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Ann Thorac Surg 2004;77:1745-1750
© 2004 The Society of Thoracic Surgeons

Original article: general thoracic

Experience with programmed steroid treatment with thymectomy in nonthymomatous myasthenia gravis

Shunsuke Endo, MDa*, Tsutomu Yamaguchi, MDa, Noriko Saito, MDa, Shinichi Otani, MDa, Tsuyoshi Hasegawa, MDa, Yukio Sato, MDa, Yasunori Sohara, MDa

a Division of General Thoracic Surgery, Department of Surgery, Jichi Medical School, Tochigi, Japan

Accepted for publication October 16, 2003.

* Address reprint requests to Dr Endo, Division of General Thoracic Surgery, Department of Surgery, Jichi Medical School, Minamikawachi-machi, Kawachi-gun, Tochigi 329-0498, Japan.
e-mail: tcvshun{at}jichi.ac.jp


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Comment
 References
 
BACKGROUND: The benefit of thymectomy in myasthenia gravis management is recognized but the perioperative course can fluctuate. The goal of this study was to assess the feasibility and clinical benefit of dose-escalated steroid therapy with thymectomy for nonthymomatous myasthenia gravis.

METHODS: We reviewed the records of 69 myasthenia gravis patients who were followed up after undergoing transsternal thymectomy with extended anterior mediastinal dissection in our hospital between 1976–2000. Forty-eight patients in the programmed treatment group who had dose-escalated and de-escalated steroid therapy during the perioperative period comprised 17 patients with ocular myasthenia gravis and 31 patients with generalized myasthenia gravis. Clinical benefits and clinical remission, which was diagnosed when the patients were symptom-free without medications for at least 1 year, were compared with those of 21 patients in the occasional treatment group who received medications occasionally over the perioperative period.

RESULTS: Postoperative respiratory failure and myasthenic crisis did not occur in the programmed treatment group but did occur in 6 patients in the occasional treatment group. Remission rates in the programmed treatment group (mean follow-up, 6.4 years) were 30% at 3 years, 38% at 5 years, and 46% at 10 years; rates in the occasional treatment group (mean follow-up, 9.6 years) were 25% at 3 years, 25% at 5 years, and 45% at 10 years.

CONCLUSIONS: Programmed steroid therapy in patients with nonthymomatous myasthenia gravis is feasible and it provides clinical benefit when fluctuating symptoms occur during the perioperative period.


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Comment
 References
 
Since the report of Blalock and associates in 1939 [1] the value of thymectomy for the treatment of myasthenia gravis (MG) has been well known to surgeons and neurologists. However the clinical condition of the patient can remain unstable not only during the perioperative period but also in the several months to years after thymectomy [2]. Immunosuppressive therapy by alternate-day administration of steroids before thymectomy was shown by Yamaguchi and associates to help stabilize the patient's condition afterward [3]. Patients have undergone thymectomy after programmed dose-escalated prednisolone treatment in our department since 1991. We reviewed the records of these patients to evaluate perioperative morbidity and mortality, adverse effects of steroid treatment, and efficacy of the programmed treatment in terms of short- and long-term clinical outcome. The results were compared with those of patients who underwent thymectomy with occasional medical treatment mainly before 1991.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Comment
 References
 
One-hundred twenty-nine patients underwent thymectomy for MG between 1976 and the end of 2000 in our surgical division. We selected for review 69 nonthymomatous MG patients who underwent transsternal thymectomy with extended anterior mediastinal dissection and were followed up in our hospital. MG patients who underwent simple thymectomy and thymomatous MG patients were excluded from the study. Patients were divided into two groups on the basis of perioperative treatment: a programmed treatment group that was given the programmed dose-escalated steroid treatment described below and an occasional treatment group that was treated before and after surgery as needed with different combinations of anticholinesterase agents and steroids. The programmed treatment group comprised 48 patients and the occasional treatment group comprised 21 patients. The average alternate-day dose of prednisolone in the programmed treatment group was 94 ± 12 mg. Abnormal blood sugar on the afternoon of the prednisolone administration day was marked in 4 patients in the programmed treatment group. The blood sugar of these patients was controlled with insulin or by reducing the dose of the prednisolone. Only 1 patient in the programmed treatment group required anticholinesterase agents occasionally when symptoms fluctuated before the operation. In the occasional treatment group, 16 patients received anticholinesterase agents, 4 patients received no anticholinesterase agent, and 1 patient received pulsed steroid therapy with anticholinesterase agent. Most patients in the programmed treatment group underwent thymectomy in our department after 1990. Most patients in the other group underwent thymectomy before 1991 (Figure 1).



