Myasthenia Gravis (MG) is a severe autoimmune condition caused by an antibody-mediated obstruction of neuromuscular conveyance that causes weakness in the skeletal muscles and rapid fatigue. Skeletal muscles involved in MG disorder include controlling breathing, facial expression, eye movement, talking, chewing, and swallowing, among others. Although the myasthenia gravis means grave in Greek and Latin, most cases are not that deadly since there are treatments that help control symptoms, allowing people to live a normal life. Muscle weakness that aggravates after activity durations and improves after durations of rest indicates MG disorder. The sudden appearance of MG disorder may hinder the immediate recognition of symptoms of MG disorder. Some of the common symptoms include weakness of the eye muscles, blurred vision, shortness of breath, changes in facial expression, and weakness in hands, legs, and fingers. The disorder can affect anyone at any age, but it is more common in young women between 20 to 30 years and adult men of 50 years and above. This research paper explores the causes, impacts on the anatomy and physiology of the body system, prevention, and treatment of MG disorder.
Normal Anatomy of the Major Body System Affected by MG
Myasthenia Gravis affects the normal functioning of the musculoskeletal system. The muscular system includes skeletal muscles, and the muscular system comprises tendons that connect muscles to the bones. The skeletal muscle includes bones that articulate with each other to form the joints that provide a firm yet mobile skeleton in support of the articular ligaments, bursae, and cartilage. The skeletal muscles are grouped into four, namely, the head and neck muscles which include the facial expression muscles, the orbit, tongue, pharynx, neck, and larynx muscles (Putri, 2022). The second group is the trunk muscles, including the back muscles, lateral and anterior abdominal muscles, and pelvic muscles. The other one is the muscles of the upper limbs, which include the hand, forearm, hand, and shoulder muscles. The last one is the lower limb muscles, which comprise the leg, foot, hip, and thigh muscles.
The Trunk Muscles Anatomy
The skeletal muscles also contain the myocyte cells or muscle fibres covered by connective tissues known as endomysium. The myocytes cells are found in packs known as fascicles and are held together by a layer of connective tissue known as the perimysium. The fascicles join to create muscles, covered by a layer of connective tissue called epimysium (Robson and Syndercombe Court, 2019). The epimysium combines with the perimysium to form the muscle tendon that connects the muscles to the bone periosteum. The tendons and ligaments are inserted into the bone in an enthesis site. The site where the muscles and tendons move over the bone edge contains fluid-filled sacs known as Bursas.
Normal Physiology of the Major Body System Affected by MG
The musculoskeletal system provides the human body stability, support, movement, and shape (Putri, 2022). Skeletal muscles work antagonistically to create movements in the body. The motor nerves facilitate the movement function of skeletal muscles by providing signals to shorten and pull the bones towards each other. Skeletal muscle contraction occurs either isometrically or isotonically. Isometric contraction happens if there is no change in the length of the muscle during a contraction, while isotonic is when the tension remains the same as the muscle length changes. The contraction of the muscles begins in the nervous system, where a signal known as action potential is created (Pham and Puckett, 2020). The neuromuscular junction (NMJ) forms a chemical synapse between the nerve and the muscle fibre, called the neuromuscular junction (NMJ). The action potential from the motor neuron releases acetylcholine (ACh) into the NMJ, which transmits the electrical impulses from the motor neuron to the receptors in the muscles. The ACh stimulates chemical reactions in the muscle fibre, which involves calcium ions release, causing the rearrangement of the contractile proteins in the muscle fibre. The proteins slide over each other, causing contraction. However, the chemical process reverses when the nerve signal diminishes, causing the muscle to relax.
Mechanism of Myasthenia Gravis
The motor nerve can release the contents of each vesicle of ACh by exocytosis in the case of a healthy neuromuscular junction. The continued release of ACh by the motor nerve activates the inherent ion mediums of AChRs in the postsynaptic membrane causing depolarization. Then the motor nerve action potential opens calcium channels triggering exocytosis of many ACh vesicles leading to more depolarization. In healthy persons, the endplate potential that causes depolarization is sufficient to activate the postsynaptic voltage-gated sodium channels (VGNaCs) in order to create a muscle action potential. Conversely, in the neuromuscular junction affected by myasthenia gravis, AChR antibodies activate complement resulting in membrane attack damage to the architecture of the post-junctional membrane (Phillips and Vincent, 2016). Moreover, divalent antibodies, including AChR internalization, cause depletion of the amount of the postsynaptic AChR leading to the production of less volume of EPP. Therefore, the EPP fails to reach the necessary amount needed for the activation of postsynaptic VGNaCs, thus unable to create a muscle action potential resulting in muscle weakness.
Seemingly, in a healthy muscle-specific kinase (MuSK)-mediated postsynaptic disparity pathway at the NMJ, neural agrin produced by the terminal the motor nerve connects to lipoprotein receptor-related protein 4 (LRP4), which leads to dimerization of MuSK when in low-density. The dimerization causes MuSK phosphorylation, and the involved proteins of the MuSK route recruit Rapsyn to the phosphorylated AChRs resulting in the stability of the AChRs postsynaptic clusters (Phillips and Vincent, 2016). However, postsynaptic differentiation is affected by the MuSK model of MG; the autoantibodies of MuSK are mainly subclass of immunoglobulin. MuSK autoantibodies lead to the blockade of the agrin-LRP4-MuSK complex assembly. The MuSK kinase signalling interruption causes delayed postsynaptic AChR cluster disassembly, resulting in a decrease in EPP volume, thus causing the failure of the muscle action potential, increasing muscle weakness.
