Drug-induced myasthenic syndromes …

Neuromuscular Disorders

Updated 04.16.2023
Released 02.17.1995
Expires For CME 04.16.2026

Drug-induced myasthenic syndromes

Authors: Miguel Chuquilin MD, Varun Jain MD

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Editor: Michael K Hehir MD

Drug-induced myasthenic syndromes

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Introduction

Overview

Drug-induced myasthenic syndromes are caused by numerous medications. Some of them, such as the classic example of D-penicillamine, may induce a disturbance of the immune system that results in the development of myasthenia gravis, whereas many other agents directly compromise neuromuscular transmission. Furthermore, agents that affect synaptic transmission may unmask subclinical myasthenia gravis or exaggerate the weakness in patients with preexisting disorders of neuromuscular transmission. We will discuss these agents briefly. This article focuses on medications suspected to produce an autoimmune reaction leading to myasthenia gravis. Immune checkpoint inhibitors are an increasingly utilized class of anticancer drugs. These include ipilimumab, which targets cytotoxic lymphocyte-associated protein 4 (CTLA-4), and nivolumab and pembrolizumab, which target programmed cell death protein 1 (PD-1). Clinical presentation of myasthenia gravis associated with immune checkpoint inhibitors is often atypical, with considerable overlapping myopathy, cardiopulmonary involvement, and high mortality rate. Management of drug-induced myasthenic syndromes requires withdrawal of the offending agents and standard immunotherapy, including high-dose corticosteroids, intravenous immunoglobulin, and plasma exchange.

Key points

	• Drug-induced myasthenic syndromes are caused by various classes of medications.
	• D-penicillamine was the first drug recognized to cause an autoimmune process similar to spontaneous myasthenia gravis. Since then, several other drugs have been identified.
	• Many other agents produce weakness by direct compromise of neuromuscular transmission.
	• Atypical myasthenia gravis has been associated with a class of immune checkpoint anticancer drugs, including anti-programmed cell death protein 1 and anti-cytotoxic lymphocyte-associated protein 4 monoclonal antibodies.

Historical note and terminology

Myasthenia gravis is an autoimmune disorder characterized by fluctuating weakness of voluntary muscles, with a propensity for involvement of ocular muscles. It is the prototype for a class of diseases referred to as neuromuscular transmission disorders. Within this group are Lambert Eaton syndrome, congenital myasthenic syndromes, botulism, and a wide array of drug-induced myasthenic syndromes. The pathogenic link of all these conditions is a reduction in effectiveness of neuromuscular transmission leading to weakness, often characterized by premature fatigue.

For decades certain therapeutic agents have been known to interfere directly with neuromuscular transmission (See Table 1) by affecting either presynaptic or postsynaptic function. The earliest and most commonly reported manifestation of drug-induced neuromuscular blockade was preoperative or postoperative respiratory distress, with delayed spontaneous respiration recovery after administration of certain aminoglycoside antibiotics (95; 04). Psychotropic drugs of the phenothiazine family were later found to be capable of acting similarly (75). Many more drugs were subsequently discovered to directly affect the neuromuscular junction. Such agents may cause weakness directly, unmask subclinical myasthenia gravis, or aggravate preexisting myasthenia gravis (an up-to-date list of these potential drug-disorder interactions is maintained on the website of the Myasthenia Gravis Foundation of America). The U.S. Food and Drug Administration has designated a “black box” warning for telithromycin and fluoroquinolones for myasthenia gravis exacerbation. Many other drugs have been associated with myasthenic exacerbation in a small number of case reports. It is difficult to determine whether those relationships are causal.

D-penicillamine is the prototypical offending agent to produce an autoimmune reaction leading to myasthenia gravis, although scattered reports exist for other drugs, such as interferon, chloroquine, and trimethadione. First recognized in 1975, D-penicillamine causes a condition identical to autoimmune myasthenia gravis in patients with rheumatoid arthritis (13). There are also reports of myasthenia gravis associated with D-penicillamine treatment for scleroderma (28) and forWilson disease (23; 74).

Advances in understanding immune dysregulation in cancer led to the development of a class of anticancer drugs, the immune checkpoint inhibitors. These drugs are monoclonal antibodies that block the interaction between immune checkpoint proteins on the surface of cytotoxic T cells and their ligands, allowing for increased activation of T cells and a greater immune response against tumors. They target cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), or programmed death-ligand 1 (PD-L1). Ipilimumab (targeting CTLA-4) was the first to be approved by the U.S. Food and Drug Administration in 2011 for melanoma. Other approved immune checkpoint blockade therapies include pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, and durvalumab (133). Neurologic side effects of these drugs are rare but include cases of polyneuropathies, Guillain Barré syndrome, polyradiculitis, myositis, posterior reversible encephalopathy syndrome, aseptic meningitis, enteric neuropathy, transverse myelitis, encephalitis, etc., as well as myasthenia gravis (47; 38; 48; 78; 22; 56; 71; 35).

