Neuropharmacology & Neurotherapeutics
Gene therapy of cerebrovascular disease
Aug. 24, 2021
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Drug-induced myasthenic syndromes are caused by numerous medications of various classes. Some medications, 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 produce weakness by direct compromise of neuromuscular transmission. Agents that affect synaptic transmission may unmask subclinical myasthenia gravis or exaggerate the weakness in patients with disordered neuromuscular junction. They do not truly “induce” myasthenic syndromes. We will discuss these agents briefly. The focus of this review is medications suspected to produce an autoimmune reaction leading to myasthenia gravis. This article will draw particular attention to an increasingly utilized class of anticancer drugs, the immune checkpoint inhibitors. 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, as well as having cardiopulmonary involvement and high mortality rate. Management of drug-induced myasthenic syndromes requires withdrawal of the offending agents and standard immunotherapy, including high-dose corticosteroid, intravenous immunoglobulin, and plasma exchange.
• Drug-induced myasthenic syndromes are caused by numerous medications of various classes.
• 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 new class of immune checkpoint anticancer drugs, including anti-programmed cell death protein 1 and anti-cytotoxic lymphocyte-associated protein 4 monoclonal antibodies.
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, which is 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 recovery of spontaneous respiration after administration of certain aminoglycoside antibiotics (87; 04). Psychotropic drugs of the phenothiazine family were later found to be capable of acting in a similar way (68). Many more drugs were subsequently discovered to have direct effects at 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. Other than the established drugs, 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 20 years ago (12), D-penicillamine causes a condition identical to autoimmune myasthenia gravis in patients with rheumatoid arthritis. There are also reports of myasthenia gravis associated with D-penicillamine treatment for scleroderma (26) and for Wilson disease (22; 67).
Advances in the understanding of immune dysregulation in cancer led to the development of a new 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 (123). 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 (43; 34; 44; 71; 21; 52; 65; 31).
The drugs listed in Table 1 have been described to compromise neuromuscular transmission (Mehrizi 2012; 72).
Type of drug
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
Aminoglycosides: gentamicin, tobramycin, kanamycin, neomycin, streptomycin, netilmicin
Fluoroquinolones: levofloxacin, moxifloxacin, ciprofloxacin, ofloxacin, gatifloxacin, norfloxacin, trovafloxacin, pefloxacin, and prulifloxacin (51)
Ketolides: telithromycin (80)
Macrolides: erythromycin, azithromycin, clarithromycin
Polypeptide antibiotics: vancomycin, colistin, polymyxin B
Others: clindamycin, lincomycin, nitrofurantoin, ritonavir
Phenytoin (diphenylhydantoin), mephenytoin, trimethadione, ethosuximide, barbiturates, carbamazepine, gabapentin, benzodiazepines
Chloroquine, mefloquine, pyrantel
Beta-blockers: propranolol, oxprenolol, timolol, practolol, atenolol
Calcium channel blockers: verapamil
Others: quinidine, quinine, procainamide, bretylium, trimetaphan, propafenone, disopyramide, reserpine
Timolol, betaxolol, echothiophate
Corticosteroids (early exacerbations with high-dose therapy), estrogen
Trihexyphenidyl, riluzole, botulinum toxin
Statins (88), D-L-carnitine, tropicamide (70), iodinated radiographic contrast, magnesium, tandutinib (61), imiquimod (124)
• The described drugs are thought to induce myasthenia gravis through effects on the immune system, including increased acetylcholine receptor (AChR) antibody production leading to an autoimmune reaction and immune dysregulation.
• The presentation of myasthenic symptoms seems to occur at any point along the course of treatment with the offending drug, with the exception of immune checkpoint inhibitors which consistently present within 2 to 12 weeks of treatment. Symptoms usually completely resolve with discontinuation of the drug and a limited course of treatment.
• The onset of myasthenia gravis from immune checkpoint inhibitors is thought to be from immune dysregulation and is often more rapid and more severe, often involving the cardiopulmonary system, with mortality rates up to 20%.