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  		Fig 1. Number of patients with nonthymomatous myasthenia gravis undergoing transsternal thymectomy with extended anterior mediastinal dissection at Jichi Medical School, 1976–2000. (Programmed Tx = programmed steroid treatment; Occasional Tx = occasional medical treatment.)

 
We reviewed the patient's medical records for preoperative treatment, operative morbidity, mortality, and short- and long-term clinical outcome on the basis of symptoms and medications. Data were obtained by meticulous review of the hospital's and physician's inpatient and outpatient records, of interviews with the patients and their neurologists, and of patient's responses to a written questionnaire administered at the end of 2002.

Programmed steroid treatment
All patients with no septic ulcer observed gastroscopically were given an H2 blocker. Prednisolone was given every other day starting with 5 mg. Dose escalation in 5-mg steps continued up to 1.5 mg/kg (maximum 120 mg). Care was taken not to exacerbate the disease. When fluctuating symptoms occurred during dose escalation, low-dose steroid was also administered on the nonprednisolone administration days. Human insulin was given to patients with a blood sugar abnormality. On the day of surgery and on the first postoperative day, 300–500 mg of water-soluble hydrocortisone was given intravenously. From the third postoperative day, 1.5 mg/kg of prednisolone was administered orally every other day. The dose was reduced 5–10 mg per month according to clinical symptoms.

Transsternal thymectomy with extended anterior mediastinal dissection
Transsternal thymectomy was performed in both groups via median sternotomy under general anesthesia by a few skilled surgeons in our department. The mediastinal fatty tissue, including the thymus, bilateral pleura, and superior mediastinal lymph nodes around the larynx and trachea, was resected completely from the lower end of the thyroid to the diaphragm and laterally from the bilateral mediastinal pleura to the phrenic nerves.

Definition of response
Patients were evaluated in both groups in terms of medications and symptoms every year after thymectomy. For patients who underwent programmed steroid therapy the dosage was reviewed from the outpatient records every year after thymectomy. Patients who were symptom-free and did not require any further medication for at least 1 year were considered in remission, ie, complete stable remission according to the Jaretzki classification system [4]. Patients who died during follow-up were considered permanent nonresponders regardless of the cause of death.

Data analysis
Postoperative respiratory insufficiency with or without MG crisis was noted when a patient underwent mechanical ventilation for more than 24 hours during the first 3 days after surgery. Wound complication was noted when wound infection or dehiscence occurred.

Outcome was assessed from the medication records every year after thymectomy. Short-term outcome was evaluated from these records 3 years after thymectomy and long-term outcome was evaluated 5 and 10 years after thymectomy.

The data are expressed as mean and standard deviation. For analysis of differences in categorical variables between the two groups, the {chi}2 test was used and for analysis of differences in continuous variables the Student's t test was used. To identify predictors of postoperative respiratory insufficiency and of short- and long-term clinical remission, multivariate analysis was performed by forward stepwise logistic regression with programmed treatment, age, time to surgery, pathologic findings, severity of MG, and the year of surgery used as explanatory variables. A p value of 0.05 or less was considered significant.


   Results
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 Abstract
 Introduction
 Patients and methods
 Results
Comment
 References
 
Clinical course in the two study groups
Patient characteristics are shown per group in Table 1. The severity of the disease, age, sex, time to surgery, and complications including collagen disease and thyroiditis did not differ statistically between the two groups. The time to surgery in patients in the programmed treatment group with ocular MG was shorter than that in the occasional treatment group but the difference was not statistically significant (p = 0.2493).


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  		Table 1. Patient Characteristics

 
Operative morbidity and mortalityTable 2
No operative death occurred (Table 2). No patient in the programmed treatment group experienced respiratory insufficiency; 6 patients in the occasional treatment group experienced respiratory insufficiency. A myasthenic crisis occurred in 5 patients and resolved with anticholinesterase agents. Pneumonia occurred in 1 patient and resolved with antibiotic agents. Respiratory failure occurred statistically more often in the occasional treatment group than in the programmed treatment group (p = 0.0005). When programmed treatment and other preoperative variables were entered into a forward stepwise logistic regression model to identify independent predictors of postoperative respiratory insufficiency, programmed steroid treatment was found to be the largest impact (Table 3). One patient in the programmed-treatment group had a neck wound infection caused by methicillin-resistant S. aureus that was resolved with open drainage.