The drugs listed in Table 1 have been described to compromise neuromuscular transmission (76; 80). The drugs listed in Table 2 have been reported to cause a myasthenic syndrome through an immune response (112).

Table 1. Drugs that Compromise Neuromuscular Transmission

Type of drug	Drugs
Anesthetics	General anesthetics: benzodiazepines, ketamine, propanediol ether, proparacaine, methoxyflurane and others Local anesthetics: lidocaine, procaine, proparacaine and others Neuromuscular blocking drugs: vecuronium, atracurium, succinylcholine, and others
Antibiotics/antivirals	Aminoglycosides: gentamicin, tobramycin, kanamycin, neomycin, streptomycin, netilmicin Fluoroquinolones: levofloxacin, moxifloxacin, ciprofloxacin, ofloxacin, gatifloxacin, norfloxacin, trovafloxacin, pefloxacin, and prulifloxacin (55) Ketolides: telithromycin (88) Macrolides: erythromycin, azithromycin, clarithromycin Polypeptide antibiotics: vancomycin, colistin, polymyxin B Penicillins Tetracyclines Sulfonamides Others: clindamycin, lincomycin, nitrofurantoin, ritonavir
Anticonvulsants	Phenytoin (diphenylhydantoin), mephenytoin, trimethadione, ethosuximide, barbiturates, carbamazepine, gabapentin, benzodiazepines
Antifungal agents	Voriconazole
Antimalarial agents	Chloroquine, mefloquine, pyrantel
Antimigraine agents	Calcitonin gene-related peptide (CGRP) receptor antagonist: Aimovig®
Cardiovascular drugs	Beta-blockers: propranolol, oxprenolol, timolol, practolol, atenolol Calcium channel blockers: verapamil Others: quinidine, quinine, procainamide, bretylium, trimetaphan, propafenone, disopyramide, reserpine
Ophthalmic medications	Timolol, betaxolol, echothiophate
Hormonal medications	Corticosteroids (early exacerbations with high-dose therapy), estrogen
Neurologic drugs	Trihexyphenidyl, riluzole, botulinum toxin
Psychiatric drugs	Phenothiazines, lithium
Others	Statins (96), D-L-carnitine, tropicamide (77), iodinated radiographic contrast, magnesium, tandutinib (66), imiquimod (134)

Table 2. Drugs Reported to Cause a Myasthenic Syndrome Through an Immune Response

Drug class	Drugs
Immune checkpoint inhibitors	Anti-PD-1 (nivolumab and pembrolizumab), anti-PD-L1 (atezolizumab, avelumab, and durvalumab), and anti-CTLA-4 (ipilimumab and tremelimumab)
Interferon	Interferon alpha, interferon beta
Tyrosine-kinase inhibitors	Lorlatinib, imatinib
D-Penicillamine

Clinical manifestations

Presentation and course

	• Drug-induced myasthenic syndromes may present similarly to spontaneous myasthenia gravis, with the hallmark of fluctuating and fatigable weakness of voluntary muscles.
	• Clinical presentation of myasthenia gravis associated with immune checkpoint inhibitors is often atypical, with considerable overlapping myopathy, as well as having cardiopulmonary involvement
	• The onset time seems to occur at any point along the course of treatment with the offending drug, except immune checkpoint inhibitors, which consistently present within 2 to 12 weeks of treatment.
	• Symptoms usually resolve entirely with discontinuation of the drug and a limited course of treatment.

Drug-induced myasthenic syndromes are characterized by progressive, typically symmetric, muscle weakness. The most common manifestations are those of autoimmune myasthenia gravis: ptosis, diplopia, dysphagia, and dysarthria, as well as weakness of the limbs and respiratory muscles with characteristic premature fatigue. The clinical pattern varies with different drugs, and not all of the symptoms are present in individual cases.

Symptoms and signs of the myasthenic syndrome can appear days to months after the institution of the offensive drug. Isolated ocular symptoms and unilateral ptosis have been described (70; 97; 86).

This section describes the clinical manifestations of medications that affect the immune system leading to myasthenia gravis. These are separate from drugs that cause weakness by directly affecting synaptic transmission found in Table 1.

D-penicillamine. With D-penicillamine, symptoms usually start 4 months to 9 months after initiation of treatment (13; 02) but occasionally as late as 5 years to 8 years into therapy (74; 70). The symptoms are generally mild and may predominantly involve the extraocular muscles.

