Disorders of the Neuromuscular Junction
Nerves connect with muscles at the neuromuscular junction. There, the ends of nerve fibers connect to special sites on the muscle's membrane called motor end plates. These plates contain receptors that enable the muscle to respond to acetylcholine, the chemical messenger (neurotransmitter) released by the nerve to transmit a nerve signal across the neuromuscular junction. After a nerve stimulates a muscle at this junction, an electrical signal flows through the muscle, causing it to contract.
Disorders in which the neuromuscular junction malfunctions include myasthenia gravis, botulism, and Eaton-Lambert syndrome. In addition, many drugs (including very high doses of some antibiotics), certain insecticides (organophosphates), curare (an extract from plants used in hospitals to paralyze people in preparation for surgery), and the nerve gases used in chemical warfare can cause the neuromuscular junction to malfunction. For example, some of these substances prevent the normal breakdown of acetylcholine after the nerve impulse has been transmitted to the muscle.
Myasthenia Gravis
Myasthenia gravis is an autoimmune disorder in which communication between nerves and muscles is impaired, resulting in episodes of muscle weakness.
Myasthenia gravis is more common among women. It usually develops in women between the ages of 20 and 40. However, the disorder may affect men or women at any age.
In myasthenia gravis, the immune system produces antibodies that attack one type of receptor on the muscle side of the neuromuscular junction--the receptors that respond to the neurotransmitter acetylcholine. What causes the body to attack its own acetylcholine receptors--an autoimmune reaction--is unknown. According to one theory, a malfunction of the thymus gland may be involved. In the thymus gland, certain cells of the immune system learn how to differentiate between the body and foreign substances. The thymus gland also contains muscle cells (myocytes) with acetylcholine receptors. Myasthenia gravis may result because for unknown reasons, the thymus gland instructs the immune system cells to produce antibodies that attack the acetylcholine receptors. People may inherit a predisposition to this autoimmune abnormality. About 10% of people who have myasthenia gravis have a tumor of the thymus gland (thymoma). About half of thymomas are cancerous (malignant).
Antibodies against acetylcholine receptors, which circulate in the blood, may pass from a pregnant woman through the placenta to the fetus. In 12% of babies born to women who have this disorder, the transfer of antibodies produces neonatal myasthenia, in which the baby has muscle weakness that disappears several days to a few weeks after birth. The remaining 88% of babies are not affected.
Symptoms
Episodes during which symptoms worsen (exacerbations) are common. At other times, symptoms may be minimal or absent.
The most common symptoms are weak, drooping eyelids; weak eye muscles, which cause double vision; and excessive fatigue of specific muscles after exercise. In 40% of people with myasthenia gravis, the eye muscles are affected first, but 85% eventually have this problem. In 15% of people, only the eye muscles are affected, but in most people, the whole body is affected. Difficulty speaking and swallowing and weakness of the arms and legs are common. Hand grip may alternate between weak and normal; this fluctuating grip is called milkmaid's grip. The neck muscles may become weak. Sensation is not affected.
When a person with myasthenia gravis uses a muscle repetitively, the muscle usually becomes weak. For example, a person who once could use a hammer well becomes weak after hammering for several minutes. However, muscle weakness varies in intensity from hour to hour and from day to day, and the course of the disease varies widely.
About 15% of people have severe episodes (called myasthenia crisis). They may become extremely weak, but even then, they do not lose sensation. In about 10% of people who have a myasthenia crisis, the muscles needed for breathing weaken; this condition is life threatening.
Diagnosis
Doctors suspect myasthenia gravis in people with episodic weakness, especially when the muscles of the eyes or face are affected or when weakness increases with use of the affected muscles and disappears with rest. Because acetylcholine receptors are damaged, drugs that increase the levels of acetylcholine can be given as a test to help confirm the diagnosis. Edrophonium is most commonly used. When injected intravenously, it temporarily improves muscle strength in people with myasthenia gravis.
Other diagnostic procedures include electromyography to evaluate nerve and muscle function and blood tests to detect antibodies to acetylcholine. Computed tomography (CT) or magnetic resonance imaging (MRI) of the chest is performed to assess the thymus gland and to determine whether a thymoma is present.
