Natural
Myasthenia course
Immunosuppression The principal drugs used to suppress the immune system in myasthenia gravis are prednisone (a glucocorticoid) and azathioprine. The response to these treatments can take weeks to many months, with the maximal effect taking months to years.1,2 Prednisone Prednisone or another corticosteroid is the primary immunosuppressant used in myasthenia gravis. Sustained improvement or remission can be achieved while patients remain on treatment. A typical course for generalised myasthenia gravis would use 1 mg/kg prednisone daily (0.5 mg/kg for ocular myasthenia gravis) until clinical control is achieved and then weaning either directly or by initial conversion to alternate daily dosage, with the determination of a maintenance dose by trial and error during a slow withdrawal of medication over many months. Deterioration in myasthenia gravis can occur in the first few weeks of treatment so the dose is often increased slowly. The mean time to maximal effect of prednisone in myasthenia gravis is six months - much longer than most expect. Azathioprine Azathioprine is used as a steroid sparing drug and additional immunosuppressant with prednisone. In a randomised trial, after three years of treatment, 63% of patients with myasthenia gravis taking azathioprine were off all prednisone, versus 20% taking placebo, but no effect was seen in the first year.2Compared to the metabolic consequences of continued corticosteroids, the problems of azathioprine seem significantly less. However, the long-term consequences do include an increased risk of skin cancers and a small possible increase in the risk of haematological malignancies. About one-fifth of patients cannot take azathioprine due to rash, hepatitis, myelosuppression, nausea or vomiting, but this is usually evident within two weeks to two months. Some doctors routinely use azathioprine for patients with generalised myasthenia gravis still requiring more than 10 mg prednisone per day at six months, or if severe disease is obvious earlier. Other drugs If not using azathioprine, other steroid-sparing drugs used include mycophenolate mofetil, cyclosporin, methotrexate and cyclophosphamide. Experience with these drugs is generally derived from retrospective series. None of these have proven efficacy in randomised trials except for cyclophosphamide, and choice of drug depends on age and competency of the patient plus local experience of the physician. In practice they are frequently used with apparent success, but like azathioprine the response is often slow. Mycophenolate mofetil is a pharmacologically similar alternative to azathioprine but two recent randomised controlled trials failed to demonstrate benefit in myasthenia gravis.* The duration of both trials was less than a year. As it works in the same pathway as azathioprine this may have been inadequate and it remains widely used. Rituximab, a monoclonal antibody specific to CD20 (on B cells), or bone marrow ablation with autologous transplant are treatments of last resort. Remove or block autoantibodies
Plasma exchange removes autoantibodies and intravenous immunoglobulin is thought to block autoantibodies. These treatments take effect within days, but only last weeks before treatment needs to be repeated. They have a key role in stabilising severe myasthenia gravis and in preparation for surgery, or in pregnancy. Plasma exchange is expensive and only available in major hospitals. It requires good intravenous or alternatively central catheter access, but a central line increases the risk of infection. Intravenous immunoglobulin, a purified blood product, is also very expensive and is in limited supply. Its mode of action remains unclear. Thymectomy Thymectomy has a possible immunomodulatory role in the absence of thymoma. Results of a global randomised trial are awaited.† The effect of a thymectomy appears to take years. Non-randomised retrospective data suggest there is an increased complete remission rate from thymectomy when it is performed within 2-3 years of the onset of disease. This treatment involves major surgery with midline sternotomy, although minimally invasive approaches are becoming available. Other than surgical complications there are no known long-term adverse effects. Thymectomy for thymoma does not on average improve myasthenia gravis, but is required to remove the tumour. Drugs that worsen myasthenia gravis Neuromuscular blocking drugs used for intubation and muscle relaxation in surgery cause profound deterioration in myasthenia gravis with marked prolongation and severity of neuromuscular dysfunction. The diagnosis of myasthenia gravis should be considered if patients fail to breathe spontaneously or are weak after an anaesthetic. Aminoglycosides such as gentamicin partially block the neuromuscular junction and dramatically worsen myasthenia gravis. Beta blockers have a generally mild adverse effect (adrenergic stimulus is mildly beneficial for myasthenia gravis) and the need to use them should be carefully considered. Anticholinergics of all types logically have a deleterious effect on the neuromuscular junction. In practice a muscarinic anticholinergic such as propantheline is sometimes used to control the adverse effects of pyridostigmine on the gut. Many other drugs have been cited as provoking deterioration in myasthenia gravis or have myasthenia gravis listed as a contraindication to use in the product information. This includes tetracyclines and quinolones, which in practice are only occasionally problematic. Sedatives such as narcotics and benzodiazepines have no direct effect on the neuromuscular junction but obviously are contraindicated if hypercapnia or respiratory failure are a risk. Conclusion Myasthenia gravis is a readily treatable condition and many patients can expect to have little disability. It should be acknowledged that of the residual disability, a considerable amount comes from the treatment. Attempts to re-establish immune tolerance of the acetylcholine receptor to cure the condition have not yet borne fruit. No revolution in treatment is expected in the near future. The author thanks Dr Marcella Cox for a critical review of the manuscript and Mr Bob Haynes for graphic design of the figure. The author gratefully acknowledges the support of the Australian Myasthenic Association in NSW, the NSW Muscular Dystrophy Association and the Muscular Dystrophy Association of the United States of America. Stephen Reddel is an investigator of the United States National Institutes of Health (NIH) randomised clinical thymectomy trial currently underway. The NIH has paid for a trial workshop including travel. He has also received a consultancy fee from Aspreva, marketing company of mycophenolate mofetil for use in autoimmune diseases. | 
