THERAPEUTIC STRATEGIES FORMYASTHENIA GRAVIS Patricia A. Keys and Robert P. Blume

ABSTRACT: Myasthenia gravis (MG) is a complex autoimmune neurologic disorder of unknown etiology, characterized by fluctuating skeletal muscle weakness most commonly involving the muscles of the head, neck, and upper extremities. Autoantibodies directed against acetylcholine receptors on the postjunctional membrane decrease the numbers of functional acetylcholine receptors and cause membrane alterations, resulting in neuromuscular transmission failure. Diagnosis is established by history and physical examination, the "Tensilon Test," and acetylcholine receptor antibody titers. Treatment modalities include drug therapy, thymectomy, and plasmapheresis. The drugs most commonly employed are anticholinesterases, corticosteroids, and immunosuppressive agents. Cyclosporine and intravenous immunoglobulin are promising investigational treatments. The purpose of the article is to review current concepts in the pathophysiology, immunopathology, diagnosis, and treatment of MG. Special emphasis is placed on the autoimmune form of the disease and the drugs employed in its management Standard regimens as well as some experimental treatment modalities are reviewed.

D1ep Ann Pharmacother 1991;25:1101-8.

is a complex autoimmune neurologic disorder, characterized by fluctuating weakness and abnormal fatiguability of the skeletal muscles. Most of our understanding of the complex pathophysiology of MG has evolved in the last 50 years, paralleling advances in the fields of immunology, biotechnology, and neurophysiology. Likewise, effective drug and nondrug alternatives for management of the myasthenic patient have increased in number and sophistication. Aggressive therapeutic intervention has greatly improved survival rates and quality of life for the vast majority of patients suffering from this as yet incurable disease. The purpose of this article is to review current concepts in the pathophysiology and treatment of MG. Attention is focused on the acquired (autoimmune) form of the disease. Less commonly encountered congenital, neonatal, and drug-induced forms of MG are discussed in detail elsewhere in the literature.v-' Standard regimens as well as experimental treatment modalities are reviewed.

Incidence and Prevalence MG is estimated to affect between I in 10 000 and I in

20000 individuals in the population, with no major geographic or racial predilection.' People of all ages may be affected, although onset before age 10 and after age 70 is rare. Peak age at onset is between 20 and 40 years, with women affected two to three times more commonly than men of the same age. Later-onset disease (after age 40) affects women less selectively. A subset of the affected population presents with concomitant thymomas (l0-15 percent of cases); the majority are men between 50 and 60 years of age at the time of diagnosis.v Familial occurrence is uncommon, except in the congenital nonimmune form of the disease. Ten to IS percent of infants born to myasthenic mothers may show transient, self-limiting myasthenic weakness lasting 1-12 weeks postpartum because of transplacental transfer of antibodies (neonatal myasthenia).'>

MYASTIiENIA GRAVIS (MG)

PATRICIA A. KEYS, Phann.D., is an Assistant Professor of Clinical Pharmacy, Department of Clinical Pharmacy, School ofPhannacy. Duquesne University, Pittsburgh, PA 15219; and ROBERT P. BLUME, M.D., is the Chief, Division of Neurology, and the Director, Myasthenia Gravis Treatment Center, Mercy Hospital of Pittsburgh, Pillsburgh, PA. Reprints: Patricia A. Keys. Phann.D.

This article is approved for continuing education credit.

Pathophysiology The primary defect in acquired (autoimmune) MG has been traced to the neuromuscular junction (NMJ). Abnormalities typically found include widening of the postsynaptic cleft, simplification and shortening of the normally highly folded postsynaptic membrane, and a 70-90 percent reduction from normal in the number of postjunctional acetylcholine receptors (AchRs). These abnormalities result in reduced effective postjunctional AchR activation, with motor endplate potentials below the threshold necessary to trigger muscle action potentials, and eventual neuromuscular transmission failure.1,3,s. 1I

Immunopathology The motor endplate abnormalities in MG are thought to be the result of one or more autoimmune processes. Sensitive radioimmunoassay techniques have shown that 90 percent of patients with generalized MG and 75 percent of those with disease limited to the ocular muscles have measurable numbers of circulating polyclonal AchR-binding autoantibodies (anti-AchR).3,7,12,13 Anti-AchR titers correlate poorly with disease severity, although titers are generally lower in patients with isolated ocular disease and higher in patients with thymoma.P-" These antibodies, which appear to be specific to patients with MG, are postulated to

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mediate AchR inactivation or destruction by one (or more) of the following mechanisms.vv-!' 1. Direct blockade. By this mechanism, anti-AchR blocks the action of acetylcholine (Ach) by attaching directly to the actual AchR binding site of the postjunctional membrane. 2. Steric hindrance. In this model, the anti-AchR attaches not to the actual AchR binding site, but to a site on the receptor sufficiently close to the actual site to block Ach access. 3. Antigenic modulation. Antigenic modulation involves the crosslinking of AchRs by antibodies that facilitate AchR destruction through endocytosis and lysosomal degradation. The result is increased receptor turnover rate in excess of the regenerative capabilities of the cell, causing an overall reduction in the absolute number of AchRs. 4. Complement-mediated focal lysis. In this scheme, anti-AchR binds to the AchR in such a way as not to block access to the receptor site, but to activate complement that destroys the postjunctional membrane at given points. The eventual result is "simplification" of the postjunctional membrane with loss of some of its normal folds and clefts. The possibility that multiple antibody-mediated autoimmune mechanisms may playa role in the immunopathology of MG has important clinical implications. This theory may serve to explain the fluctuating clinical course of the disease in anyone patient at different points in time. In addition, it may serve to explain the wide interpatient variability in the severity of disease and response to different treatment modalities.' The thymus gland appears to be the site where autosensitization of T cells against AchR antigenic determinants occurs. The thymus gland is abnormal in 75- 80 percent of myasthenic patients. Typical pathologic findings include hyperplasia of the lymphoid follicles and an alteration in the normal percentage of B and T cells present. In 10-15 percent of cases, a malignant thymoma is present. These abnormal thymus glands have been shown in some instances to synthesize and release increased amounts of thymic hormones, especially thymopoietin. Thymopoietin has shown high binding affinity for the AchR and the potential to negatively modulate Ach effect at the NMJ. Thymectomy produces clinical improvement in the majority of myasthenic patients."

