Myasthenia Gravis

Myasthenia gravis (MG) is a rare neuromuscular disease but the most common condition affecting the neuromuscular junction (NMJ)in skeletal muscle.^1-3 The hallmark of MG is generalized fatigability and muscle weakness, which develop as a consequence of reduced transmission of electrical impulses across the NMJ.³ Weakness can affect the ocular, bulbar, respiratory, axial, and limb muscles.⁴ 

MG occurs predominantly in women younger than 40 years and in men older than 50 years. The prevalence of this disease in the United States is estimated to be 14 to 20 per 100,000 population.^2,3 

Causes

MG is commonly caused by an antibody-mediated autoimmune response in which various antibodies attack and injure receptors in muscles ​that receive nerve impulses. An increased frequency of human leukocyte antigens (HLAs) in patients with MG indicates that genetic susceptibility may play a role in the development of MG.¹ The proteins that typically trigger the development of antibodies are nicotinic acetylcholine receptor (n-AChR), muscle-specific kinase (MuSK), and lipoprotein-related protein 4 (LPR4).³ The abnormal autoimmune reaction results in decreased transmission at the NMJ and consequently weak muscle contraction.¹

MG can develop after an infection or surgery or after the administration of drugs. It can also develop in individuals with genetic susceptibility.³ Abnormalities of the thymus have also been associated with MG. Approximately 10% of patients with MG patients present with a thymoma (thymic tumor), and approximately 70% with hyperplastic changes.^2,3 

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Types and Symptoms

The symptoms of MG are typically mitigated by rest; however, they may progress during the course of the disease. MG can affect any voluntary muscle but most frequently affects the muscles of the eyes, face, throat, neck, and limbs.⁵ Disease limited to the eye muscles, ocular myasthenia, may be confused with stroke in the brainstem; disease that affects several muscle groups is described as generalized myasthenia.¹

Weakness affecting the eyes is often the first sign of the disease. Patients present ptosis, diplopia, or both.¹ The dysarthria and dysphagia that occur after the development of weakness in the muscles of the face, jaw, and throat pose safety and nutritional concerns.¹ Weakness in the neck, arms, and legs can impair walking and make it difficult to hold up the head.⁵ Myasthenic crisis develops as a complication of MG in 10% of patients.^1,3 Myasthenic crisis, characterized by severe generalized weakness of the respiratory muscles (intercostal muscles and diaphragm),^1-3 is a medical emergency in which respiratory assistance is required to prevent respiratory failure.^1,2 Other complications of MG include adverse effects of the long-term administration of medications, including opportunistic infections and lymphoproliferative disease.³

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Diagnosis and Approaches to Treatment

MG can be diagnosed with a neurological examination, blood analysis, and tests to evaluate nerve and muscle function.⁵ 

During a neurological examination, the medical team assesses the patient’s reflexes, muscle strength, and balance. Blood tests can detect the antibodies that are affecting neuromuscular transmission.^5,6 

Repetitive nerve stimulation and single-fiber electromyography (EMG) provide information about nerve conduction and the electrical activity occurring between the brain and skeletal muscles.^1,5 Computed tomography or magnetic resonance imaging of the thymus is also used as a tool to diagnose MG.^1,5 Other diagnostic procedures, such as edrophonium chloride and ice pack tests, are typically used to diagnose ocular MG.³

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Treatment

After MG has been diagnosed, treatment should be individualized according to the age of the patient and the severity of the symptoms. Improvement and remission are possible, particularly if treatment is implemented when the disease is in an early phase.²

Many treatments are available for MG. Medications such as cholinesterase inhibitors (Mestinon), corticosteroids (prednisone), and immunosuppressants (azathioprine, mycophenolate mofetil, cyclosporine, methotrexate, tacrolimus) can be prescribed either to facilitate communication between the nerves and muscles or to control the production of antibodies.^1,5 Monoclonal antibodies such as rituximab (Rituxan^®) and eculizumab (Soliris^®) can be prescribed for patients whose disease does not respond to other therapeutic approaches.^1,5

Other therapies may be administered to a patient who has worsening symptoms or is about to undergo a surgical procedure. An infusion of intravenous immunoglobulin or plasmapheresis may reduce the quantity of antibodies impairing NMJ transmission.^3,5 These therapeutic approaches are also used during a myasthenic crisis because of their quick onset of action.³ 

Surgical removal of the thymus is indicated for a patient with any type of MG who presents with a thymoma, who has seronegative non-thymomatous MG, or who has non-thymomatous AChR MG in an early phase.³ 

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References

1. Myasthenia gravis. National Organization for Rare Disorders (NORD). Accessed February 3, 2022.

2. Howard JF Jr. Clinical overview of MG. Myasthenia Gravis Foundation of America. Accessed February 3, 2022.

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

4. Hehir MK, Silvestri NJ. Generalized myasthenia gravis: classification, clinical presentation, natural history, and epidemiology. Neurol Clin. 2018;36(2):253-260. doi:10.1016/j.ncl.2018.01.002

5. Myasthenia gravis. Symptoms and causes. Mayo Clinic. Accessed February 3, 2022.

6. Mantegazza R, Cavalcante P. Diagnosis and treatment of myasthenia gravis. Curr Opin Rheumatol. 2019;31(6):623-633. doi:10.1097/BOR.0000000000000647

Reviewed by Debjyoti Talukdar, MD, on 2/4/2022.

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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.