Disorders of the Neuromuscular Junction
When considering causes of weakness, it’s very helpful to imagine an electrical message shooting from the cortex of the brain down to the contracting muscle. Along the way, the impulse travels through the spinal cord into the anterior horn, out the spinal nerve roots, down the peripheral nerves, and finally to the neuromuscular junction.
The neuromuscular junction is where the electrical signal causes neurotransmitters to be released from vesicles at the end of the nerve (the terminal). The neurotransmitters cross a small gap between the nerve terminal (the synapse ) and the surface of the muscle (the endplate). Waiting for the transmitters on the other side of the gap are special receptors that fit the transmitter like a lock to a key. When there’s a fit, a cascade of ions leads to muscular contraction.
The neurotransmitter used to signal between nerve and muscle is acetylcholine. There are several ways that this passing of acetylcholine neurotransmitter between nerve and muscle can be interrupted. Three of the best examples are myasthenia gravis, Lambert-Eaton syndrome, and botulinum toxicity.
With a prevalence between 150 to 200 people per million, myasthenia gravis is the most common of neuromuscular disorders, and one of the best understood of all neurological diseases. The disease causes muscle weakness due to blocked neurotransmitter receptors on the muscle. Antibodies normally meant to attack invading infections mistake the acetylcholine receptors for a pathogen and attack. Exercise tends to make the weakness worse. Between 60 to 70 percent of people with myasthenia gravis have a problem with the thymus, and 10 to 12 percent have a thymoma. A variety of other treatments are available.
Lambert-Eaton Myasthenic Syndrome (LEMS)
Lambert-Eaton is often what’s termed a paraneoplastic syndrome, meaning that antibodies related to cancer are also attacking part of the nervous system. Unlike myasthenia gravis, in which the attacked structures are on the muscle, the problem in LEMS is with the end of the motor nerve. Calcium channels normally open and signal for the release of neurotransmitters, but cannot do so in LEMS because antibodies have attacked the channel. As a result, no neurotransmitter is released, and the patient experiences weakness because the muscle cannot receive a signal to contract. With repeated exercise, the deficit can be overcome; so in LEMS, symptoms sometimes briefly improve with repeated effort.
Botulinum toxin is sometimes intentionally used by doctors to force muscles to relax in cases of dystonia. In its nontherapeutic form, the toxin is produced by bacteria and can cause a paralysis that starts with the muscles of the face and throat and descends over the rest of the body. Like other crises of the neuromuscular junction, this can be a medical emergency requiring intubation. The toxin attacks proteins that allow vesicles full of neurotransmitters inside the pre-synaptic neuron to dock at the end of the nerve prior to emptying into the space between nerve and muscle. Treatment is an antidote to the botulinum toxin, which should be given as soon as possible.
Other Neuromuscular Junction Disorders
Certain drugs, such as penicillamine and some statins, can rarely cause an autoimmune reaction that mimics myathenia gravis. Many other medications can worsen or bring on a crisis in someone who already has myasthenia gravis.
Testing for Diseases of the Neuromuscular Junction
Beyond a physical examination, the first step in diagnosing a disease of the neuromuscular junction is an electromyogram and nerve conduction study. These can not only help distinguish between myasthenia gravis, botulinum toxicity, and Lambert-Eaton but can also help rule out other disorders such as motor neuron disease, including amyotrophic lateral sclerosis.
Disorders of the neuromuscular junction can be very serious, requiring intubation and ventilation to help breathing if the weakness becomes severe enough. The mechanisms of the disorders are quite different, requiring different treatments. Proper diagnosis is the first step to regaining both strength and safety.
- Hal Blumenfeld, Neuroanatomy through Clinical Cases. Sunderland: Sinauer Associates Publishers 2002.
- Ropper AH, Samuels MA. Adams and Victor’s Principles of Neurology, 9th ed: The McGraw-Hill Companies, Inc., 2009.