Update on Drugs that May Cause or Exacerbate Myasthenia Gravis

Ann M. McNamara David R.P. Guay

Myasthenia gravis (MG) is a relatively uncommon disorder of neuromuscular transmission, with an incidence of 1 in 10,000 to 1 in 20,000 in the general population. Although the incidence of MG is low, more patients with MG may be encountered in the long-term care setting as a result of the growth of subacute care, where patients may be cared for following exacerbations. Also, patients with MG often require longer follow-up medical care after procedures, and subacute care may be an option. True immune-mediated MG, similar to idiopathic MG, may be caused by numerous pharmacologic agents. In addition, numerous medications used to treat unrelated illnesses may cause serious complications in MG patients by further exacerbating the derangement in neuromuscular transmission present in idiopathic MG. Unfortunately, with few exceptions, the absolute risk of these effects for a given agent is unknown.

The last extensive review of drugs causing or exacerbating MG was published in 1984.¹ We performed a comprehensive computerized MEDLINE search of pertinent articles appearing over the past 12 years and provide herein an update on drugs causing or exacerbating MG (Table 1).

Pathophysiology

A brief review of the pathophysiology of MG is essential to understanding both true drug-induced MG and drug-associated exacerbation of MG by nonimmunologic mechanisms.

The predominant defect noted in myasthenic patients is a reduction of available acetylcholine (Ach) receptors (ACR) at the neuromuscular junction (NMJ), thought to result from an autoimmune abnormality.² The autoimmune response to ACR-resulting in the production of anti-ACR antibodies-is regulated by ACR-specific T helper cells. These antibodies, most of them directed against the main immunogenic region of the receptor alpha subunit, produce the majority of their damage by activation of the complement cascade, leading to the generation of membrane attack complexes and the attraction of macrophages, with resultant endplate membrane lysis. These antibodies are also capable of cross-linking adjacent ACR molecules, resulting in increased ACR turnover in the endplate membrane. This process, known as antigenic modulation, results in decreased ACR density. Lastly, there is blockade of the function of the ACR remaining after the complement-mediated and antigenic modulation effects have occurred. However, the initiating factor for this autoimmune disorder is as yet unknown.

In most cases, the mechanisms by which medications exacerbate MG are not clear. The following mechanisms have been suggested and are discussed further within each drug classification:

• Autoimmune or immunosuppressive mechanism
• Respiratory depression
• Hypokalemia-induced muscle weakness
• Decrease in anticholinesterase response
• Interference with transmission at the neuromuscular junction (e.g., inhibiting release of acetylcholine or depressing response to acetylcholine)
• Blocking calcium channels, which could possibly affect skeletal muscle nerve transmission

Clinical Presentation

Initial presentation of MG most often involves the muscles innervated by the cranial nerves. Ptosis, diplopia, and blurring of vision are common, and residents may have difficulty with swallowing, phonation, and, in severe cases, respiration. The proximal muscle groups of the lower and upper extremities also may be affected. Weakness is usually symmetrical, but the disease process may present as weakness in a single muscle. The disease may occur in patients of any age or gender and may range in severity from a mild nonprogressive form involving only the eyes to the severe, generalized condition that is rapidly progressive and often fatal.^2,3

Corticosteroids

Corticosteroids are used in the management of myasthenia gravis, with 60%-90% of patients benefiting from therapy. However, approximately 50% of patients can experience exacerbations of myasthenic weakness with the initiation of corticosteroid therapy. In up to 10% of patients, corticosteroid therapy can result in severe decompensation that requires ventilatory support. Refractoriness to anticholinesterase medications may also be seen.^1,3

Two additional case reports of cortico-steroid therapy causing steroid myopathy in MG patients have been recently published. As in previous cases, these patients in these new reports also were taking anticholinesterases.^4,5

Because of the potential for serious exacerbations, consideration should be given to hospitalization of MG patients for initiation of corticosteroid therapy.