In this section the clinical manifestations of medications that affect the immune system leading to myasthenia gravis are described. These are separate from drugs that cause weakness by directly affecting synaptic transmission found in Table 1.
Drug-induced myasthenic syndromes are characterized by progressive, and 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 institution of the offensive drug. Isolated ocular symptoms and unilateral ptosis have been described (Liu and Bienfang 1990; 89; 78).
D-penicillamine. With D-penicillamine, symptoms usually start 4 months to 9 months after initiation of treatment (12; 02) but occasionally as late as 5 years to 8 years into therapy (67; Liu and Bienfang 1990). The symptoms are generally mild and may be limited to extraocular muscles.
Most patients with D-penicillamine-induced myasthenia gravis have increased serum levels of acetylcholine receptor (AChR) antibodies (67; 120), although there is at least 1 case report of a patient with both increased serum levels of AChR and muscle-specific kinase (MuSK) antibodies (86). 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. In addition, electrophysiological studies have shown reduced miniature endplate potential amplitude, and morphological studies have shown reduced bungarotoxin binding, changes typical of acquired myasthenia gravis (120). 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), although the titers of AChR antibodies are significantly higher in longstanding idiopathic myasthenia gravis than in the D-penicillamine-induced disorder (119). 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 (37).
Recovery from D-penicillamine-related myasthenia takes place 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 deficiency of cytochrome c oxidase 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 (79). 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; 57; 62; 66; 84; 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 (109). 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 (40; 90; 28; 108).
Interferon beta. Evidence for 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 (08). Another 2 patients 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 (25). 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 completed 2-week treatment course of interferon beta for chronic hepatitis C infection (41). 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 (101; 102). 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 (85; 96; Brüggemann et al 1996; 54; 95). 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 (23). There are mixed reports about hydroxychloroquine causing myasthenia gravis. In 1 study, Jallouli and colleagues concluded hydroxychloroquine treatment appears to be safe in patients diagnosed with both systemic lupus erythematosus and myasthenia gravis (47). 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 (118). 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 (55). 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.
Trimethadione. Trimethadione had been reported to occasionally alter the immune state and induce systemic lupus erythematosus or nephrotic syndrome (Rallison et al 1961; 111). In 1966, Peterson reported an 11-year-old girl who developed nontender swelling of the thyroid gland, generalized myasthenia gravis, and nephrotic syndrome with positive agglutination test a few months after starting on trimethadione for epilepsy. Antithymic and antimuscular antibodies were present during the illness but later resolved. Patient was symptom-free without any medications for myasthenia gravis 4.5 months after trimethadione was discontinued (83). 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 (09). 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 (92). “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 that are 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 (78). Although etanercept therapy been found to be effective in some patients with corticosteroid‐dependent myasthenia gravis (97), 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 (30). The patient had fatigable facial weakness and bilateral upper limb weakness on exam, 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 (30). 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 and single-fiber electromyography testing and elevated titer of AChR antibodies (35). Two other cases were later reported (99; 11). Etanercept has also been associated with many neurologic disorders, including chronic inflammatory demyelinating polyneuropathy, Guillain‐Barré syndrome, multiple sclerosis, acute transverse myelitis, and others (105; 53; 94; 01; 115).
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 (126). At least 14 cases have been reported in the literature (49). In 1 study, the onset of myasthenic symptoms ranged from 2 to 6 weeks and 2 out of the 4 patients developed pruritus and a rash before the development of myasthenic symptoms (65). 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 (63; 50; 73).
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 (65). 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 (49). A systematic review by Johansen and colleagues highlights the atypical clinical presentation of these cases (48). 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. There was a lower percentage of patients 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%) (48; 49). 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 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 (29). 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 (76).
Cemiplimab was approved in 2018 for cutaneous squamous cell carcinoma. During the study of cemiplimab in patients with B-cell malignancies, 1 patient who had idelalisib therapy 8 months prior developed life-threatening myositis and myasthenia gravis following 2 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 (16). 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 (113).
