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Ann Thorac Surg 1999;67:1568-1571
© 1999 The Society of Thoracic Surgeons

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Original Articles

Prognostic factors for myasthenia gravis treated by thymectomy: review of 61 cases

^a Department of General and Digestive Surgery, La Paz University Hospital, Madrid, Spain
^b Department of Thoracic Surgery, La Paz University Hospital, Madrid, Spain

Accepted for publication January 14, 1999.

Address reprint requests to Dr Nieto, C/Don Ramón de la Cruz 97, 6° B, 28006 Madrid, Spain
e-mail: iprieto{at}intermic.com

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
Background. Medical treatment for myasthenia gravis (MG) involves the use of anticholinesterase agents, immunosuppressive drugs, plasmapheresis, and gammaglobulin. However, these agents result in a complete clinical remission rate as low as 15%. As a consequence, thymectomy, preferably by transsternal approach, has become increasingly accepted as an efficacious procedure for MG, with reported complete clinical remission rates as high as 80%.

Methods. We have the clinical records of 61 patients diagnosed with MG at La Paz University Hospital, Madrid, Spain, from January 1977 to December 1994. All patients underwent thymectomy. The purpose of this investigation was to determine the major prognostic factors predicting MG outcome after operation.

Results. Our results indicate that patients with a length of the disease from onset to operation shorter than 8 months have the best prognosis. Ossermann stages I and III are also associated with higher complete clinical remission rates. In contrast, neither age nor sex were found to be significantly related to MG outcome after thymectomy, although female patients have better prognosis than men, and the younger the patient the more likely is complete clinical remission. Pathologic findings after the operation were not found to be of prognostic value either.

Conclusions. We conclude that thymectomy is a beneficial procedure for MG patients, with a complete clinical remission rate of 46% at 5 years postoperatively in our series. Therefore we advocate thymectomy for MG patients as early as possible in the course of disease because time elapsed from diagnosis to operation is the main determinant of the outcome.

	Introduction

Top Abstract Introduction Material and methods Results Comment References

 
Myasthenia gravis (MG) is an autoimmune disorder resulting from the binding of antibodies to acetylcholine receptors, which gives rise to weakness and fatigue of the voluntary musculature [1]. Medical treatment involves the use of anticholinesterase agents, immunosuppressive drugs, plasmapheresis, and gammaglobulin, with reported complete clinical remission rates (CCRRs) as low as 15%. Accordingly, thymectomy has become an increasingly accepted procedure for treatment of MG, as it can achieve CCRRs as high as 80% in accordance with most of the reports published in the literature. The purpose of the present investigation was to assess the results obtained by thymectomy for MG in a series of 61 patients as well as to determine the major prognostic factors influencing the outcome after operation.

	Material and methods

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We have reviewed the clinical records from 61 patients diagnosed with MG at La Paz University Hospital, Madrid, Spain, from January 1977 to December 1994. All patients underwent thymectomy at the Department of Thoracic Surgery. Ossermann classification was used for staging, with patients’ clinical stage distribution as follows: grade I (ocular involvement); grade IIa (mild generalized ocular myasthenia); grade IIb (moderate generalized myasthenia involving bulbar musculature); grade III (acute fulminant form); and grade IV (severe late myasthenia).

Midtranssternal incision was the surgical approach for 58 patients and transcervical incision was performed in 3. In all cases thymectomy was followed by removal of neighboring fat tissue. In all cases, complete thymus excision through extracapsular approach was performed. Neighboring fat was also excised, extending removal as far as the neck to the level of the thyroid gland.

Measurements of thymectomy outcome were performed according to Milichat and Dodge criteria as follows: A, complete remission of symptoms; B, significant clinical improvement with medication; C, moderate clinical improvement with medication; D, unchanged stable clinical status; and E, clinical worsening. Kaplan-Meier survival curves were used to determine time to complete clinical remission (CCR).

Postoperatively, all patients started medical treatment with one or more of the following therapies: anticholinesterase agents and corticosteroids.

Prognostic factors presumably influencing CCR after thymectomy in our study were sex, age, pathologic findings from thymus study after operation, clinical status according to Ossermann classification, and time elapsed from diagnosis to operation. Univariate and multivariate analyses by Cox stepwise regression model were made. Data statistical analysis was conducted by the program BMDP (Statistical Software, version 7.0, 1993) (BMDP Statistical Software, Inc, Chicago, IL).

