Myasthenia gravis - Treatment

Treatment of myasthenia includes symptomatic therapy with acetylcholinesterase inhibitors and therapy aimed at modifying the natural history of the disease (thymectomy, immunosuppression with corticosteroids, azathioprine and/or cyclosporine, plasmapheresis, intravenous immunoglobulin). Although knowledge of the pathogenesis of myasthenia undoubtedly helps to explain the beneficial effects of these treatments, unfortunately, there are no large, double-blind, controlled trials to determine which treatment is most appropriate for a particular patient at a particular time. As a result, different specialists recommend different treatment regimens for myasthenia.

Anticholinesterase drugs may increase muscle strength by prolonging the half-life of AChR at the neuromuscular junction, increasing the likelihood that the neurotransmitter will be able to cross the widened synaptic cleft and interact with the reduced numbers of AChR on the muscle membrane. Pyridostigmine is the most widely used acetylcholinesterase inhibitor. Treatment is usually initiated at a dose of 60 mg given up to 4 to 6 times daily. A sustained-release form of pyridostigmine containing 180 mg is available and is usually given at bedtime to maintain muscle strength in the early morning hours and to allow the patient to swallow the morning dose. The pharmacological action of a dose of 60 mg begins after 30-60 minutes and reaches a peak after 2-3 hours, and then weakens within 2-3 hours. Muscle sensitivity to the drug is variable, therefore, to increase their strength, the dose and frequency of administration of the drug must be increased. However, the need to take the drug in a dose exceeding 120 mg more often than every 3 hours rarely occurs. It is important to note that with an increase in the dose of an acetylcholinesterase inhibitor, strength may increase in some muscles, while in others it may decrease. During the treatment period, it is necessary to carefully monitor that the improvement in the function of certain muscle groups is not accompanied by a deterioration in respiratory function, which should be especially carefully monitored. Side effects of acetylcholinesterase inhibitors include diarrhea, painful spasms, increased bronchial secretion, most of which are easily corrected. Because acetylcholinesterase inhibitors provide only symptomatic improvement, they are often combined with immunosuppressive therapy, which affects the course of the disease.

Corticosteroids undoubtedly have a positive effect in myasthenia, but there is no consensus among specialists on the optimal scheme of their use. The therapeutic effect of corticosteroids is probably associated with their influence on immune processes, but the specific mechanisms of their action in myasthenia remain unclear. As with other autoimmune diseases, starting treatment with high doses of corticosteroids can achieve a more rapid effect than prescribing lower doses. Side effects are the main factor limiting the duration of corticosteroid therapy. These side effects include diabetes mellitus, gastric ulcer, arterial hypertension, weight gain, fluid retention, aseptic bone necrosis, osteoporosis, cataracts. Concerns are also raised by the possibility of recurrent infections, which often occur with the use of any treatment regimen. If the patient has one of these conditions (for example, diabetes mellitus, gastric ulcer), corticosteroids are contraindicated before treatment.

The use of corticosteroids in myasthenia is associated with particular risk, since high doses can provoke a rapid increase in weakness, especially of the respiratory muscles. Depending on the dose and route of administration, this complication may occur 4-7 days after the start of treatment. Therefore, high doses of corticosteroids should be prescribed only with the possibility of careful monitoring of the patient's condition. In cases of severe weakness of the oropharyngeal or respiratory muscles, hospitalization is usually indicated in order to ensure monitoring of the neurological status, respiratory function, and response to treatment. In severe generalized myasthenia in patients with swallowing disorders and mild to moderate respiratory failure, in the absence of contraindications, high doses of intravenous methylprednisolone (1000 mg/day for 5 days) can be used with careful monitoring of blood sugar, blood pressure, and respiratory function. Calcium preparations and H2-receptor antagonists should be prescribed at the same time. If respiratory function worsens, the patient should be transferred to the intensive care unit and other immunotherapy methods, such as plasmapheresis and intravenous immunoglobulin, should be considered. As symptoms subside, the patient is switched to oral prednisolone every other day. Some centers have successfully administered intravenous methylprednisolone using slightly different regimens.

In cases of mild weakness, patients can be treated on an outpatient basis, initially prednisolone is prescribed at a dose of 60 mg/day daily, and after several weeks, the drug is gradually switched to every other day. Subsequently, the prednisolone dose is reduced by 10 mg per month to the minimum dose that ensures the maintenance of the clinical effect. Usually, the maintenance dose is 15-20 mg every other day. However, even when taking a dose of 60 mg/day, some patients suddenly experience increasing weakness. In this regard, some specialists begin treatment with a dose of 20 mg/day, and then increase the dose by 10 mg weekly until a dose of 60 mg/day is reached. Then, they gradually switch to taking the drug every other day. By slowly increasing the dose of the corticosteroid, it is possible to avoid a sudden deterioration in respiratory function, but with this scheme, the therapeutic effect develops more slowly, and the likelihood of other side effects does not decrease. The need for a gradual reduction in the corticosteroid dose is dictated by the desire to balance clinical improvement in the form of increased muscle strength with the increasing risk of side effects. However, if the corticosteroid dose is reduced too quickly, myasthenia symptoms may increase.

