Myasthenia gravis: treatment

Treatment of myasthenia includes symptomatic therapy with acetylcholinesterase inhibitors, as well as therapy aimed at changing the natural course of the disease (thymectomy, corticosteroid immunosuppression, azathioprine and / or cyclosporine, plasmapheresis, intravenous immunoglobulin). Although the knowledge of myasthenia pathogenesis undoubtedly helps to explain the positive effect of these treatments, unfortunately, large double-blind controlled studies have not been conducted, the results of which would help determine which treatment method is most appropriate for a particular patient at a given time. As a result, different specialists recommend unequal treatment regimens for myasthenia gravis.

Anticholinesterase drugs can increase muscle strength by extending the half-life of ACh in the neuromuscular synapse, which increases the likelihood that the neurotransmitter will be able to overcome the enlarged synaptic cleft and interact with AChR on the muscular membrane, whose number is reduced. Of the inhibitors of acetylcholinesterase the most widely used is pyridostigmine. Treatment usually begins with a dose of 60 mg, which is prescribed up to 4-6 times a day. A sustained-release dosage form of pyridostigmine containing 180 mg of the drug and usually administered before bedtime is issued to maintain muscle strength in the early morning hours and allow the patient to swallow the morning dose of the drug. The dose of 60 mg starts in 30-60 minutes and reaches a peak after 2-3 hours, and then is weakened within 2-3 hours. The sensitivity of the muscles to the drug is variable, in this connection, to increase their strength, the dose and frequency of taking the drug it is necessary to increase. However, the need to take the drug in a dose exceeding 120 mg, more often than every 3 hours, occurs rarely. It is important to note that with increasing the dose of the acetylcholinesterase inhibitor in some muscles, the force may increase, while in others it may decrease. During the treatment period, care must be taken to ensure that the improvement in the function of certain muscle groups is not accompanied by a worsening of the function of breathing, which should be particularly closely monitored. Side effects of acetylcholinesterase inhibitors include diarrhea, painful spasms, increased bronchial secretion, most of which are easily amenable to correction. 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 on myasthenia gravis, but experts do not agree on the optimal scheme for their use. The therapeutic effect of corticosteroids is probably related to their effect on immune processes, but the specific mechanisms of their action in myasthenia are unclear. As with other autoimmune diseases, starting treatment with high doses of corticosteroids, one can get 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, hypertension, weight gain, fluid retention, aseptic necrosis of bones, osteoporosis, cataracts. Fears also cause the possibility of recurrent infections, which often occur when using any treatment regimen. If a patient already before treatment reveals one of these conditions (for example, diabetes mellitus, peptic ulcer disease), then corticosteroids are contraindicated.

The use of corticosteroids in myasthenia gravis is associated with a special risk, because their high doses can provoke a rapid increase in weakness, especially the respiratory muscles. Depending on the dose and mode of administration of the drug, this complication can occur 4-7 days after the start of treatment. Consequently, high doses of corticosteroids can be prescribed only if there is the possibility of careful monitoring of the patient's condition. With severe weakness of oropharyngeal or respiratory muscles, hospitalization is usually indicated in order to provide control of neurological status, respiratory function and response to treatment. In severe generalized myasthenia in patients with impaired swallowing and mild or moderate respiratory failure, in the absence of contraindications, intravenous high-dose methylprednisolone (1000 mg / day for 5 days) can be used with careful monitoring of blood sugar, arterial pressure, respiratory function. At the same time, calcium preparations and H2-receptor antagonists should be prescribed. If the respiratory function worsens, the patient should be transferred to the intensive care unit and consider using other immunotherapy methods, such as plasmapheresis and intravenous immunoglobulin. With decreasing symptoms, the patient is transferred to prednisolone, administered orally every other day. In some centers, methylprednisolone is successfully administered iv in a slightly different way.

With mild weakness, patients can be treated on an outpatient basis, initially prednisolone is prescribed at a dose of 60 mg / day daily, and after a few weeks they gradually switch to taking the drug every other day. Subsequently, the dose of prednisolone is reduced by 10 mg per month to the minimum dose that maintains the clinical effect. Usually the maintenance dose is 15-20 mg every other day. However, even with taking a dose of 60 mg / day in some patients suddenly growing in weakness. In this regard, some specialists start treatment with a dose of 20 mg / day, and then weekly increase the dose by 10 mg to achieve a dose of 60 mg / day. After that they gradually switch to taking the drug every other day. Slowly increasing the dose of corticosteroid, you can avoid sudden deterioration of respiratory function, but using this scheme, the therapeutic effect develops more slowly, and the likelihood of other side effects does not decrease. The need to gradually reduce the dose of corticosteroid is dictated by the desire to balance the clinical improvement in the form of increased muscle strength with an increasing risk of side effects. However, with too rapid a decrease in the dose of corticosteroids, the symptoms of myasthenia gravis may increase.

