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Eur J Cardiothorac Surg 2003;24:187-191
© 2003 Elsevier Science NL

Maximal thymectomy in children with myasthenia gravis

Mohamed Essaa, Yasser El-Medanya, Waseem Hajjara, Zohair Haririb, Faisal Al-Mulhimb, Mustafa Salihc, Mahmoud Ashoura, Khaled Al-Kattana*

a Thoracic Surgery Unit, Department of Surgery, College of Medicine, King Khalid University Hospital, King Saud University, Riyadh 11472, Saudi Arabia
b King Faisal Specialist Hospital, Riyadh, Saudi Arabia
c Pediatric Neurology Unit, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia

Received 28 September 2002; received in revised form 21 April 2003; accepted 26 April 2003.

* Corresponding author. Tel.: +966-1-467-1920; fax: +966-1-467-9493
e-mail: alkattan{at}ksu.edu.sa


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 Appendix A. Conference...
 References
 
Objectives: We performed this study to evaluate the benefit of thymectomy in children with myasthenia gravis (MG). Methods: Over a period of 15 years from 1986 to 2001, we collected data on 30 children with MG and retrospectively reviewed the outcome of maximal thymectomy. Results: There were 23 females and seven males with a mean age of 13.2 years (range 4–16). The mean duration of the disease was 19.3 months (range 2–144). According to Osserman classification, there were 14 children in class II; 12 in class III; and four children in class IV. One child in class IV required postoperative ventilation and one was re-explored to drain a pericardial effusion secondary to central line leak. We found ectopic thymic tissue in 10 cases (33.3%). During a mean follow-up period of 53.5 months (range 9–180), complete remission was noted in 13 children (43.4%) and improvement in 14 (46.6%). The remaining three children (10%) did not improve following surgery. Univariate analysis (P<0.05) showed that ectopic thymic tissue is a significant prognostic factor for outcome. Conclusion: Maximal thymectomy appears to provide a high rate of remission and improvement in children with MG. However, the presence of ectopic thymic tissue has poor prognostic value.

Key Words: Myasthenia gravis • Maximal thymectomy • Children


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 Appendix A. Conference...
 References
 
Myasthenia gravis (MG) is an autoimmune disease characterized by relapsing muscle weakness and fatigability secondary to defective neuromuscular transmission. MG in children is rare, comprising 11% of all myasthenic patients [1]. The natural course of MG in children remains largely undetermined and because of the rarity of the disease in this age group, the consensus on the benefit of thymectomy is still unclear, hence a satisfactory evaluation of thymectomy has been difficult to achieve [2]. Thymectomy is now the standard treatment modality for patients with MG, and the current data, with a favorable cure, or symptomatic improvement rates of up to 80% of patients, support the role of surgery. Different surgical approaches have been recommended with varied outcome [3]. Although most of the data are for the adult age group, some centers reviewed their experience in children with equally encouraging results. The controversy in thymectomy for MG in children remains in identifying the predictors of outcome and the long-term results of surgery [2,4–7].


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 Appendix A. Conference...
 References
 
Between July 1986 and June 2001, 30 patients below the age of 16 years with MG underwent surgery at King Khalid University Hospital and King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. This group represents 20% of all cases of MG who had thymectomy during this period (30 from 150 patients). Data for the children were collected and reviewed retrospectively.

Diagnosis was initially based on clinical manifestation of the disease and was confirmed by positive tensilon test in all patients. Computerized scanning of the mediastinum was routinely performed to rule out associated thymoma. Anti-acetylcholine receptor antibody (anti-Ach R Ab) tests were carried out in 22 patients. Osserman classification was used to evaluate the severity of the disease: class I (occular), class II (mild generalized weakness), class III (moderate generalized weakness) and class VI (severe generalized weakness). The total medication doses, and the severity of the disease on treatment were recorded. All patients received anti-cholinesterase inhibitors; 14 patients (47.1%) received steroids and two patients (7.1%) received azathioprine. Before operation, all patients had a mean of three sessions of plasmapheresis with tapering of the steroid intake to nil. This protocol was adopted with the aim of not only improving patient status preoperatively, but also decreasing the incidence of postoperative morbidity. Patients received their regular dose of pyridostigmine until the morning of operation. A specialized team, using no muscle relaxant or ultrashort acting muscle relaxant conducted general anesthesia.