Most patients with D-penicillamine-induced myasthenia gravis have increased serum levels of acetylcholine receptor (AChR) antibodies (74; 130), although there is at least 1 case report of a patient with both increased serum levels of AChR and muscle-specific kinase (MuSK) antibodies (94). Moreover, after D-penicillamine withdrawal serum antibodies decrease in parallel with clinical improvement, suggesting a reversible effect of the drug on the immune system rather than the unmasking of a latent myasthenia gravis. Electrophysiological studies have shown reduced miniature endplate potential amplitude, and morphological studies have shown reduced bungarotoxin binding, changes typical of acquired myasthenia gravis (130). Indeed, most features of D-penicillamine-induced myasthenia are similar to those of generalized idiopathic myasthenia gravis of recent onset (less than 4-month duration); however, the titers of AChR antibodies are significantly higher in longstanding idiopathic myasthenia gravis than in the D-penicillamine-induced disorder (129). Also, HLA antigens Bw35 and DR1 are associated with D-penicillamine-induced myasthenic syndrome; the relative absence of DR4 suggests that this disorder is genetically distinct from rheumatoid arthritis (41).

Recovery from D-penicillamine-related myasthenia occurs within 2 to 6 months after withdrawal of the drug and may occur spontaneously without additional therapy; anticholinesterase drugs usually can be discontinued without any recurrence of the myasthenic symptoms.

Anecdotal evidence, often based on a limited number of case reports, suggests that other agents may also lead to myasthenic syndrome through immune reactions.

Interferon alpha. Interferon alpha was first reported to be associated with myasthenia gravis in 1995. Two patients developed myasthenia gravis during interferon alpha 2b treatment (07). One patient developed symptoms of generalized myasthenia gravis 3 months after starting interferon for treatment of bladder carcinoma. He had positive serum AChR antibody testing, myopathic findings on EMG, and cytochrome c oxidase deficiency on a muscle biopsy. His symptoms resolved after discontinuation of interferon and treatment for myasthenia gravis, but his serum remained positive for AChR antibodies when tested 4 years later. The second patient developed seropositive generalized myasthenia gravis 5 months after starting interferon for non-Hodgkin lymphoma. Similarly, his serum also remained positive for AChR antibodies when tested about 1 year later. In the same year, a 66-year-old man with psoriasis developed seropositive generalized myasthenia about 6 months after starting recombinant interferon alpha-2a therapy for chronic myelogenous leukemia (87). Subsequently, myasthenia has been reported in other patients during treatment of interferon alpha for malignancy or chronic hepatitis C, some of whom with presence of thymoma and some with serious respiratory crisis (07; 61; 67; 73; 92; 05). It is unclear whether these cases were truly de novo induction of myasthenia. Many of them might have undiagnosed subclinical myasthenia prior to treatment (119). There also have been reports suggesting that myasthenia gravis may occur independently in association with hepatitis C infection, but more evidence is needed to support this claim (44; 98; 32; 118).

Interferon beta. Evidence for the association between interferon beta and myasthenia gravis is very limited. No convincing cases have been reported so far. The first case of myasthenia gravis in a patient on interferon beta therapy for multiple sclerosis was reported by Blake and Murphy in 1997. The patient developed seropositive myasthenia gravis 11 days after starting interferon beta-1b subcutaneously injection. She had relapses of myasthenia despite discontinuation of interferon beta-1b and treatment with pyridostigmine. Her AChR antibody titer remained elevated 6 months after interferon beta was discontinued. It was unclear whether the onset of myasthenia gravis in this patient was merely coincidental or was associated with the interferon beta-1b use (09). Another 2 twoatients with multiple sclerosis were reported by Dionisiotis and colleagues to develop weakness, episodic double vision, and dysphagia along with positive AChR antibodies while treated with interferon beta (27). They developed these symptoms 9 and 12 months after initiation of the interferon-beta. Both then had a favorable response to pyridostigmine. Discontinuation of interferon beta and repeat serum studies were not reported in either patient. Harada and colleagues described a patient who developed seropositive myasthenia gravis several days after completion of a 2-week treatment course of interferon beta for chronic hepatitis C infection (45). She was found to have thymic enlargement and diagnosed with severe interferon beta-related exacerbation of myasthenia gravis. However, her tissue from thymectomy showed invasive thymoma, and she underwent radiation therapy.

Chloroquine, hydroxychloroquine. One patient with rheumatoid arthritis and another with systemic lupus erythematosus developed typical clinical, physiological, and pharmacological myasthenia gravis following prolonged treatment with chloroquine (110; 111). With discontinuation of the drug, the serum AChR antibodies slowly disappeared, as did the clinical and electrophysiological abnormalities. Later, there have been reports that chloroquine can also cause myasthenic syndrome with rapid reversibility by a direct toxicity effect on neuromuscular transmission (93; 104; 11; 58; 103). In 1 case, a 53-year-old woman with intermittent chloroquine use as an antimalarial agent over 21 years developed persistent mild ocular myasthenic symptoms and a cardiac conduction disturbance even after chloroquine was discontinued (24). There are mixed reports about hydroxychloroquine causing myasthenia gravis. In one study, Jallouli and colleagues concluded hydroxychloroquine treatment appears to be safe in patients diagnosed with both systemic lupus erythematosus and myasthenia gravis (51). However, in 2 subsequent case reports, hydroxychloroquine was associated with myasthenia gravis. The first case was a 29-year-old female with systemic lupus erythematosus treated with hydroxychloroquine who presented with weakness and ptosis and was found to have positive AChR antibodies. Treatment was stopped, and the patient’s symptoms improved, although AChR antibodies remained positive (128). The second case was a 47-year-old man who presented with fatigable diplopia after taking 1 dose of hydroxychloroquine (200 mg) for COVID-19 prophylaxis (59). Single-fiber EMG confirmed neuromuscular transmission disturbances consistent with myasthenia gravis, but serology testing was negative. He was treated with pyridostigmine, and in 3 months, he was symptom-free and EMG had returned to normal. Hydroxychloroquine-induced MuSK antibody-positive myasthenia has also been described by Bhaskar and Abdul Rani (08). The patient developed symptoms in the second week after starting hydroxychloroquine and improved after stopping it in addition to taking steroids and pyridostigmine.