The hallmark feature of MG is progressive exhaustion and eventual paralysis of the contractile response of a local skeletal muscle group to a persistent, repetitive stimulus for activity. This paralysis, in tum, is usually partially or completely reversed by rest.' Certain voluntary muscle groups are predisposed to being affected. The muscles of the eye are most commonly involved. Ptosis, or drooping of the upper eyelid(s) and/or diplopia, are the most common presenting symptoms (60 percent), and are frequently accompanied by weakness of the muscles responsible for eye closure (orbicularis oculi). Bulbar symptoms (paralysis of the muscles of facial expression, mastication, and swallowing) and weakness of the muscles of the trunk and proximal extremities are less D1ep. The Annals ofPharmacotherapy

Table 1. Osserman's Classification of Adult Myasthenia Gravis' I. II.

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common initial presentations (20 percent). Respiratory insufficiency and/or generalized weakness are seldom initial complaints. Atrophy accompanying localized weakness is likewise rare (less than 5 percent), although it is more common in elderly patients.' The Osserman classification system is commonly employed to stage the severity of the disease in a given patient (Table 1). Staging is based on the extent of muscular involvement and rate of progression of symptoms. It establishes a general prognosis for an individual patient and predicts potential response to drug therapy. In 10-30 percent of cases, the disease remains localized to the ocular muscles. More commonly, fluctuating weakness progresses at a variable rate to involve the other muscle groups mentioned previously, especially the proximal muscles of the extremities and the muscles controlling facial expression, chewing, and swallowing. Restricted mobility, exercise intolerance, reduced socialization, and malnutrition may result. On the average, maximum severity is reached within three years of diagnosis. The typical course of MG is marked with multiple exacerbations and remissions. Approximately 10 percent of patients will experience a spontaneous remission during the first three years of the disease, typically of less than one year's duration. An additional 15-20 percent of patients with generalized disease and 30 percent with limited ocular disease experience remissions that are delayed as long as 10-15 years after a diagnosis is established.' Exacerbations can occur at any time but are most common in the first five to seven years following diagnosis. A number of external factors may precipitate an exacerbation, although the typical affected patient has a history remarkable for a recent deterioration in general clinical condition (Table 2). A long list of drugs have been reported to exacerbate MG, including commonly prescribed cardiovascular agents, anticonvulsants, opiate analgesics, antirheumatic agents, and

•

IV.

Ocular myasthenia Generalized myasthenia A. Mild. generalized myasthenia with slow progression; no crises; drug-responsive B. Moderate. generalized myasthenia; severe skeletal and bulbar involvement. but no crises; drug response less than satisfactory Acute fulminating myasthenia; rapid progression of severe symptoms with respiratory crises and poor drug response; high incidence of thymoma; high mortality Late severe myasthenia. same as class III but with progression over two years from class I to II

"Adapted from Reference 15.

Table 2. Precipitating Factors in Myasthenic Exacerbations' Drugs (see Table 3) Emotions Hot environment Hyperthyroidism "Adapted from Reference 1.

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antimalarials (Table 3). A discussion of the mechanisms for the deleterious effects of these agents is beyond the scope of this article, but is presented in the literature." Because of the wide variety and large number of drugs reported to cause problems in the myasthenic patient, caution should be taken when prescribing or dispensing medications for problems not limited to or related to their primary disease. Severe exacerbations ("myasthenic crises") are medical emergencies, defined clinically as sudden dramatic increases in disease severity that occasionally result in paralysis of the diaphragm muscle and respiratory failure. Myasthenic crises are rare occurrences today with improved patient care. The mortality rate from myasthenic crisis has declined from 50 to 80 percent reported before 1960 to less than 5 percent today. I Fortunately for many patients, MG tends to lose some of its intensity and variability approximately five to seven years after its onset. However, extreme inter- and intrapatient variability in the course of the disease makes establishing an accurate prognosis for an individual patient almost impossible at the time of diagnosis. The poorest prognosis exists for patients with malignant thymoma diagnosed between the ages of 40 and 60. 1

Diagnosis The history and physical fmdings in early MG are often equivocal and may lead to misdiagnoses of related neuromuscular, central nervous system, or hysterical illnesses. Specific neurologic and pharmacologic testing procedures are required in most instances to establish a definitive diagnosis. The classic diagnostic pharmacologic test for MG involves the administration of the short-acting acetylcholinesterase (AchE) inhibitor, edrophonium (Tensilon). The "Iensilon Test" involves the intravenous administration of a 2-mg test dose of edrophonium followed in 30- 60 seconds by another 8-mg dose. A positive clinical response, consisting of subjective and objective evidence of improvement in pre-edrophonium muscle contractility, is usually seen within 30 - 60 seconds of the second dose and lasts 4 to 5 minutes.P Identification of measurable titers of anti-AchR is being increasingly used to confirm the diagnosis of MG. The availability of a sensitive assay has improved the reliability of this procedure."