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  		Table 2. Operative Morbidity

 

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  		Table 3. Multivariate Analysis of Preoperative Variables Associated With Postoperative Respiratory Insufficiency

 
Postoperative treatment
Among the 48 patients in the programmed treatment group, 16 were weaned from medications within 2 years after thymectomy and 13 had complete remission at 3 years after thymectomy. Among the 21 patients in the occasional treatment group, 8 required steroid administration due to no clinical improvement after thymectomy. Acetylcholinesterase inhibitor alone was given to 13 patients in the occasional treatment group, 5 of whom were completely weaned from medications 3 years after thymectomy.

Remission
One patient in the programmed treatment group died of respiratory failure at 6 years and 1 died of leukemia at 5 years. One patient in the occasional treatment group died of respiratory failure at 3 years. Thirty-two patients in the programmed treatment group and 20 patients in the occasional treatment group were followed up for 5 years. Thirteen patients in the programmed treatment group and 20 patients in the occasional treatment group were followed up for 10 years. Mean follow-up was 6.4 years in the programmed treatment group and 9.6 years in the occasional treatment group when 10 years was used as the cutoff point. Remission occurred in 13 of 44 patients (30%) in the programmed treatment group at 3 years, in 12 of 32 patients (38%) at 5 years, and in 6 of 13 patients (46%) at 10 years. In the other group, remission occurred in 5 of 20 patients (25%) at 3 years, in 5 of 20 patients (25%) at 5 years, and in 9 of 20 patients (45%) at 10 years (Fig 2A). Four patients in the occasional treatment group who underwent steroid therapy because of fluctuating symptoms or refractory MG after thymectomy achieved remission thereafter. Among patients with generalized MG, remission occurred in 7 of 28 patients (25%) at 3 years after thymectomy, in 6 of 20 patients (30%) at 5 years, and in 7 of 14 patients (50%) at 10 years. Remission in the occasional treatment group occurred in 4 of 14 patients (29%) at 3 years, in 4 of 14 patients (29%) at 5 years, and in 4 of 8 patients (50%) at 10 years (Fig 2B). Among patients with ocular MG, remission in the programmed treatment group occurred in 6 of 16 patients (38%) at 3 years after thymectomy, in 6 of 12 patients (50%) at 5 years, and in 2 of 5 patients (40%) at 10 years. In the other group, remission occurred in 1 of 6 patients (17%) at 3 years, in 1 of 6 ocular MG patients (17%) at 5 years, and in 2 of 6 patients (33%) at 10 years (Fig 2C).



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  		Fig 2. Annual changes in the percentage of patients in remission according to severity of myasthenia gravis (MG). (A) Annual changes in the percentage of patients in remission. (B) Annual changes in the percentage of patients with generalized MG in remission. (C) Annual changes in the percentage of patients with ocular MG in remission. (Programmed Tx = programmed steroid treatment; Occasional Tx = occasional medical treatment.)

 
No independent predictors of short- and long-term clinical remission were found in the forward stepwise regression model. The programmed steroid treatment was the largest impact as a predictor for clinical remission at 3 and 5 years with ocular MG but it was insignificant.


   Comment
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 Abstract
 Introduction
 Patients and methods
 Results
 Comment
References
 
Effective treatment for MG represents one of the great medical triumphs of the last half-century. MG is a disease involving impaired neuromuscular transmission caused by immunologic abnormalities and presynaptic disturbances. The symptoms of MG result from the destruction of the acetylcholine receptor (AchR) [5] which appears to be a consequence of both T cell and humorally mediated activities of the immune system [6]. Effective treatments were developed from 1950–1970 including acetylcholinesterase inhibitors, prednisolone, and other immunosuppressive medications. In the 1970s thymectomy became an increasingly accepted form of therapy. In the 1980s both plasma exchange and intravenous immunoglobulin were used to treat severe MG [7]. However no definite guidelines for MG treatment have been established. The following issues must be addressed before guidelines can be established: surgical procedure, surgical indications, timing of surgery, and the patient's condition including the severity of MG, age, the presence of thymoma, the interval from the onset of symptoms to treatment, and the different treatment courses [8].