Trimethadione. Trimethadione was reported to occasionally alter the immune state and induce systemic lupus erythematosus or nephrotic syndrome (121). In 1966, Peterson reported an 11-year-old girl who developed non-tender swelling of the thyroid gland, generalized myasthenia gravis, and nephrotic syndrome with a positive agglutination test a few months after starting on trimethadione for epilepsy. Antithymic and antimuscular antibodies were present during the illness but later resolved. The patient was symptom-free without any medications for myasthenia gravis 4.5 months after trimethadione was discontinued (91). Booker and colleagues also reported a similar case of an 8-year-old girl who developed reversible generalized myasthenia gravis 6 months after initiation of trimethadione treatment. However, during the illness, antinuclear antibodies were present, but no antimuscle antibodies were detected (10). Sales of trimethadione were discontinued in the United States in 1996.

Riluzole. A patient with amyotrophic lateral sclerosis treated with riluzole for 3 months developed ptosis and diplopia and had physiological and serological findings suggesting autoimmune myasthenia gravis. The condition improved after cessation of the drug and the AChR antibody titers gradually decreased (100). “Myasthenia” was reported as a possible infrequent adverse event during riluzole treatment in controlled amyotrophic lateral sclerosis trials, but the frequency of events was not more than the placebo (fda.gov).

Etanercept, adalimumab (tumor necrosis factor-alpha antagonist). Etanercept and adalimumab are tumor necrosis factor-alpha inhibitors used to treat autoimmune diseases. Existing case reports have described etanercept inducing-myasthenia gravis, but a study also documented a case of seronegative ocular myasthenia gravis that presented after 18 months of adalimumab treatment and resolved with discontinuation of the drug and treatment with pyridostigmine (86). Although etanercept therapy is effective in some patients with corticosteroid‐dependent myasthenia gravis (105), cases of myasthenia gravis diagnosed while on long-term etanercept therapy have been reported. Fee and Kasarskis reported a 66-year-old male with diabetes mellitus who developed dysarthria and dysphagia after 6 years of etanercept therapy for rheumatoid arthritis (34). The patient had fatigable facial weakness and bilateral upper limb weakness on examination, an elevated titer of AChR antibodies, and electrophysiologic studies consistent with neuromuscular transmission defect. One month after discontinuing the drug, the patient’s symptoms began to improve. In about 6 months, his repetitive nerve stimulation test became normal, and his symptoms were mostly resolved. His titer of AChR antibodies remained elevated when tested 2 years later (34). Galassi and associates described a 68-year-old female who developed fluctuating fatigability 7 to 8 months after initiation of etanercept treatment for psoriatic arthritis. She had positive repetitive stimulation, single-fiber electromyography testing, and elevated titer of AChR antibodies (39). Two other cases were later reported (108; 12). Etanercept has also been associated with many neurologic disorders, including chronic inflammatory demyelinating polyneuropathy, Guillain‐Barré syndrome, multiple sclerosis, acute transverse myelitis, and others (115; 57; 102; 01; 125).

Tyrosine-kinase inhibitors. Myasthenia gravis has been reported with the use of tyrosine-kinase inhibitors (TKIs) in the treatment of different cancers. A patient treated with lorlatinib for non-small cell lung cancer was reported to have AChR positive-myasthenia gravis 6 months after initiation (26). At least two cases of AchR-positive myasthenia gravis have been reported after initiation of imatinib to treat chronic myeloid leukemia (107; 62).

Immune checkpoint inhibitors.

Ipilimumab (anti-CTLA-4). Ipilimumab was the first immune checkpoint inhibitor to be approved by the U.S. Food and Drug Administration, and myasthenia gravis was reported during the clinical development program of ipilimumab (136). At least 14 cases have been reported in the literature (53). In one study, the onset of myasthenic symptoms ranged from 2 to 6 weeks and two of the four patients developed pruritus and a rash before the development of myasthenic symptoms (71). Three out of 4 patients had positive serum AChR antibodies. One patient was also diagnosed with myositis with elevated creatine kinase. All received treatment for myasthenia, and there was no associated mortality (68; 54; 81).

