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Table of Contents
REVIEW ARTICLE
Year : 2020  |  Volume : 17  |  Issue : 2  |  Page : 90-93

The dilemma of thymectomy in myasthenia gravis


1 Department of Neurology, Institute of Neurosciences, Indraprastha Apollo Hospitals, New Delhi, India
2 Attending Consultant, Critical Care, Max Super Speciality Hospital, New Delhi, India

Date of Submission16-Apr-2020
Date of Acceptance25-Apr-2020
Date of Web Publication18-Jun-2020

Correspondence Address:
Pushpendra Nath Renjen
Institute of Neurosciences, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi - 110 076
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/am.am_23_20

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  Abstract 


Myasthenia gravis (MG) is an autoimmune disease that affects the neuromuscular junction causing fluctuating weakness of skeletal muscles. It is considered a rare disease with an estimated prevalence of 7.77/100,000. Surgical treatment is done by simple or extended thymectomy. Although thymectomy has been used in the treatment of MG since 1941, the role of thymectomy for MG is not completely understood. Perhaps, one of the longest unresolved issues in thoracic surgery is the role of thymectomy in the treatment of MG. Persistent questions and issues involve not only the surgical approach to thymectomy, but also the role of thymectomy itself in the treatment of MG. This article focuses on the review of thymectomy in MG patients.

Keywords: Autoimmune, myasthenia gravis, thymectomy, thymoma


How to cite this article:
Renjen PN, Chaudhari DM, Mishra A. The dilemma of thymectomy in myasthenia gravis. Apollo Med 2020;17:90-3

How to cite this URL:
Renjen PN, Chaudhari DM, Mishra A. The dilemma of thymectomy in myasthenia gravis. Apollo Med [serial online] 2020 [cited 2020 Jul 11];17:90-3. Available from: http://www.apollomedicine.org/text.asp?2020/17/2/90/287083




  Introduction Top


Myasthenia gravis (MG) is an autoimmune disease that affects the neuromuscular junction, causing fluctuating weakness of skeletal muscles.[1] It is considered a rare disease with an estimated prevalence of 7.77/100,000.[2] The origin of autoimmune dysfunction in patients with MG is unknown, but thymic abnormalities and defects in immune regulation play important roles in patients with anti-acetylcholine receptor (AChR) antibodies. The thymus is essential for T-cell differentiation and establishment of central tolerance.[3],[4] There are also genetic and hormonal components associated with the production of antibodies.[5] Drug therapy is carried out with medications that increase neuromuscular transmission, immunosuppressive drugs, plasmapheresis, immunoglobulins, and monoclonal antibodies.[6]

Surgical treatment is done by simple or extended thymectomy.[7],[8] Although thymectomy has been used in the treatment of MG since 1941,[9] the role of thymectomy for MG is not completely understood. In a review published by Cochrane in 2013,[10] there were no studies included (empty review), and the authors' conclusion is that there is insufficient evidence to support the use of thymectomy in nonthymomatous MG, and that randomized and quasi-randomized studies are needed.


  Unresolved Issues in Myasthenia Gravis Management Top


Perhaps, one of the longest unresolved issues in thoracic surgery is the role of thymectomy in the treatment of MG. Persistent questions and issues involve not only the surgical approach to thymectomy, but also the role of thymectomy itself in the treatment of MG. Many of these issues remain unclear because of the lack of controlled prospective studies. Analysis has also been complicated by the absence, until very recently, of accepted objective definitions of the severity of the illness and response to therapy as well as variable patient selection, timing of surgery, type of surgery, and methods of analysis of results. Without resolution of these issues by properly controlled prospective studies, there can be no unequivocally valid comparison of the various thymectomy techniques and treatment options.[11]

Surgical removal of the thymus has been an alternative treatment for this disease since Blalock [12] performed a successful thymectomy in a 26-year-old woman with MG and thymus cysts. Then, Blalock [12] published a study about twenty patients with MG treated with transsternal thymectomy. In the following decade, a large number of studies investigating the role of thymectomy in MG have been reported from the United States and the United Kingdom.[12] Over time, with improvements in perioperative care, the results of thymectomy have improved, and thymectomy has found its place in the treatment integrity of MG. The benefit of the thymectomy still continues to be questioned by some authors. In addition, there are still debates on the timing of thymectomy, treatment type in early ages, and surgical approaching techniques.[13]


