149 - Benign Tumors, Cysts, and Duplications of the Esophagus
Editors: Shields, Thomas W.; LoCicero, Joseph; Ponn, Ronald B.; Rusch, Valerie W.
Title: General Thoracic Surgery, 6th Edition
Copyright 2005 Lippincott Williams & Wilkins
> Table of Contents > Volume II > The Mediastinum > Section XXIX - Primary Mediastinal Tumors and Syndromes Associated with Mediastinal Lesions > Chapter 174 - Myasthenia Gravis
Chapter 174
Myasthenia Gravis
David S. Younger
This chapter provides an overview of the pathogenesis, diagnosis, and treatment of myasthenia gravis (MG). Other reviews by this author and my colleagues (1997) and co-authored with Raksadawan (2001) have appeared in the recent literature.
HISTORICAL ASPECTS
The history of MG is controversial. The first description of a patient with MG appeared in 1644 in correspondence from colonial Jamestown, Virginia, pertaining to Indian Chief Opechankanough, according to Marsteller (1988). In 1685, Sir Thomas Willis described a patient with bulbar symptoms that could have been psychogenic. The clinical syndrome of MG was identified by Wilks (1877), Erb (1879), and Goldflam (1893). In 1895, Jolly named the disease myasthenia gravis pseudoparalytica. By 1900, Campbell and Bramwell reported 60 cases. The efficacy of physostigmine was shown by Walker in 1934. One year later (1935), he suggested the chemical nature of neuromuscular transmission at motor end plates. Harvey and Masland (1941) summarized the salient electrophysiologic features of MG. In the same year, Blalock and co-workers (1941), and later Keynes (1946), described transsternal thymectomy in MG that included as complete a removal of the gland as possible, whether or not a tumor was suspected preoperatively.
In 1960, an autoimmune cause of MG was suggested by Simpson and by Nastuk and colleagues. However, the immunologic basis of MG awaited basic understanding of acetylcholine (ACh) release at motor end plates, as subsequently described by Katz and Miledi (1967). In 1973, Patrick and Lindstrom injected rabbits with acetylcholine receptor (AChR) from the electric organ of eels, intending to make antireceptor antibodies and to see if these antibodies blocked the function of AChR in intact electric organ cells. The antibodies did block, and the immunized rabbits became paralyzed and died. Experimental autoimmune myasthenia gravis (EAMG), so named, resulted from the autoimmune attack against native AChR. Fambrough and associates (1973) applied -bungarotoxin to motor point biopsy samples from patients with MG and found a marked reduction in the number of AChR, averaging 20% of controls. Within the next several years, investigators reproduced the essential clinical and morphologic correlates of human MG in animals by passive transfer of human myasthenic serum and AChR-specific monoclonal antibodies.
PATHOPHYSIOLOGY
Acetylcholine Receptor Module
The 1980s and 1990s witnessed spectacular progress in the understanding of the microstructure, physiology, and molecular composition of the nicotinic AChR. This, in turn, has been applied to the clinical problem of MG. The receptor is a gated receptor channel and intrinsic membrane glycoprotein of molecular weight 290,000, composed of five subunits, with the stoichiometry 2 . Distinct but related genes encode the individual subunits, and complementary DNA for each have been cloned, showing remarkable homology.
Neuromuscular Junction Physiology
The mechanisms of the end-plate current (EPC) and end-plate potential (EPP) have been elucidated by noise analysis and patch or voltage clamping. In response to an incoming nerve action potential, highly localized regions of the nerve terminal (Fig. 174-1) release approximately 200 quantal packets, each containing 6 to 10,000 molecules of ACh. Binding of ACh to specific sites on the AChR results in the transient openings of the AChR channel that allows a net influx of Na+ ions, thus producing the depolarizing potential. The circular arrangement of the five subunits delineates a 2.5-nm channel whose narrowest point is 0.65 nm in diameter. Each subunit contains four membrane-spanning alpha-helices termed M1 to M4, with the M2 segment effectively lining the channel. More quantal packets of ACh
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are released into the synaptic cleft, and more receptor channels are present than are needed to depolarize the muscle fiber to threshold. This creates a safety factor. Even when the number of receptors is reduced experimentally, the EPP does not fall below the threshold needed to generate a muscle action potential. The autoimmune attack on AChR, which leads to the reduction in the number of functioning receptors at myasthenic end plates, also leads to many EPPs falling below threshold. This translates into muscle weakness and fatigue, particularly with repetitive or sustained contraction.
