Disorders of neuromuscular transmission affect the neuromuscular junction. They may involve

• Postsynaptic receptors (eg, in myasthenia gravis—see Peripheral Nervous System and Motor Unit Disorders: Myasthenia Gravis)
• Presynaptic release of acetylcholine (eg, in botulism)
• Breakdown of acetylcholine within the synapse (eg, due to drugs or neurotoxic chemicals)

Common features of these disorders include fluctuating fatigue and muscle weakness with no sensory deficits.

Eaton-Lambert syndrome: This disorder is due to impaired acetylcholine release from presynaptic nerve terminals (see Overview of Cancer: Neurologic paraneoplastic syndromes).

Botulism: Also due to impaired release of acetylcholine from presynaptic nerve terminals, botulism develops when toxin produced by Clostridium botulinum spores irreversibly binds to a specific receptor (synaptotagmin II) on the presynaptic terminal cholinergic nerve endings (see Anaerobic Bacteria: Botulism). The result is severe weakness, sometimes with respiratory compromise. Other systemic symptoms may include mydriasis, dry mouth, constipation, urinary retention, and tachycardia due to unopposed sympathetic nervous system activity (anticholinergic syndrome). These systemic 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 sec of exercise or with rapid (50-Hz) repetitive nerve stimulation.

Drugs or toxic chemicals: Cholinergic drugs, organophosphate insecticides, and most nerve gases block neuromuscular transmission by excessive acetylcholine action that depolarizes postsynaptic receptors. Miosis, bronchorrhea, and myasthenic-like weakness (cholinergic syndrome) result.

Aminoglycoside and polypeptide antibiotics decrease presynaptic acetylcholine release and sensitivity of the postsynaptic membrane to acetylcholine. At high serum levels, these antibiotics may increase neuromuscular block in patients with latent myasthenia gravis. Long-term penicillamineSome Trade Names
CUPRIMINE
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treatment may cause a reversible syndrome that clinically and electromyographically resembles myasthenia gravis. Excessive Mg po or IV (with blood levels approaching 8 to 9 mg/dL) can also induce severe weakness resembling a myasthenic syndrome.

Treatment consists of eliminating the drug or toxic chemical and providing necessary respiratory support and intensive nursing care. AtropineSome Trade Names
ATROPEN
ATROPINE-CARE
SAL-TROPINE
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0.4 to 0.6 mg po tid decreases bronchial secretions in patients with cholinergic excess. Higher doses (eg, 2 to 4 mg IV q 5 min) may be necessary for organophosphate insecticide or nerve gas poisoning.

Disorders With Neuromuscular Manifestations

Stiff-person syndrome: This syndrome (formerly called stiff-man syndrome) affects the CNS but has neuromuscular manifestations. It may be idiopathic, autoimmune, or paraneoplastic (most often associated with breast, lung, or colon cancer or with Hodgkin lymphoma). Clinical manifestations are similar in all types. The autoimmune type often occurs with type 1 diabetes, as well as other autoimmune disorders including thyroiditis, vitiligo, and pernicious anemia. Autoantibodies against several proteins involved in GABA (γ-aminobutyric acid) synapses are present in the autoimmune type, affecting primarily inhibitory neurons that originate in the anterior horn of the spinal cord.

Muscle stiffness, rigidity, and spasms progress insidiously in the trunk and abdomen and, to a lesser degree, in the legs and arms. Patients are otherwise normal, and examination detects only muscle hypertrophy and stiffness. EMG shows only the electrical activity of normal contraction.

Only symptomatic therapy is available. DiazepamSome Trade Names
VALIUM
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is the drug of choice; it most consistently relieves muscle stiffness. If diazepamSome Trade Names
VALIUM
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is ineffective, baclofenSome Trade Names
LIORESAL
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, given orally or intrathecally, can be considered. Corticosteroids are reportedly effective but have many long-term adverse effects. Results of plasma exchange are inconsistent, but IV immune globulin (IVIG) appears to result in improvement lasting up to a year.

Isaacs' syndrome: Isaacs' syndrome (neuromyotonia) is generally thought to be a channelopathy and sometimes occurs as a paraneoplastic syndrome. It may also occur in other disorders (eg, myasthenia gravis, thymoma, cancer, amyloidosis) or can be inherited. Cause is unknown. Abnormalities are thought to originate in a peripheral nerve because they are abolished by curare but usually persist after general anesthesia.

The limbs are most affected. The sine qua non is myokymia—continuous muscle twitching described as bag-of-worms movements. Other symptoms include carpopedal spasms, intermittent cramps, increased sweating, and pseudomyotonia (impaired relaxation after a strong muscle contraction but without the typical waxing-and-waning EMG abnormality of true myotonia). CarbamazepineSome Trade Names
TEGRETOL
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or phenytoinSome Trade Names
DILANTIN
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may relieve these symptoms. Plasma exchange and IVIG are usually beneficial.

Last full review/revision August 2012 by Michael Rubin, MDCM

Content last modified November 2012