  Myasthenia Gravis Diagnosis Top


Diagnosis can be easily done in a patient with advanced oculobulbar symptoms and a typical myasthenic face. However, diagnosis may be delayed in patients who are only suffering from ptosis, diplopia, and chewing or speaking difficulties. Diagnostic steps in MG are as follows:

  1. The presence of increased complaints with activity and spontaneous remissions in anamnesis
  2. Improvement in muscle strength with acetylcholinesterase (edrophonium test)
  3. Repetitive nerve stimulation test: Stimulation potentials are recorded by giving three stimulations to a nerve in a second. More than 15% reduction in response is considered as positive
  4. Single-fiber electromyography
  5. Anti-AChR antibody detection: It can be investigated by radioimmunoassay. It is specific for MG. It is 85% positive in generalized disease, but in ocular myasthenia, positivity is <50%.[14],[15]



  Classification Top


MG has two clinical forms: ocular and generalized. Weakness in the ocular form is limited to the eyelids and extraocular muscles. However, in generalized patients with myasthenia, in addition to these, there are weaknesses at different degrees in the bulb, extremity, and respiratory muscles. Myasthenic weakness typically fluctuates during the day; it is usually the least in the morning and worsens later in the day, especially after prolonged use of involved muscles.

The progress of the disease is variable and usually progressive. Maximal weakness develops during the 1st year in two-thirds of the patients. In 15%–25% of patients, myasthenic crisis, usually with severe respiratory failure, occurs within thefirst 3 years. Over the years, myasthenic complaints have diminished, but the disease is characterized by fluctuations in remissions and relapses.[16] Untreated weakness becomes permanent after 15–20 years, and atrophy can occur in the most affected muscles. Modified Osserman classification is used to determine the clinical status of the patients [Table 1].[17]
Table 1: Osserman classification system[17]

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Separation of MG by subtypes is useful in terms of pathogenesis, diagnosis, and treatment approach. The disease is classified according to the muscles involved, starting age, presence of antibodies, and thymoma. The most classic form is generalized, early-onset, anti-AChR-positive, and thymoma-free form [Table 2].[14]
Table 2: Classification of myasthenia gravis disease[14]

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  Treatment Options in Myasthenia Gravis Top


There are four primary approaches in the treatment of MG:

  1. Symptomatic treatment with anticholinesterase agents: Pyridostigmine (mestinon) is the most commonly used drug. Its effect starts in 30 min and reaches a maximum level in 2 h
  2. Immunosuppressive treatment: Corticosteroids, azathioprine, and cyclosporine are used for this purpose. Prednisone is often preferred as a corticosteroid. It must be known that at the beginning of the treatment, myasthenic complaints may exacerbate in the 1st week; the dose should be gradually increased, and moderate-to-severe generalized patients should be treated by admission. Recovery starts within weeks; the dose should be adjusted by reducing once the desired level is reached within the months. Azathioprine is used in patients who do not receive steroids, who do not respond to steroids, and who are trying to reduce steroid doses. Cyclosporine is a potent immunosuppressant that stops the interleukin-2 release from T-helper cells
  3. Plasma exchange and rapid immunomodulating treatments with intravenous immunoglobulins: They are used in situ ations requiring rapid recovery, such as myasthenic crisis or preparation for thymectomy operation
  4. Thymectomy: Thymus is considered to play a role in MG pathogenesis. Most patients with MG and AChR autoantibodies have thymus anomalies. Hyperplasia in 60%–70% of cases and thymoma in 10%–15% of cases were detected.[18],[19]



  Thymectomy Top


In patients with a thymoma and MG, thymectomy should be performed to remove the tumor.[20] A benefit after total thymectomy has been reported for this subgroup; an even greater benefit of total thymectomy has been reported for patients with early-onset MG without a thymoma. The thymus has a key role in inducing AChR antibody production in patients with MG.[21] Many studies have compared the outcomes for patients who undergo thymectomy with the outcomes for those who do not, and nearly, all the studies have shown a better outcome in the thymectomy group.[22],[23]