All patients underwent transcervical–transternal ‘maximal’ thymectomy according to the technique described by Jeretzki and Wolff [8]. The extrathymic tissues removed were sent for histopathologic examination in separate containers. All patients, except one, were extubated at the end of the procedure and initially re-commenced on half their preoperative medication doses. This was modified during hospitalization according to the clinical status.

Complete follow-up was available to all patients for a mean period of 53.5 months (range 9–180 months). At final follow-up, patients were considered in complete remission if they were asymptomatic and on no medications, and improved if they were on less medication with no symptoms or better symptoms and the same medication. Failure of surgical treatment was considered if they were still on their preoperative doses with no improvement in symptoms.


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 Appendix A. Conference...
 References
 
There were 23 females (77.1%) and seven males (23.1%) with a 3.3:1 ratio, with an average of 13.2 years (range 4–16 years). Ninety percent of the patients were above the age of 10 years. The duration of the disease ranged between 2 and 144 months (mean 19.3 months). Sixty-three percent of the patients were symptomatic for less than 1 year. Generalized muscle weakness was the presenting symptom in all patients. According to Osserman classification, there were no patients with ocular MG and there were 14 children (47.1%) in class II, 12 (40%) in class III and four (13%) in class IV. Twenty percent of these patients (six children) experienced respiratory failure, which required mechanical ventilation during their illness.

Anti-Ach R Ab test was carried out in 22 children (73%) and the results were positive in 19 children (86%). Preoperatively, 14 children (47%) were on steroid therapy. Two patients (6.5%) had associated diseases, one with ulcerative colitis and the other with breast fibroadenosis. There was no operative mortality and two patients (6.5%) developed postoperative complications: one child in class IV required postoperative mechanical ventilation and the other was re-explored to drain a pericardial effusion secondary to central line leak.

None of the patients had thymoma. Thymic hyperplasia was found in 26 cases (86.7%), and normal thymus in four (13.3%). Ectopic thymic tissue was found in 10 cases (33.3%).

All patients completed follow-up with a mean period of 4.5 years (range 9–180 months). At the last follow-up, complete remission was noted in 13 children (43.4%) and improvement in 14 (46.6%). The remaining three children (10%) did not improve after surgery. The total benefit of thymectomy, which is the sum of remission rates and improvement, occurred in 27 children (90%).

Remission rate was 33.3% (10 cases) at 3 years and 46.6% (14 cases) at 5 years. Univariate analysis (P<0.05) of factors influencing outcome of surgery (sex, duration, Osserman classification, preoperative steroid therapy, anti-Ach R Ab, histopathology, and ectopic thymic tissue) showed that ectopic thymic tissue is a significantly poor prognostic factor for outcome (P=0.004) (Table 1).


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  		Table 1. Univariate analysis of factors influencing thymectomy for MGa

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
Appendix A. Conference...
 References
 
MG is a rare disease of childhood, accounting for 11% of all patients with MG [1]. MG in childhood was first documented in the late 19th century and thought to be rare until the early 1900s when the prostigmine test became widely employed. In a large series published in 1956, Teng and Osserman [9], found that 10% of MG occurred in patients below the age of 17 years. In our series, MG in children accounts for 20% of the total number of patients operated upon for MG (30 from 150 patients). The juvenile form of MG is identical to the adult form with presentation at an earlier age. Diagnosis is between 1 and 17 years, with 75% of patients presenting after the age of 10 [9]. All the patients in our series were below the age of 16 years and 90% above the age of 10. In children, MG affects females four to six times more frequently than males, and a tumor-bearing thymus gland is rare [1,9]. In our series, 77% of patients were female and none had thymoma. Generalized muscle weakness was the presenting symptom in our patients, with 47% in class II, 40% in class III and 13% in class IV according to Osserman classification. Twenty percent of patients experienced respiratory failure requiring mechanical ventilation before surgery. There were no patients with ocular MG.

In previous studies, it has been difficult to obtain a satisfactory evaluation of therapy for children with MG because of the small number of patients with the disease and the lack of controls [1,6]. Although lacking major evidence for efficacy, thymectomy is now a well-accepted treatment modality for children with MG [10]. Several studies address thymectomy in children with generalized weakness and conclude that thymectomy is generally effective and has a higher percentage of remission than medical therapy. The remission after surgery is usually sustained whereas spontaneous remission is generally followed by relapses [1,2,4–7,9–11].

