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Ann Thorac Surg 2007;84:1694-1698. doi:10.1016/j.athoracsur.2007.06.043
© 2007 The Society of Thoracic Surgeons
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Original Articles: General Thoracic

Different Characteristics of Nonthymomatous Generalized Myasthenia Gravis With and Without Oropharyngeal Involvement

Lei Yu, MDa,*, Jianye Li, MDa, Shan Ma, MDa, Jian Jiang, MDa, Tianyou Wang, MDb, Ziv Gamliel, MDc, Yun Jing, MDa, Xiaojun Zhang, MDa, Mark J. Krasna, MDc

a Departments of Thoracic Surgery and Neurology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
b Department of Thoracic Surgery, Beijing Youyi Hospital, Beijing, China
c Division of Thoracic Surgery, St. Joseph Medical Center, Towson, Maryland

Accepted for publication June 15, 2007.

* Address correspondence to Dr Yu, Department of Thoracic Surgery, Beijing Tongren Hospital, Capital Medical University, No.1 Dongjiaominxiang St, Dongcheng District, Beijing City, 100730, China (Email: yulei1118{at}sohu.com).


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 
Background: Thymectomy represents a safe and valid approach for patients with myasthenia gravis. However, some factors may influence the efficacy of thymectomy. The objective of this study was to evaluate the clinical characteristics of generalized myasthenia gravis with oropharyngeal involvement and compare the postoperative outcome of generalized myasthenia gravis without and with oropharyngeal involvement.

Methods: From 1991 to 2002, there were 202 patients with nonthymomatous generalized myasthenia gravis (GMG), who underwent thymectomy by the transsternal approach or thoracoscopy. According to the clinical classification of the Myasthenia Gravis Foundation of America (MGFA), these patients have been subdivided into two groups: GMG without oropharyngeal involvement and GMG with oropharyngeal involvement. Complete stable remission, as defined by the MGFA Medical Task Force, was the primary endpoint for efficacy.

Results: In all, 182 patients were followed up for at least 5 years. There were 135 cases of GMG without oropharyngeal involvement and 47 cases of GMG with oropharyngeal involvement. There were significant differences in postoperative pneumonia, ventilatory support time, and myasthenic crisis between patients with GMG with and without oropharyngeal involvement (p values were 0.040, 0.021, and 0.007, respectively). At 5 years of follow-up, the cumulative probability of reaching complete stable remission in GMG without oropharyngeal involvement was 18.5% at the end of the first year, and rose steadily in subsequent years (26.7%, 37.0%, 39.1%, and 40% at 2, 3, 4, and 5 years, respectively). In GMG with oropharyngeal involvement, it was 6.4%, 14.9%, 23.4%, 29.9%, and 31.9%, respectively, in the continual follow-up years. The first 3 years were associated with a significantly greater probability of achieving complete stable remission (p = 0.047 for the first year, p = 0.025 for the second one, and p = 0.048 for the third one). The later 2 years had no significant difference on complete stable remission.

Conclusions: Laryngeal myasthenia gravis is more severe and the prognosis after thymectomy is not as optimistic as for patients without oropharyngeal involvement.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 
Myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction with clinical characteristics of fatigability and weakness of the skeletal muscles. In most cases, the first noticeable symptom is weakness of the eye and limb muscles. Ocular symptoms such as ptosis and diplopia are considered the most common presenting complaints. Oropharyngeal muscle involvement causing difficulty in swallowing, slurred speech, and dysphagia is not an uncommon feature of MG [1]. In particular, some experts believe that severe pharyngeal dysfunction correlates with a poor prognosis [1–4]. However, there are few clinical studies that analyze the characteristics of the oral and pharyngeal phase [4–7], and less attention is paid to the treatment of generalized myasthenia gravis (GMG) with oropharyngeal involvement. The objective of this study was to evaluate the clinical characteristics of GMG with oropharyngeal involvement and compare the postoperative outcome of GMG without and with oropharyngeal involvement.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 Acknowledgments
 References
 