Treatment
Drugs that increase the amount of acetylcholine, such as pyridostigmine (taken by mouth), may be given. Long-acting capsules are available for nighttime use to help people who experience severe weakness or difficulty swallowing when they awaken in the morning. Doctors must periodically adjust the dose, which may have to be increased during episodes of weakness. However, doses that are too high can cause weakness that is difficult to distinguish from that caused by the disorder. Also, the effectiveness of these drugs may decrease with long-term use. Increasing weakness, which may be due to a decrease in the drug's effectiveness, must be evaluated by a doctor with expertise in treating myasthenia gravis.
Common side effects of pyridostigmine include abdominal cramps and diarrhea. Drugs that slow the activity of the digestive tract, such as atropine or propantheline, may be needed to counteract these effects.
Doctors may also prescribe a corticosteroid, such as prednisone, or an immunosuppressant, such as azathioprine, to suppress the autoimmune reaction. These drugs may produce improvement within a few months.
When drugs do not provide relief or when a person has a myasthenic crisis, plasmapheresis (see Section 14, Chapter 171) may be used. In plasmapheresis, toxic substances (in this case, the abnormal antibody) are extracted from the blood.
If a thymoma is present, the thymus gland must be surgically removed to prevent the thymoma from spreading. If no thymoma is present, the need to remove the thymus gland is uncertain.
Botulism
Botulism is an uncommon, life-threatening poisoning caused by toxins produced by the bacterium Clostridium botulinum.
The toxins that cause botulism, which are very potent poisons, can severely damage nerves. These toxins are called neurotoxins because they damage nerves. Botulism toxins paralyze muscles by inhibiting the release of the neurotransmitter acetylcholine from nerves. Botulism is usually a type of food poisoning. Another type of food poisoning may result from ingesting a neurotoxin sometimes present in shellfish (see Section 9, Chapter 122).
Causes
The bacterium Clostridium botulinum forms reproductive cells called spores. Like seeds, spores can exist in a dormant state for many years, and they are highly resistant to destruction. When moisture and nutrients are present and oxygen is absent (as in the intestine or sealed jars or cans), the spores start to grow and produce toxins. Some toxins produced by Clostridium botulinum are not destroyed by the intestine's protective enzymes. Clostridium botulinum is common in the environment, and spores can be transported by air. Many cases of botulism result from ingesting or inhaling small amounts of soil or dust.
Different forms of botulism are distinguished based on the cause.
Foodborne botulism occurs when food contaminated with the toxins is eaten. The most common sources of foodborne botulism are home-canned foods, particularly foods with a low acid content, such as asparagus, green beans, beets, and corn. Less common sources include chopped garlic in oil, chili peppers, tomatoes, foil-wrapped baked potatoes that have been left at room temperature too long, and home-canned or fermented fish. However, about 10% of outbreaks result from eating commercially prepared foods, most commonly, vegetables, fish, fruits, and condiments (such as salsa). Beef, milk products, pork, poultry, and other foods have also caused botulism.
Wound botulism occurs when a wound is contaminated with Clostridium botulinum. Inside the wound, the bacteria produce toxins that are absorbed into the bloodstream.
Infant botulism develops in infants who eat food containing spores of the bacteria rather than previously formed toxins. The spores then grow in the infant's intestine and produce toxins. The cause of most cases is unknown, but some cases have been linked to the ingestion of honey. Infant botulism occurs most commonly among infants aged 2 to 3 months.
Adult intestinal colonization botulism also results from eating food containing spores of the bacteria, but it occurs in older children and adults who have an intestinal disorder (such as colitis) or who have recently had surgery on the intestine. Only a few cases have been reported.
Symptoms
Symptoms of foodborne botulism develop suddenly, usually 18 to 36 hours after toxins enter the body, although symptoms can start as soon as 4 hours or as late as 8 days after ingesting the toxins. The more toxin ingested, the sooner the person becomes sick. Usually, people who become sick within 24 hours of eating contaminated food are the most severely affected.
The first symptoms of foodborne or wound botulism commonly include dry mouth, double vision, drooping eyelids, and an inability to focus on nearby objects. The pupils of the eyes do not constrict normally when exposed to light during an eye examination. However, in foodborne botulism, the first symptoms are often nausea, vomiting, stomach cramps, and diarrhea. People who have wound botulism do not have any digestive symptoms.
Nerve damage by the toxins affects muscle strength but not sensation. Speaking and swallowing become difficult. The muscles of the arms and legs and the muscles involved in breathing become progressively weaker as symptoms gradually move down the body. Breathing problems may be life threatening. The mind usually remains clear.
