Myasthenia Gravis

Myasthenia gravis (MG) is a rare autoimmune disease characterized by the production of antibodies to various proteins in the neuromuscular junction (NMJ).^1,2 Several antigens trigger antibody production, specifically nicotinic acetylcholine receptor (n-AChR), muscle-specific kinase (MuSK), and lipoprotein-related protein 4 (LPR4).³ Patients with MG experience muscle weakness and fatigue as a result of impaired neuromuscular transmission.¹ The ocular, facial, and limb muscles are frequently affected. Myasthenic crisis, in which the respiratory muscles are severely impaired, may also occur.¹

The Thymus in Myasthenia Gravis

In cases of MG, the thymus may exhibit histological abnormalities such as hyperplasia or a thymoma.² The thymus, a lymphoid tissue organ located in the upper chest, is described as being active mainly during early childhood and inactive by early adulthood.^1,4 The gland contributes to the production of antibodies, playing an important role in the maturation of T lymphocytes.¹ 

Thymomas are the most common type of thymic tumor, with an incidence of 1 to 5 per million people. They are found in approximately 8.5% to 15% of patients with MG.⁵ In MG, an abnormal thymus is associated with the increased production of inflammatory molecules such as cytokines; these in turn affect the function of regulatory T cells, promoting B-cell recruitment and the development of ectopic germinal centers.^6,7 Hyperplasia and T-cell infiltration indicate involvement of the thymus in producing antibodies to NMJ proteins.³

Thymectomy Procedure 

Thymectomy is surgical removal of the thymus gland. It is not usually used to treat active MG but is believed to improve long-term outcome.⁴

Removal of the thymus is indicated for patients with any subtype of MG who present with a thymoma and for patients with non-thymomatous n-AChR MG (particularly those between 15 and 50 years old; the procedure should be performed within 1 to 2 years after disease onset). Thymectomy is also indicated for patients with seronegative non-thymomatous MG.³ 

A phase 3 international clinical trial involving 126 participants evaluated the potential benefits of thymectomy in patients without a thymoma. The trial included patients aged 18 to 65 years with a recent diagnosis of non-thymomatous n-AChR MG. Participants were randomized to treatment with a thymectomy plus prednisone or prednisone only.⁸ After 3 years of follow-up, the patients who had undergone thymus resection had a lower Quantitative Myasthenia Gravis (QMG) score. In addition, within the thymectomy group, the dose of immunosuppressant required for disease management was lower, and fewer adverse events and hospitalizations due to myasthenic crisis were reported.⁸

A thymectomy should be considered when a patient is neurologically optimized. This approach ensures a safer postoperative period and decreases the risk for myasthenic complications with increased weakness.^5.9 

The preoperative evaluation should include an anesthesiologic assessment and an assessment of any coexisting diseases. The administration of immunoglobulins or plasmapheresis can be considered for high-risk patients.⁵ The classic surgical procedure for thymus resection uses a trans-sternal approach.^10,11 Because it is invasive, this surgical technique can affect the patient’s pulmonary function, which may already be impaired by MG. Therefore, the patient may be at high risk for pulmonary complications.⁵ Currently, less invasive options are available, such as video-assisted thoracoscopic and robotic video-assisted thoracoscopic surgery. Because they entail shorter hospital stays, reduced perioperative morbidity, and better cosmesis, these options are recommended for juvenile patients with MG.^2,9-11  

During the surgical removal of a thymoma, other structures, such as lung parenchyma and blood vessels, may have to be resected.⁵ The histologic grade of the tumor, excision margins, and metastasis are factors to be considered as the medical team decides whether any further chemotherapy or radiotherapy is necessary and establishes a monitoring plan.^5,9 

References

1. Myasthenia gravis. National Organization for Rare Disorders (NORD). Accessed February 7, 2022

2. Berrih-Aknin S, Le Panse R. Thymectomy in myasthenia gravis: when, why, and how? Lancet Neurol. 2019;18(3):225-226. doi:10.1016/S1474-4422(18)30467-8

3. Beloor Suresh A, Asuncion RMD. Myasthenia gravis. StatPearls [Internet]. Updated August 11, 2021. Accessed February 7, 2022.

4. Thymectomy resource center. Myasthenia Gravis Foundation of America. Accessed February 7, 2022.

5. Comacchio GM, Marulli G, Mammana M, Natale G, Schiavon M, Rea F. Surgical decision making: thymoma and myasthenia gravis. Thorac Surg Clin. 2019;29(2):203-213. doi:10.1016/j.thorsurg.2018.12.007

6. Berrih-Aknin S, Le Panse R. Myasthenia gravis: a comprehensive review of immune dysregulation and etiological mechanisms. J Autoimmun. 2014;52:90-100. doi:10.1016/j.jaut.2013.12.011

7. Gradolatto A, Nazzal D, Truffault F, et al. Both Treg cells and Tconv cells are defective in the myasthenia gravis thymus: roles of IL-17 and TNF-α. J Autoimmun. 2014;52:53-63. doi:10.1016/j.jaut.2013.12.015

8. Wolfe GI, Kaminski HJ, Aban IB, et al. Randomized trial of thymectomy in myasthenia gravis. N Engl J Med. 2016;375(6):511-522. doi:10.1056/NEJMoa1602489

9. Farmakidis C, Pasnoor M, Dimachkie MM, Barohn RJ. Treatment of myasthenia gravis. Neurol Clin. 2018;36(2):311-337. doi:10.1016/j.ncl.2018.01.011

10. Goldstein SD, Culbertson NT, Garrett D, et al. Thymectomy for myasthenia gravis in children: a comparison of open and thoracoscopic approaches. J Pediatr Surg. 2015;50(1):92-97. doi:10.1016/j.jpedsurg.2014.10.005

11. Wagner AJ, Cortes RA, Strober J, et al. Long-term follow-up after thymectomy for myasthenia gravis: thoracoscopic vs open. J Pediatr Surg. 2006;41(1):50-54; discussion 50-54. doi:10.1016/j.jpedsurg.2005.10.006

Reviewed by Hasan Avcu, MD, on 2/22/2022.

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Diana Diez Gaspar, PharmD, PhD

Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.