Patient Population
From 1991 to 2002, there were 202 patients with nonthymomatous GMG at our department. These patients underwent thymectomy by the transsternal approach (n = 153) or video-assisted thoracic surgery (VATS [n = 49]). Myasthenia gravis was diagnosed by neurologists according to standard clinical, pharmacologic, and electrophysiologic criteria [8]. Antiacetycholine (Anti-AChR) antibody titers were assayed by an immunoprecipitation method using human AChR antigen [9]. According to the clinical classification of the Myasthenia Gravis Foundation of America (MGFA) [10], these patients have been subdivided into two groups: GMG without oropharyngeal involvement (149, including class IIa, class IIIa, and class IVa) and GMG with oropharyngeal involvement (53, including class IIb, class IIIb, and class IVb). In all, 55.4% of patients with GMG with oropharyngeal involvement and 83.8% of patients with GMG without oropharyngeal involvement were positive for anti-AChR antibodies; and 92.6% of patients with GMG with oropharyngeal involvement undergoing laryngeal electromyography were positive. Extensive clinical and immunologic evaluations were performed to assess patients suitable for thymectomy, and postoperative check-ups were scheduled at least twice a year for 6 subsequent years. The mediastinum was evaluated before thymectomy by contrast-enhanced computed tomography. Before and after thymectomy, all MG patients were evaluated using the quantitative MG scoring system by the same neurologists [11]; all were evaluated twice in the first year and at least once a year for 5 or more years.

The study was approved by the Human Research Ethics Board of Beijing Tongren Hospital, Capital Medical University. Patients were warned regarding the potential risks before surgery, and signed consent forms if they agreed to undergo thymectomty.

Surgical Technique
The transsternal approach was performed from 1991 to 2001, and VATS thymectomy has been done since 2001. Briefly, the transsternal approach of extended thymectomy was performed through median sternotomy. The incision extended for an additional 2 cm above the suprasternal notch in the direction of the neck. Mediastinal dissection extended from the most anterior-posterior portion, along the phrenic nerves, to the area inferior to the thyroid. All prepericardial fat anterior to the phrenic nerves, as well as the thymus itself, was removed en bloc. Subsequently, a delicate, careful dissection was performed to remove all fat from the space between the aorta and vena cava, near the cephalic vessels. For most patients, the drains below the incision were removed between 24 and 48 hours after surgery.

Video-assisted thoracic surgery thymectomy can be performed through left or right approaches [12, 13]. For the right-sided approach, after double-lumen intubation, the patient is placed in a 45-degree off-center position and three trocars are inserted. The dissection is begun inferiorly by incising the mediastinal pleura along the anterior border of the phrenic nerve and proceeds mainly by blunt maneuvers. All mediastinal tissue including fat is swept away from the phrenic nerve, and the right inferior horn is dissected off the underlying pericardium. Afterward, the gland is dissected off the retrosternal area beginning just below the internal mammary pedicle and continuing leftward until the left mediastinal pleura is visualized. The lower half of the gland is then retracted upward, and the thymic veins are identified clipped and divided. Subsequently, the dissection proceeds cephalad, superior to the innominate vein, into the lower cervical region. The superior horns are progressively dissected free by blunt maneuvers with the aid of gentle traction applied downward on the thymus. All mediastinal fat that is found in the pretracheal space, along the internal mammary pedicles, in the aortopulmonary window, as well as in the right or left pericardiophrenic angles, is completely excised. At the end of the procedure, one chest tube is inserted through the most medial port in the dissected mediastinal area.

The transsternal approach was an extended thymectomy classified as T-3a and VATS thymectomy as T-2a in the MGFA classification [10].

Endpoints
Primary endpoint
The primary effectiveness outcome of GMG with oropharyngeal involvement and without after thymectomy was the rate of complete stable remission (CSR), which was defined as no symptoms or signs of MG and no therapy for at least 1 year according to MGFA postintervention status [10].

Secondary endpoint
The secondary measure of effectiveness outcome was the time to CSR. These endpoints were ascertained in all cases by direct physical examination of the patients. We also noted the duration and bleeding of the operation, number of admissions to intensive care unit, side effects, computed tomography evaluation, and length of stay in hospital after surgery to provide indications of the efficiency and practicability of the operation.