Azathioprine at a dose of 2-3 mg/kg/day has a positive effect in a significant proportion (70-90%) of patients with myasthenia. As clinical trials show, the effectiveness of monotherapy with prednisolone or azathioprine, as well as their combination, does not differ significantly. However, in severe cases with resistance to prednisolone, a combination of prednisolone and azathioprine can be effective. The disadvantages of azathioprine include the slow development of the clinical effect (it occurs only after 3-6 months). Treatment with azathioprine is usually started with a dose of 50 mg/day, then it is increased by 50 mg every 3 days until a daily dose of 150-200 mg is reached. Particular attention should be paid to the possibility of developing hematological complications and liver damage. The irritating effect on the gastrointestinal tract can be weakened if azathioprine is taken fractionally after meals. The possibility of a mutagenic effect excludes the use of azathioprine in fertile women. The use of azathioprine is also limited by its relatively high cost.

According to some data, cyclosporine causes significant improvement in patients with myasthenia gravis who have not previously been treated with immunosuppressive agents. Treatment with cyclosporine begins with a dose of 5 mg/kg/day, which is prescribed in 2 doses at 12-hour intervals under control of the drug level in the serum. The use of cyclosporine is limited by its high cost and possible side effects, including toxic effects on the kidneys and liver, arterial hypertension, which, however, can be corrected by reducing the dose of the drug. However, due to the high cost and the risk of side effects, most clinicians do not consider cyclosporine the drug of choice for myasthenia gravis.

Plasmapheresis is indicated mainly in cases of sudden increase in myasthenia symptoms, when it is necessary to increase muscle strength in preparation for surgery, when side effects of corticosteroids develop, and when other treatments are ineffective. Plasmapheresis causes an improvement that may last only a few days, but sometimes lasts for many weeks. Most often, 6 sessions are performed with a replacement of 2 liters over 9 days. After the procedure, 30 mg of prednisolone and 100 mg of cyclophosphamide are prescribed daily to avoid a rebound increase in symptoms. After the end of the plasmapheresis course, the prednisolone regimen is changed - the patient alternates doses of 50 mg and 10 mg of the drug every other day, cyclophosphamide is prescribed for 1 month, and then discontinued. The combination of plasmapheresis with the two indicated immunosuppressive agents allows to extend its usually time-limited effect for several months. As a result, many patients treated with this regimen do not require repeat plasmapheresis until after 1 year. Side effects with this regimen are usually minimal. The use of plasmapheresis is limited mainly by high cost and possible complications, such as pain and infection, associated with the placement of a shunt to provide access to the vascular bed.

Intravenous immunoglobulin is also successfully used in myasthenia. On average, the effect of immunoglobulin appears after a few days and lasts for several weeks, but the reaction varies greatly among patients. If there are contraindications to the use of corticosteroids and plasmapheresis, intravenous administration of immunoglobulin may be the method of choice. In myasthenia, immunoglobulin is prescribed in the same dose as in other neuromuscular diseases, namely 2 g / kg. It is administered intravenously in several doses over 2-5 days. To maintain the effect, "pulse therapy" is used with intravenous administration of 600 mg / kg of immunoglobulin once a month. Although the mechanism of action of immunoglobulin in myasthenia is not precisely known, it is probably the same as in other diseases: due to the presence of antiidiotypic antibodies that block the Fc components of antibodies, immunoglobulin prevents complement deposition, the development of an immune reaction, and the production of cytokines. The side effects of immunoglobulin - chills, headache, fever - have been described earlier. The main factor limiting the use of intravenous immunoglobulin is its high cost. In a recent study, 87 patients with myasthenia gravis with worsening symptoms were randomized into two groups, which were treated with three sessions of plasmapheresis or intravenous immunoglobulin (400 mg / kg) for 3-5 days. The effect was noted with the use of both methods, but with the use of immunoglobulin, side effects were somewhat less common. The sample size in this study was quite small, and larger, well-designed, controlled trials are needed to compare the efficacy of plasmapheresis and IV immunoglobulin and determine the optimal regimen for their use.

Thymectomy also undoubtedly has a positive effect on myasthenia. Its effect continues to increase even 7-10 years after the operation, with the remission rate being approximately 50%. Improvement is observed in both men and women and is long-lasting. In women with early onset of the disease, hyperplasia of the thymus gland, high titer of antibodies to AChR, the effect appears earlier, but it is not always more significant. In patients over 60 years of age, the functioning thymus tissue is very limited in size, and therefore the effectiveness of thymectomy may be lower. Optimal preparation for surgery in patients with severe weakness may require preliminary plasmapheresis or immunosuppressive therapy. In the hands of an experienced surgeon, transsternal transthoracic access creates the best conditions for maximum removal of thymus tissue. Postoperative treatment, carried out in the intensive care unit by experienced specialists, ensures a good final result. The presence of a thymoma in the anterior mediastinum, detected by computed tomography, requires surgical intervention. In the postoperative period, the sensitivity of patients to acetylcholinesterase inhibitors increases sharply, therefore, caution is required when using these drugs in the first 24-36 hours after surgery.

The development of a myasthenic crisis with respiratory and swallowing difficulties requires emergency hospitalization. A decrease in the vital capacity of the lungs below 2 L is an indication for transfer to an intensive care unit experienced in the treatment of respiratory failure. With further deterioration of respiratory function and a decrease in the vital capacity of the lungs below 1 L or 25% of the expected value, intubation and artificial ventilation are indicated. Particular attention should also be paid to the water-electrolyte balance and the possible development of infection. In the intensive care unit, in the absence of infection, plasmapheresis is indicated to accelerate recovery. In the presence of infection, intravenous immunoglobulin is preferable in combination with adequate antibacterial therapy. Although immunosuppressive therapy can also be effective, a more important factor determining the outcome of the crisis is, apparently, adequate supportive and, above all, respiratory therapy, carried out by experienced specialists. Today, the prognosis for myasthenia patients has improved dramatically, with more than 90% of them able to return to a full, productive life.

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