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Fig. 174-1. Neuromuscular junction. Vesicles (V) release their acetylcholine (ACh) contents at specialized release sites. After crossing the narrow synaptic space (arrow), ACh reaches the ACh receptors, which are most densely situated at the peaks of the junctional folds (JF). Acetylcholinesterase (AChE) in the clefts rapidly hydrolyzes the ACh. M, mitochondria. From Drachman DB: Myasthenia gravis. Part 1. N Engl J Med 298:136, 1978. With permission. |
Autoimmune Etiopathogenesis
The hypothesis that MG originates in the thymus gland, first suggested by Weigert in 1901, has been difficult to prove. The initial event in the pathogenesis of myasthenia, loss of self-tolerance, is not well understood, but a primary role of the thymus gland in the pathogenesis of the disease seems likely for several intuitive reasons. The thymus contains all of the elements theoretically necessary for activation of AChR-specific T cells. They include local antigen-presenting cells (APCs) or in this case myoid cells, that take up AChR derived from myoid cells, process it, and then express AChR-derived peptide fragments on their surface in the context of the trimolecular complex. The latter includes the APC, AChR-specific antigen linked to the major histocompatibility complex class II molecules, and AChR-specific reactive T cells. Although myoid cells are equally abundant in normal and myasthenic thymuses, hyperplastic glands contain many more myoid cells than atrophic glands. AChR-specific T cells are enriched in myasthenic thymus glands with and without epithelial cell tumors (thymomas). Whether the AChR-specific T cells in the myasthenic thymus always resided there or return after a sojourn in the peripheral immune system is not known. 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. In actively induced or passively transferred EAMG, where the myasthenic process is initiated outside the gland, germinal centers are not observed. Finally, transplantation of myasthenic thymus fragments into mice with severe combined immunodeficiency results in the production of pathogenic mouse antibodies.
DIAGNOSIS
Nosology and Classification
The term myasthenia has traditionally been used interchangeably for the acquired autoimmune form of the disease, and the term myasthenic has been used for other syndromes of the neuromuscular junction. Similarly, the classification of MG has been difficult. Early attempts emphasized duration of symptoms because it was believed that the disorder might be progressive. More recent attempts have emphasized indices of maximal severity, functional status, and response to therapy, as discussed by Jaretzki and associates (1988). Recent interest, as reflected in the report of Jaretzki and colleagues (2000), in a unified approach to clinical investigation has spurred more exact nosology, classification, and comparative methods of analysis of patient outcome.
Clinical Aspects
The clinical diagnosis of autoimmune acquired MG is made by recognizing a pattern of weakness that has the features of fluctuation and variability over the course of a day, over months, or years, leading to perceptible exacerbations and remissions. The distribution of weakness is characteristic, affecting ocular, facial, oropharyngeal, and limb muscles. The useful Osserman and Genkins classification is listed in Table 174-1. The diagnosis is confirmed by unequivocal and reproducible improvement after intravenous administration of edrophonium chloride, a rapidly acting anticholinesterase drug. Formal diagnosis is bolstered by eliciting a decremental response to repetitive nerve stimulation as well as the detection of AChR antibodies in the serum. Selective involvement of limb or respiratory muscles, sparing ocular or oropharyngeal muscles, is rarely if ever encountered.
Table 174-1. Osserman and Genkins Classification | |
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Electrophysiologic Findings
All patients should undergo computed tomography (CT) of the mediastinum to search for thymic enlargement and thymic tumors because that generally signifies glandular hyperplasia or tumor that can be easily removed by surgery, always without a presurgical biopsy, and with the expectation of clinical improvement. The electrophysiologic evaluation of MG includes repetitive stimulation and single-fiber electromyography. A decremental response of 12% to 15% or more of successive compound muscle action potentials after 3-Hz stimulation and aggravation of the block for several minutes after brief exercise are indicative of the postsynaptic defect in neuromuscular junction transmission. Single-fiber electromyography (SFEMG) quantitates transmission at individual end plates while the patient voluntarily activates the muscle under examination. Action potentials are recorded from two muscle fibers in the same motor unit near the single fiber electrode. The variability in the time between the two potentials, which varies among consecutive discharges, is termed jitter, and is calculated as the mean difference between consecutive interpotential intervals. Jitter normally varies from 10 to 50 m. Blocking occurs when consecutive impulses do not follow. A typical finding in MG is normal jitter in some potential pairs and increased jitter in others. As a rule, 20 potential pairs are studied in each muscle. Up to 85% of patients with generalized and 10% with ocular MG reveal abnormal decrement in a hand or shoulder muscle, and 86% of patients with generalized and 63% of those with ocular disease reveal abnormalities on single-fiber electromyography, as recorded by Sanders (1987). With the addition of a second muscle, single-fiber electromyography is positive in 99% of patients with generalized MG, making it a more sensitive method of analysis.
