Myasthenia gravis is an autoimmune disease with impaired neuromuscular transmission that meets all the criteria for an autoimmune disease: (1) an antibody is present in almost all patients with the disease; (2) the antigen against which the antibody is directed plays an important role in the pathogenesis of the disease; (3) passive immunization of experimental animals with the antibody can replicate the disease; (4) active immunization of animals with the antigen can also induce the disease; and (5) Treatment to reduce the level of antibodies can alleviate the symptoms of the disease. There are many diagnostic and therapeutic methods for myasthenia gravis, but its therapeutic effect is not yet satisfactory. This paper reviews the current status of diagnostic and therapeutic methods for myasthenia gravis. Du Xiubo, Department of Pediatrics, The First Affiliated Hospital of Henan College of Traditional Chinese Medicine
1 Diagnostic methods of myasthenia gravis
Myasthenia gravis is not uncommon, and is often prone to omission and misdiagnosis. The diagnostic methods are: (1) Clinically, random muscle weakness that is aggravated after activity and alleviated after rest, with morning heaviness and evening lightness. (2) Pharmacologically, a positive cholinesterase inhibitor test, commonly used abroad as the vincristine test, and domestically as neostigmine methosulfate. The vincristine test is purely empirical and will not be helpful in suspicious cases. The neostigmine methosulfate test is more time-consuming, but can be observed more carefully and can be repeated. (3) Neurophysiologically, there are two methods of examination, one is low-frequency repetitive electrical stimulation of peripheral nerves with decreasing amplitude, and the other method is the broadening of tremor on single-fiber electromyography. The electrophysiological examination is relatively sensitive and reliable in detecting the patient’s neuromuscular junction dysfunction using repetitive electrical stimulation of peripheral nerves. Repetitive peripheral nerve stimulation detects approximately 90% of generalized myasthenia gravis and 30% to 60% of oculomotor myasthenia gravis. The most sensitive electrophysiologic test is the single-fiber EMG, which can detect EMG abnormalities in 95%-99% of patients with myasthenia gravis, and when the detected EMG is normal, myasthenia gravis can almost be excluded. Although this method is sensitive, it is not the preferred method because it requires the skill of the examiner and the cooperation of the person being examined. (4) Immunologically, elevated serum acetylcholine receptor antibodies contribute to the diagnosis. Negative serum acetylcholine receptor antibodies also do not rule out myasthenia gravis because only 80%-90% of generalized myasthenia gravis and 30%-50% of oculomotor myasthenia gravis can be detected with serum acetylcholine receptor antibodies. In some patients with myasthenia gravis who cannot detect serum acetylcholine receptor antibodies, the presence of serum anti-muscle tyrosine kinase antibodies may be detected, as about 30%-40% of generalized myasthenia gravis and very few ocular myasthenia gravis with negative serum acetylcholine receptor antibodies can be detected. Neither serum aIlti-AChRAbs nor serum anti-MuSK Abs are detectable in about 5% of patients. (5) Immunopathologically, a decrease in the number of post-synaptic membrane folds at the neuromuscular junction, flattening, and a decrease in functional acetylcholine receptors on them, is helpful in confirming the diagnosis. For non-teaching hospitals that generally do not have neurophysiological equipment, the diagnosis can be made on the basis of the first two items alone. For teaching hospitals that are equipped, the last three tests are useful for research.
2 Treatment of myasthenia gravis
2.1 Cholinesterase inhibitors
Cholinesterase inhibitors are effective drugs for symptomatic treatment of myasthenia gravis, which can transiently improve neuromuscular junction transmission, but cannot fundamentally change the immunopathological process of myasthenia gravis. These drugs improve the symptoms of almost all patients with myasthenia gravis, but the improvement of symptoms often does not last long, so most patients will need other treatments. Long-term use of cholinesterase inhibitors can exacerbate pathological changes at the neuromuscular junction, as evidenced by reduced sensitivity to these drugs, increased need for them, and more pronounced side effects. Oral cholinesterase inhibitors are often used in the treatment of myasthenia gravis, and injectable cholinesterase inhibitors are often used in the diagnostic tests of myasthenia gravis and in the rescue of myasthenia gravis crisis.
2.2 Adrenal corticosteroid therapy
Despite the lack of popular case-control studies of corticosteroids for myasthenia gravis, corticosteroids are the most commonly applied and effective immunosuppressive agents. During the first months of treatment, serum acetylcholine receptor antibody levels decrease and most patients achieve clinical improvement, but they also suppress lymphocyte differentiation and proliferation, redistribute lymphocytes in tissues, alter cytokine expression, inhibit macrophage function and antigen presentation and expression, and reduce the patient’s immunity, all common pitfalls of hormone therapy. They can be administered in high doses for several months or in low doses for several years. The common methods of administration are “high-dose shock, tapered maintenance therapy” and “medium-dose shock, low-dose maintenance therapy”.