Prevention
According to the 2021 updates from the National Institute of Neurological Disorders and Stroke and Myasthenia Gravis Foundation of America, there are no determined methods of preventing Myasthenia Gravis (Shaibani et al., 2021). Individuals with MG disorder are advised to adhere to the following steps to avoid the crisis. The steps include observing hygiene, avoiding sick people, treating infections immediately, avoiding too much heat or cold, avoiding overexertion, and learning effective ways of managing stress.
Treatment
The treatment strategy for MG disorder depends on the intensity of the symptoms in the patients. According to the Myasthenia Gravis Foundation of America, the strength of MG disorder can be divided into three categories, namely; Class 1and 2 (mild), Class 3 (moderate), and Class 4 and 5 (severe) (AL-Zwaini and Ali, 2019). In classes I and 2, mild weakness of some muscles such as eye, limb, axial, and respiratory muscles are observed, among others are observed. In class 3, moderate weakness of the eye, limb, axial, and respiratory, among others, is observed. In class 4, severe weakness in the eye, limb, axial, and respiratory muscles, among others, is observed. In class 5, the symptoms are severe, and cannulation is required to maintain the airway. MG is treated through various therapeutic options, such as pharmacologic therapy, immunosuppressive agent, therapeutic plasma exchange (TPE(), intravenous immunoglobulin (IVIG), and Thymectomy. Pharmacologic therapy is used in the treatment of MG through reversible AChE reversal inhibitor administration, pyridostigmine, and is very effective in the generalized and acular patients (AL-Zwaini and Ali, 2019). However, this therapy is not much effective in MG patients with anti-MuSK antibodies. Steroid and immunosuppressive agents should be considered when administering pharmacologic therapy to patients with poor pyridostigmine response. The use of immunosuppressive agents like corticosteroids helps in the prevention of worsening from acular to generalized. However, the use of rituximab in the treatment of refractory MG may indicate improvement and less usage of corticosteroids and TPE (AL-Zwaini and Ali, 2019). Therapeutic plasma exchange deals with the removal of a patient’s plasma and replacing it with a fresh one. This results in the removal of autoantibody against AChRs, causing a short-term improvement of NMJ conveyance, thus increasing the strength of the muscle. TPE is most effective for severe generalized, refractory, and myasthenia crisis MG patients. The use of Intravenous immunoglobulin (IVIG) involves cytokines inhibition and complement deposition, autoantibodies competition, Fc receptor interference on macrophages and immunoglobulin receptor on B cells, and interference with sensitized T cells (AL-Zwaini and Ali, 2019). IVIG is used to treat severe MG and MuSK-MG, refractory and juvenile MG, and myasthenia crisis. Thymectomy is used to treat patients with thymoma and those aged between 10 to 50 years with generalized MG without thymoma. Thymectomy is the most effective for generalized MG patients, but it is not recommended for patients with antibodies against MuSK, LRP4, or origin antibodies (AL-Zwaini and Ali, 2019). Also, Thymectomy can lead to spontaneous remission if applied to ocular MG patients within the first two years after diagnosis.
Conclusion
Myasthenia Gravis is a rare severe autoimmune disorder caused by an antibody-mediated obstruction of neuromuscular transmission and causes weakness in the skeletal muscles. Different MG patients’ subsets create autoantibodies with specific, isotypic, and pathogenic mechanisms. The failure of neuromuscular transmission and postsynaptic AChRs loss is a result of the convergence of various pathogenic mechanisms. Agrin signalling provides more effective protection of the functioning of the NMJ. Additionally, divalent antibodies, including AChR internalization, cause depletion of the amount of the postsynaptic AChR leading to the production of less volume of EPP, leading to a muscle action potential that results in muscle weakness. Seemingly, the MuSK kinase signalling interruption leads to delayed postsynaptic AChR clusters disassembly, resulting in a decrease in EPP volume, thus causing the failure of the muscle action and potential increasing muscle weakness. Finally, Thymectomy is the most effective for generalized MG patients, but it is not recommendable for patients with antibodies against MuSK, LRP4, or origin antibodies.
References
AL-Zwaini, I. J., & Ali, A. M. (2019). Introductory Chapter: Myasthenia Gravis-An Overview. Selected Topics in Myasthenia Gravis.
Pham, S., & Puckett, Y. (2020). Physiology, Skeletal Muscle Contraction.
Phillips, W. D., & Vincent, A. (2016). Pathogenesis of myasthenia gravis: update on disease types, models, and mechanisms. F1000Research, 5.
Putri, Y. R. (2022). Anatomy And Physiology of Human Body. Get Press.
Robson L & Syndercombe Court D (2019) Bone, Muscle, skin and connective tissue. In: Naish J, Syndercombe Court D (eds) Medical Sciences. Edinburgh: Elsevier.
Shaibani, A., Zahra, A., & Sultani, H. A. (2021). Coping with Myasthenia Gravis. AuthorHouse.
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