Anti-AChR Antibodies
Three ACh receptor assays are available for serologic evaluation of MG. They include AChR binding, blocking, and modulating antibody assays. The postulated actions of AChR antibodies include accelerated degradation, endocytosis, cross-linking of receptors, functional blockade, and complement-mediated lysis of end plates by the membrane attack complex leading to flattening and simplification of postsynaptic junctional folds. The binding assay is positive in up to 90% of patients with generalized MG and should be the first line of testing, with a specificity of more than 99%, as recorded by Somnier (1993).
As noted by Vincent and Newsom-Davis (1985), approximately 12% to 17% of patients with generalized MG lack demonstrable serum AChR antibodies; this is termed seronegative MG. These patients do not differ clinically from those with elevated titers, and exhibit similar favorable clinical responses to anticholinesterase or immunosuppressant drugs, plasmapheresis, and thymectomy. The pathogenesis of seronegative MG may not differ from that of antibody-positive cases. There are several possible explanations for the failure to detect antibodies with conventional assays. If serum antibody titers are low, the assay may fail to detect antibodies adequately because of binding at end plates. Other possible confounding factors may be low affinity or excessive variability in antibody reactivity to epitopes of the assayed antigen. Alternatively, antibodies may be directed at sites other than the main binding sites, or at sites hidden during extraction of AChR. Antibodies to AChR may not be detected with denervated or immature AChR. A short duration of disease and concomitant immunotherapy
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before the assay may also contribute to seronegativity. Significantly reduced numbers of AChR were noted in motor end-plate biopsy samples of patients with seronegative generalized and ocular MG. Passive transfer of sera from seronegative patients to laboratory animals results in a disorder clinically similar to that induced by seropositive sera. Immunoglobulin is usually not bound to extracted AChR at end plates of seronegative patients, implying that the disorder might result from a circulating plasma factor capable of inhibiting AChR function at sites other than the binding site for ACh.
Genetic Myasthenia
Genetic factors play a pivotal role in the pathogenesis of congenital myasthenic syndromes but not in autoimmune MG. The number of congenital myasthenic syndromes continues to grow. Loss of the safety factor for normal neuromuscular transmission characterizes all of them. The site of the defect may be presynaptic, synaptic, or postsynaptic. Two presynaptic myasthenic disorders are due to defects in ACh resynthesis or to a paucity of synaptic vesicles with reduced quantal release. End-plate ACh deficiency causes a synaptically mediated disorder. The postsynaptic disorders are associated with a kinetic abnormality of AChR with or without AChR deficiency, or with AChR deficiency without a primary kinetic abnormality. Those with AChR deficiency and a kinetic abnormality include a syndrome with a short open time, a slow-channel syndrome associated with a prolonged open time due to delayed channel closure, a slow-channel syndrome due to increased affinity of AChR for ACh causing repeated reopenings during prolonged ACh occupancy, and another syndrome in which the nature of the kinetic abnormality is not elucidated. Those without AChR deficiency include the low-affinity fast-channel syndrome and the high-conductance fast-channel syndrome. The disorders associated with AChR deficiency without a primary kinetic abnormality are caused by nonsense mutations in a subunit gene. Clues to a congenital myasthenic syndrome include a positive family history, onset in the neonatal period, infancy, or childhood with progression during adolescence or adulthood, lack of significant response to anticholinesterase drugs, and absent serum AChR antibodies. Investigation of these syndromes requires sophisticated morphologic and electrophysiologic studies of the neuromuscular junction, usually available at only a few medical centers with a specific interest in these disorders. A motor-point muscle biopsy in a suspected patient should be processed for cytochemical localization of ACh and immune deposits at the end plates. Electron microscopic and cytochemical studies can be used to determine the size and density of synaptic vesicles and the morphology of nerve terminals, and postsynaptic membranes. Quantitative assessment of AChR binding sites is performed using peroxidase-labeled -bungarotoxin on muscle tissue samples. In vitro microelectrode studies, including noise analysis and patch-clamp recordings, provide information about the kinetic properties of AChR channels. The application of molecular genetics to the detection of mutations in AChR subunit genes has revealed new insights into and valuable correlations with the observed channel abnormalities.
TREATMENT
Neurologists must choose the sequence and combination of available therapies, including anticholinesterase and immunosuppressant medication, thymectomy, plasmapheresis, and intravenous immune globulin (IVIG).