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 (93; 127). During the phase 1b trial of durvalumab plus tremelimumab in nonsmall cell lung cancer, 1 patient in the treatment group died due to complications arising from myasthenia gravis (03).
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 (10). 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 (65).
A 70-year-old man with a history of seropositive myasthenia gravis, hypertension, glaucoma, atrial fibrillation, and stroke was in stable condition 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. 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 that he increase 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.
Myasthenia gravis is caused by 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 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; 45). 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, and/or the generation of muscle action potential at the end plate membrane. 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 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 (121; 81; 82). 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; 60). Aminoglycosides cause a neuromuscular blockade by competitively inhibiting the release of acetylcholine from the presynaptic membrane and impairing depolarization of the postsynaptic membrane (18). Macrolides cause a postsynaptic blockade of AChR (58).
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 (106; 51). 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 (74). 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 (42). Similarly, chloroquine can promote the production of acetylcholine receptor autoantibodies, an effect that is reversible, pointing to likely an immune-mediated mechanism (101; 102). However, chloroquine may also produce a rapidly reversible myasthenic syndrome without autoantibodies (10).
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 (19). 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 (38). Mice studies of interferon beta have shown that it acts directly on thymic epithelial cells, causing overexpression of AChR, that could theoretically lead to myasthenia gravis (20).
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 (36).
Imiquimod may be associated with development of myasthenia gravis through its agonistic effect towards toll-like receptors 7 and 8 (100). This then leads to 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 (124).
Ritonavir and other anti-HIV medications may be associated with myasthenia gravis through effects of immune reconstitution (103).
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 (17; 65). 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 (123). 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 (116; 32; 91; 71). 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 (59).
While 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 (33). 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 (123).
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 development of autoimmune disorders, such as systemic lupus erythematosus and rheumatoid arthritis (71). PD-1-deficient mice developed spontaneous autoimmune diseases, including a fatal autoimmune dilated cardiomyopathy (75). 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 (14). PD-L1 interacts with CTLA-4 and CD80 to inhibit T cell proliferation (13; 125). 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.
• The incidence and prevalence of drug induced myasthenia gravis varies depending on the causative agent.
Between 2% and 7% of patients with rheumatoid arthritis treated with D-penicillamine develop a drug-induced myasthenic syndrome (02). The frequency seems to be much lower in D-penicillamine-treated patients with scleroderma (107) or Wilson disease (56), suggesting an underlying susceptibility to an immune-mediated process.
A 2008 to 2018 study of adverse neurologic events associated with immune checkpoint inhibitors reported in Vigibase, the World Health Organization pharmacovigilance database, found 197 (0.57%) cases of neuromuscular junction dysfunction tied to monotherapy with PD1 inhibitors compared to just 14 (0.15%) cases associated with CTLA-4 monotherapy and 17 (0.36%) cases associated with combination therapy (49). In an earlier retrospective study in Japan, the overall prevalence of immunotherapy-related myasthenia gravis following nivolumab was 0.1% (110). The incidence of other drug-induced myasthenic syndromes is probably low. A retrospective chart review at a single academic medical center between 2011 and 2016 showed that of 127 patients with myasthenia gravis who visited the emergency department, the most common medication associated with a myasthenia exacerbation was azithromycin, followed by fluoroquinolones and beta blockers (39).
• The best prevention of drug-induced myasthenia gravis is avoidance of documented causative medications; however, especially in cases with poor evidence, it may be better to treat and monitor closely for new or worsening of existing myasthenia symptoms.
Avoidance of medications known to produce myasthenic syndrome is the best prevention (see Table 1 above), especially those medications with a black box warning from the Food and Drug Administration to avoid in patients with existing myasthenia gravis, like fluroquinolones and telithromycin. Because patients with DR1+ may be particularly susceptible to D-penicillamine-induced myasthenia gravis (42), testing for HLA-DR1 prior to the initiation of therapy may identify potentially susceptible patients. It is important to bear in mind that many of the drugs in Table 1 have only been reported in occasional cases to worsen myasthenia. Some of these anecdotal observations may be just chance coincidences. Thus, it would be inappropriate to ban the use of all these drugs, as there would be very few drugs left that patients with myasthenia could take. More importantly, patients with preexisting myasthenia gravis or other autoimmune conditions should monitor for signs and symptoms of new or worsening disease when taking an offending drug and notify their physicians immediately to discontinue the drug if symptoms appear.
