Extended thymectomy for treating patients with Myasthenia gravis (MG)

Abstracts

INTRODUÇÃO: Diversas variações da timectomia podem ser realizadas, dentre elas a transesternal ampliada. A literatura sugere que, quanto mais extenso o procedimento para ressecção da glândula e tecidos do mediastino anterior, melhores os resultados e prognóstico. OBJETIVO: Avaliar retrospectivamente a resposta à timectomia ampliada em portadores de Miastenia gravis. MÉTODO: Foram avaliados 46 portadores de Miastenia gravis, submetidos à plasmaferese pré-operatória e à timectomia ampliada, entre agosto de 1992 e janeiro de 2003, divididos em três grupos, segundo o tempo decorrido desde o início dos sintomas: menor que 12 meses, 13 a 24 meses e maior que 25 meses. RESULTADOS: Trinta e um pacientes eram do sexo feminino e 15 do masculino. A média de idade foi de 30 anos. O tempo médio de evolução da doença foi de 26,3 meses. O acompanhamento ambulatorial pós-operatório foi em média de 26,6 meses. Quanto ao grau de resposta à timectomia, 89% dos pacientes tiveram boa resposta, sendo que 50% apresentaram remissão completa. Ocorreu um óbito nesta série. O exame anatomopatológico demonstrou que a hiperplasia tímica foi o achado mais freqüente. Apenas 3 pacientes (6,5%) apresentaram timomas benignos. Em 5 pacientes (10,8%) encontramos tecido tímico extraglandular: na gordura peritímica em 2 deles, na gordura pericárdica em 1, junto ao nervo frênico esquerdo em outro e na janela aorto-pulmonar em outro. CONCLUSÃO: A timectomia ampliada para tratamento da Miastenia gravis mostrou-se segura, eficiente, e apresentou alta porcentagem de remissão completa. Houve a detecção de tecido tímico extraglandular em alguns pacientes. Tão logo seja feito o diagnóstico, está indicada como terapêutica associada à plasmaferese pré-operatória e à medicamentosa, independentemente da idade, patologia tímica, e início dos sintomas.

Timectomia; Miastenia gravis; Doenças neuromusculares

ORIGINAL ARTICLE

Extended thymectomy for treating patients with Myasthenia gravis (MG) ^*

Raul Lopes Ruiz Jr; Samuel Marek Reibscheid^(TE-SBCT); Antonio José Maria Cataneo^(TE-SBCT); Luis Antonio de Lima Rezende

^{Correspondence}

ABSTRACT

BACKGROUND: Extended thymectomy is one of several types of thymectomy. Literature suggests that the outcome and prognosis will be enhanced by performing a more extensive resection of the gland and of the anterior mediastinum tissue.

OBJECTIVE: To retrospectively evaluate response of MG patients to extended thymectomy.

METHOD: From August 1992 to January 2003, forty-six MG patients were submitted to preoperative plasmapheresis and extended thymectomy. According to the time elapsed since onset of symptom they were divided into three groups; < 12 months, 13 to 24 months, and > 25 months.

RESULTS: There were 31 female and 15 male patients, mean age 30 years and average evolution time 26.3 months. Outpatient post-operative follow-up was on the average of 26.6 months. Level of response was good, 50% had full remission and a further 39% had good response. There was one death. The most common histopathology finding was thymic hyperplasia. Only 3 patients (6.5%) had benign thymomas; 5 (10.8%) had extra glandular thymic tissue: 2 in the perithymic fat and 3 in the pericardiac fat adjacent to the left phrenic nerve and aortal-pulmonary window.

CONCLUSION: Treatment of MG by extended thymectomy is safe and efficient with high levels of complete remission. Extra glandular thymic tissue was found in some patients. As soon as diagnosis is completed, thymectomy is indicated together with plasmapheresis and medication, independent of age, onset of symptoms, and thymus pathology.

Key words: Thymectomy/methods. Myasthenia gravis/ pathology. Neuromuscular diseases/rehabilitation.

Abbreviations used in this paper:

MG – Myasthenia gravis

Introduction

Various authors have reported on the benefits of thymectomy in the treatment of myasthenia gravis (MG).^(1-8) Variations of this procedure have been reported.^(2,3) One such variation is extended thymectomy (maximal or total resection).^(9-14) Studies have suggested that the more extensive the resection of the gland and anterior mediastinal mass, the better the prognosis.^(1,9,15) extraglandular thymic tissue is frequently found, reinforcing the idea that the extended procedure is necessary.^(1,11,15) The objective of this retrospective study was to evaluate the response of MG patients to extended thymectomy.

Methods

A retrospective study was carried out to evaluate the response to extended thymectomy in 46 patients diagnosed with MG. The patients were treated in the Serviço de Cirurgia Torácica of the Hospital das Clínicas of the Faculdade de Medicina de Botucatu da Universidade Estadual Paulista (UNESP) between August 1992 and January 2003. The Research Ethics Committee approved the study.

