Medical Therapies in Myasthenia Gravis
by David S. Younger, MD, and Natte Raksadawan, MD

Reprinted from Chest Surgery Clinics of North America, May 2001, p.329-334.|

HISTORICAL ASPECTS

Many historical aspects of myasthenia gravis (MG) have been reviewed and extraordinary progress has been achieved in the elucidation of the pathogenesis, diagnosis, and management of MG. In the twentieth century, some of the most important breakthroughs in neuromuscular disease involved MG. It is instructive for students of myasthenia to appreciate the historical achievements in the order of their occurrence and the many individuals who contributed to the understanding of the disease. The characteristic clinical syndrome, that is, fluctuating ocular, facial, oropharyngeal, and limb muscle weakness, was recognized by the end of the nineteenth century. Decades later, three important observations were made that translated into effective methods of diagnosis. The first was the demonstration of the efficacy of the acetylcholinesterase inhibitor drug physostigmine in MG and, later, edrophonium chloride for rapid diagnosis of suspected patients. The second was the decremental response to repetitive motor nerve stimulation in patients with MG that belied the postsynaptic defect in neuromuscular transmission. The third important observation was the extraction of pathogenic acetylcholine receptor (AChR) antibodies bound to the end-plates in affected patients, which laid the basis for serologic testing.

A cohesive understanding of MG followed the appreciation of the ultrastructural, physiologic, and molecular structure and function of the nicotinic postsynaptic AChR receptor and associated gated ion channel and the role of thymus-derived T cells and bone marrow-derived B cells. The evidence for an autoimmune mechanism in MG now has been established firmly. The antigen, native AChR, is known. The antibody, the anti-AChR, is elevated in the sera of patients with the disease and interacts with the target antigen. Passive transfer of the antibody produces a model disease, namely experimental autoimmune MG. Reduction of the antibody ameliorates the disease. The cause of the disease remains unknown, however, and in recent years, attention has focused on the role of the thymus gland.

ROLE OF THE THYMUS GLAND

The hypothesis that MG originates in the thymus gland, first suggested by Weigert in 1901, has been difficult to prove; however, several observations support a primary role of the gland in the pathogenesis of the disease.

The thymus contains all of the elements theoretically necessary for activation of AChR-specific autoimmune T cells. They include local antigen-presenting cells (APC) that take up AChR derived from myoid cells, process it, and then express AChR-derived peptide fragments on their surface in the context of main histocompatibility complex (MHC) class II molecules and AChR-specific reactive T cells that recognize the peptide fragments of AChR in the context of MHC II molecules and then become activated. Although myoid cells are equally abundant in normal and myasthenic thymuses, hyperplastic glands contain many more myoid cells than atrophic glands, and in the myasthenic thymus, many more myoid cells are in intimate contact with strongly reactive MHC-positive interdigitating cells, the most efficient APC of the gland. AChR-specific T cells are enriched in myasthenic thymus glands with and without a thymoma. Whether the AChR-specific T cells in the myasthenic thymus always reside there or return after a sojourn in the peripheral immune system is unknown. The peripheral blood of patients with MG contains an enhanced portion of these autoreactive T cells that are capable of recruiting AChR-responsive B cells for the production of pathogenic anti-AChR antibodies.

Thymectomy suppresses experimental autoimmune MG 29 and in passively transferred experimental autoimmune MG in which the myasthenogenic process is initiated outside the gland, germinal centers are not observed, and transplantation of myasthenic thymus fragments into mice with severe combined immunodeficiency results in the production of pathogenic mouse antibodies.

Additionally, the success of transcervical and trans-sternal thymectomy procedures in promoting sustained remission and improvement and the often-observed fall in antibody titers, especially in patients with noninvoluted hyperplastic glands, further strengthen the role of the thymus gland. Since the earliest reports of the success of thymectomy in patients with MG with or without a thymoma, the technical goal of surgery has been a complete removal of the thymus gland as possible, even though it may be technically difficult because the gland consists of multiple lobes and small scattered foci in the neck and mediastinum. Advanced age, severity of disease, and associated medical problems in patients with generalized disease are rarely a barrier to thymectomy given the current advances in operative and intensive care. Notwithstanding, there is still a need for universally acceptable nomenclature, clinical grading systems, statistical methods of analysis, and controlled clinical trials to compare the effectiveness of available thymectomy procedures.