Table 3. Drugs to Avoid in the Presence of Myasthenia Gravis' Analgesics narcotics Antibiotics aminoglycosides c1indamycin lincomycin polymyxin B sulfate sulfonamides tetracyclines Anticonvulsants barbiturates ethosuximide magnesium sulfate paraldehyde phenytoin trimethadione "Adapted from Reference 16.

Antimalarials chloroquine quinine Antirheumatics chloroquine colchicine penicillamine Cardiovascular agents beta-blockers diuretics lidocaine phenytoin procainamide hydrochloride quinidine trimethaphan camsylate

Other techniques useful in establishing a diagnosis include repetitive stimulation of appropriate peripheral nerves, single fiber electromyography, motor-point biopsy, radiologic evidence of thymoma, or giving birth to a myasthenic child. In ocular disease, limited electromyography of the eye muscles, tonography, and nystagmography may be employed. I

Treatment The fluctuating nature of the myasthenic process and wide interindividual variation in disease presentation, coupled with insufficient numbers of controlled clinical trials, make it difficult for practitioners to make valid comparisons of the efficacy of different treatment regimens. Thus, an optimum therapeutic approach to management of MG remains controversial. There are three major treatment modalities employed in MG-drug therapy, thymectomy, and plasmapheresis. Clinicians must determine the sequence or combination of therapies to be used on an individual patient basis. DRUG THERAPY

There are three groups of drugs traditionally used to treat MG: cholinesterase inhibitors, corticosteroids, and irnmunosuppressives. Cholinesterase Inhibitors (Anticholinesterases). Cholinesterase inhibitors (anticholinesterases) have been used as symptomatic therapy in MG since 1934. Anticholinesterases exert their pharmacologic effect indirectly, by competitively inhibiting AchE, the enzyme responsible for hydrolyzing Ach into inactive acetyl and choline radicals in the synaptic cleft of the NMJ. As a result of AchE inhibition, relatively more Ach is available for activating postsynaptic neuromuscular receptors. Increased receptor activation results in some improvement in muscle strength in the majority of treated patients. The pathophysiology of MG is such, however, that AchR availability limits the extent of improvement possible from anticholinesterase therapy in a given patient. The available cholinesterase inhibitors are pyridostigmine bromide, neostigmine bromide, ambenonium chloride, and edrophonium chloride. Pharmacokinetic information related to the available anticholinesterases is limited and of questionable value in optimizing dosage. Most of the available data are summarized in a review by Aquilonius and Hartvig. The anticholinesterases are cleared rapidly by both renal and hepatic elimination processes, have small volumes of distribution, and, therefore, short elimination half-lives, necessitating multiple daily drug administration for optimum clinical effect." No consistent correlation between plasma anticholinesterase concentration and overall improvement in myasthenic symptoms has been demonstrated. This lack of a therapeutic window in the plasma concentration-response relationship causes most clinicians to adopt a conservative, stepwise approach to titrating drug dosage in order to obtain the desired therapeutic response and avoid toxicity. In the majority of clinical settings, pyridostigmine is the drug of choice for oral administration. Pyridostigmine has better oral bioavailability, causes fewer gastrointestinal complaints, and has a longer half-life, allowing less frequent administration than neostigmine and ambenonium. Treat-

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ment is usually initiated with low doses (e.g., 15-30 mg tid or qid). The quantity and frequency of administration are adjusted upward every two to three days until either the desired response or adverse effects ensue. A typical maintenance dose regimen for pyridostigmine in an adult myasthenic patient might be 30 -120 mg administered every three to four hours. Seldom do patients benefit from dosages exceeding 120 mg every two to three hours. Dosage requirements may vary fourfold or more among patients with a similar degree of disease involvement. 1.17 Assessment of benefit is largely based on the clinical judgments of both the practitioner and the patient. Optimal dosage is often difficult to determine, as different muscle groups may have different thresholds for improvement. If this is the case, response priorities must be established jointly by physician and patient, and dosage titrated accordingly. Edrophonium is occasionally used as a quick test to determine if a dosage maximum has been achieved or if further dosage increases may be of benefit, before intolerable toxicity intercedes. I Adverse effects are common when initiating anticholinesterase therapy, even when low doses are first employed. Adverse effects are usually attributed to excessive muscarinic receptor stimulation and include nausea, vomiting, diarrhea, bradycardia, micturition, bronchospasm, increased sweating, salivation, and lacrimation. These muscarinic effects generally decrease after a few weeks of continuous therapy, but may be dose-limiting. Administration with milk or food may help to minimize gastrointestinal discomfort. Concomitant administration of low-dose atropine sulfate (0.125- 0.25 mg) has been advocated in some cases to reduce muscarinic adverse effects. This practice is controversial because atropine may mask important symptoms of cholinergic excess. Anticholinesterase overdosage results in symptoms of excess motor endplate depolarization and nicotinic receptor stimulation. A "cholinergic crisis," with increasing weakness resembling myasthenic crisis, may ensue. I Children appear to clear anticholinesterases at a faster rate than adults; however, the mg/kg dosage of drug necessary to reverse neuromuscular blockade is approximately half that required by average adult patients. It is postulated that this discrepancy is the result of enhanced AchR sensitivity in younger patients. I Pediatric therapy is initiated with 7 mg/kg or 200 mg/m 2/d, divided into five or six oral doses, using either tablets or syrup (12 mg/ml.)." Dosage requirements in patients with MG may vary from day to day, corresponding with intrinsic disease exacerbations and remissions as well as a variety of external factors, such as physical and psychologic stresses. A drug regimen should be established that allows the patient to schedule dosage to produce peak effect when needs are greatest (e.g., 30-45 minutes prior to meals or anticipated exercise). When anticholinesterase therapy has been stabilized, patients may be instructed to increase or decrease dosage according to their individual needs!S,19 Pyridostigmine is also available as a 180-mg, extendedrelease tablet (Mestinon TImespan) with an average duration of effect of six to eight hours. It may be particularly useful for patients who require round-the-clock medication administration that would otherwise interrupt normal sleep patterns or result in excessive early morning weakness and difficulty arising from bed. The sustained-release product 1104 •