Even in the absence of complete remission, most patients benefit from thymectomy by improvement of their symptoms or reduction of their medications, specifically steroids. In addition, thymectomy is indicated in the rare group of pediatric patients with thymoma [7].

In the early study of Millichap and Dodge [12], the medically treated group, followed for an average of 9.7 years, had a 14% incidence of remission. Surgically treated patients followed for an average of 3.4 years after thymectomy had a 28% remission rate. For those operated on within the first 2 years after onset of symptoms, the remission rate was 50%. In a retrospective analysis in 149 patients with juvenile MG, the remission rate during the first year after thymectomy was 10 times higher than the spontaneous remission rate [13]. The data from Mayo Clinic indicate a spontaneous remission rate of 8% over 3 years after medical therapy as compared with 38% postthymectomy [14–16].

In this series, with a mean follow-up period of approximately 4.5 years, we noted complete remission rate in 43.4% and improvement in 46.6% with total benefit from surgery in 90%. Patients operated upon within the first year after the onset of their disease had a remission rate of 44%, which was not statistically significant in comparison with the remaining patients.

Although controversy exists regarding the preferred surgical approach, complete excision of thymus is important and crucial [3,7]. The transcervical approach claims to decrease the need for mechanical ventilatory support, the length of hospital stay, and mortality rates (0.2%) compared to transthoracic thymectomy (3%) [9]. In comparison, maximal thymectomy resulted in a higher remission rate than those reported after transcervical or transternal approach alone [3,17]. We earlier reported that 39.5% of our patients undergoing maximal thymectomy showed ectopic thymic tissue at 19 locations, and the presence of ectopic thymic tissue was associated with poor operative outcome. We advocate maximal thymectomy with a wide exposure of the mediastinum, and neck to assure complete resection of all thymic and ectopic thymic tissues [1,3,8,17].

Thymectomy performed in experienced centers is safe, with low morbidity, and no detrimental effects due to thymectomy in childhood have been reported [2,10]. In our overall experience, we had no mortality and 12.5% postoperative morbidity, with no phrenic or recurrent nerve paresis. Sternal dehiscence or impaired wound healing did not occur after maximal thymectomy [3,17]. In our pediatric series, postoperative complications occurred in two patients (6.5%) and were unrelated to the surgical approach. One child in class IV required postoperative ventilation, and one was re-explored to drain a pericardial effusion secondary to central line leak.

Preoperative preparation with cholinesterase inhibitors, plasma exchange and intravenous immunoglobulin is prudent to optimize the patient's strength and respiratory function, thus reducing postoperative complications [7]. Our preoperative preparation included tapering of the steroid intake and an average of three sessions of plasmapheresis. A specialized team with epidural analgesia, using no muscle relaxant or ultrashort acting muscle relaxant conducted anesthesia. We previously reported that forced vital capacity and forced midexpiratory flow between 25 and 75% are predictors for postoperative ventilation [18,19]. Postoperatively, patients were re-started on half their preoperative medication dose, which was then adjusted during hospitalization according to the clinical status to avoid postoperative cholinergic crisis [3].

In our pediatric series, univariate analysis (P<0.05) of gender, duration of the disease, Osserman classification, preoperative steroid, anti-acetylcholine esterase antibodies, histopathology, and ectopic thymic tissue, showed that only ectopic thymic tissue is a significantly poor prognostic factor for outcome. Despite maximal thymectomy, ectopic thymic tissue remains a poor prognostic factor suggesting the possibility of the presence of ectopic thymic tissue in locations, which cannot be accessed surgically. However, we believe that only with this procedure, most of the ectopic thymic tissue could be removed and that may explain our better results in comparison to other techniques.

Other studies showed that severity of the disease is not a factor influencing the outcome after thymectomy [9], but in our study we observed that the three cases without improvement after thymectomy were found in severe form of the disease (class III and VI), suggesting that severity of the disease may also influence the outcome. There was no difference in the response to thymectomy for sex and age of onset [4]. Seybold et al. [15] suggested that operation within 2 years of onset results in a higher remission rate, but Ryniewicz and Badurska [20] found no correlation between the improvement rate after thymectomy and prior duration of the disease. There is also no correlation between the clinical course following thymectomy and the presence of a normal gland histologically [6].