In about two thirds of infants with infant botulism, constipation is the first symptom. Then the muscles become paralyzed, beginning in the face and head and eventually reaching the arms, legs, and muscles involved in breathing. Problems range from mild lethargy and slowness in feeding to extensive loss of muscle tone and difficulty breathing.
Adult intestinal colonization botulism causes similar symptoms, but they are delayed. Symptoms develop up to 47 days after ingestion of the spores.
Diagnosis
Doctors may be able to diagnose foodborne botulism on the basis of symptoms. However, the symptoms are often mistakenly thought to result from more common causes of muscle weakness, such as stroke. A likely food source provides an additional clue. For example, when botulism occurs in two or more people who ate the same food prepared in the same place, the diagnosis is clearer. The diagnosis is confirmed when the toxins are detected in the person's blood or when the bacteria are detected in a culture of the person's stool. Toxins may also be identified in the suspected food.
The diagnosis of wound botulism is confirmed when the toxins are detected in the blood or when the bacteria are detected in a culture of tissue from the wound.
Detecting the bacteria or the toxins in a sample of an infant's stool confirms the diagnosis of infant botulism.
Electromyography (in which the electrical activity of muscles is recorded (see Section 6, Chapter 77)) may be useful. It shows abnormal muscle responses after electrical stimulation in most cases of botulism.
Prevention and Treatment
The spores of Clostridium botulinum are highly resistant to heat and may survive boiling for several hours. However, the toxins are readily destroyed by heat. Therefore, cooking food at 176° F (79.9° C) for 30 minutes almost always destroys toxins and prevents foodborne botulism. Stored foods can cause botulism if they were inadequately cooked before they were stored. The bacteria can produce some toxins at temperatures as low as 37.4° F (3° C), a typical refrigerator temperature.
Proper home and commercial canning techniques and adequate heating of home-canned food before serving are essential. Boiling home-canned food for 10 minutes destroys the toxins. Canned foods that are discolored or smell spoiled should be discarded. Also, cans that are swollen or leaking should be discarded. Oils infused with garlic or herbs should be refrigerated. Potatoes that have been baked in aluminum foil should be kept hot until served. Children younger than 2 years should not be fed honey because Clostridium botulinum spores may be present.
Any food that may be contaminated should be disposed of carefully. Even tiny amounts of toxins ingested, inhaled, or absorbed through the eye or a break in the skin can cause serious illness. Skin contact should be avoided as much as possible, and the hands should be washed immediately after handling the food.
If a wound becomes infected, promptly seeking medical attention can reduce the risk of wound botulism.
A person who may have botulism should go to the hospital immediately. Laboratory procedures to confirm the diagnosis are performed, but treatment often cannot be delayed until the results are known. To rid the person's body of any unabsorbed toxin, doctors may induce vomiting, wash out the stomach (a procedure called gastric lavage), and give the person a laxative to speed the passage of intestinal contents.
Vital signs (pulse, breathing rate, blood pressure, and temperature) are measured often. If breathing problems begin, the person is transferred to an intensive care unit and may be temporarily placed on a ventilator. Such treatment has reduced the percentage of deaths due to botulism from about 70% in the early 1900s to less than 10%.
A substance that blocks the action of the toxins (antitoxin) is given as soon as possible after botulism has been diagnosed. It is most likely to help if given within 72 hours of when symptoms begin. The antitoxin may slow or stop further physical deterioration, so that the body can heal itself over a period of months. However, the antitoxin cannot undo damage already done. The antitoxin is not recommended for infant botulism, but its effectiveness for this type of botulism is being studied.
The person may need to be fed through an intravenous tube. Infants may need to be fed through a thin plastic feeding tube (a nasogastric tube) passed through the nose and down the throat.
Some people who recover from botulism feel tired and are short of breath for years afterward. They may need long-term physical therapy.
Eaton-Lambert Syndrome
Eaton-Lambert syndrome is an autoimmune disease that causes weakness.
Eaton-Lambert syndrome is caused by antibodies that interfere with the release of acetylcholine rather than attack acetylcholine receptors (as in myasthenia gravis (see Section 6, Chapter 95)). Eaton-Lambert syndrome usually results from certain cancers, especially lung cancer.
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