A recent international, randomized, controlled trial involving 126 patients with early-onset or late-onset MG confirmed a distinct benefit from early thymectomy, supporting thymectomy in patients with generalized disease, a disease duration of <3–5 years, an age of <60–65 years, and symptoms not fully relieved by anticholinesterase drugs.[24] Patients who underwent thymectomy, as compared with those who did not receive surgical treatment, had significant reductions in symptoms, immunosuppressive drug treatment, and exacerbations during 3 years of observation. The differences were regarded as clinically meaningful. All thymic tissues need to be removed, including the tissue embedded in mediastinal fat. Video- and robot-assisted methods minimize the surgical procedure, are preferred by most patients, and provide the same benefit as traditional open, transsternal thymectomy as long as all tissue is removed.

Guidelines and consensus statements recommend early thymectomy for patients with early-onset MG.[25],[26],[27] These patients most often have thymic hyperplasia. Thymectomy should also be considered in children.[28] Most patients with late-onset disease have an atrophic thymus.[21] However, thymic hyperplasia can occur in younger patients in the late-onset subgroup. Thymectomy should also be considered in patients with generalized MG who have AChR antibodies and whose symptoms developed at the age of 50–65 years, 67 especially when the biomarkers show similarities with early-onset disease. Current evidence does not support thymectomy in patients with MG and muscle-specific kinase or lipoprotein-related protein 4 antibodies.[26] Thymectomy is also not recommended for patients with ocular myasthenia, since there is insufficient evidence that surgery prevents generalization or results in remission. However, it has been argued that thymectomy should be considered for the treatment of ocular MG when drug treatment has failed, the patient has AChR antibodies, and neurophysiological tests indicate a risk of generalized disease.[29]

Thymectomy is usually not recommended for patients in whom all muscle antibody tests are negative. However, some of these patients have AChR antibodies that are not detected by routine assays. Therefore, in patients with negative muscle antibody tests who have generalized disease with biomarkers similar to those in patients with early-onset disease, thymectomy may be considered if the disease fails to respond to immunosuppressive drugs.[26]

Thymectomy for the treatment of MG is based on several lines of evidence that support a central role of the thymus in the pathogenesis of the disease.[30],[31] Thymomas are present in 10% of patients with MG, and thymectomy is considered to be mandatory to prevent further spread.[31] Up to 70% of the remaining patients with MG have hyperplastic thymic changes that are not seen in healthy persons.[4],[30] However, the success of immunotherapy has raised questions regarding whether such an operation is necessary.[25] A U. S. database suggests that hospital admissions for thymectomy in patients with MG fell dramatically after 2000.[32] Planned analysis of trial data to assess for correlation between histologic findings and response to thymectomy has not yet been conducted. Extended transsternal thymectomy requires median sternotomy and is associated with a resection of 85%–95% of the thymic tissue.[4],[26],[27],[28],[29],[30],[31],[32],[33]

The MGTX did not test less invasive thymectomy approaches that have similar effectiveness and shorter postoperative recovery times and better cosmesis.[34],[35] One concern is that surgeons who use minimally invasive techniques may leave behind ectopic thymic tissue in perithymic and pericardial fields.[33] In some studies, ectopic thymus has had a negative effect on outcomes at a follow-up of more than 7 years.[36] Furthermore, numerous reports describe patients with MG as not having clinical improvement after incomplete thymic resections.[37],[38] Randomized trials to compare resectional techniques are needed.


  Conclusions Top


Randomized trial of thymectomy in MG medication-controlled, rater-blinded trial showed a benefit of thymectomy in patients with MG over a period of 3 years with respect to clinical outcomes, requirements for prednisone and azathioprine therapy, the number of symptoms and the distress level related to immunosuppressive agents, and the need for hospitalization to manage disease exacerbations.[24]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Abstract
Introduction
Unresolved Issue...
Myasthenia Gravi...
Classification
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Thymectomy
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