	Results

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Thirty-eight patients (62.2%) were women and 23 (37.7%) were men aged between 11 and 65 years. Application of Ossermann classification yielded the following: grade I, 2 patients; grade IIa, 19; grade IIb, 38; and grade III, 2. No patients met the criteria for grade IV. Before thymectomy 25 patients were on anticholinesterase agents, 5 on corticosteroids, and 2 on plasmapheresis, with the remaining patients having been treated with a combined regimen of these drugs (Table 1). Time elapsed from diagnosis to operation was 2 years in 49 patients (80.3%) and longer than 2 years in 12 (19.6%).

Postoperative pathologic study of the thymus revealed hyperplasia in 31 cases (50.8%), thymoma in 11 (18.03%), thymic involution in 9 (14.7%), thymolipoma in 6 (9.8%), and thymus with unremarkable findings in 4 (6.5%).

Two patients (3.2%) died within 2 and 6 years postoperatively, one of an invasive thymoma and the other one of bronchopneumonia, respectively. The patient who died of an invasive thymoma had a tumor with predominantly epithelial cells. Follow-up ranged from 8 months to 19 years (Fig 1). According to Milichat and Dodge criteria, 29 patients (47.5%) had CCR, 28 (45.9%) significant clinical improvement, and 4 (6.5%) moderate clinical improvement. With respect to correlation of the studied prognostic factors to CCR, it is noteworthy that 18 female patients achieved CCR as compared with 11 men, but this difference did not reach statistical significance (p = 0.87).

View larger version (22K): [in this window] [in a new window]   Fig 1. Outcome of MG patients over the postoperative follow-up.

Concerning pathologic findings, 16 patients (41.6%) with hyperplastic gland achieved CCR as compared with 2 (18.1%) with thymoma, 5 (55.5%), with involuted thymus, 4 (66.6%) with thymolipoma, and 2 (50%) with thymus with unremarkable pathologic findings. These differences did not reach statistical significance (p = 0.65).

With regard to length from onset to operation, 17 patients with a length shorter than 8 months had CCR (range, 1 to 20 months). Time from diagnosis to operation less than 8 months was strongly associated with CCR, this difference being statistically significant (p = 0.03). Moreover, this was the only single prognostic factor in our study proving statistically significant by both univariate and multivariate analyses.

As to Ossermann clinical staging, among patients reaching CCR, 2 were stage I; 3, stage IIA; 15, stage IIB; and 1, stage III. Patients in stage I and III were most likely to reach CCR, this difference being statistically significant (p = 0.029).

Therefore, our results clearly indicate that time from diagnosis to operation shorter than 8 months and Ossermann stages I and III are the only prognostic factors among those factors taken into account in our study that undoubtedly influence MG outcome after thymectomy. Sex, age, and pathology, in turn, seem not to be significantly associated with outcome, although female and younger patients are more likely to achieve CCR after the operation.

	Comment

Top Abstract Introduction Material and methods Results Comment References

 
Myasthenia gravis is an autoimmune disease impairing neuromuscular transmission because of the binding of antibodies to acetylcholine receptors. T cells and humoral components of the immune system are known to be involved in the pathophysiologic mechanisms [2, 3]. The condition may affect individuals in any age group, with a peak incidence in women in their thirties and forties and in men aged between 60 and 70 [1]. Onset is characteristically ill-defined, with weakness and fatigue of muscles being the most frequent presenting complaints. Symptomatology exacerbation is caused by stress, exercise, and menstruation. Transient improvement of symptoms is occasionally observed after sleep and rest. Initially involved site is most often the eye, with about 80% of patients experiencing generalized muscular weakness [1].

Myasthenia gravis diagnosis is made on clinical grounds as well as by positive responses to the edrophonium chloride test and single-fiber electromyography. In 85% of patients there is evidence of positive values to antiacetylcholine receptor antibodies, but this titer is not correlated to symptomatology severity [1, 3].

Medical treatment for MG consists of anticholinesterase agents, such as pyridostigmine bromide, which have proved efficacious for neuromuscular transmission improvement; corticosteroids, immunosuppressives, and plasmapheresis for serum antibody concentration reduction. Nevertheless, a CCRR as low as 15% after medical treatment has been reported.

