Introduction
M.J. is a 42-year-old female who presented with a history of bilateral ptosis and diplopia lasting for a period of 3 years. The patient reports dysphagia, dysarthria, shortness of breath, and a generalized decrease in muscle tone. The symptoms were gradual in onset and worsened with time which necessitated her hospital visit. The condition had impacted her daily activity as a swimming coach as she could no longer swim and issue instructions clearly to her students. She had also become dependent on her daughter for support to ambulate and manage her daily activities. She reports using prednisolone to manage the condition for the past three years. She reports the disorder having weakened her body and impaired her normal functioning. She felt lonely at times and left out as she missed out on her training sessions and her swimming students. The patient also reports having tried various complementary therapies that did not cure the condition completely.
In her past medical history, she had been admitted following a myasthenia crisis one year ago which was managed with pyridostigmine and responded well to therapy. She also reports using chloroquine in her twenties and quinidine for her arrhythmias. These two drugs have been documented to increase the risk of myasthenia gravis. She has no family history of this autoimmune condition. On further assessment, she had a positive Tensillon’s test and a positive ice pack test, pointing to myasthenia gravis. Her muscle strength rapidly improved with edrophonium, a short-acting anticholinesterase agent. Her ptosis also improved rapidly following ice pack placement over the upper eyelids. The anti-Ach receptor antibodies were positive, the MUSK receptor antibodies were negative.
Pathophysiology of Myasthenia Gravis
Myasthenia Gravis is a rare type of acquired autoimmune condition that is secondary to antibody-mediated inhibition of neuromuscular junction transmission of impulses causing progressive muscle weakness (Sriwastava et al., 2021). Myasthenia gravis occurs when the body produces autoantibodies against the postsynaptic nicotinic acetylcholine receptors. The binding of the IgG1 antibody onto the nAChR results in the complement-mediated destruction of the receptors (Sriwastava et al., 2021). Depletion of these receptors makes it difficult to excite skeletal muscles as there will be no ligand-mediated opening of sodium channels. This makes it hard to transmit an action potential from the motor nerves to the muscle fibers (Sriwastava et al., 2021). Decreased muscle excitability causes generalized weakness, fatigability, ptosis, and diplopia.
The real stimulus for the development of autoantibodies is not clearly known but a history of thymoma has been linked to myasthenia gravis (Sriwastava et al., 2021). Defective thymus proliferation releases defective B and T cells. Defective B cells proliferate into defective plasma cells which release antibodies targeting self-receptors resulting in antibody-mediated complement destruction of nAChRs (Sriwastava et al., 2021). Various medications have also been implicated in the development of anti-acetylcholine receptor antibodies. Penicillamine, chloroquine, and quinidine have been implicated in the pathophysiology of Myasthenia gravis (Safa et al., 2019). Ocular involvement is the most common symptom where the patient complains of blurred vision or double vision at times accompanied by ptosis that resolves with an ice pack test.
Another type of postsynaptic receptor that is affected in myasthenia gravis is the muscle-specific tyrosine kinase receptor (MUSK receptor) (Safa et al., 2019). The MUSK receptor stimulates the expression of nAChR and maintains these receptors in the postsynaptic membrane. Thus, the release of autoantibodies that target these receptors aggravates muscle weakness and fatigue (Safa et al., 2019). Complimented mediated destruction of the MUSK receptors reduces the number of new nAChR being formed to replace the degenerated and destroyed nAChRs. This results in progressive skeletal muscle weakness, a decreased force of skeletal muscle contraction, and generalized body weakness in an individual.
MUSK antibodies have no thymoma relation but are most common in women. This type of myasthenia gravis resulting from anti-MUSK autoantibodies is referred to as generalized myasthenia and it mainly presents with bulbar symptoms (Safa et al., 2019). These symptoms include weakness of the pharyngeal and laryngeal muscles causing difficulty in swallowing and slow slurred speech and dysarthria (Safa et al., 2019). Respiratory muscle involvement is common resulting in myasthenia crisis where the patient presents with respiratory distress and requires nonmechanical ventilation to be resuscitated.
Management of Myasthenia Gravis
The mainstay management of Myasthenia Gravis depends on the exact subtype of the condition (Lazaridis & Tzartos, 2020). The most commonly available therapies are corticosteroids for immune modulation, long-term suppression of the immune system, anticholinesterase therapy, plasmapheresis, thymectomy, and the use of interventional agents. Anticholinesterase agent pyridostigmine is the first-line medication that mainly improves the symptoms by inhibiting the enzyme responsible for breaking down acetylcholine (Lazaridis & Tzartos, 2020). Neostigmine can be used in place of pyridostigmine.
Corticosteroids like prednisolone are also used in the management of myasthenia gravis. Prednisolone mainly inhibits the proliferation of lymphocytes which have been implicated in the pathophysiology of myasthenia gravis (Lazaridis & Tzartos, 2020). By inhibiting the differentiation of B cells into plasma cells, autoantibodies are not produced thus minimizing the complications of the condition. Corticosteroids are used for a longer duration to alleviate the symptoms (Lazaridis & Tzartos, 2020). Rapidly acting immunomodulating agents like intravenous immunoglobulins are also employed in the management of myasthenia gravis.
