively high in children and more prevalent in females. Possible hormonal factors in addition to the status of the immunologic system are probably involved. It is known that in childhood the thymus is large and there are large numbers of thymocytes; with age there is a slow regression. Even after thymectomy there is a slow disappearance of the thymocytes, which possibly explains the delay of weeks to many months before improvement or remission occurs. Regarding the transcervical approach for thymectomy, I spoke with Doctor Paul Kirchner who has been one of the strong advocates of this technic. He believes it is the method of choice for the usual patient with myasthenia but considers it inappropriate when thymoma is present because of the limited exposure and access. On occasion it has been necessary to convert the transcervical approach into a median sternotomy because of fragmentation of the gland or uncontrollable mediastinal bleeding. Doctor Jamplis, I think you can reassure your colleagues that the sternotomy approach is the most widely used and probably the safest, although we certainly should be willing to look critically at other methods if the facts warrant. As far as the immunologic aspects of this disease are concerned, we are now beginning a prospective study testing patients with a nonspecific chemical antigen dinitrochlorobenzene (DNCB), before and after operation at intervals to see whether the autoimmune system is altered in any way by thymectomy. I think this may offer some clues prognostically as well as possibly therapeutically.
The American Journal of Surgery