Nivolumab, pembrolizumab, cemiplimab (anti-PD-1). Myasthenia gravis associated with programmed cell death protein 1 inhibitors also occurs within a relatively short timeframe, ranging from 2 to 12 weeks, from the initiation of therapy. However, the serology for AChR antibody is often negative (71). The rates of myasthenia gravis are higher in men (60.98%) compared to women (39.02%) taking anti-PD-1 therapy and the average age at onset of symptoms was 70.28±10.50 (53). A systematic review by Johansen and colleagues highlights the atypical clinical presentation of these cases (52). They identified 85 patients in the literature who developed neuromuscular disorders related to the use of nivolumab or pembrolizumab monotherapy or concurrent with other immunologic agents such as ipilimumab. They found that 27% of the patients were diagnosed with myasthenia gravis (15/23) or exacerbation of preexisting myasthenia gravis (8/23), 23% with neuropathy, 34% with myopathy, and 16% with a combination of the above. Regardless of the diagnoses assigned, patients often reported to have overlapping symptoms, especially myasthenia gravis and myopathy. One retrospective chart review identified at least two patients with an immune checkpoint inhibitor overlap syndrome that resulted in death (69). A lower percentage of patients were diagnosed with myasthenia gravis with anti-AChR seropositivity and a high prevalence of oculomotor and bulbar symptoms in patients diagnosed with myopathy. Thorough workup to obtain the correct diagnosis is paramount as the rate of cardiopulmonary complications and the rate of mortality are high (approximately 20%) (52; 53). Higher death rates were associated with myasthenia gravis that presented in combination with myocarditis and myositis. In a query of the U.S. Food and Drug Administration’s Adverse Events Reporting System (FAERS) from 2003 to 2018 focusing on ocular myasthenia, complications were found to be greatest with nivolumab (N = 3) followed by pembrolizumab (N = 1) and were not observed in the other anti-PD monotherapies (33). In 1 case report of a patient with metastatic melanoma receiving pembrolizumab, the presentation of myasthenia and paraspinal myositis was associated with extraocular muscle atrophy (84).

Cemiplimab was approved in 2018 for cutaneous squamous cell carcinoma. During the study of cemiplimab in patients with B-cell malignancies, one patient who had idelalisib therapy 8 months prior developed life-threatening myositis and myasthenia gravis following two doses of cemiplimab. The patient received high-dose corticosteroids and plasmapheresis with eventual improvement. The incidence of myasthenia gravis was 0.4% (n=2) (drug approval package: LIBTAYO [cemiplimab-rwlc]; available at: fda.gov).

Atezolizumab, avelumab, durvalumab (anti-PD-L1). Both new onset and exacerbation of myasthenia gravis have been reported with atezolizumab. In the first case, the patient presented with paraneoplastic myasthenic crisis and was diagnosed with stage 4 lung adenocarcinoma. About 1 year later, she was started on second-line therapy with atezolizumab. Six weeks later, she developed dyspnea and weakness and was intubated and treated for myasthenic crisis (17). In the second case, the patient was started on atezolizumab every 3 weeks for urothelial carcinoma. After the second dose of atezolizumab, the patient developed generalized myasthenia gravis with elevated creatinine kinase and seropositivity for antistriated muscle antibodies and AChR-blocking antibodies. Despite treatment with prednisone and intravenous immunoglobulin, the patient developed cardiac arrhythmia and arrest (123). Atezolizumab can result in fatal myasthenia and myositis (29).

Avelumab-associated myasthenia gravis has been reported in a patient who developed seronegative myasthenia and respiratory failure while being treated for metastatic ovarian cancer, and another case while being treated for metastatic lung adenocarcinoma. Both patients responded well to treatment for myasthenia gravis (101; 137). During the phase 1b trial of durvalumab plus tremelimumab in nonsmall cell lung cancer, one patient in the treatment group died due to complications arising from myasthenia gravis (03).

A retrospective review of the quality control database at Yale New Haven Hospital identified 18 neurologic cases associated with immune checkpoint inhibitors, of which 17% were myasthenia gravis (30).

A pharmacovigilance study of the FAERS database between January 2014 to December 2019 identified 3619 neurologic case reports among 50,000 immune-checkpoint-related reports: anti-PD-1 (nivolumab and pembrolizumab), anti-PD-L1 (atezolizumab, avelumab, and durvalumab), and anti-CTLA-4 (ipilimumab and tremelimumab) (79). The analysis demonstrated that immune checkpoint inhibitor use was associated with a higher risk of neurologic complications, for which the relative odds ratio of developing myasthenia gravis was 23.28% (79). Furthermore, older age, certain cancer types (such as melanoma, non-small cell lung cancer, and urogenital cancer), and the use of dual immune checkpoint inhibitors were related to a higher risk of mortality from these neurologic complications (79). The mean age of onset for patients to develop immune checkpoint inhibitor-related myasthenia gravis was 69.2 years of age (79). Immune checkpoint inhibitor-related myasthenia gravis and myositis also occurred at a median time of 1 month after initiation of the immune checkpoint inhibitor versus a median time of 2 months for other neurologic adverse effects (79). Time-of-onset for all neurologic adverse effects was the earliest for anti-PD-L1 (79).