Antibiotics

In the 1984 review,¹ a number of antibiotics were identified as having the potential to cause a transient worsening of MG or to have a theoretical potential to cause a worsening of MG because of their depressant effect on the NMJ. These included streptomycin, dihydrostreptomycin, kanamycin, polymyxins A and B, bacitracin, sulfonamides, viomycin, colistin, clindamycin, chloroquine, and the tetracyclines (although there was disagreement concerning the clinical relevance of the effect of the tetracyclines).¹

Since the last review, the list of antibiotics that have the potential to exacerbate MG has expanded to include the fluoroquinolones, erythromycin, imipenem-cilastatin, ampicillin, and pyrantel pamoate.

At least four cases of fluoroquinolone antimicrobial agents unmasking or worsening MG have been described in the literature. In one case, the patient received norfloxacin and developed worsening MG. Six months later, the patient was given norfloxacin again to determine whether the drug was responsible for the exacerbation. Within two hours, she developed muscle weakness.⁶ Exposure to ciprofloxacin unmasked subclinical MG in another patient. The patient developed severe dysphagia, dysarthria, and ptosis that correlated with fatigue. When ciprofloxacin was discontinued, ptosis persisted, but the severe bulbar symptoms resolved within a few days.⁷ Another case suggests that the effect of fluoroquinolones could be dose-related. The patient tolerated ciprofloxacin 500 mg twice daily but developed muscle weakness and respiratory distress with ciprofloxacin 750 mg twice daily.⁸ Oral ofloxacin was reported to have caused worsening MG, with improvement noted upon discontinuation of the drug.⁹

Some believe the quinolone moiety could be responsible for this effect. Chloroquine, quinine, and quinidine also have a quinolone moiety, and these drugs have a curare-like effect and decrease the excitability of the motor endplate.¹⁰ These cases suggest that fluoroquinolone antimicrobial agents should be used judiciously in patients with MG; if their use is necessary, therapy should be initiated with the lowest effective dose and the patient monitored carefully.

Two recent cases involving intravenous erythromycin have been reported in the literature. The first case involved intravenous administration of erythromycin leading to a myasthenic crisis.¹¹ Before this report, only mild exacerbations of weakness had been reported in patients receiving erythromycin. In the second case, a patient was switched to intravenous erythromycin and ceftazidime because of continuing fevers. Thirty minutes after the second dose of erythromycin, the patient experienced difficulty with speech, swallowing, and coughing. The dose was decreased from 1 gram to 750 mg, and three more doses of erythromycin were administered at eight-hour intervals. Each time, the patient experienced worsening symptoms. Upon discontinuation of erythromycin, the patient no longer manifested any symptoms.¹² Erythromycin has been shown to decrease the motor unit potential amplitude in healthy subjects. Even though it did not produce clinical signs of weakness in the healthy subjects studied, erythromycin should be used cautiously in patients with MG.^11,12 Based on these two case reports, erythromycin should be added to the list of medications that should be used with caution in patients with MG. Intravenous erythromycin was administered in both cases; administration by this route may cause more severe effects in MG patients.

Imipenem-cilastatin has caused deteriorating MG in one patient. After the condition responded to edrophonium, imipenem-cilastatin was discontinued, and the patient's neurologic status returned to baseline within 48 hours after discontinuation of the drug. The authors stated that the manufacturer also has another case on file wherein imipenem-cilastatin therapy resulted in the development of MG.¹³

Two cases of ampicillin exacerbating idiopathic MG have been reported. One patient suffered from chronic sinusitis and received ampicillin on several occasions. During therapy with ampicillin, she noticed that her MG symptoms consistently worsened. An ampicillin challenge consisting of a 1,500 mg intravenous dose and a 500 mg oral dose resulted in complete bilateral ptosis and marked proximal limb weakness. The second case involved an exacerbation of MG during ampicillin therapy that diminished after discontinuation.¹⁴

One report of pyrantel pamoate, an anthelmintic agent, unmasking MG suggests cautionary use in MG patients.¹⁵ Pyrantel works by blocking neuromuscular transmission in the parasite. In rabbits, parenteral administration results in paralysis and death. Toxic neuromuscular effects in humans have not been described.

Cardiovascular Drugs

A number of cardiovascular agents with the potential to exacerbate MG were identified in the last review article¹: quinine, quinidine, procainamide, beta blockers, trimethaphan, procaine, and lidocaine.

Cardiovascular agents recently associated with exacerbation of MG include the calcium-channel blockers verapamil and nifedipine, and the acebutolol beta blocker.