Acetylcholinesterase Inhibitors
Virtually all patients use pyridostigmine (Mestinon, ICN Pharmaceuticals, Costa Mesa, CA, U.S.A.) at some time, usually as initial therapy. Optimal dosage is determined by the patient's symptoms, commencing with 60 mg every 4 hours while awake, and increasing the dose to 120 to 180 mg until undesirable side effects offset clinical benefit. Chronic administration is not known to cause a decline in effectiveness or deleterious effects, or appreciably modify the natural history of the disease; ultimately, other modalities must be used.
Corticosteroids
Prednisone is the most widely used immunosuppressive agent in MG. As early as 1935, Simon reported sustained remission in a patient after daily injections of aqueous extracts of the anterior lobe of the pituitary gland. Torda and Wolff (1949) documented partial remissions in five patients treated with adrenocorticotrophic hormone (ACTH). Subsequently, they demonstrated improvement in 10 of 15 additional patients. However, Torda and Wolff (1951) noted that all their patients experienced transient worsening, and one died. The unfavorable experiences of Shy and associates (1950), as well as Grob and Harvey (1952) and Millikan and Eaton (1951) overshadowed initial promising results, and enthusiasm for corticosteroids waned for almost 20 years until Warmolts and Engel (1972) and Jenkins (1972) demonstrated efficacy of chronic ACTH and chronic oral prednisone therapy. Although corticosteroids exert an immunosuppressive effect at various levels of the immune system, the effects on activated T and B cells and on APCs are believed to be the most important in the beneficial response in MG. According to the report of Pascuzzi and colleagues (1984) long-term administration resulted in eventual improvement in 69% to 80% of patients, but 48% of patients had initial exacerbations and two thirds had undesirable or serious side effects. Gradually increasing the dose of
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prednisone averts exacerbations of weakness. There has been uncertainty as to the optimal regimen even among experts. To illustrate, in 1974 the regimen of 25 mg alternating daily, increasing by 12.5 mg every three doses to a maintenance dose of 100 mg, was associated with dramatic or moderate improvement in 11 of the 12 patients thus treated by Seybold and Drachman (1974). Twenty years later, the same group recommended beginning prednisone with 15 to 20 mg daily, increasing by 5 mg every 2 to 3 days to a maximum of 50 to 60 mg daily, followed by alternate-day dosing.
Azathioprine
The beneficial effect of azathioprine (Imuran, Faro Pharmaceuticals, Bedminster, NJ, U.S.A.) was first reported in 1969 by Mertens and co-workers. It has since gained worldwide acceptance, with response rates equal to those of prednisone as monotherapy for patients with generalized disease. Azathioprine is appropriate therapy for patients who exhibit poor responsiveness, intolerance, or frequent relapses while receiving corticosteroids; in those deemed unsuitable candidates for thymectomy because of age or comorbid disease; and in patients with epithelial tumors of the thymus (thymoma). There are, however, three drawbacks to its use: (a) idiosyncratic side effects occur in about 10% of patients but are mainly gastrointestinal and flulike and rarely necessitate permanent withdrawal of the medication, (b) bone marrow suppression occurs in all patients, and (c) there is a long delay in the onset of the therapeutic effect of 3 to 6 months or more. Taking all these factors into account, most clinicians concur with slow advancement of the dose over weeks, from 50 mg/day to maintenance levels of 2 to 3 mg/kg/day with careful monitoring of liver function, peripheral white blood cell counts, and platelet counts.
Cyclosporine
Tindall and associates (1993) reported the favorable effects of cyclosporine A in MG in a placebo-controlled trial and later in controlled double-blind studies in comparison with prednisone and azathioprine in 1987. Cyclosporine inhibits T cell dependent antibody responses by reversibly suppressing the clonal expansion of activated helper T cells. It also inhibits the inflammatory intermediate interleukin-2 (IL-2). Administration of cyclosporine can prevent the expression and induction of EAMG. Long-term use is associated with dose-dependent and cumulative nephrotoxicity owing to endothelial vascular injury and interstitial fibrosis, hypertension, and headache.
Plasmapheresis and Intravenous Immunoglobulin
Plasmapheresis and IVIG are administered during myasthenic exacerbations to produce short-term clinical improvement, often within days of commencing treatment. Plasmapheresis rapidly lowers AChR antibody titers, which may account for its beneficial effects. The effectiveness of IVIG results from the inhibition of specific idiotype-antiidiotype antibody interactions, downregulation of autoantibody production, inhibition of binding to the AChR, and amelioration of complement-mediated lysis of AChR. Drawbacks to both include high cost, the need for specialized equipment and staff, potential shifts of body fluids, electrolyte disturbances, and the need for indwelling catheters for vascular access. IVIG can be associated with a flulike syndrome, aseptic meningitis, renal failure, headache, hypotension or hypertension, anaphylaxis in IgA-deficient patients, and a small but finite risk for transmissible disease.