Erenumab. Erenumab is a human monoclonal antibody that antagonizes calcitonin gene-related peptide receptor function and is approved for chronic migraines. Recently, Marusic and colleagues described a patient who developed intermittent daily ptosis 2 months after being started on erenumab (72). Symptoms improved after withdrawing the drug. Acetylcholine receptor antibodies and MuSK antibodies were negative. This seems to be a case of ocular myasthenia-like symptoms in the setting of erenumab.

Prognosis and complications

The prognosis is usually good, with complete recovery expected when the causative agent is discontinued. Recovery may occur within days to up to 18 months following discontinuation of therapy (11). If drug exposure unmasks myasthenia gravis, the prognosis is related to the underlying disease. One exception is myasthenia gravis associated with programmed cell death protein 1 inhibitor use. The prognosis is poor. Besides withdrawal of the immune checkpoint inhibitor, high-dose steroids, more potent immunosuppressive or immunomodulatory agents, and cardiorespiratory supports may be required (71).

Clinical vignette

A 70-year-old man with a history of seropositive myasthenia gravis, hypertension, glaucoma, atrial fibrillation, and stroke was in stable condition and receiving mycophenolate mofetil, furosemide, warfarin, alendronate, calcium, and vitamin D. He underwent a gradual corticosteroid reduction and achieved a dose of 12.5mg every other day of prednisone when he contacted his neurologist stating that he no longer could ride his stationary bike for more than 5 minutes (previously, he did so for 20 minutes), had difficulty chewing, and severe ptosis of the left lid. The patient denied symptoms of intercurrent infection, had been compliant with reducing steroids by only 5 mg every month, and denied use of any new medications. Evaluation of serum electrolytes, thyroid function, and complete blood count was normal. The physician concluded that the patient was having a myasthenic exacerbation and recommended increasing corticosteroids to 30 mg every other day. The following week, he called his neurologist to inform him that, in fact, he had started an eye drop for glaucoma the week prior to the worsening of his condition. He read on the Internet that the medication contained a beta-blocker, so he had contacted his ophthalmologist and discontinued the medication. He returned to an excellent level of functioning within the next week.

Biological basis

Etiology and pathogenesis

Myasthenia gravis is caused by an autoimmune attack against proteins at the muscle endplate. The autoimmune process arises from a breakdown in self-tolerance, producing a T cell-driven antibody production. Presumably, a combination of individual susceptibility and exposure to a toxic agent leads to a breakdown in tolerance in a similar manner to spontaneous autoimmune myasthenia gravis.

Agents that compromise neuromuscular transmission do so by several mechanisms. There are postulated mechanisms for the offending agents, but there are very few comprehensive studies to provide proofs. For discussion of the mechanisms, please see the articles by Barrons and Howard (06; 49). The disturbances may be at several aspects of the synaptic transmission: the propagation of the nerve action potential, the release of the synaptic vesicles, the synthesis of acetylcholine, the activation of the acetylcholine receptors, the action of the cholinesterase, or the generation of muscle action potential at the end plate membrane. A single agent may possess multiple mechanisms. For example, lidocaine, procaine, and other local anesthetic agents interfere with propagation of the nerve action potential at the nerve terminal and reduce acetylcholine release presynaptically. They also reduce sensitivity of the postjunctional membrane to acetylcholine. Magnesium competitively blocks calcium entry at the motor nerve terminal and interferes with neuromuscular transmission by inhibiting the release of acetylcholine, but there may also be a mild postsynaptic effect. Lithium can accumulate inside the presynaptic motor nerve terminal. It reduces acetylcholine synthesis and quantal release of acetylcholine but also may affect acetylcholine receptor turnover (131; 89; 90). Procainamide, a class 1A antiarrhythmic, exerts an inhibitory effect at the postsynaptic level by decreasing sensitivity of the postjunctional membrane to acetylcholine. It also acts presynaptically to a lesser extent by decreasing the average number of acetylcholine quanta released per nerve impulse (04; 65). Aminoglycosides cause a neuromuscular blockade by competitively inhibiting the release of acetylcholine from the presynaptic membrane and impairing depolarization of the postsynaptic membrane (19). Macrolides cause a postsynaptic blockade of AChR (63).