One case involved severe exacerbation of MG during verapamil therapy. Withdrawal of verapamil resulted in slight improvement, and corticosteroid therapy was initiated to induce remission because of the severity of the patient's condition.¹⁶ Verapamil blocks voltage-dependent calcium channels in cardiac smooth muscle. The effect on skeletal muscle has not been as well studied, but some evidence suggests that it does affect nerve transmission. Lee and Ho¹⁷ found that during consecutive doses of verapamil in five MG patients, the evoked integrated electromyographic responses of the thenar muscles was inhibited significantly to 84.5 (± 3.3)% and 79.25 (± 3.52)% of control values at 36 mg/kg and 72 mg/kg; the responses of 12 patients in the control group who did not have MG were not affected. This suggests a dose-dependent neuromuscular transmission inhibition in MG patients with doses greater than 36 mg/kg. This dose is less than the therapeutic dosage range (0.1-0.3 mg/kg) of verapamil.¹⁷

Sudden medication-related worsening of myasthenic symptoms in a man with recently diagnosed MG was reported. Four days after the initiation of prednisone and pyridostigmine therapy, the patient was started on nifedipine for hypertension. The patient subsequently manifested a sudden deterioration of respiratory function and died later the same day following cardiorespiratory arrest.¹⁸ Another author, commenting on this case, believed that this effect could have resulted from prednisone administration.¹⁹

Beta blockers worsen MG by a depressant effect on the neuromuscular junction. Propranolol, oxprenolol, practolol, pindolol, and sotalol have been implicated, as reviewed previously.¹ Worsening of MG symptoms two weeks after the initiation of acebutolol 400 mg twice daily was reported in one patient. Even though therapy with this drug was discontinued, the patient eventually died from this exacerbation. The authors reiterated that particular care should be taken when beta-blocker therapy, especially in high doses, is contemplated in patients with MG.²⁰

An additional case of procainamide-induced, myasthenia-like weakness and dysphagia has been described. However, in this case, myasthenic symptoms were felt to be due to elevated serum concentrations of procainamide and its metabolite, n-acetylprocainamide (NAPA).²¹

Anticonvulsant and Psychotropic Drugs

Phenytoin, ethosuximide, trimethadione, paraldehyde, trichloroethanol, chlorpromazine, lithium, amitriptyline, amphetamines, droperidol, haloperidol, and imipramine have been implicated (either directly via case reports or indirectly via experimental studies on neurotransmission) as potentially exacerbating MG. These cases or studies are described in the 1984 review.¹ Few data have emerged since that time regarding the effect of anticonvulsants and psychotropics on MG, with only one additional case report of lithium unmasking MG.²²

Analgesics

Caution is recommended when narcotic analgesics are used in patients with MG because of the combination of their respiratory depressant effects and the potentiating effect of neostigmine on their analgesic effects.¹

Recently, successful use of intrathecal morphine for thymectomy in a morbidly obese MG patient was reported. These authors felt that more direct delivery of the drug to the spinal opioid receptors provides more potent analgesia and less ventilatory depression and sedation compared with intramuscular or intravenous administration.²³

One case of cocaine abuse unmasking and exacerbating MG has been described recently.²⁴

Eyedrops

Reports cited in the 1984 review article implicated ocular timolol in exacerbations of MG and ocular echothiophate in precipitation of cholinergic crisis in MG patients receiving concurrent cholinesterase inhibitor therapy.¹

More recent reports similarly have documented that ocular administration of timolol may unmask latent MG²⁵ or worsen clinically stable MG.²⁶ The mechanism of this phenomenon is unknown, although beta blockers exert a depressant effect on the neuromuscular junction.^27,28 In addition, ocular administration of tropicamide and proparacaine have been reported to precipitate a myasthenic syndrome.²⁹ An additional case of cholinergic toxicity resulting from the use of ocular echothiophate iodide (an irreversible cholinesterase inhibitor) and leading to a misdiagnosis of MG has been reported.³⁰

Neuromuscular Blocking Agents

Use of neuromuscular blockers (NMBs), either of the competitive (prototype tubocurarine) or depolarizing (prototype succinylcholine) type, may present difficulties in patients with myasthenia. Patients may be up to 100 times more sensitive to the effects of competitive NMBs than patients without MG.¹

