Treatment

A controlled clinical trial has never been reported for any medical or surgical modality used to treat myasthenia gravis. All recommended regimens are empirical and experts disagree on treatments of choice. Treatment decisions should be based on knowledge of the natural history of disease in each patient and the predicted response to a specific form of therapy. Treatment goals must be individualized according to the severity of disease, the patient's age and sex, and the degree of functional impairment. The response to any form of treatment is difficult to assess because the severity of symptoms fluctuates. Spontaneous improvement, even remissions, occur without specific therapy, especially during the early stages of the disease.

Cholinesterase Inhibitors

ChE inhibitors retard the enzymatic hydrolysis of ACh at cholinergic synapses, so that ACh accumulates at the neuromuscular junction and its effect is prolonged. ChE inhibitors cause considerable improvement in some patients and little to none in others. Strength rarely returns to normal. Pyridostigmine bromide (Mestinon) and neostigmine bromide (Prostigmin) are the most commonly used ChE inhibitors. No fixed dosage schedule suits all patients. The need for ACh inhibitors varies from day-to-day and during the same day in response to infection, menstruation, emotional stress, and hot weather. Different muscles respond differently; with any dose, certain muscles get stronger, others do not change, and still others become weaker. Adverse effects of ChE inhibitors may result from ACh accumulation at muscarinic receptors on smooth muscle and autonomic glands and at nicotinic receptors of skeletal muscle. Central nervous system side effects are rarely seen with the doses used to treat myasthenia gravis. Gastrointestinal complaints are common; queasiness, loose stools, nausea, vomiting, abdominal cramps, and diarrhea. Increased bronchial and oral secretions are a serious problem in patients with swallowing or respiratory insufficiency. Symptoms of muscarinic overdosage may indicate that nicotinic overdosage (weakness) is also occurring. Excessive nicotinic receptor overdosage results in Myasthenic Crisis characterized by severe generalized weakness and respiratory failure.

Thymectomy

Thymectomy is recommended by many physicians for most patients with myasthenia gravis. Most reports do not correlate the severity of weakness before surgery and the timing or degree of improvement after thymectomy. The maximal favorable response generally occurs 2 to 5 years after surgery. However, the response is relatively unpredictable and significant impairment may continue for months or years after surgery. Sometimes, improvement is only appreciated in retrospect. The best responses to thymectomy are in young people early in the course of their disease, but improvement can occur even after 30 years of symptoms. Patients with disease onset after the age of 60 rarely show substantial improvement from thymectomy. Patients with thymomas do not respond as well to thymectomy as do patients without thymoma. A large, international multi-center clinical trial began in 2006 to determine the role of thymectomy in steroid-treated patients.

Corticosteroids

Marked improvement or complete relief of symptoms occurs in more than 75% of patients treated with prednisone, and some improvement occurs in most of the rest. Much of the improvement occurs in the first 6 to 8 weeks, but strength may increase to total remission in the months that follow. The best responses occur in patients with recent onset of symptoms, but patients with chronic disease may also respond. The severity of disease does not predict the ultimate improvement. Patients with thymoma have an excellent response to prednisone before or after removal of the tumor. The most predictable response to prednisone occurs when treatment begins with a daily dose of 1.5 to 2 mg/kg/day. About one-third of patients become weaker temporarily after starting prednisone, usually within the first 7 to 10 days, and lasting for up to 6 days. Treatment can be started at low dose to minimize exacerbations; the dose is then slowly increased until improvement occurs. Exacerbations may also occur with this approach and the response is less predictable. The major disadvantages of chronic corticosteroid therapy are the side effects.

 

Immunosuppressant Drugs

Azathioprine reverses symptoms in most patients but the effect is delayed by 4 to 8 months. Once improvement begins, it is maintained for as long as the drug is given, but symptoms recur 2 to 3 months after the drug is discontinued or the dose is reduced below therapeutic levels. Patients who fail corticosteroids may respond to azathioprine and the reverse is also true. Some respond better to treatment with both drugs than to either alone. Because the response to azathioprine is delayed, both drugs may be started simultaneously with the intent of rapidly tapering prednisone when azathioprine becomes effective. Approximately one-third of patients have mild dose-dependent side effects that may require dose reductions but do not require stopping treatment.

Cyclosporine inhibits predominantly T-lymphocyte-dependent immune responses and is sometimes beneficial in treating myasthenia gravis. Most patients with myasthenia gravis improve 1 to 2 months after starting cyclosporine and improvement is maintained as long as therapeutic doses are given. Maximum improvement is achieved 6 months or longer after starting treatment. After achieving the maximal response, the dose is gradually reduced to the minimum that maintains improvement. Renal toxicity and hypertension, the important adverse reactions of cyclosporine. Many drugs interfere with cyclosporine metabolism and should be avoided or used with caution.

Cyclophosphamide has been used intravenously and orally for the treatment of myasthenia gravis. More than half of patients become asymptomatic after one year. Side effects are common. Life-threatening infections are an important risk in immunosuppressed patients, but in our experience, this risk is limited to patients with invasive thymoma. The long-term risk of malignancy is not established, but there are no reports of an increased incidence of malignancy in patients with myasthenia gravis receiving immunosuppression. Mycophenolate mofetil (MMF) selectively inhibits the proliferation of activated B and T lymphocytes. It also suppresses the formation of antibodies active in complement-dependent lysis and antibody-dependent, cell-mediated cytotoxicity, a necessary feature to promote many autoimmune diseases. While case reports, pilot studies and retrospective series have demonstrated a potential role for MMF as a corticosteroid-sparing agent and as adjunctive or primary therapy in refractory MG, a large clinical trial did not show superiority of MMF as a corticosteroid-sparing agent. Similar findings were found for methotrexate (MTX). Others are using both as a preferred treatment because of their faster onset of action when compared to azathioprine. Both the MMF and MTX trials have been criticized for study design failings and the fact that prednisone was a much better drug than anyone thought it was. Despite these failings the majority of experts continue to use MMF as a primary and secondary treatment for MG.  Eculizumab, a humanized monoclonal antibody to the fifth component of complement (C5), was shown to be successful in improving strength in patients with refractory (failing at least 2 immunotherapies for at least 1 year) generalized myasthenia gravis. This first-in-kind therapy is currently in Phase 3 trials.

Plasma Exchange

Plasma exchange is used as a short-term intervention for patients with sudden worsening of myasthenic symptoms for any reason, to rapidly improve strength before surgery, and as a chronic intermittent treatment for patients who are refractory to all other treatments. The need for plasma exchange, and its frequency of use is determined by the clinical response in the individual patient. Almost all patients with acquired myasthenia gravis improve temporarily following plasma exchange. Maximum improvement may be reached as early as after the first exchange or as late as the fourteenth. Improvement lasts for weeks or months and then the effect is lost unless the exchange is followed by thymectomy or immunosuppressive therapy. Most patients who respond to the first plasma exchange will respond again to subsequent courses. Repeated exchanges do not have a cumulative benefit.

Intravenous Immune Globulin (IVIG)

Several groups have reported a favorable response to high-dose (2 grams/kg infused over 2 to 5 days) IVIG. Possible mechanisms of action include down-regulation of antibodies directed against AChR and the introduction of anti-idiotypic antibodies. Improvement occurs in 50 to 100% of patients, usually beginning within 1 week and lasting for several weeks or months. The common adverse effects of IVIG are related to the rate of infusion. The mechanism of action is not known but is probably non-specific down regulation of antibody production. Most recently a subcutaneous form of the preparation is available and may be used as an alternative treatment option, especially in patients with limited intravenous access.