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is seldom employed in the daytime management of MG. The majority of patients benefit more from frequent administration of the short-acting preparations coincident with periods of anticipated maximal activity.l,l8,20 Pyridostigmine is also available as a parenteral formulation (5 mg/rnL) for intramuscular or very slow intravenous administration. The parenteral preparation is approximately 30 times more potent than the same dose administered orally. Appropriate dosage conversion is essential when changing the route of administration. Other anticholinesterase agents (e.g., neostigmine bromide, ambenonium chloride) are rarely employed in the long-term maintenance of patients with MG. Neostigmine is occasionally used in patients with severe renal failure, as it is more reliant on the hepatic route of elimination than pyridostigmine. Ambenonium is the least studied of the available systemic anticholinesterases. Although its duration of effect is similar to that of pyridostigmine, and like pyridostigmine, results in fewer muscarinic effects than neostigmine, it is reported to have a narrower therapeutic index than either of the latter two drugs. The lower incidence of muscarinic adverse effects associated with initiating ambenonium therapy may place the patient at greater risk for cholinergic overdosage from rapid escalations of dose. A single justification for use of ambenonium may be in the patient with a significant bromide hypersensitivity.-" Whereas neuromuscular function in the majority of myasthenic patients is improved to some extent with anticholinesterase treatment, original muscle strength and endurance (especially ocular muscle function) is seldom completely restored. Greatest benefits are usually seen in cases of mild generalized disease, where the rapid onset of effect of anticholinesterases is an important advantage. More aggressive therapeutic measures are usually necessary in moderate to severe, progressive MG, especially if there is oropharyngeal or respiratory muscle involvement. The use of anticholinesterases as primary therapy in MG has recently been questioned because they do not alter the pathologic progression of the autoimmune process at the motor endplate. Experiments using rat models administered long-term anticholinesterase therapy have demonstrated deleterious effects on muscle endplate morphology and function. Desensitization of postjunctional AchRs, reduction of muscle endplate potential amplitude and frequency, and degeneration of postsynaptic membrane folds, resulted in worsening of myasthenic symptoms with prolonged treatment.w Corticosteroids. Corticosteroids have been used successfully in the management of MG since 1935, with 60 -90 percent of treated patients experiencing beneficial effects.19·25 The specific mechanism of action for corticosteroids in MG is not well understood. Corticosteroids have been shown to protect AchRs from the effects of autoantibodies and/or cell-mediated destruction, and also to exert direct lympholytic and antiinflammatory effects.P-" When selecting patients for corticosteroid therapy, potential benefits must be weighed against risk of adverse effects. Corticosteroids may be effective in any stage of MG, but are most consistently employed in patients with severe symptoms (Osserman's class 3-4) whose response to maximal tolerated anticholinesterase therapy is less than satisfactory, and who do not have any significant con-

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traindications to corticosteroid treatment.v-" Response rates are better in older patients with late- onset disease than in younger patients of either sex. Duration of illness and a history or presence of thymoma do not appear to influence response. 24,26 A number of different treatment protocols for corticosteroid use in MG have received attention in the literature. Well-controlled studies comparing efficacy and risk for the different regimens in large numbers of patients are lacking. Prednisone is the corticosteroid of choice in most regimens. In analyzing the literature, two major strategies for initiating prednisone therapy emerge-high dose and low dose. Proponents of the high-dose regimen advocate the oncedaily administration of prednisone 60-80 mg until a clinical response is sustained for at least three days, after which time patients are converted to a high-dose alternate day regimen;23,24,26 advocates of less aggressive regimens initiate therapy with either high doses of prednisone on alternate days21,22 or low doses of prednisone on daily or alternate days and increase dosage until symptoms are controlled.Pr" Regardless of the method with which corticosteroid therapy is initiated, once clinical benefit is observed for at least one month on a high-dose, alternate-day regimen, slowly tapering back to a minimally effective dose is recommended. A dosage reduction schedule of 10 mg every two months has been reported to be safe and effective in achieving this end. If patients cannot be tapered to a dose of less than 40-50 mg of prednisone every other day, or one that does not cause adverse effects, concomitant use of a corticosteroid-sparing agent, such as azathioprine, may permit further corticosteroid dosage reduction. I There is a variable and relatively slow onset of clinical benefit with all of the oral corticosteroid regimens (range 2-6 wk). The high-dose regimen has the advantage of producing the fastest onset of effect. Patients receiving alternateday therapy often complain of fluctuating weakness on off days in addition to a more delayed onset of improvement. I Risks associated with corticosteroid therapy cannot be minimized. Exacerbations in myasthenic weakness occur in approximately 50 percent of patients when initiating therapy, with up to 10 percent of patients experiencing severe decompensation requiring ventilatory support. 20'25 Measurable worsening of symptoms typically occurs between the first and seventeenth days of initiating therapy (mean 4.2). The less aggressive regimens have been reported to produce a lower frequency and severity of exacerbations than high-dose regimens. 19.22,25 The potential for a serious exacerbation has led most practitioners to hospitalize patients for initiation of corticosteroid therapy. Serious metabolic and endocrine abnormalities associated with long-term corticosteroid administration (e.g., accelerated osteoporosis, peptic ulcer disease, diabetes, hypertension, cataracts) have been reported in up to one-third of patients on high-dose regimens. Fewer complications have been reported in patients treated with less aggressive regimens. 19·22,25 Maximal improvement in myasthenic weakness is usually observed after 6-12 months of continuous corticosteroid therapy. In a study conducted at the University of VIrginia, 31/116 patients (27.6 percent) treated using prednisone 60-80 mg/d until onset of improvement, followed by lower-dose, alternate-day therapy, achieved clinical remission (complete absence of myasthenic symptoms). Thirteen of the 31 were tapered off all medications upon