2.3 Chemical immunosuppressive therapy
At present, the commonly used chemical immunosuppressants include cyclophosphamide, azathioprine, cyclosporine A, FK506 and so on. These drugs are suitable for patients with severe myasthenia gravis with tuberculosis, ulcer disease or diabetes; patients with recurrent symptoms after thymectomy and plasma exchange; and patients with decreasing effect of long-term hormone application and hormone dependence. Cyclophosphamide can destroy intracellular DNA and inhibit RNA synthesis, and has an effect on both humoral and cellular immunity due to the inhibition of secretion and proliferation of immunologically active cells, which is especially significant in B-lymphocytes. Oral or intravenous cyclophosphamide has been effectively used in the treatment of myasthenia gravis, with most patients experiencing symptom disappearance after the la of treatment. This delay in efficacy and its inherent side effects (gastrointestinal reactions, alopecia, liver damage, hemorrhagic cystitis, leukopenia and thrombocytopenia) limit its use. Azathioprine is a purine analog that reduces the synthesis of nucleotides and inhibits the proliferation of T and B cells. It has been used alone since 1970 for the treatment of myasthenia gravis, and a randomized, double-blind pilot study has demonstrated its effectiveness. Cyclosporine-A is a potent immunosuppressive agent that may inhibit CD4+ T helper cells and toxic cells by inhibiting IL-2 release or inhibiting the IL-2 receptor. Its effectiveness in the treatment of myasthenia gravis was initially found by a small randomized, placebo-controlled trial, which was later refuted by a large group of similar trials. However, a large number of retrospective studies support a hormone-like effect. fK506 has a more potent anti-proliferative effect on activated T cells because it interferes with the production of IL-2, which is required for the conversion of cells from the resting G0 to G1 phase. More retrospective studies have concluded that it has a therapeutic effect on myasthenia gravis with few side effects, and only a few patients may experience elevated blood pressure, lipids and gastrointestinal bleeding.
2.4 Thymectomy
Thymus lesions play an important role in the development of myasthenia gravis, and about 70% to 80% of myasthenia gravis patients have thymus lesions. The use of thymectomy in the treatment of myasthenia gravis has been controversial, and many retrospective studies have reached different conclusions, but in these studies, different surgical approaches, different criteria for determining treatment efficacy, and different statistical methods have been used. Currently, most authors believe that thymectomy can lead to better long-term outcomes for patients and that thymectomy is one of the most important tools in the treatment of myasthenia gravis. Thymectomy should be performed with good selection of indications and attention to perioperative management in order to reduce the rate of postoperative complications and improve the surgical efficacy of the patient.
2.5 Plasma exchange therapy and intravenous gammaglobulin infusion therapy
Plasma exchange and intravenous immunoglobulin are often used in the emergency management of severe myasthenia gravis. Plasma exchange displaces plasma containing disease-causing substances in the patient’s body, resulting in a rapid decrease in plasma antibody concentrations and thus providing effective and rapid relief of symptoms. Gammaglobulin therapy is often administered intravenously at high doses to treat myasthenia gravis. The mechanisms of gammaglobulin therapy are complex and include inhibition of cytokines, competition for autoantibodies, inhibition of complement, prevention of Fc receptor and Ig receptor binding to macrophages and B cells, respectively, and prevention of antigen recognition by sensitized T cells. There are some patients with myasthenia gravis in whom hormones alone or in combination
or the immunosuppressive drugs mentioned above do not relieve symptoms, or some patients cannot tolerate the side effects of these drugs, and cyclophosphamide combined with bone marrow transplantation may be effective in these patients. In addition to the above commonly used treatments, immunomodulatory therapy and Chinese herbal medicine are also used in the treatment of myasthenia gravis.
Currently, there is a lack of studies with good statistical validity and perfect design to evaluate treatments for myasthenia gravis, and there is still no specific treatment for myasthenia gravis autoimmunity. However, many specific approaches using immunosorbent mechanisms to remove pathogenic antibodies from the body have recently been explored, providing additional approaches for the precise treatment of myasthenia gravis. With the understanding of autoimmune diseases and myasthenia gravis, it is believed that new approaches to block or eliminate autoimmune responses will be available in the near future.