Most investigators have concluded that the results of thymectomy are much better than the results of medical treatment alone [6, 8–14]. Few patients with MG are now treated for long without surgery. The exact mechanism by which the thymus affects the course of MG in unclear. It is likely that thymectomy removes a source of autosensitization and depletes the specific T-suppressor cell population responsible for the AchR breakdown [6]. However definitive study of the effectiveness of thymectomy has not been carried out. The extent of thymic resection and the operative approach have become increasingly controversial. Furthermore patients with fluctuating MG after thymectomy require other treatment modalities including administration of acetylcholinesterase inhibitors and steroids. Corticosteroids are used as first-line medical therapy for moderate-to-severe MG but they have well-known adverse effects [15, 16]. The dosing schedule of prednisolone for MG management is not standardized. The initial dose of prednisolone recommended is 60 mg/d [17]. In the 1970s it was learned that patients who undergo alternate-day prednisolone therapy show steady improvement without the initial period of drug-related worsening that can occur during the early period of daily steroid therapy [18]. Alternate-day therapy provides an increased benefit on the day of prednisolone administration at a lower dose. In our hospital alternate-day prednisolone treatment was used in most patients with fluctuating or refractory MG after thymectomy. We have used dose-escalated alternate-day steroid treatment before thymectomy since 1991. A maximum prednisolone dose of 120 mg every other day is prescribed.

This study comparing the clinical course of patients after combined modality treatment, ie, programmed steroid treatment with thymectomy with the clinical course of patients after occasional treatment, has helped to clarify the role of steroid treatment in surgical intervention. Comparison of the clinical benefits of thymectomy combined with programmed steroid treatment for MG against those of occasional medical treatment with thymectomy is difficult [19]. Our review showed that 1 patient in the occasional treatment group had occasional steroid treatment before surgery and some patients in both groups were treated with other agents when clinical symptoms did not improve after thymectomy. Remission occurred not after thymectomy but after steroid treatment in 4 patients in the occasional treatment group. In this study we focused on remission rates of patients who were asymptomatic and medication-free for at least 1 year.

The characteristics of patients who underwent the programmed medical treatment including sex, age, underlying disease, severity of MG, and time to surgery were similar to that of patients who underwent occasional medical treatment. In pathologic study atrophic thymus was found in the programmed treatment group more often but not statistically more often than in the other group. The proliferation of lymphoid thymic tissue might have been inhibited by the steroid treatment before surgery [20]. Therefore our results do not agree with previous findings that MG patients with mild hyperplastic thymus responded well to thymectomy [21]. Management of patients with ocular MG has been open to debate [2, 22, 23]. We believe that ocular MG is essentially the same disease as generalized MG because 60% of patients in our department who had ocular symptoms advanced to generalized MG by the time of surgery as previously reported [22, 23]. Therefore patients with ocular MG were treated under the same program. The short-term outcome of the programmed treatment group with ocular MG was slightly but not significantly better than that of the ocular MG group treated occasionally. We provide two reasons for this. First, the time to surgery in the occasional treatment group was slightly longer. Second, ocular MG may respond better to steroid treatment [23]. Some patients with ocular MG in the occasional treatment group were in complete remission, not after thymectomy but after steroid treatment.

Our programmed steroid treatment strategy had the following advantages: fewer occurrences of respiratory insufficiency, myasthenic crisis, and cholinergic crisis. Several factors including surgical stress, anesthesia, and drugs used in the perioperative period can cause crisis events [24]. The reported need for postoperative ventilation after transsternal thymectomy ranges from 10%–50% [25]. The benefits we observed may encourage surgeons and MG patients to try programmed treatment. Neurologists, who can reduce doses of prednisolone according to symptoms after thymectomy, may also consider our approach. Within the first 5 years after thymectomy the remission rate in the programmed treatment group was in no way inferior to that in the occasional treatment group, especially in patients with ocular MG. Most of the nonresponders in the occasional treatment group achieved remission with steroid treatment. A strategy for nonresponders undergoing programmed treatment is needed.

Continuous use of a steroid is not desirable for fear of poor wound healing and the occurrence of postoperative infection [16]. Only 1 of our patients suffered a wound abscess due to infection by methicillin-resistant S. aureus that was harbored preoperatively in the patient's nose. Preoperative bacterial examination of the nasopharynx is a necessary precaution. A blood sugar tolerance test is also necessary. In patients with a blood sugar abnormality on the day of prednisolone administration, insulin should be given.

In conclusion our review showed the feasibility and efficacy of combined modality treatment for MG. However questions regarding the kind of MG patient for whom this treatment is indicated, the optimal dose of prednisolone before thymectomy, and the management of the nonresponders were not answered. Further investigations are necessary.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Comment
 References
 

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