achieving remission; remissions lasted 6 months to 9 years (mean 3.9 y); 18 patients required minimal doses of corticosteroids (prednisone 5-30 mg qod) to sustain remission. Overall 80.2 percent of patients showed some benefit and were able to reduce and simplify their anticholinesterase regimens." Parenteral corticosteroids have been used in unresponsive or acutely ill patients. Arsura et al. administered highpulse doses of methylprednisolone sodium succinate 2 g iv at five-day intervals in patients experiencing myasthenic crises. Response rate was similar to that observed with the oral regimens previously described. However, the highdose intravenous regimen produced fewer exacerbations in MG symptoms and a faster onset of improvement. In addition, the high-dose intravenous regimen allowed patients to be converted to smaller oral corticosteroid maintenance doses and resulted in fewer adverse effects overall." Genkins et al. employed ten-day courses of adrenocorticotropic hormone gel (100 IV/d) in severe unresponsive cases of MG and demonstrated restored responsiveness to anticholinesterases and major clinical improvement. Respiratory insufficiency occurred frequently, limiting use to hospitalized patients in the intensive care setting." Immunosuppressives. Immunosuppressive agents other than corticosteroids have been employed in the management of severe MG since the early 1970s. Azathioprine is the most commonly used agent; however, success has been reported using a variety of other immunosuppressives, including cyclophosphamide, mercaptopurine, and methotrexate. Well-designed studies comparing the relative efficacy of different immunosuppressive agents in MG are lacking. The specific mechanism by which immunosuppressives affect MG remains to be determined. Success is generally attributed to direct lympholytic and antiinflammatory actions that result in decreased numbers of circulating antibodies directed toward AchRs. 29 Immunosuppressive therapy is indicated primarily in patients with Osserman class 3 or 4 disease whose symptoms are inadequately controlled, or who are intolerant of the adverse effects of maximal doses of anticholinesterases and corticosteroids. Additionally, immunosuppressives may be employed in combination with corticosteroids as "steroidsparing" agents, allowing prednisone dosage to be reduced so as to minimize or prevent the occurrence of adverse effects.28,29 Immunosuppressives have been employed on a limited basis as initial therapy in European investigations.v however, that protocol is not widely accepted in the US. Azathioprine, a purine antagonist antimetabolite, is the best-studied immunosuppressive used against MG. The usual starting dosage is 2-3 mg/kg/d administered in three to six divided doses. 29'33 Treatment is continued until improvement is noted or until adverse effects intervene. Response is slower than that seen with corticosteroids, with improvement beginning at 2- 4 months and maximizing at 6-15 months." Sixty to 80 percent clinical response rates have been reported using this regimen, with 30 - 40 percent of responders achieving complete remission of variable duration. Reduction in anti-AchR concentrations typically parallels response." Once maximal response is achieved, dosage may be tapered to a maintenance dose of 1()() mg/d. Adverse effects associated with azathioprine include bone marrow suppression (10-20 percent), hepatic enzyme alterations, gastrointestinal intolerance, and rashes,"

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Less consistent response rates and a higher incidence of serious adverse effects have been associated with the use of other immunosuppressives.v-" Experimental Treatments. A number of experimental drug therapies have been employed with variable success in the management of MG. The two most promising investigational agents to date are cyclosporine and intravenous immunoglobulin (IVIG). Preliminary data suggest that cyclosporine may be an effective alternative to other available immunosuppressants for the management of moderate to severe, generalized MG, unresponsive to anticholinesterases and corti costeroids.34-.18 Treatment protocols to date have employed doses of 5-6 mg/kg/d, adjusted for renal function and trough whole blood concentration. The time for clinical response is similar to that observed with corticosteroid therapy, with onset of effect in 2- 4 weeks, maximizing in 8-12 weeks. Nephrotoxicity, the major dose-limiting adverse effect of cyclosporine therapy, has been reported in a few patients, but has been nonprogressive with a reduction in dosage and reversible on discontinuation of the drug. Hematopoietic adverse effects appear to be less of a problem with cyclosporine than with other immunosuppressive agents. The precise mechanism for the effect of cyclosporine in MG is not well understood. Cyclosporine acts by inhibiting the synthesis and release of lymphokines, especially interleukin-2, which is presumed to selectively influence the clonal expansion and functional activation of individual lymphocyte subsets, (predominantly T-helper cells).J4·.18 Cyclosporine, then, most directly affects cellular immunity. MG, however, is understood to be primarily a disease of defective humoral immunity. The results of these studies suggest that a cellularly mediated effector mechanism may play more of a role in the pathogenesis of MG than was previously believed. Cyclosporine may act by suppressing T-helper cell activation of the B cells that regulate the production of anti-AchRs, or by inducing suppressor cells that inhibit antibody production by primed lymphocytes..18 The safety and efficacy of cyclosporine in long-term management of MG are questions that have not been resolved by studies to date. Patientmonitoring and compliance issues must be addressed. Outcomes from properly randomized, controlled trials, involving larger numbers of patients and long-term follow up, must be obtained before the role of cyclosporine in the long-term management of MG is clear. High-dose (400 mg/kg/d), short courses (5 d) of IVIG have been reported to produce rapid (mean 3.6 d) and sustained (average 52 d) improvement in muscle strength in patients experiencing exacerbations in MG, with only mild rebound deteriorations of short duration (1.5 d), and no significant adverse effects." The mechanism of action of IVIG in MG is unknown. IVIG may compete with anti-AchRs or displace them from their binding sites, thereby "protecting" the AchRs from injury.39.40 Alternatively, treatment with IVIG preparations containing anti-ideotype antibodies has been shown to decrease the synthesis of autoantibodies in experimental animals; a similar mechanism may be operative in human subjects with MG.41 A major drawback in selecting patients for IVIG therapy is cost, averaging approximately $1000 per dose, thereby limiting the use of IVIG to the acute care setting. ll06

