Drug-induced myasthenic syndromes

Hsin-Pin Lin MD PhD (

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

)
Miguel Chuquilin MD (

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

)
Emma Ciafaloni MD, editor. (

Dr. Ciafaloni of the University of Rochester received consulting fees from Biogen and Pfeizer and research grants from Sarepta and Santhera.

)
Originally released February 17, 1995; last updated November 18, 2019; expires November 18, 2022

This article includes discussion of drug-induced myasthenic syndromes. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

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 a new 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.

Key points

 

• Drug-induced myasthenic syndromes are caused by numerous medications of various classes.

 

• D-penicillamine leads to an autoimmune process similar to spontaneous myasthenia gravis.

 

• 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.

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, 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 (Pridgen 1956; Argov and Mastaglia 1979). Psychotropic drugs of the phenothiazine family were later found to be capable of acting in a similar way (McQuillen et al 1963). 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 (Bucknall et al 1975), 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 (Drosos et al 1993) and for Wilson disease (Czlonkowska 1975; Masters et al 1977).

Advances in the understanding of immune dysregulation in cancer have 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 (Wei et al 2018). 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 (Hodi et al 2010; Friedman et al 2016; Hottinger 2016; Michot et al 2016; Cuzzubbo et al 2017; Kao et al 2017; Makarious et al 2017; Fellner et al 2018).

The drugs listed in Table 1 have been described to compromise neuromuscular transmission (Mehrizi 2012; Myasthenia Gravis Foundation of America 2019).

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

Aminoglycosides: gentamicin, tobramycin, kanamycin, neomycin, streptomycin, netilmicin

Fluoroquinolones: levofloxacin, moxifloxacin, ciprofloxacin, ofloxacin, gatifloxacin, norfloxacin, trovafloxacin, pefloxacin, and prulifloxacin (Jones et al 2011)

Ketolides: telithromycin (Perrot et al 2006)

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

Cardiovascular drugs

Beta-blockers: propranolol, oxprenolol, timolol, practolol, atenolol

Calcium channel blockers: verapamil

Others: quinidine, quinine, procainamide, bretylium, trimetaphan

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 (Purvin et al 2006), D-L-carnitine, tropicamide (Meyer et al 1992), iodinated radiographic contrast, magnesium, tandutinib (Lehky et al 2011)

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