Statistical Analyses
Statistical analysis was performed using the Statistical Package for the Social Sciences (version 11.5; SPSS, Chicago, Illinois). All continuous data are expressed as a mean ± SD. Categorical variables were analyzed by Fisher’s exact test. Continuous variables were analyzed as appropriate by the two-sample t test or the Mann-Whitney U test. All p values less than 0.05 were considered significant.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 Acknowledgments
 References
 
Among 202 patients with GMG, 182 were followed up for at least 5 years. These included 140 who underwent the transsternal approach and 42 who underwent VATS. Twenty patients were lost to follow-up. There were 135 cases of GMG without oropharyngeal involvement, and there were 47 cases of GMG with oropharyngeal involvement. The main clinical and pathologic characteristics of the two groups at the time of surgery are summarized in Table 1. Findings at the time of thymectomy are described in Table 2. Operative complications including heart failure, severe bleeding, and injury to the phrenic nerve occurred equally in both groups.


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  		Table 1 Clinical Features of Generalized Myasthenia Gravis (GMG) Patients Who Underwent Thymectomy
 

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  		Table 2 Features During Thymectomy
 
As is shown in Table 3, there were significant differences in postoperative pneumonia, ventilatory support time, and the incidence of myasthenic crisis between patients with GMG with and without oropharyngeal involvement (p values were 0.040, 0.021, and 0.007, respectively).


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  		Table 3 Analysis of Conditions Related to Surgical Procedure Between Two Groups
 
The cumulative probability of reaching CSR in GMG without oropharyngeal involvement was 18.5% at the end of the first year, and rose steadily in subsequent years (26.7%, 37.0%, 39.1%, and 40.0% at 2, 3, 4, and 5 years, respectively; Table 4); for GMG with oropharyngeal involvement, it was 6.4%, 14.9%, 23.4%, 29.9%, and 31.9%, respectively, in the continual follow-up years. No exacerbation occurred in any patient after CSR had been achieved. The first 3 years were associated with a significantly different probability of achieving CSR (p = 0.047 for the first year, p = 0.025 for the second year, and p = 0.048 for the third year). The later 2 years had no significant difference on CSR.


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  		Table 4 Comparable Analysis of Achievement of Complete Stable Remission in Two Groups
 
Among MGFA postintervention status, our "effective" rate includes CSR, pharmacologic remission, minimal manifestations, and improvement; and "worse" consists of worsening, exacerbation, and death (Table 5). Besides the significant difference in the postintervention status, there were 2 deaths in GMG with oropharyngeal involvement. One patient died of respiratory failure due to myasthenia crisis nearly 2 years after thymectomy; he had experienced myasthenia crisis three times during this period. The other died of cardiopulmonary arrest 1 year after thymectomy.


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  		Table 5 Different Postintervention Status Between Two Groups 5 Years After Thymectomy
 

   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
Acknowledgments
 References
 
Myasthenia gravis, an autoimmune disorder of the neuromuscular junction, is usually recognized because of ocular complaints or limb weakness. But difficulties with speech and swallowing as an early symptom of MG are often neglected, and few reports of this exist. Difficulty in swallowing and slurred speech as the first signs occurs in as many as 27% of cases [14, 15]. Otolaryngologic manifestations include dysphonia, dysphagia, weakness of mastication, and weakness of facial musculature. Alterations in voice consist of hypernasality, difficulty sustaining pitch, vocal fatigue, intermittent aphonia, and stridor [4]. Some experienced clinicians believe that oropharyngeal involvement is more dangerous, and perhaps different, than limb weakness, and thus should be identified separately by the classification system. We considered it useful to analyze particular characteristics of laryngeal MG, compared with other GMG.