Azathioprine at a dose of 2-3 mg / kg / day has a positive effect in a significant part (70-90%) of patients with myasthenia gravis. As clinical trials show, the efficacy of monotherapy with prednisolone or azathioprine, as well as their combination, is not significantly different. However, in severe cases with resistance to prednisolone, the effect can bring a combination of prednisolone and azathioprine. The shortcomings of azathioprine include slow development of the clinical effect (it occurs only after 3-6 months). Treatment with azathioprine usually begins with a dose of 50 mg / day, then it is increased by 50 mg every 3 days to achieve a daily dose of 150-200 mg. Particular attention should be given to the possibility of developing hematological complications and liver damage. Irritant effect on the gastrointestinal tract can be weakened if taking azathioprine fractional after meals. The possibility of a mutagenic effect excludes the use of azathioprine in fertile women. The use of azathioprine also limits its relatively high cost.

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

Plasmapheresis is indicated mainly with the sudden increase in the symptoms of myasthenia gravis, if necessary, increase muscle strength in preparation for surgery, with the development of side effects of corticosteroids, as well as in the ineffectiveness of other therapies. Plasmapheresis causes an improvement that can last only a few days, but sometimes lasts many weeks. Most often, 6 sessions are carried out with the replacement of 2 liters for 9 days. After the procedure, 30 mg of prednisolone and 100 mg of cyclophosphamide are prescribed daily to avoid a ricochetous increase in symptoms. After the end of the course of plasmapheresis the scheme of taking prednisolone is changed - the patient alternates between 50 mg and 10 mg of the drug every other day, cyclophosphamide is prescribed for 1 month and then canceled. The combination of plasmapheresis with the two indicated immunosuppressive agents makes it possible to lengthen its usually time-limited effect by several months. As a result, in many patients who are treated according to this scheme, the need for repetition of plasmapheresis arises not earlier than in 1 year. Adverse reactions with this regimen are usually minimal. The use of plasmapheresis mainly limits the high cost and possible complications, such as pain and infections associated with the imposition of a shunt to provide access to the vascular bed.

When myasthenia gravis is successfully used and intravenous immunoglobulin. On average, the effect of immunoglobulin appears after several days and persists for several weeks, but the reaction in different patients is very variable. In the presence of contraindications to the use of corticosteroids and plasmapheresis, iv injection of immunoglobulin can be a method of choice. With myasthenia, the immunoglobulin is administered at the same dose as with other neuromuscular diseases, namely 2 g / kg. It is administered iv in several doses for 2-5 days. To maintain the effect, resort to "pulse therapy" with intravenous administration of 600 mg / kg of immunoglobulin once a month. Although the mechanism of action of immunoglobulin in myasthenia is not known precisely, it appears to be the same as in other diseases: due to the presence of anti-idiotypic antibodies blocking the Fc components of antibodies, immunoglobulin prevents complementation, the development of the immune response, and the production of cytokines. The side effects of immunoglobulin - chills, headache, fever - are described earlier. The main factor limiting the use of IV immunoglobulin is high cost. In a recent study, 87 patients with myasthenia with symptomatic deterioration were randomized into two groups, treated with three sessions of plasmapheresis or IV immunoglobulin (400 mg / kg) for 3-5 days, respectively. The effect was noted in the application of both methods, but with the use of immunoglobulin, side effects were observed less frequently. The sample in this study was rather small, therefore, larger, properly organized controlled trials are needed to compare the effectiveness of plasmapheresis and intravenous immunoglobulin and to determine the optimal pattern of their use.

Timectomy, undoubtedly, also has a positive effect on myasthenia gravis. Its effect continues to grow even after 7-10 years after surgery, with a remission rate of approximately 50%. Improvement is noted in both men and women and is prolonged. In women with an early onset of the disease, hyperplasia of the thymus gland, a high titer of antibodies to AChR, the effect manifests itself earlier, but it is not always more significant. In patients older than 60 years the functioning tissue of the thymus is very limited in size, therefore the effectiveness of thymectomy may be lower. Optimum preparation for the operation of patients with severe weakness may require preliminary plasmapheresis or the appointment of immunosuppressive therapy. In the hands of an experienced surgeon, transcutaneous transthoracic access creates the best conditions for maximum removal of the thymus tissue. Postoperative treatment, conducted in the intensive care unit by experienced specialists, provides a good end result. The presence of thymoma in the anterior mediastinum, detected in computed tomography, requires surgical intervention. In the postoperative period, the sensitivity of patients to acetylcholinesterase inhibitors rises sharply, therefore caution is needed when using these drugs in the first 24-36 hours after the operation.

The development of myasthenic crisis with violation of breathing and swallowing requires emergency hospitalization. A decrease in the vital capacity of the lungs below 2 liters is an indication for transfer to an intensive care unit with experience in the treatment of respiratory failure. With further deterioration in the function of respiration and a decrease in the vital capacity of the lungs below 1 L or 25% of the proper 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, the use of plasmapheresis is shown to accelerate recovery. In the presence of infection, the use of iv immunoglobulin in combination with adequate antibiotic therapy is preferable. Although immunosuppressive therapy may also be effective, the more important factor determining the outcome of a crisis is apparently adequate supportive and, above all, respiratory therapy conducted by experienced specialists. Currently, the prognosis for patients with myasthenia gravis has dramatically improved, and more than 90% of them are able to return to full productive life.

[1], [2], [3], [4], [5]