Maximal thymectomy appears to provide a high rate of remission and improvement in children with MG. It is safe and performable with low morbidity. The presence of ectopic thymic tissue has poor prognostic value. We believe that maximal thymectomy is the recommended surgical approach as it detects the presence of ectopic thymic tissue and positively affects the outcome in children with MG.


   Footnotes
 
Presented at the 16th Annual Meeting of the European Association for Cardio-thoracic Surgery, Monte Carlo, Monaco, September 22–25, 2002.


   Appendix A. Conference discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 Appendix A. Conference...
References
 
Dr W. Weder (Zurich, Switzerland): I am interested in the findings regarding the ectopic tissue since I'm favoring to perform this procedure minimally invasive, thoracoscopically, and the area we do not explore is the retrocaval area and also not the aortic window. We probably could, but we don't do it. You said 3 patients had ectopic tissue in the aortopulmonary window and in the retrocaval area. Are these also the patients who had no benefit at all from surgery or were these other cases, because the other ectopic tissue in the neck and at the cardiophrenic angle can be easily removed thoracoscopically as well.

And I disagree with your statement that sternotomy has a low morbidity. I think for a young woman, it is certainly not a very pleasant incision.

Dr Al-Kattan: I probably totally agree. We only found 2 patients with retrocaval and the aortopulmonary window, and in our overall series we had almost 150 patients, and, as you said, we noted that the ectopic thymic tissue is also associated with poor outcome. So the question is whether there is a significance of doing an extra procedure, like adding the neck incision to find ectopic thymic tissue in the neck, while the outcome is still going to be poor. This is the debate we always do. The question is, what I find, when these patients have recurrence after surgery, you feel that maybe there is some tissue you didn't remove. When I get a patient from another hospital who did not have the full-blown maximal thymectomy and he has a recurrence, with frequent admission to the hospital, I dare to reopen him again, but when he comes after a maximal thymectomy, I say I don't think anything extra will be done. So probably maybe if you reserve the extensive surgery for those who recur, it might be a good idea, although we are now in the process of doing a bit less invasive and starting the thoracoscopic procedures and adopting this policy that patients who recur, we go in and look for not residual thymic tissue but ectopic thymic tissue and try to remove more fat through an open procedure.

Dr T. Grodzki (Szczecin, Poland): I'm back to the ectopic tissue because it's the most controversial. Theoretically you removed the ectopic tissue. If there was no improvement, it means that somewhere in the body there was other ectopic tissue. First of all, the first question, did you try to find another ectopic focus? And the second question, and I ask it in a little bit of a provocative way, if you perform extended mediastinoscopy, you remove the ectopic tissue and there is no regression, maybe it's better to perform simple thymectomy.

Dr Al-Kattan: First, among the ectopic patients, we had a good number of improvements, although no complete remission, and that's also of value, because for some of these children, if you can just get them off steroids, you've really gained a lot, because they are young and spontaneous remission without surgery is poor from the historical studies we have. So I would be aggressive. That is not an expensive thing to do if you're going to get this patient at least off steroids and reduce his medications. So improvement also counts, not necessarily remission.

The second thing, we are actually currently doing this. We have done several studies to try to detect any signs of ectopic thymus preop. We tried isotope scan because there have been reported cases of uptake with the thymus gland with the ectopic. We are going to present probably by next year a paper about PET scan involvement in myasthenia gravis. But I'll tell you, this is our prospective studies, because we are also interested to detect ectopic elsewhere, and our initial results are not encouraging except in cases with thymoma, but nonthymoma myasthenia gravis, we have failed to detect any positive markers that can influence the type of surgery performed.


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 Appendix A. Conference...
 References
 

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  11. Seybold M.E. Thymectomy in childhood myasthenia gravis. Ann N Y Acad Sci 1998;841:731-741.[Free Full Text]
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  16. Andrews P.I., Massey J.M., Howard J.F., Jr, Sanders D.B. Race, sex and puberty influence onset, severity, and outcome in juvenile myasthenia gravis. Neurology 1994;44:1208-1214.[Abstract/Free Full Text]
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