Some patients with laryngeal MG are asymptomatic as it is hard to diagnose the onset of the disease. A combination of diagnostic tests for MG including the Tensilon test, curare test, repetitive stimulation test, serum assay for anti-AChR antibody, and single-fiber electromyography makes it easier to diagnose laryngeal MG. Atypical symptoms like hypernasality, difficulty sustaining pitch, vocal fatigue, intermittent aphonia, and stridor [16–20] often lead to a wrong diagnosis. A delay in diagnosis of 1 or 2 years is not unusual in cases of laryngeal MG. Five of 9 patients with myasthenic crisis before surgery were diagnosed because of oropharyngeal weakness needing ventilatory support in the intensive care unitU. Among our 47 cases with laryngeal MG, nearly half initially consulted an otolaryngologist at the onset of the disease. We, therefore, advocate otolaryngologists should be familiar with the clinical features and diagnostic studies that can aid in identifying this infrequently diagnosed disease.

Myasthenic crisis is the most serious life-threatening event in GMG patients. At some point in their illness, usually within 2 to 3 years after diagnosis, 12% to 16% of myasthenia patients experience crisis [21, 22]. That is most likely in patients whose history includes previous crisis, oropharyngeal weakness, or thymoma. Several events, such as infections, aspiration, physical and emotional stress [23], and changes in medications, are temporally associated with the development of crises and may therefore be triggers. For patients with laryngeal MG, it seems that myasthenic crisis may occur early. Preoperative myasthenic crisis occurrence in GMG with oropharyngeal involvement in this series showed a significant difference from GMG without oropharyngeal involvement (p = 0.038) and has been reported to occur within 2 to 3 months after onset.

In most instances, the symptoms of MG can be controlled with a combination of treatments including thymectomy. Together, these treatments can improve the quality of life for the MG patient. Thymectomy may lessen the severity of myasthenic symptoms [24]; however, the degree to which the symptoms are lessened differs in each patient. Length of stay in the hospital also varies for each patient.

As it is shown in Table 3, myasthenic crisis may be more prone to happen in postoperative patients with laryngeal MG. There was significant difference between GMG with and without oropharyngeal involvement in the number of patients with postoperative myasthenic crisis. The higher rates of postoperative pneumonia and longer ventilatory support time are due to the more severe respiratory muscle weakness caused by the disease in GMG with oropharyngeal involvement.

Finally, the CSR rates of laryngeal MG were significantly lower than those of GMG without oropharyngeal involvement in the first 3 years after operation. Although variables such as sex, age at onset (less than 40 years), thymectomy, and histologic diagnosis of thymic hyperplasia did not differ significantly in the two groups (Tables 1 and 2), the GMG without oropharyngeal involvement group showed a significantly greater probability of achieving CSR in the first 3 years (p < 0.05). According to our findings, the long-term results of CSR (the fourth and fifth year), representative of events expected from patients undergoing thymectomy, seem similar between the two groups. However, Table 5 shows that the effective rates 5 years after thymectomy between the two groups showed a significant difference (p = 0.031).

There were 2 deaths in the clinical study; these were patients with GMG with oropharyngeal involvement. One patient died of respiratory failure due to myasthenic crisis nearly 2 years after thymectomy; he had experienced myasthenic crisis three times during this period. The other died of cardiopulmonary arrest 1 year after thymectomy. In all, we think that the postoperative result of GMG with oropharyngeal involvement is not as good as that for GMG without such involvement.

It has been thought that the efficacy of thymectomy correlates with the amount of thymic tissue removed, how soon it is performed after disease onset, patient age, and presence of thymoma [25]. From the analysis above, oropharyngeal involvement may have a direct impact on the MG prognosis. The rate that these patients progress into myasthenic crisis is relatively high compared with that for patients without oropharyngeal involvement. Therefore, it is suggested that more attention should be paid to patients with laryngeal MG before and after thymectomy. For patients with laryngeal MG, thymectomy seems to have a more actively preventive role on rate and severity of myasthenic crisis attacks.

In conclusion, laryngeal MG is more severe and the prognosis after thymectomy is not as optimistic as it is for patients without oropharyngeal involvement. Therefore, special care should be taken to diagnose and treat laryngeal MG.


   Acknowledgments
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
References
 
This study has been supported by the International Union Against Cancer (UICC).


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 

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