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THYMECTOMY

The benefits of thymectomy (surgical excision of the thymus gland) in MG have been recognized since 1941. In the past 20 years thymectomy has emerged as first-line practice in most medical centers for good surgical candidates (i.e., otherwise healthy patients) recently diagnosed with MG. Although results are not immediate, thymectomy produces complete remission in up to 35 percent of patients and improvement in as many as 80 percent of patients without thymomas in the first 3-5 years following surgery.5.7,20 Clinical improvement may not be evident for 10 years postsurgery in up to 25 percent of patients. Improvements in anesthesia, respiratory management, and surgical technique account for almost zero mortality from the procedure today. Usual candidates for thymectomy are patients between the ages of 15 and 40 with severe generalized active disease of less than 3-5 years' duration. Thymectomy before adolescence is of concern because of the potential threat to growth rate. The age maximum may be extended to 50-60 years in patients with newly diagnosed late-onset disease and no major surgical risk factors, whose expected postsurgical longevity is at least 10-15 years." Patients are often treated with corticosteroids prior to surgery to reduce postoperative risk and to provide a more rapid and predictable response than that seen with thymectomy alone." The rationale for thymectomy in MG is still not fully understood. Its relatively low risk, coupled with the overall improvement in the clinical course of the disease and response to subsequent therapies seen in the majority of postsurgical patients, justify its continued use. PLASMAPHERESIS

Therapeutic plasma exchange (TPE) or plasmapheresis is a method of removing toxic elements from the circulation. It is performed by first removing blood, centrifuging the plasma (containing the toxin) from the formed elements, and reinfusing the formed elements together with a plasma replacement. TPE has been used to remove a variety of unwanted substances from the blood, including toxins, metabolic substances, antibodies, and complement.v In MG, the toxic substance to be removed by TPE is anti-AchR. Use ofTPE in MG has been shown to substantially reduce the numbers of circulating anti-AchR, producing a sometimes dramatic, albeit temporary, clinical improvement in treated patients." Effectiveness, defmed by the magnitude and duration of the response, is dependent on the rate at which the body resynthesizes antibody, and the degree to which the pathogenic material, in this case anti-AchR, is accessible through the circulation. Benefits and adverse effects are further based on the volumes of fluids exchanged and frequency of the procedures. Usually four to five exchanges over a seven- to ten-day period remove more than 90 percent of circulating antibodies. The procedure may be repeated at two- to four-week intervals for a more sustained effect. The actual protocol for TPE varies widely among centers and sometimes within the same center.4244 The replacement solution may consist of a mixture of albumin, dextran, and glucose-Ringer solution combined with additional gammaglobulins or fresh frozen plasma,

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Myasthenia Gravis

albumin alone, or purified protein fraction. Overall benefits achieved do not appear to relate to the type of replacement solution employed, but the risk of adverse effects may be higher with fresh frozen plasma." Lack of controlled trials, the temporal nature of the response, the potential for adverse effects associated the TPE procedure, and cost limit the number of myasthenic patients treated with TPE. Use of TPE is generally limited to the following situations: short-term intervention in preparation for thymectomy (to reduce the postoperative risk of respiratory failure); relief of weakness before the effects of immunosuppressive therapy accrue; the relief of acute myasthenic weakness threatening respiration or swallowing; and treatment of chronic severe disease unresponsive to maximal drug therapy," The most frequently encountered adverse effects associated with TPE include hematoma, paresthesias secondary to citrate anticoagulation, and vasovagal reactions. Less commonly, risk of local infection, transfusion-related infections (hepatitis and AIDS), peripheral nerve trauma, air emboli, hypovolemic reactions, bleeding resulting from depletion of platelets or other coagulation components, extracorporeal hemolysis, respiratory distress, cardiac arrhythmias, and hypersensitivity reactions should be considered.s-" Cost, in addition to risk of adverse effects, must be considered in employing TPE, especially in long-term management. In 1984, the reported cost per TPE procedure performed varied from $400 to $1600. 44 The cost per procedure in 1991 increased by approximately $200 over 1984 figures (local survey). Future Trends

The prognosis for the patient diagnosed with MG today is much improved over that of only 50 years ago. Between 1940 and 1958, only 39 percent of patients with generalized disease improved with the drugs available at that time; the mortality rate was 30 percent. Today, most myasthenic patients are returned to full productive lives and less than 1 percent die as a direct consequence of their disease." However, the vast majority of patients suffering from this as yet incurable disease are destined to a lifetime of medication, with its inherent adverse effects and expense. Researchers continue their efforts to find more specific and effective treatments or a cure. Biotechnology is a current focus of research interest. Promising ongoing research projects include developing anti-ideotypes (antiantibodies) directed against the anti-AchR responsible for the development of MG, artificially producing suppressor T lymphocytes specific for the AchR, and gene cloning for the subunits of mammalian muscle AchR. 37 Summary

Patient accessibility to current information about MG and its treatment is an invaluable component of any treatment regimen. The drugs used to treat MG have complex mechanisms and serious toxicities. The pharmacist's role in patient education and monitoring is an essential component of the total patient care plan. ~ Special thanks to Philip W. Keys, Pharm.D., Bruce Livengood, Pharm.D., and John G. Lech, Pharm.D., for their patience and assistance in completing this manuscript.

