Disorders of Neuromuscular Transmission

Lambert-Eaton myasthenic syndrome

Lambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune neuromuscular junction disorder involving impaired acetylcholine release from presynaptic nerve terminals; it is due to loss of P/Q-type voltage-gated calcium channels on the presynaptic nerve terminals. Repetitive nerve testing at rapid rates (20 to 50 hertz [Hz]) or a single supramaximal stimulation before and after 10 seconds of maximal isometric exercise shows an incremental response of up to 400%. Increases of > 100% are considered diagnostic of a presynaptic disorder of neuromuscular transmission, but an increment of ≥ 60% is highly suggestive. Malignancy is highly associated with LEMS, with 50 to 60% of patients going on to develop small cell lung cancer (1).

Botulism

Botulism develops when toxin produced by Clostridium botulinum spores irreversibly binds to a specific receptor (synaptotagmin II) on the presynaptic terminal cholinergic nerve endings, impairing release of acetylcholine. The result is severe weakness, sometimes with respiratory compromise and difficulty swallowing. Other symptoms may include mydriasis, dry mouth, constipation, urinary retention, and tachycardia due to unopposed sympathetic nervous system activity (anticholinergic syndrome). These clinical findings are absent in myasthenia gravis.

In botulism, electromyography (EMG) detects a mild decremental response to low-frequency (2- to 3-Hz) repetitive nerve stimulation but a pronounced incremental response after 10 seconds of exercise or with high-frequency (50-Hz) repetitive nerve stimulation.

Medications or toxic chemicals

Cholinergic medications, organophosphate insecticides, and most nerve gases (eg, sarin) block neuromuscular transmission through the presence of excessive acetylcholine that depolarizes postsynaptic receptors. Cholinergic syndrome results, characterized by miosis, bronchorrhea, abdominal cramps, diarrhea, and myasthenic-like weakness.

Other medications that may cause neuromuscular block include:

• Aminoglycoside and polypeptide antibiotics: Decrease presynaptic acetylcholine release and sensitivity of the postsynaptic membrane to acetylcholine; at high serum levels, may increase neuromuscular block in patients with latent myasthenia gravis.

• Penicillamine: Long-term use may cause a reversible syndrome that clinically and electromyographically resembles myasthenia gravis.Penicillamine: Long-term use may cause a reversible syndrome that clinically and electromyographically resembles myasthenia gravis.

• Magnesium supplements, oral or IV: In excess (blood levels approaching 8 to 9 mg/dL [4 to 4.5 mmol/L]) can cause severe myasthenia-like weakness.

• Immune checkpoint inhibitors (eg, ipilimumab, nivolumab, pembrolizumab): Although infrequent (< 1% of patients), immune-related adverse effects include myasthenia gravis symptoms.Immune checkpoint inhibitors (eg, ipilimumab, nivolumab, pembrolizumab): Although infrequent (< 1% of patients), immune-related adverse effects include myasthenia gravis symptoms.

Treatment consists of eliminating the medication or toxic chemical and providing necessary respiratory support and intensive nursing care. Atropine decreases bronchial secretions in patients with cholinergic excess. Higher doses (eg, 1 to 6 mg IV/IM/SC every 5 minutes) may be necessary for organophosphate insecticide or nerve gas poisoning.Treatment consists of eliminating the medication or toxic chemical and providing necessary respiratory support and intensive nursing care. Atropine decreases bronchial secretions in patients with cholinergic excess. Higher doses (eg, 1 to 6 mg IV/IM/SC every 5 minutes) may be necessary for organophosphate insecticide or nerve gas poisoning.

Reference

1. 1. Lipka AF, Verschuuren JJGM. Lambert-Eaton myasthenic syndrome. Handb Clin Neurol. 2024;200:307-325. doi:10.1016/B978-0-12-823912-4.00012-8