MEDICAL THERAPY IN MYASTHENIA GRAVIS

After ascertaining the diagnosis of MG in a given patient on clinical, electrophysiologic, and serologic grounds, and after excluding a thymoma by radiographic and serologic testing, the treating neurologist must decide the sequence and combination of currently available medical therapies to promote improvement or remission before proceeding to elective thymectomy.

First-line therapy in MG commences with the administration of pyridostigmine, an anticholinesterase inhibitor given in doses of 1 to 3 (60mg) tablets at 3 to 4-hour intervals while awake, titrated to facial, neck, and limb weakness, with ocular and oropharyngeal symptoms often being the least responsive. Three factors limit its use as monotherapy, however. First, increasing doses can lead to undesirable side effects including abdominal cramping, diarrhea, excessive secretions, and sweating. The effectiveness of pyridostigmine generally waivers several months after initial diagnosis. Chronic administration is not known to cause a decline in effectiveness. It does not appreciably change the natural history of the disease, and ultimately, other modalities must be used to prevent disease progression.

Prednisone is the most widely used immunosuppressive agent in MG. In 1935, Simon reported sustained remission in a single patient after daily injections of extracts of the anterior lobe of the pituitary gland. Torda and Wolff later documented partial remissions among 15 of 20 patients treated with adrenocorticotrophic hormone. All experienced transient worsening, however, and one died. The later unfavorable experiences of Grob and Harvey8 and Millikan and Eaton overshadowed these initial promising results, and enthusiasm waned for decades until Cape and Utterbach, Warmolts and Engel, and Jenkins, demonstrated the efficacy of chronic adrenocorticotrophic hormone and prednisone in MG. Corticosteroids exert nonspecific immunosuppression at virtually all levels of the immune system from the presentation of antigen presenting cells in the thymus, to the activation of B and T cells, the secretion of autoantibodies, and stabilization of the immune attack at skeletal muscle receptor end-plates. Up to one half of patients experience initial exacerbation after commencement of therapy, and roughly two thirds can have an undesirable or life-threatening side effect shortly after commencement of therapy. Although the unwanted side effects are lessened with gradual increments of the dose of prednisone, there is still I uncertainty as to the optimal initial regimen.

In 1969, Mertens and co-workers reported the effectiveness of azathioprine in MG. Mertens Matell, and Cornelio and colleagues later documented response rates equal to prednisolone and prednisone in controlled and uncontrolled series of patients with generalized disease. Azathioprine is a purine analog that metabolizes to the cytotoxic derivative 6-mercaptopurine. It exerts favorable action in MG caused by the inhibition of T-cell activation and T-cell dependent antibodymediated responses. It is appropriate therapy for patients with generalized disease who show poor response, have frequent side effects, relapse while receiving prednisone, are unsuitable candidates for thymectomy because of age or comorbid disease, or have MG with thymoma, before and after thymectomy. There are three drawbacks to its use. First, idiosyncratic side effects occur in approximately 10% of patients. Most effects are gastrointestinal and flu-like and rarely necessitate permanent withdrawal of the medication, but there may be serious pancreatitis or gastritis severe enough to warrant hospitalization. Second, bone marrow suppression occurs in nearly all patients. Third, there is usually a long delay in the onset of the therapeutic effect of 3 months or more. Taking all of these factors into account, most clinicians concur with slow advancement of the dose over weeks, from 50 mg/d to maintenance levels of 2 to 3 mg/kg/d with careful monitoring of liver and marrow function.

In 1987, Tindall reported the favorable benefit of cyclosporine in myasthenia in a placebo-controlled trial and later in controlled doubleblind studies in comparison with prednisone and azathioprine. Cyclosporine inhibits T-cell dependent antibody responses by reversibly suppressing the clonal expansion of activated helper T cells. It also prevents the expression and induction of experimental autoimmune MG. Its long-term use is associated with cumulative and dose-dependent renovascular injury, renal insufficiency, hypertension, and interstitial fibrosis.