One case of exquisite sensitivity to pancuronium at a subparalyzing dose of 1 mg in a "premyasthenic" patient has been published recently.³¹

Several recent studies have further assessed MG patents' resistance to succinylcholine, noted in early case reports.¹ These have included two case reports ^32,33 and two dose-response studies.^34,35

In one study, conducted in 10 control gynecologic/orthopedic surgical patients and five MG patients undergoing thymectomy, the mean dose-response curve in the MG patients was shifted to the right of the curve for controls, with significant twofold to 2.6-fold increases in the 50%, 90%, and 95% effective doses (ED) for NMB. The authors believed that, despite documentation of resistance, the usual clinical doses of succinylcholine (1.0 mg/kg-1.5 mg/kg) should be adequate in MG patients unless very rapid intubation is necessary, in which case a dose of 1.5 mg/kg to 2.0 mg/kg should be used.³⁴ In another study conducted in a control group of 10 lumbar laminectomy surgical patients and 10 MG patients undergoing thymectomy, the pharmacodynamics of 0.5- and 1-mg/kg doses were evaluated. At the 0.5 mg/kg dose level, succinylcholine resistance was noted in 60% of MG patients and none of the control patients, a significant difference. No resistance was noted in either group at the 1-mg/kg dose level. Nondepolarizing block did not develop in any control subjects at either dose level, in 40% of MG patients at the 0.5 mg/kg dose level, and did develop in all of MG patients at the 1 mg/kg dose level, again a significant difference.³⁵

The dose-response curve for succinylcholine in a single MG patient in true remission (defined as asymptomatic and receiving no treatment) has been evaluated. The values of ED₅₀, ED₉₅, and the infusion dose requirement to maintain 90%-95% depression of single twitch response were similar to control patient values in the literature, suggesting that succinylcholine resistance may not occur in MG patients who are in true remission.³³

A retrospective review has documented the safe use of succinylcholine to facilitate intubation in 30 MG patients undergoing thymectomy (mean dose = 100 mg, range 50-175 mg).³⁶

Numerous reports of the effects of the newer NMBs-such as mivacurium, atracurium, and vecuronium-in MG patients have appeared over the past decade. Three cases of mivacurium use in MG patients have been reported,^37-39 with supersensitivity and prolonged blockade reported in one of these cases.³⁸

Eight cases of atracurium use in this patient population have been reported.^40-46 In most cases, atracurium dose requirements were much lower than those in normal patients, while the time course of responses to NMBs approximated those noted in normal patients. A dose-response study was conducted in five MG patients undergoing thymectomy, with the results compared to those in 10 historical control patients. Atracurium appeared to be 1.7 to 1.9 times as potent in MG patients as in control patients, based on ED₅₀, ED₉₀, and ED₉₅ values. However, the time course of NMBs, based on time to 25% first twitch recovery and recovery index, appeared to be similar in both groups.⁴⁷

Two cases of vecuronium use in MG patients have been reported,^48,49 with prolonged blockade reported in one patient.⁴⁹ Several studies have documented enhanced potency of vecuronium in MG patients versus controls after both bolus dosing and maintenance infusion administration.^50-53 For example, in one study of six MG patients undergoing thymectomy, doses only 40% of normal produced satisfactory NMB.⁵⁰ In another study, MG patients required mean dose reductions of 57-60% for satisfactory NMB, and time to recovery was significantly prolonged compared with controls.⁵¹ In yet another dose-response study, MG patients were twofold more sensitive to vecuronium than controls, with significant differences in ED₅₀, ED₉₀, and ED₉₅ values.⁵² Lastly, another dose-response study established increased sensitivity to vecuronium in MG patients, as well as significantly reduced infusion requirements to maintain NMB (70% reduction from control), and significant correlation of ED₉₅ with titer of anti-ACR antibodies.⁵³ The only comparative study of atracurium versus vecuronium in MG patients was too flawed to draw conclusions as to which agent might be preferable in this patient population.⁵⁴

In summary, newer NMBs appear to be reasonably safe to use in MG patients, provided that dosage reduction and careful monitoring of dynamic response is performed.