SURGICAL TREATMENT
Thymectomy
The earliest transsternal procedures were performed for removal of thymic tumors. The beneficial results in nonthymoma patients, including the salient abnormal histologic changes and possible contributing factors to the pathogenesis of MG, were appreciated afterward. Two concepts suggested an intrathymic pathogenesis for MG. The success of early and total thymectomy, and the often-observed fall in antibody titers, especially in patients with noninvoluted hyperplastic thymus glands, further strengthened the role of the thymus gland in the primary immunopathogenesis of MG. The technical goal of surgery is complete removal of the thymus gland. Total thymectomy can be difficult because the gland consists of multiple lobes in the neck and mediastinum, and small foci usually lie outside the field of classical or extended transsternal or transcervical surgical approaches.
Epithelial Tumors of the Thymus (Thymomas)
All authorities agree that transsternal thymectomy with exploration of the neck and mediastinum for thymic tissue should be performed for patients suspected of thymoma to prolong survival, prevent tumor recurrence, and induce remission or an asymptomatic status. In my experience, the prognosis of MG with a noninvasive epithelial thymic tumor after surgery alone, and invasive tumors with surgery and radiation therapy or chemotherapy or both, seems to be equally favorable when treated early and aggressively. Controversy abounds in the choice of chronic immunosuppressant agents in myasthenia with thymoma. It has been my 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 disease. Patients with noninvasive and low-grade invasive tumors, including medullary and mixed cortical and epithelial
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thymoma (type A and AB thymoma), with little or no risk for recurrence even when there is capsular invasion, rarely require adjuvant therapy. Cortical thymoma (type B1 and B2 thymoma) demonstrates 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 (type B3 thymoma) should be treated with postoperative irradiation and followed carefully with CT of the chest for signs of recurrence. Patients with exacerbation of myasthenia should be suspected of microscopic tumor recurrence and should be watched carefully for detectable tumor relapse, as which point chemotherapy and reoperation may be necessary.
MYASTHENIC CRISIS
Forty years ago, a patient with MG had about a 50:50 chance of surviving a crisis, defined as the need for mechanical ventilatory support. Approximately 16% of all patients experience a crisis, as reported by Cohn and myself (1981), a figure that has not changed appreciably. Progressive weakness, oropharyngeal symptoms, refractoriness to anticholinesterase medication, and intercurrent infection precede crisis in most of these patients. It is now standard practice to treat severe MG in an intensive care unit because of the ready availability of monitoring to assist in the correct timing of intubation and extubation and the availability of aggressive respiratory and medical therapies to reduce the need for tracheostomy. The overall mortality of crisis has decreased from 50% to 6% in the past four decades, 1960 to 2000. Crisis is a temporary exacerbation, regardless of the proximate cause. The goal is to keep the patient alive until the transient morbidity of viral or bacterial infection, aspiration pneumonitis, surgery, or other complications subsides and responsiveness to anticholinesterase medication returns. In the past, edrophonium was administered to differentiate myasthenic from cholinergic crisis. That issue is now moot because cholinergic crisis is exceedingly rare and withdrawal of anticholinesterase medication is necessary for improvement in both.
THERAPIES ON THE HORIZON
The ultimate goal of therapy in MG is a cure or, at the least, prevention or inhibition of the immune response to skeletal muscle AChR. A number of therapies that selectively or specifically interfere with the immune pathogenesis of the disease have been envisioned and may prove useful in the future. Selective immunotherapy inhibits only cells of the immune system, without affecting other cells and without the side effects of generalized immunosuppression. Some examples include genetically engineered agents that are toxic to IL-2 and thereby kill activated T cells, such as DA13389, or that interfere with costimulatory signals for T-cell activation, such as CTLA-4. Specific immunotherapy goes a step further by attempting to inhibit the specific autoimmune response to AChR. Such strategies are of theoretic interest at present and include the elaboration of AChR-specific suppressor cells, induction of tolerance to AChR-specific T cells, inactivation of AChR-specific T cells using targeted APCs, and genetically modified B cells.
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READING REFERENCE
Blalock A: Thymectomy in the treatment of myasthenia gravis. Report of 20 cases. J Thorac Surg 13:316, 1944.
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