Plasmapheresis and intravenous immunoglobulin (IVIg) therapy have been used widely in the treatment of MG to effect rapid short term improvement. Appropriate patients are those with a temporary exacerbation of the disease including crisis, those receiving pyridostigmine awaiting the effectiveness of corticosteroids or azathioprine, patients refractory to the tapering of corticosteroids, and for patients undergoing the preoperative preparation of thymectomy. IVIg therapy is not a substitute for plasmapheresis and vice versa because they act through different mechanisms. In some instances combining the two may be advisable, such as in the treatment of severe exacerbations or impending crisis. The major drawbacks to both therapies are the high cost and need for specialized staff and equipment, including a large bore indwelling catheter for plasmapheresis and the miniscule but finite risk for transmissible disease. The salutary action of IVIg therapy in MG is believed to occur through the action of blocking idiotypic antibodies, neutralization of pathogenic antibodies, suppression of antibody mediated responses, the accelerated catabolism of pathogenic immunoglobulin G antibodies including AChR antibody, suppression of pathogenic cytokines, and the inhibition of C5b-9 membrane attack complex-mediated AChR receptor lysis.

Potentially less toxic forms of immunotherapy for MG, not yet available, involving "selective or specific" immunosuppression or immunomodulation is envisioned in the not so distant future.

Myasthenia gravis with thymoma presents additional challenges to diagnosis and treatment. 16 Although the detection of thymoma most often follows the clinical diagnosis of MG, the latter may follow detection or removal of the tumor. Patients with thymoma have an increased tendency for associated autoimmune disorders that may require specific additional treatment including limbic encephalitis, neuromyotonia and peripheral neuropathy, polymyositis and dermatomyositis, pure erythrocyte aplasia, pancytopenia, rheumatoid arthritis, hyperthyroidism, systemic lupus erythematosus, giant cell myocarditis, Addison's disease, and cryoglobulinemia. Extrathymid malignancies also occur with increased frequency including those of the breast, liver, lung, stomach, thyroid, lymphoproliferative cancers, and carcinoid tumors. Whereas Lambert-Eaton syndrome and MG can occur separately with thymoma, and both Lambert-Eaton syndrome and MG have at times been documented in the same patient, the presence of all three together has not been shown convincingly.

There is general agreement that patients with MG and thymoma should undergo early thymectomy to prolong survival, prevent thymoma recurrences, and induce remission or asymptomatic myasthenic status. In the authors' experience, the prognosis of MG with a benign thymoma after surgery alone and malignant thymoma with surgery and radiotherapy or chemotherapy seems to be equally favorable when treated early and aggressively. Controversy abounds in the choice of chronic immunosuppressive agents in myasthenia with thymoma. It has been the authors' experience to institute azathioprine at the time of tumor diagnosis and to continue the medication after surgery because such patients often have more severe and brittle myasthenia. Patients with benign or particularly low-grade tumors, including medullary and mixed cortical and epithelial thymomas, with no risk for recurrence even when there is capsular invasion, rarely require adjuvant therapy. Cortical thymomas demonstrate a low but significant risk for relapse and may be treated with azathioprine therapy alone if there is no sign of capsular invasion. Patients with intermediate and highly malignant well-developed thymic carcinoma and other high-grade thymic carcinomas should be treated with postoperative radiation and followed carefully with CT of the chest for signs of recurrence. Patients with exacerbation of myasthenia after a stable period postoperatively should be suspected of harboring microscopic thymoma and watched carefully for tumor relapse, at which point chemotherapy and reoperation may be necessary.

SUMMARY

Forty years ago, a patient with MG probably had a fifty-fifty chance of surviving a myasthenic crisis, defined as the need for mechanical ventilatory support Approximately 16% of all -patients experience a crisis,, a figure that has not changed appreciably since then. Progressive weakness, oropharyngeal symptoms, refractoriness to anticholinesterase medication, intercurrent infection, and invasive procedures including needle biopsies of thymic gland masses, and reactions to contrast agents used in the performance of CT of the chest have been implicated in the development of crisis. It is now standard practice to treat severe crisis in an intensive care unit. The ready availability of intensive care in most hospitals belies the fall in the mortality of myasthenic crisis to 6% over the past several decades. Crisis is a temporary exacerbation, regardless of the proximate cause, and the goal is to keep the patient alive until it subsides, usually in 2 weeks. In the past, edrophonium was used to differentiate myasthenic crisis from cholinergic crisis, but that is now moot because withdrawal of cholinesterase medication is necessary for improvement in both situations. The underlying immunologic derangements in myasthenic crisis are not well understood, but there is a rapidly fatal antibody-mediated syndrome that bears resemblance to crisis and is associated with inflammation and necrosis of the end-plate region.

REFERENCES

A complete list of references can be found in Chest Surgery Clinics of North America, May 2001, p.334-336.