In a quest to avoid use of NMBs in MG patients, alternative approaches such as regional anesthesia,⁵⁵ epidural anesthesia,⁵⁶ and total intravenous anesthesia with althesin, etomidate, or propofol ^57-59 have been advanced, although the number of patients studied has been small to date.

Antirheumatic Agents

In the 1984 review, d-penicillamine (d-pen) was implicated as causing MG, while chloroquine and colchicine were found to exacerbate the condition.¹ An additional case of chloroquine-associated MG-which appeared during receipt of a daily dose of 500-mg (but not 250-mg dose)-has recently been reported.⁶⁰

Since 1984, 25 additional cases of d-pen-associated MG have been reported.^60-72 d-pen-associated MG is usually indistinguishable from idiopathic MG (based on clinical signs/symptoms and laboratory findings). It also shares pathophysiologic features with idiopathic MG. However, the immunological reaction to d-pen is thought to be a new autoimmune response, rather than an enhancement of ongoing autoimmunity. It does not appear to correlate with the dose or the duration of therapy. Fortunately, d-pen-associated MG usually remits quickly after discontinuation of d-pen and institution of cholinesterase inhibitor therapy.

One case of MG associated with bucillamine, a compound closely related to d-pen, has been reported.⁷³

Miscellaneous Medications

Miscellaneous agents identified in the 1984 review article as theoretically or actually capable of causing or exacerbating MG included thyroid supplementation, intravenous sodium lactate, amantadine, emetine, diphenhydramine, diuretics, barbiturates, and tranquilizers.¹ Since that time, other agents have been added to this list: ergonovine, trihexyphenidyl, cyclosporine, alpha-interferon, desferrioxamine, methimazole, gadolinium, and intravenous contrast media.

Ahmad described a case of precipitation of MG in a "cured" myasthenic administered 0.2 mg of intravenous ergonovine as a provocative test for coronary artery spasm.⁷⁴

A small series of MG patients with chronic obstructive pulmonary disease exacerbated by cholinesterase inhibitors but favorably responsive to inhaled ipratropium (but not to inhaled beta agonists) has been described.⁷⁵ Trihexyphenidyl, an anticholinergic agent frequently used in the management of Parkinson's disease, has been found to aggravate idiopathic MG.⁷⁶

A case of clinical MG developing in a renal transplant patient who received cyclosporine has also been reported. A causal relationship could not be established definitively because of the absence of anti-ACR antibodies, a finding possibly resulting from the immunosuppressant effects of cyclosporine.⁷⁷

Three cases of MG developing during alfa-interferon therapy of malignancies (chronic myelogenous leukemia, bladder carcinoma, non-Hodgkin's lymphoma) have been described. All three patients had classical clinical symptoms, had positive serum anti-ACR antibodies, and responded to cholinesterase inhibitor/corticosteroid therapy.^78,79 This effect is explained by the well-known association of interferon therapy with autoimmune disorders.⁸⁰

One case of MG following the administration of desferrioxamine as iron-chelation therapy has been reported. The onset of MG was delayed (two years following commencement of desferrioxamine therapy), but the presentation was classical (signs/symptoms, positive edrophonium test results, positive serum anti-ACR antibodies, and positive response to cholinesterase inhibitors). However, a cause-and-effect relationship could not be definitely established.⁸¹

Antithyroid therapy with methimazole has been reported to exacerbate MG, possibly secondary to its immunomodulatory properties.⁸²

Also, intravenous administration of gadolinium-DTPA has been reported to exacerbate MG,⁸³ probably because of its NMB activity.⁸⁴

Five recent cases of MG exacerbated by contrast medium (iothalamic acid, sodium and meglumine diatrizoate) have been reported.^85-87 The mechanism of this effect is unknown, although studies in the experimental rabbit model of MG suggest that direct NMJ blockade, partially reversible with intravenous calcium, occurs.86 Of interest, a retrospective review of the records of 233 radiographic procedures involving contrast media in 136 MG patients did not reveal any cases of myasthenic crisis attributable to media. However, the authors still recommended caution when using contrast media in MG patients.⁸⁸

Conclusion

Caution is recommended when prescribing medications to patients with myasthenia gravis for problems unrelated to the condition. In addition, drugs should always be considered in the differential diagnosis of muscle weakness and other symptoms consistent with MG.

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