Since Blalock first published in 1941 on a series of MG patients undergoing thymectomy (as cited in DeFilippi and colleagues [4]), this surgical treatment has become an increasingly accepted procedure, resulting in CCRRs as high as 42% and clinical improvement in up to 94% of cases [3]. In our series of MG patients, CCRR at 5 years postoperatively was 46%.

Several explanations for the mechanisms through which thymectomy dramatically influences MG outcome have been proposed. On the one hand, the thymus is thought to contribute to acetylcholine receptor antibody production [1, 5, 6] because the gland is known to contain certain muscular cells exhibiting acetylcholine receptors on their cell surface, and, on the other, it has been noted that abnormal amounts of cells are produced in the thymus with a subsequent T4/T8 fraction increment found in MG patients. Furthermore, these patients characteristically exhibit increased thymopoietin hormone levels [5].

In an earlier series of MG patients, a transcervical approach for thymectomy was advocated because it resulted in fewer postoperative complications and less mortality as compared with a transsternal approach [7]. However, the latter, originally advocated by Blalock, has been shown to result in a higher CCRR and more remarkable clinical improvement, presumably because of removal of fat and tissue surrounding the thymus, which can be more easily performed with the transsternal than with the transcervical approach [3]. To this discussion, it is noteworthy to take into account that ectopic thymic tissue has been found in up to 72% of the fat from that removed anterior to the mediastinum. The important prognostic role played by this tissue in thymectomy success is now fully recognized [1, 8]. Accordingly, midtranssternal approach is the favored procedure for thymectomy in our hospital.

A number of factors influencing success of thymectomy for MG have been reported. Thus, female patients and those younger than 40 years have been said to have higher CCRRs, but our results indicate that neither sex nor age are significantly associated with outcome, although the younger the patient, the more likely he or she is to achieve CCR. This lack of statistical significance for sex and age is in accordance with results reported by other authors [9]. Again, findings from pathologic study of thymus after thymectomy have been reported to closely correlate to outcome. Thus, hyperplastic thymus has been found in 50.8% of cases, thymic involution in 14.7%, thymoma in 18%, thymolipoma in 9.8%, and unremarkable pathologic findings in 7%. Hyperplastic thymus has been associated with the highest CCRR [10], whereas MG patients with thymoma seem to have the lowest CCRRs and more postoperative morbidity [7, 11]. Patients with invasive (Masaoka stages II and IV) and epithelial thymomas have been reported to have the lowest CCRRs and survival rates [6, 12, 13]. Although it has been reported that a better outcome after thymectomy for MG patients occurs in Ossermann stages I and II [3], we found a higher CCRR in patients in stages I and III [1, 9, 14].

Also it has said that the shorter the time from diagnosis to operation the better is the outcome after thymectomy [7]. Our results fully agree with this finding. Thus, we observed CCR to be most likely in those patients whose disease had a duration from diagnosis to operation shorter than 8 months. Because it was the only single prognostic factor detected by both univariate and multivariate analyses, we conclude that time from diagnosis to operation is by far the most important single determinant for MG outcome after thymectomy.

Finally, it should be kept in mind that MG with ocular involvement remains a controversial indication for thymectomy because unsatisfactory results have often been reported. Yet it is our belief that thymectomy should be tried in all patients with MG with ocular involvement, because two thirds of them will develop generalized disease and thymectomy is likely to result in positive response in a far from negligible number of cases [9]. In fact, the 2 patients with ocular MG in our series remain in CCR at 6 and 8 years postoperatively.

Therefore, our results clearly indicate that time from diagnosis to operation shorter than 8 months and Ossermann stages I and III are the only prognostic factors among those taken into account in our study that undoubtedly influence MG outcome after thymectomy. Sex, age, and pathology, in turn, seem not to be significantly associated with outcome, although female and younger patients are more likely to achieve CCR after the operation.

In summary, on the basis of our results we conclude that thymectomy is a beneficial procedure for MG patients, with a CCRR of 46% at 5 years postoperatively in our series, and that the length of the disease from onset to operation is by far the main prognostic factor, with a length shorter than 8 months strongly associated with excellent prognosis.

	References

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