The primary diagnosis to consider in drug-induced myasthenic syndromes is the unmasking of acquired, autoimmune myasthenia gravis. Although rarer, Lambert Eaton syndrome should also be considered. Congenital myasthenic patients typically have a history of progressive weakness, often dating to birth. Stressful events, such as drug exposure, could exacerbate weakness in such patients. In patients with exposure to immune checkpoint inhibitors, other neuromuscular disorders, such as neuropathy and myopathy, or a combination of atypical neuromuscular conditions, should also be considered.
Key tests and procedures:
• Edrophonium test
• Electromyography with repetitive nerve stimulation
• Serum AChR antibodies
When the clinical presentation suggests a neuromuscular transmission disorder, the diagnostic evaluation includes edrophonium test, electromyography with repetitive nerve stimulation, and serum acetylcholine receptor antibodies. If a patient is negative for acetylcholine receptor antibodies, it may be appropriate to obtain testing for antibodies to the muscle specific kinase. In cases of immune checkpoint inhibitor induced myasthenia gravis, it may also be helpful to check for elevated CK level and antistriated muscle antibodies, as they can be useful biomarkers for coinciding myositis and/or myocarditis that are often associated with a worse prognosis (104). Of course, a detailed history for drug exposure, which should include specific inquiry about alternative medications, should lead to the consideration of a drug-induced myasthenic syndrome.
• Discontinue the offending drug and standard treatment for myasthenia gravis including anticholinesterase agents and standard immunotherapy.
The best management is to discontinue the causative drug. Treatment with anticholinesterase drugs may be effective, even while the offensive drug is being administered. Just as in idiopathic myasthenia gravis, standard immunotherapy with high-dose corticosteroids, intravenous immunoglobulin, and plasma exchange may also provide benefit. If treatment with the drug is resumed, the myasthenic syndrome most likely will relapse. To illustrate this point, in the case of a 77-year-old patient with stage 4 melanoma responsive to pembrolizumab, it was decided that the risk of withdrawing treatment after she developed symptoms of diplopia and dysphagia on her fourth infusion outweighed the risk of myasthenia gravis recurrence. The patient was started on nivolumab therapy along with pyridostigmine bromide and corticosteroid treatment at 20 mg per day without recurrence of symptoms for 7 months (112). When symptoms recurred, the corticosteroid was gradually increased to 35 mg per day with good response and nivolumab was discontinued.
In the case of hypermagnesemia, intravenous infusion of 1 gram of calcium gluconate over 3 minutes may provide temporary relief. If the patient has renal failure, has developed cardiac arrhythmia, or has severe hypermagnesemia, emergency dialysis is warranted.
The primary risk for iatrogenic disease of the neuromuscular junction in pregnancy comes in the form of 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.
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 (77), and rapid inhalation induction with halothane-nitrous oxide (98) both have been shown to be safe and effective in myasthenic patients. Sugammadex was introduced as a novel drug in anesthetics. It is a modified l-cyclodextrin that is able to 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 (27; 46) and in patients with myasthenia gravis (117; 24; 122). 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 (15).
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 (114).
Emma Ciafaloni MD FAAN
Dr. Ciafaloni of the University of Rochester received personal compensation for serving on advisory boards and/or as a consultant for Alexion, Avexis, Biogen, PTC Therapeutics, Ra Pharma, Sarepta, Strongbridge Biopharma PLC, and Wave; and for serving on a speaker’s bureau for Biogen. Dr Ciafaloni also received research and/or grant support from Orphazyme, Santhera, and Sarepta.See Profile
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