References I. OSTERHUIS H. Myasthenia gravis: clinical neurology and neurosurgery monographs. Vol 5. New York: Churchill Livingstone, 1984. 2. RODRIGUEZ M,GOMEZ MR, HOWARD FM, et al. Myasthenia gravis in children: long-term follow-up. Ann Neuro/1983;13:504-1 O. 3. ENGEL AG. Myasthenia gravis and myasthenic syndromes. Ann Neural 1984;16:519-34. 4. KURTZKEJF, KURLAND LT.Clinical neurology. New York: Harper & Row, 1983:80-8. 5. LISAK RP. Myasthenia gravis: mechanisms and management. Hasp Pract {Om 1983;3:101-9.

6. ROWLAND LP,LAYZER RB. Clinical neurology. New York: Harper & Row, 1977:67-77. 7. HERRMAN C Jr, LINDSTROM JM,KEESEY JC,et aI. Myastheniagraviscurrent concepts. Interdepartmental conference, University of California at Los Angeles (specialty conference). West J Med 1985;142:797809. 8. ADAMS RD,VICTOR M.Principles of neurology. New York: McGrawHill, 1985:1074-89. 9. HAVARD CWH, SCADDING GK. Myasthenia gravis: pathogenesis and current concepts in management. Drugs 1983;26:174-84. 10. DRACHMAN DB. Myasthenia gravis (first of two parts). N Engl J Med 1978;298: 136-42. II. SEYBOLD ME. Myasthenia gravis-a clinical and basic science review. JAMA 1983;250:2516-21.

12. LISAK RP,LEVINSON AI,ZWEIMAN B, et al. In vitro synthesis of IgG and antibodies to acetylcholine receptor by peripheral and thymic lymphocytes. In: Drachman DB, ed. Myasthenia gravis: biology and treatment. Ann N Y Acad Sci 1987;505:39-48. 13. DRACHMAN DB,DESILVA S, RAMSAY D,et al. Humoral pathogenesis of myasthenia gravis. In: Drachman DB. ed. Myasthenia gravis: biology and treatment. Ann N Y Acad Sci 1987;505:90-105. 14. BERRIH-AKNIN S, MOREL E, RAIMOND F, et al. The role of the thymus in myasthenia gravis: immunohistological and immunological studies in 115 cases. In: Drachman DB, ed. Myasthenia gravis: biology and treatment. Ann N Y Acad Sci 1987;505:50-70. 15. OSSERMAN KE. Myasthenia gravis. New York: Grune and Stratton, 1958. 16. ADAMS SL, MATTHEWS J, GRAMMER LC.Drugs that may exacerbate myasthenia gravis. Ann Emerg Med 1984;13:532-8. 17. AQUILONIUS S, HARTVIG P. Clinical pharmacokineticsof cholinesterase inhibitors. CUn Pharmacokinet 1986;11:236-49. 18. McEvoy GK, ed. American hospital formulary service drug information 91. Bethesda, MD: American Society of Hospital Pharmacists, 1991: 630-40. 19. DRACHMAN DB. Myastheniagravis (second of two parts). N Engl J Med 1978;298: 186-93. 20. ROWLAND LP. Controversiesabout the treatment of myastheniagravis. J Neural Neurosurg Psychiatry 1980;43:644-59.

21. OSTERMAN PO,HAMMARSTROM L,LEFVERT AK, et aI. Prognosticfactors and side effects of high single dose alternate day prednisone treatment of myasthenia gravis. Abstracts of the Fourth International Congress of Neuromuscular Diseases, 1978:185. 22. WARMOLTS JR, ENGEL WK. Benefit from alternate day prednisone in myasthenia gravis. N Engl J Med 1972;286:17-20. 23. PASCUZZJ RM, COSLETT HB, JOHNS TR.Long-term corticosteroidtreatment of myasthenia gravis: report of 116 patients. Ann Neural 1984;15: 291-8. 24. JOHNS TR.Managing patients who have myasthenia gravis. West J Med 1985;142:810-3. 25. SEYBOLD ME,DRACHMAN DB. Gradually increasing doses of prednisone in myasthenia gravis. N Engl J Med 1974;290:81-4. 26. JOHNS TR. Long-term corticosteroid treatment of myasthenia gravis. In: Drachrnan DB, ed. Myasthenia gravis: biology and treatment. Ann N Y Acad Sci 1987;505:568-83.