The time from initiation of the offending agent to the onset of weakness provides a clue to the pathophysiology of the neuromuscular junction disorder. In general, weakness that begins in hours to days implies a direct toxicity of the drug at the neuromuscular junction. For example, a literature review of fluoroquinolones found a median of 1 day from exposure to myasthenia gravis exacerbation and the proposed mechanism is a dose-dependent aggravation of neural transmission at the neuromuscular junction at the level of the AChR with decreased miniature endplate potentials (116; 55). Conversely, a latency of several weeks to months from the initiation of a drug to onset of weakness suggests that antibodies have formed and become active at the neuromuscular junction. The temporal course and the pathophysiology of the myasthenic syndrome induced by the anti-rheumatoid drug D-penicillamine confirm that this disorder shares the same essential features as idiopathic autoimmune myasthenia gravis (82). D-penicillamine has a reactive sulfhydryl group capable of modifying self-antigens and can provoke typical autoantibody-mediated myasthenia gravis, especially in DR1+ individuals. One study demonstrated that T cell clones from a DR1+ individual were highly specific for D-penicillamine but not its L-isomer or D-cysteine and were restricted to HLA-DR1. These clones also responded well to blood mononuclear cells prepulsed with D-penicillamine either in the absence of serum or after chloroquine treatment but not to autologous D-pen-pulsed B cell lines. Thus, D-penicillamine may directly couple to distinctive peptides resident in surface DR1 molecules on circulating macrophages or dendritic cells (46). Similarly, chloroquine can promote the production of acetylcholine receptor autoantibodies, an effect that is reversible, pointing to likely an immune-mediated mechanism (110; 111). However, chloroquine may also produce a rapidly reversible myasthenic syndrome without autoantibodies (11).

The mechanism of interferon-induced myasthenia gravis is unknown. It is postulated that the development of autoimmune diseases after treatment with interferon-alpha is most likely caused by the drug’s immunostimulatory effects (20). Studies in transgenic mice have shown that expression of interferon-gamma at the motor endplate causes generalized weakness and abnormal neuromuscular junction function, which responds to cholinesterase inhibitors. Sera from those transgenic mice and from myasthenia gravis patients recognized a previously unidentified 87 kD target antigen, suggesting that expression of interferon-gamma at the motor endplate provokes a humoral autoimmune response (42). Mice studies of interferon beta have shown that it acts directly on thymic epithelial cells, causing overexpression of AChR, which could theoretically lead to myasthenia gravis (21).

The pathogenesis of statin-induced myasthenia gravis is 2-fold. One proposed mechanism is the unmasking of latent myasthenia gravis through statin-induced myopathy. The second proposed mechanism is related to the immunomodulatory effects of statins, as evidenced by cases where patients developed de novo seropositive myasthenia gravis after starting statin therapy. It is proposed that through a reduction in cytokines and transcription factors, statins reduce Th1 cell differentiation and favor Th2 cell upregulation, which could lead to myasthenia gravis through an increase in antibody-mediated disease pathways (40).

Imiquimod may be associated with development of myasthenia gravis through its agonistic effect toward toll-like receptors 7 and 8 (109). This then leads to the induction of various proinflammatory cytokines, chemokines, and other mediators, activating other components of the immune reaction. Th-1 cells differentiate, produce tumor necrosis factor-alpha, and promote B cell growth and expression of antibodies, leading to exacerbation of myasthenia gravis (134).

Ritonavir and other anti-HIV medications may be associated with myasthenia gravis through the effects of immune reconstitution (113).

Immune checkpoint inhibitors are associated with a unique spectrum of side effects termed immune-related adverse events, attributed to general immunologic enhancement and dysregulation of autoimmunity from the drugs. Myasthenia gravis is believed to be 1 of the rare immune-related adverse events (18; 71). Immune checkpoints, such as CTLA-4 and PD-1, are regulators that normally inhibit T-cell activation to maintain self-tolerance and prevent autoimmunity.

CTLA-4 is present on the cell surface of CD4+ and CD8+ T lymphocytes to regulate T cell activation. When its expression is upregulated (by signals from T cell receptor activation and cytokines such as IL-12 and interferon-gamma), CTLA-4 outcompetes CD28 on T lymphocytes for CD80 and CD86 on antigen-presenting cells due to its higher affinity, forming a feedback inhibition loop and dampening further T cell activation (133). CTLA-4 inhibitors, like ipilimumab, unleash the brake for T cell activation to fight cancer. Myasthenia gravis associated with CTLA-4 inhibitors is likely related to this nonspecific activation of T cells, but the detailed mechanisms and its possible overlaps with idiopathic myasthenia gravis are unknown. Interestingly, single-nucleotide polymorphisms in CTLA-4 have been associated with increased susceptibility to AChR antibody-positive myasthenia gravis and other common autoimmune disorders (126; 36; 99; 78). Patients with heterozygous mutations in CTLA-4 have severe immune dysregulation. CTLA-4 has a critical quantitative role in governing T and B lymphocyte homeostasis (64).