Age, gender, onset of symptoms, thymic pathology, disease severity and medication were all evaluated in relation to outcomes.

Diagnosis of MG was based on results of anamnesis, physical examination, and electroneuromyographic studies. Prior to surgery, patients were submitted to lateral and anterior-posterior radiography, chest computer-assisted tomography, electroneuromyography and spirometry.

Patients were divided into three groups based on the length of time since the onset of symptoms (less than 12 months, from 13 to 24 months and more than 25 months).

Most patients were treated with an anticholinesterase agent (pyridostigmine bromide). Only one patient was under corticoid therapy prior to surgery. Some patients took no specific medication prior to or after surgery. Others received corticosteroids prior to surgery (dosages ranging from 5 mg to 60 mg per day). One patient presented a myasthenic crisis on postoperative day 32 and received 60 mg of a corticosteroid, administered in combination with an immunosuppressant (azathioprine).

The system of clinical classification devised by Osserman⁽¹⁶⁾ was used to classify preoperative MG severity (Chart 1). Patients with mild forms of MG were graded as class I, IIa or Iib and those with the more serious forms were categorized as class III or IV.

All patients underwent two sessions of plasmapheresis 72 hours prior to surgery. A 5% human albumin solution was used for fluid replacement. Some patients underwent another plasmapheresis session after surgery due to worsening of symptoms.

Extended thymectomy was performed via median sternotomy. The incision extended for an additional 3 cm above the furcula 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 pre-pericardial fat, the anterior mediastinal pleurae (bilaterally), cardiodiaphragmatic sinus fat pads and fat accumulation around and anterior to the phrenic nerves, as well as the thymus itself, were removed en bloc. Subsequently, a delicate, careful dissection was performed in order to remove all fat from the space between the aorta and vena cava, near the cephalic vessels, and from the area behind the thyroid, accessed from the upper portion of the incision. Using a spreader, the skin and subcutaneous tissues were opened for better viewing. Water-sealed multiperforated pleural drains were inserted bilaterally into the fifth intercostal space. The drains were removed between 24 and 48 hours after surgery.

All procedures were performed under general inhalation anesthesia and controlled ventilation. During surgery, oximetry and capnography were used, heart rate was monitored, and arterial blood gases were analyzed serially. For postoperative analgesia, we used a 72-hour peridural nerve block with continuous administration of anesthetics.

Most patients were extubated within the first 24 hours after surgery.

The response to thymectomy during the postoperative follow-up was graded in accordance with the classification system proposed by Keynes⁽¹⁷⁾ (Chart 2).

Results

In this study, 31 female and 15 male patients underwent surgery and were evaluated. The mean age was 30 years (range, 10 to 64). The mean length of disease evolution was 26.3 months, (range, 3 to 120 months). Mean length of postoperative outpatient treatment was 26.6 months, (range, 2 to 124 months). The degree of response to thymectomy was graded according to the Keynes classification system: A = 23 patients; B = 9 patients; C = 4 patients; E = 4 patients (Table 1). One patient died as the result of a pulmonary embolism, which had been clinically diagnosed. Autopsy was not performed.

Of the 46 patients, 9 (19.6%) received no medication prior to or after surgery, and corticosteroids, with or without an anticholinesterase agent, were administered to 7 (15.2%). Of the 7 patients receiving corticosteroids, only 1 was also given an immunosuppressant.

Table 2 relates postoperative evolution to gender, age and time from onset of symptoms, as well as to Osserman class.

Anatomopathological examination revealed benign thymoma in 3 patients, atrophic thymus in 6, normal thymus in 5, fibrotic thymus in 3 and thymic hyperplasia in 29 (Table 2). Extraglandular thymic tissue was found in 5 (10.8%) of the 46 patients. In 2 of these patients, the thymic tissue was located in perithymic fat. In the other 3, such tissue was found in other locations: in pericardial fat, adjacent to the left phrenic nerve and in the aortopulmonary window. Each sample sent for pathology comprised the thymus with the capsule intact, the perithymic tissues and all the fat resected from the anterior compartment of the mediastinum. Each sample component was analyzed separately.

There were neither infectious complications nor hemorrhages in the chest wall or in the pleural cavity. Patients rarely complained of pain within the first 72 postoperative hours. Subsequent pain was easily controlled with common analgesics.

In this study, there were no intraoperative or postoperative coagulation disturbances. Only one patient presented respiratory insufficiency immediately after surgery and required reintubation, remaining intubated for 3 more days.

Due to postoperative worsening of symptoms 5 (10.8%) of the patients were submitted to an additional plasmapheresis session. Of those 5 patients, 1 died, 2 achieved complete remission, and symptoms continued to worsen in 2.