Plasmapheresis works by removing the plasma with the highest concentration of autoantibodies and replacing it with fresh plasma containing zero autoantibodies. Cyclosporin is another immunosuppressant medication that targets interleukin 2 and modulates the action of T lymphocytes (Lazaridis & Tzartos, 2020). Azathioprine targets both lymphocytes, B and T cells, and is used as a first-line steroid-sparing medication. Other commonly used immunosuppressant agents include methotrexate, tacrolimus, cyclophosphamide, rituximab, and mycophenolate.
One of the novel strategies devised to manage myasthenia gravis is Eculizumab. This drug is a humanized monoclonal antibody that targets the immunopathogenesis of the condition by inhibiting the MAC complex in the neuromuscular junction in adult patients with ocular myasthenia gravis (Lazaridis & Tzartos, 2020). Other drug medications still under trial include ocrelizumab, a humanized antibody against B cells that targets the B cell receptor, CD-20. Abatacept is another novel cytotoxic drug that inhibits the costimulation of cytotoxic T lymphocytes by blocking the CD-28 receptor.
Daclizumab on the other hand antagonizes the activity of IL-2 by binding onto the CD-25 receptor but has severe side effects like encephalitis and immune-mediated hepatitis making it toxic to humans (Hübers et al., 2020). Belimumab was designed to reduce B cell activation and thus reduce antibody production by binding onto the B cell activating factor. Bortezomib, a protease inhibitor proved to aid in managing myasthenia gravis by lowering the antibody titers in myasthenia patients (Hübers et al., 2020). This drug also protected the postsynaptic membrane from complement-mediated destruction.
Thymectomy is another management plan for myasthenia gravis which has been proven to induce remission of the condition (Hübers et al., 2020). It also eliminates the need for immunosuppressant therapy over a long period of time. This is only useful in patients with positive anti-acetylcholine receptor antibodies (Hübers et al., 2020). Some medications are known to worsen myasthenia gravis thus the need to avoid such medications in these patients, aminoglycosides, chlorpromazine, diazepam, halothane, ketamine, lithium, phenytoin, nifedipine, and amlodipine.
Summary
Myasthenia gravis is an autoimmune condition affecting the muscular system. This condition stems from the destruction of acetylcholine receptors on the postsynaptic membrane by the autoantibodies generated by the plasma cells against self-receptors. Destruction of these receptors makes it difficult to stimulate muscular contraction hence progressive weak muscular contractions and fatigability (Sriwastava et al., 2021). This autoimmune disorder also affects the ocular system resulting in blurred vision, double vision, and ptosis. When the bulbar system is affected, the patient presents with difficulty in swallowing and dysarthria.
Thymoma has been linked to myasthenia gravis. Defective thymus proliferation releases defective B and T cells (Rodolico et al., 2020). Defective B cells proliferate into defective plasma cells which release antibodies targeting self-receptors resulting in antibody-mediated complement destruction of nAChRs. Various medications have also been implicated in the development of anti-acetylcholine receptor antibodies, like penicillamine.
The respiratory muscles can also be involved in the myasthenia crisis causing rapid respiratory distress in the patient following weak contractions of respiratory muscles. A Myasthenia crisis is a medical emergency that requires non-mechanical patient ventilation and the administration of anticholinesterase agents like pyridostigmine (Rodolico et al., 2020). Management of myasthenia gravis targets its own pathophysiology. Immunosuppressive agents like prednisolone, azathioprine, tacrolimus, cyclophosphamide, and methotrexate are used in long-term patient management.
Humanized monoclonal antibodies are also synthesized to manage the condition by blocking out specific sites in the neuromuscular junction (Rodolico et al., 2020). Eculizumab is a humanized monoclonal antibody that targets the immunopathogenesis of the condition by inhibiting the MAC complex in the neuromuscular junction in adult patients with ocular myasthenia gravis (Rodolico et al., 2020). Other management strategies include plasmapheresis which clears the plasma with high antibody titers, thymectomy has been documented to bring about a complete remission of myasthenia gravis in a patient with positive anti-acetylcholine autoantibodies.
References
Hübers, A., Lascano, A. M., & Lalive, P. H. (2020). Management of patients with generalised myasthenia gravis and COVID-19: four case reports. Journal of Neurology, Neurosurgery & Psychiatry, 91(10), 1124-1125. https://jnnp.bmj.com/content/91/10/1124.abstract
Lazaridis, K., & Tzartos, S. J. (2020). Myasthenia gravis: autoantibody specificities and their role in MG management. Frontiers in Neurology, 11, 596981. https://www.frontiersin.org/articles/10.3389/fneur.2020.596981/full
Rodolico, C., Bonanno, C., Toscano, A., & Vita, G. (2020). MuSK-associated myasthenia gravis: clinical features and management. Frontiers in Neurology, 11, 660. https://www.frontiersin.org/articles/10.3389/fneur.2020.00660/full
Safa, H., Johnson, D. H., Trinh, V. A., Rodgers, T. E., Lin, H., Suarez-Almazor, M. E., … & Diab, A. (2019). Immune checkpoint inhibitor-related myasthenia gravis: single center experience and systematic review of the literature. Journal for immunotherapy of cancer, 7(1), 1-11. https://link.springer.com/article/10.1186/s40425-019-0774-y
Sriwastava, S., Tandon, M., Kataria, S., Daimee, M., & Sultan, S. (2021). New onset of ocular myasthenia gravis in a patient with COVID-19: a novel case report and literature review. Journal of Neurology, 268(8), 2690-2696. https://link.springer.com/article/10.1007/s00415-020-10263-1
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