Although CTLA-4 mainly affects naïve T cells, PD-1 is primarily expressed on mature T cells and on other non-T cell subsets, including B cells, NK cells, and antigen-presenting cells to maintain peripheral tolerance and to fine-tune the degree of T cell responses. It exerts an inhibitory effect when it binds to PD-L1 or programmed death-ligand 2 (PD-L2) to directly block apoptosis, promoting T effector cell exhaustion and conversion of T effector cells to T regulatory cells (37). PD-L1 is expressed on the surface of multiple tissue types, including many tumor cells. PD-1 and PD-L1 inhibitors, such as nivolumab, pembrolizumab, and avelumab, reverse T-cell suppression and allow for greater immune response against tumors (133).

Similar to CTLA-4 inhibitors, the immunologic enhancement is nonspecific and immune-related adverse events are likely due to off-target effects. The specific immune pathways that are relevant for PD-1-induced myasthenia gravis are unknown, but it has been shown that single-nucleotide polymorphisms in PD-1 are also associated with the development of autoimmune disorders, such as systemic lupus erythematosus and rheumatoid arthritis (78). PD-1-deficient mice developed spontaneous autoimmune diseases, including a fatal autoimmune dilated cardiomyopathy (83). On the other hand, overexpression of PD-1 is associated with favorable outcomes in autoimmune diseases, possibly related to its potentiation effects on peripheral CD8 T-cell exhaustion (15). PD-L1 interacts with CTLA-4 and CD80 to inhibit T-cell proliferation (14; 135). The interaction between CTLA-4, PD-1, and other pathways likely further contributes to the immunologic enhancement and the autoimmunity dysregulation secondary to the use of immune checkpoint inhibitors.

Special considerations

Pregnancy

The primary risk for iatrogenic disease of the neuromuscular junction in pregnancy is hypermagnesemia induced by magnesium sulfate infusion in the treatment of preeclampsia and eclampsia. Temporal weakness is typically seen after diminution of deep tendon reflexes. Therefore, it is recommended that reflexes be checked hourly during magnesium sulfate administration.

Anesthesia

The anesthetic management of myasthenia is challenging because many anesthetics can worsen the disease. Competitive neuromuscular blocking agents, such as D-tubocurarine, and depolarizing agents, such as succinylcholine, should be avoided. However, mivacurium, used as a neuromuscular blocker (85), and rapid inhalation induction with halothane-nitrous oxide (106) are safe and effective in myasthenic patients. Sugammadex was introduced as a novel drug in anesthetics. It is a modified l-cyclodextrin that can encapsulate steroidal neuromuscular blocking drugs. It has been shown to provide rapid and safe reversal of deep rocuronium- and vecuronium-induced neuromuscular blockade in general patients (31; 50) and in patients with myasthenia gravis (127; 25; 132). Sugammadex should be used to reverse neuromuscular blocking agents over neostigmine in myasthenia gravis patients whenever possible because it is more reliable, especially in patients already taking anticholinesterase agents, and is associated with lower risk of postoperative respiratory adverse events (16).

Small-scale studies have shown that for patients on a stable dose, it is preferable to continue taking pyridostigmine on the day of surgery because discontinuation led to respiratory discomfort and sensitivity to vecuronium induction (124).

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Miguel Chuquilin MD

Dr. Chuquilin of University of Florida College of Medicine has no relevant financial relationships to disclose.
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Varun Jain MD

Dr. Jain of the University of Florida has no relevant financial relationships to disclose.
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Editor

Michael K Hehir MD

Dr. Hehir of University of Vermont Medical Center received a consulting fee from Immunovant, Janssen, and UCB Pharma.
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Former Authors

Alaina Giacobbe MD
Matthew Vasquez MD
Emma Ciafaloni MD FAAN
Werner Trojaborg MD PhD (original author), Linda Chang MD, Daniel Koontz MD, Henry Kaminski MD, Thomas Klopstock MD, and Hsin-Pin Lin MD PhD

Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: female>male, >1:1
Heredity: none
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-9: Myasthenia gravis without (acute) exacerbation: 358.00

Myasthenia gravis with (acute) exacerbation: 358.01
ICD-10: Myasthenia gravis: G70.0

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Drug-induced myasthenic syndromes

Associated Disorders

Chronic renal failure
Eclampsia
Hepatitis C
HIV infection
Hypercholesterolemia
- Hypermagnesemia
- Leukemia
- Preeclampsia
- Rheumatoid arthritis

Differential Diagnosis

acquired myasthenia gravis
congenital myasthenia
Lambert Eaton syndrome
neuropathy
myopathy
- combination of atypical neuromuscular conditions

Also Relevant

Drug-induced neurologic disorders
Dysphagia
Lambert-Eaton myasthenic syndrome
Myasthenia gravis
Wilson disease

Drug-induced myasthenic syndromes

Introduction

Overview

Key points

Historical note and terminology

Table 1. Drugs that Compromise Neuromuscular Transmission

Table 2. Drugs Reported to Cause a Myasthenic Syndrome Through an Immune Response

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Associated or underlying disorders

Diagnostic workup

Key tests and procedures:

Management

Special considerations

Pregnancy

Anesthesia

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Questions or Comment?

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