Discussion

According to the literature, thymectomy has been used as a treatment for myasthenia gravis since 1939.⁽²⁾ In 1988, Jaretzki et al.^(9,10) recommended the use of extended thymectomy, with complete resection of the fat in the anterior mediastinum, in order to remove extraglandular thymic tissue. It has also been shown that symptoms persist after surgery if these extrathymic areas are not excised.⁽²²⁾

In this study, extended thymectomy was performed as described by Jaretzki,⁽⁹⁾ although some modifications were made. Rather than transverse cervicotomy, we used a longer incision through skin and subcutaneous tissue (longitudinal cervicotomy) towards the thyroid space and the upper lobes of the thyroid gland. This technique allowed good access for the dissection of tissues that might contain embryonic vestiges of thymic tissue.

There were no infectious complications in the chest wall or in the pleural cavities. This may have been due to the small number of patients who were under corticosteroid therapy prior to surgery. In a similar study, infectious complications were reported to be slightly more common in immunosuppressed patients (14%) than in immunocompetent patients (9%), although the difference was not statistically significant.⁽²³⁾

There was a favorable response to thymectomy in 41 (89%) patients (Table 2), which is in accordance with other studies reporting rates of positive postoperative response from 80% to 94%.^(7,24-27) In the present study, 23 (50%) of the patients achieved complete remission without the administration of any specific medication. In comparison to other studies, in which rates of complete remission range from 12.7% to 61%,^{(1,7,8,24-27,30)} this is a relatively high percentage. We believe that the procedure we employed, in which there is more extensive resection of thymic tissue, as well as the preoperative plasmapheresis sessions, which reduce concentrations of anti-nicotinic acetylcholine receptor antibodies in the neuromuscular junction, were conducive to our positive results. In addition, plasmapheresis improves preoperative and postoperative respiratory function, resulting in early extubation. In our study, very few patients presented respiratory insufficiency immediately after surgery.⁽¹⁾

Extraglandular thymic tissue was present in 5 (10.8%) of the patients, and 2 of those were classified as “nonresponsive” (Table 2). In light of this, we concur with the statement made by Jarestski⁽¹¹⁾ that “maximal” resections are conducive to better results, with a higher incidence of complete remission. In addition, other authors have shown that poor results are due to the presence of thymic tissue remnants that continue producing anti-acetylcholine receptor antibodies.^(1,8,22)

In this study, 3 patients (6.5%) presented benign thymomas, a lower incidence than the 9% to 28% reported in the literature.^(6,23) One of those 3 went into complete remission, 1 showed clinical improvement while receiving medication in the same dosage given prior to surgery, and one presented worsening of MG symptoms. Our results regarding poor response to treatment differ from findings of other studies reporting frequent poor responses in patients with thymomas and who present early symptoms and unsatisfactory postoperative evolution.⁽¹⁵⁾ This discrepancy may be due to the small number of cases in the present study.

Whether MG should be treated with thymectomy or through exclusively nonsurgical means is still a matter of controversy.⁽¹²⁾ Many authors hold that thymectomy is indicated only if drug therapy is ineffective, whereas others recommend early thymectomy as primary therapy for MG.⁽³⁰⁾

In this study, 9 (19.6%) of the 46 patients underwent thymectomy prior to drug therapy. According to the Osserman classification system,⁽¹⁶⁾ 7 of the 9 were class IIa, 1 was class IIb, and 1 was class III. All 9 patients achieved complete remission. Extended thymectomy as primary therapy appears to have been more beneficial than exclusively clinical treatment. In addition, extended thymectomy minimized the risks and side effects of continued use of corticosteroids and immunosuppressants.

The interval between the onset of symptoms and thymectomy is an important prognostic factor.^(7,15,24,31) In the 4 patients classified as Osserman I, IIa, IIb, and III in this study, clinical symptoms worsened after surgery, although less than 12 months had elapsed between the onset of symptoms and surgery (Table 2). Again, this may be due to the small number of cases in this study.

In conclusion, extended thymectomy for MG treatment is safe and efficacious, produces high rates of complete remission without the need for specific medication and, as seen in this study, allows detection of extraglandular thymic tissue in some patients. We recommend thymectomy, in combination with preoperative plasmapheresis and drug therapy, immediately after diagnosis of MG, regardless of patient age, thymic pathology and time since onset of symptoms.

References

Submitted: 18 September 2003.

Accepted, after revision: 8 December 2003.

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*

Study carried out at the Faculdade de Medicina de Botucatu – UNESP, Botucatu, SP

Publication Dates

• Publication in this collection
  08 June 2004
• Date of issue
  Apr 2004

History

• Accepted
  08 Dec 2003
• Received
  18 Sept 2003