27. ARSURA E, BRUNNER NG, NAMBA T, et al. High dose intravenous methylprednisolone in myasthenia gravis. Arch Neural 1985;42:114953. 28. GENKINS G, KORNFELD P, PAPATESTAS AE,et aI. Clinical experience in more than 2000 patients with myasthenia gravis. In: Drachman DB, ed. Myasthenia gravis: biology and treatment. Ann N Y Acad Sci 1987;505:500-14. 29. MATELL G. Immunosuppressive drugs: azathioprine in the treatment of

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myastheniagravis. In: Drachman DB. ed. Myasthenia gravis: biology and treatment. Ann N Y Acad Sci 1987;505:588-94. 30. HERTEL G. MERTENS HG. REUTHER p. et al. The treatmentof myasthenia gravis with azathioprine. In: Dau PC. ed. Plasmapheresis and the immunobiology of myasthenia gravis. Boston: Houghton Mifflin. 1978:315-28. 31. NIAKAN E. HARATI Y.ROLAK LA. Immunosuppressive drug therapy in myasthenia gravis. Arch New'oI1986;43: 155-6. 32. MERTENS HG. HERTEL G. REUTHER P. et aI. Effect of immunosuppressive drugs (azathioprine). Ann N Y Acad Sci 1981;377:691-9. 33. WI1TE AS. CORNBLATH DR. SCHATZ NJ. et al. Monitoringazathioprine therapyin myastheniagravis. Neurology 1986;36: 1533-4. 34. TINDALL RS. ROLLINS JA.PHILLIPS JT. et al. Preliminary results of a double-blind. randomized. placebo-controlled trial of cyclosporine in myasthenia gravis. N Engl J Med 1987;316:719-24. 35. SCHALKE B. KAPPOS L. DOMMASCH D. et al. Cyclosporin A treatment of myasthenia gravis: initial results of a double-blind trial of cyclosporin A vs. azathioprine. In: Drachman DB. ed. Myasthenia gravis: biology and treatment. Ann N Y Acad Sci 1987;505: 872-5. 36. GOULON M.ELKHARRAT D.LIKIEC F.GAJDIS P. Results of a one-year open trialof cyclosporine in ten patientswith severemyastheniagravis. Transplant Proc I988;20(suppl4):211-7. 37. DRACHMAN DB. Present and future treatment of myasthenia gravis. N EnglJ Med 1987;316:743-5.

38. NYBERG-HANSEN R.GJERSTAD L. Immunopharmacological treatment in myasthenia gravis. Transplant Proc 1988;(suppl 4);20:201-10. 39. ARSURA EL.BICK A. BRUNNER NG. et al. High-dose intravenous immunoglobulin in the management of myasthenia gravis. Arch Intern Med 1986;/46:1365-8.

40. BONAVENTURA I. PONSETI J. ANNAU E. et al. High dose intravenous immunoglobulin in the managementof myastheniagravis. Arch Intern Med 1987;/47:207-8.

41. BERKMAN SA. LEE ML. GALE RP. Clinical uses of intravenous immunoglobulins. Ann Intern Med 1990;//2:278-92. 42. Consensus Conference. The utility of therapeutic plasmapheresis for neurological disorders.JAMA 1986:256: 1333-7. 43. DAU rc, LINDSTROM JM.CASSEL CK.et al. Plasmapheresis and immunosuppressive drug therapy in myasthenia gravis. N Engl J Med 1977;297:1134-40. 44. SCHUMAR KH. ROCK GA. Therapeutic plasma exchange. N Engl J Med 1984;310:762-71. 45. Councilon Scientific Affairs.Divisionof Drugs and Technology.American Medical Association. Current status of plasmapheresis and related techniques. JAMA 1985;253:819-25.

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EXTRACTO

Myastenia gravis (MO) es un desorden neurol6gico complejo de naturaleza autoinmune y de etiologia desconocida. Se caracteriza por debilidad de los rmisculos esqueletaIes principalmente los de la cabeza, cuello y extremidades superiores. Esta condici6n as causada por un fallo en la transmisi6n neuromuscular, debido a que la acci6n de anticuerpos en contra de los receptores de acetilcolina provoca una reducci6n en el mimero de receptores de aeetilcolina funcionales causando una alteraci6n en la membrana. EI diagn6stico da myastenia gravis se establece por historial, examen fisico del paciante, prueba de "Tensilon," y titulaci6n de anticuerpos para los receptores de acetilcolina. Las modaiidades de tratamiento incluyen: terapia con drogas, timectomia, y plasmaferesis. Las drogas mas comunmente usadas son anticolinesterasas, corticoesteroides, y agentes inmunosupresores. Cyclosporinas e inmunoglobulina intravenosa se encuentran en etapa de investigaci6n. EI prop6sito de este articulo es revisar conceptos actuales relacionados a la patofisiologfa, inmunologia, diagnostico, y tratamiento de myastenia gravis. Se presenta con enfasis especial la forma autoinmuna de la enfermedad y las drogas empleadas en el tratamiento. Se evaluaran tratamiento de uso corrianta asi como modalidades de tratamiento experimentaIes. DAISY RIVERA DEALMENTARO RESUME

La myasthenic grave est un desordre neurologique auto-irnrnun, complexe et d'etiologie inconnue; elle est caracterisee par une faiblesse variable des muscles squelettiques impliquant plus frequemrnent les muscles de la tete, du cou et des membres superieurs. Des autoanticorps aux recepteurs de l'acetylcholine (Ach) sur la membrane post-jonctionnelle diminuent Ie nombre de recepteurs Ach fonctionnels et produisent des alterations au niveau membranaire qui empechent la transmission neuro-musculaire. Le diagnostic est etabli par I'histoire et I'examen physique, Ie test au Tensilon et Ie titrage des anticorps aux recepteurs Ach. Les modalites de traitement incluent la pharmacotherapie, la thymectomie et la plasmapherese. Les medicaments les plus couramment employes sont les anticholinesterasiques, les corticosteroides et les agents immunosuppresseurs. A titre experimental on utilise la cyclosporine et les immunoglobulines intraveineuses. Le but de eet article est de revoir les plus recents concepts dans la pathophysiologie, l'immunopathologie, Ie diagnostic et Ie traitement de la myasthenic grave. Un interet particulier a ete mis sur la forme auto-immune de la maladie et les medicaments utilises pour Ie traitement. Sont revises les protocoles standard de traitement et les protocoles experimentaux,

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DENYSE DEMERS