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  • Updated 04.16.2023
  • Released 02.17.1995
  • Expires For CME 04.16.2026

Drug-induced myasthenic syndromes



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



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 (55)

Ketolides: telithromycin (88)

Macrolides: erythromycin, azithromycin, clarithromycin

Polypeptide antibiotics: vancomycin, colistin, polymyxin B




Others: clindamycin, lincomycin, nitrofurantoin, ritonavir


Phenytoin (diphenylhydantoin), mephenytoin, trimethadione, ethosuximide, barbiturates, carbamazepine, gabapentin, benzodiazepines

Antifungal agents


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


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


Immune checkpoint inhibitors

Anti-PD-1 (nivolumab and pembrolizumab), anti-PD-L1 (atezolizumab, avelumab, and durvalumab), and anti-CTLA-4 (ipilimumab and tremelimumab)


Interferon alpha, interferon beta

Tyrosine-kinase inhibitors

Lorlatinib, imatinib


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