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, a chemical messenger (neurotransmitter) released by the nerve to transmit a nerve impulse across the neuromuscular junction. After a nerve stimulates a muscle at this junction, an electrical impulse flows through the muscle, causing it to contract.

Overactive Nerves: Two Syndromes Sometimes nerves repeatedly send electrical impulses to muscles, resulting in overstimulation. Overstimulation is thought to be a factor in S tiff-person syndrome and Isaac's syndrome. Stiff-person syndrome: This syndrome is more common among women and often occurs in people with diabetes or certain kinds of cancer, including Hodgkin lymphoma (Hodgkin's disease). The cause may be an autoimmune reaction—when the body produces antibodies that attack its own tissues. Antibodies to an enzyme called glutamic acid decarboxylase are present, but whether they cause the symptoms is unknown. Muscles of the trunk, abdomen, and legs gradually become stiffer and enlarge. Muscles of the arms, head, and neck are affected less. The sedative diazepam can consistently relieve the muscle stiffness. Plasmapheresis, in which toxic substances are filtered from the blood, is sometimes tried but often without success. Without treatment, the disorder progresses, leading to disability and stiffness throughout the body. Isaac's syndrome: This rare disorder has no known cause. It often occurs in people with cancer. Muscles, particularly those in the arms and legs, continually twitch, moving like a bag of worms. This symptom is called myokymia. The hands and feet may intermittently have spasms and cramps. Muscle stiffness is common. Sweating may be increased. Symptoms can be relieved by carbamazepine or phenytoin, both of which are anticonvulsants.

Did You Know... Nerve gases used in chemical warfare interfere with communication between nerves and muscles.

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 formerly placed on the tip of some poison darts and used to paralyze and kill), and the nerve gases used in chemical warfare can cause the neuromuscular junction to malfunction. 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 that impairs communication between nerves and muscles, resulting in episodes of muscle weakness.

• Myasthenia gravis may result from malfunction of the immune system.
• People usually have drooping eyelids and double vision, and muscles become unusually tired and weak after exercise.
• Response to a drug given intravenously helps doctors determine whether people may have myasthenia gravis.
• Electromyography, blood tests, and imaging tests are needed to confirm the diagnosis.
• Some drugs can improve muscle strength rapidly, and others can slow progression of the disorder.

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. Rarely, it begins during childhood.

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. As a result, communication between the nerve cell and the muscle is disrupted. What causes the body to attack its own acetylcholine receptors—an autoimmune reaction—is unknown. According to one theory, 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. For unknown reasons, the thymus gland may instruct the immune system cells to produce antibodies that attack the acetylcholine receptors. People may inherit a predisposition to this autoimmune abnormality. About 65% of people who have myasthenia gravis have an enlarged thymus gland, and about 10% have a tumor of the thymus gland (thymoma). About half of thymomas are cancerous (malignant). Some people with the disorder do not have antibodies to acetylcholine receptors but have antibodies to an enzyme involved in the formation of the neuromuscular junction instead. These people may require different treatment.

The disorder may be triggered by infections, surgery, or use of certain drugs, such as nifedipine or verapamil (used to treat high blood pressure), quinine (used to treat malaria), and procainamide (used to treat abnormal heart rhythms).

Neonatal myasthenia develops in 12% of babies born to women who have myasthenia gravis. Antibodies against acetylcholine receptors, which circulate in the blood, may pass from a pregnant woman through the placenta to the fetus. In such cases, 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 of worsened symptoms (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
• Excessive weakness of affected muscles after they are used

The weakness disappears when the muscles are rested but recurs when they are used again.

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. Neck muscles may become weak. Sensation is not affected.

When people with myasthenia gravis use a muscle repetitively, the muscle usually becomes weak. For example, people who once could use a hammer well become 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), sometimes triggered by an infection. The arms and legs may become extremely weak, but even then, they do not lose sensation. In some people, the muscles needed for breathing weaken. This condition is life threatening.

Diagnosis

Doctors suspect myasthenia gravis in people with episodes of weakness, especially when the eye or facial muscles are affected or when weakness increases with use of the affected muscles and disappears with rest. Because acetylcholine receptors are damaged, drugs that increase levels of acetylcholine can be used to help confirm the diagnosis. Edrophonium, injected intravenously, is most commonly used. People are asked to exercise the affected muscle until it tires. Then they are given the drug. If it temporarily and quickly improves muscle strength, myasthenia gravis is a possible diagnosis.

Other diagnostic tests are needed to confirm the diagnosis. They include electromyography (stimulating muscles, then recording their electrical activity) and blood tests to detect antibodies to acetylcholine receptors and sometimes the other antibodies present in people with the disorder. Blood tests are also done to check for other disorders. Computed tomography (CT) or magnetic resonance imaging (MRI) of the chest is done to assess the thymus gland and to determine whether a thymoma is present.

Treatment

Drugs may be used to help improve strength quickly or to suppress the autoimmune reaction and slow progression of the disorder.

Drugs that increase the amount of acetylcholine, such as pyridostigmine (taken by mouth), may improve muscle strength. 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.

To suppress the autoimmune reaction, doctors may also prescribe a corticosteroid, such as prednisone, or an immunosuppressant, such as cyclosporine or azathioprine. These drugs are taken by mouth. Most people need to take a corticosteroid indefinitely. When the corticosteroid is started, symptoms may worsen initially, but improvement occurs within a few months. The dose is then reduced to the minimum that is effective. Corticosteroids, when taken for a long time, can have moderate or severe side effects. Thus, azathioprine may be given so that the corticosteroid can be stopped or its dose reduced. With azathioprine, improvement takes about 18 months.

Immune globulin (a solution containing many different antibodies collected from a group of donors) may be given intravenously once a day for 5 days. Over two thirds of people improve in 1 to 2 weeks, and effects may last 1 to 2 months.

When drugs do not provide relief or when a myasthenic crisis occurs, plasmapheresis (see Controlling Diseases by Purifying the Blood) may be used. In plasmapheresis, toxic substances (in this case, abnormal antibodies) are filtered 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 benefit of removing the thymus gland is uncertain.

Botulism

Botulism is an uncommon, life-threatening poisoning caused by toxins produced by the bacterium Clostridium botulinum.

• Botulism toxins, usually consumed in food, can weaken or paralyze muscles.
• Botulism may begin with dry mouth, double vision, and inability to focus the eyes or with gastric distress.
• Doctors examine samples of blood, stool, or tissue from the wound, and electromyography may be done.
• Careful food preparation and storage help prevent botulism.
• An antitoxin is used to prevent or slow the effects of the toxin.

Botulism is usually a type of food poisoning (see Gastroenteritis: Chemical Food Poisoning).

The toxins that cause botulism, which are very potent poisons, can severely impair nerve function. Because these toxins damage nerves, they are called neurotoxins. Botulism toxins paralyze muscles by inhibiting the release of the neurotransmitter acetylcholine from nerves. In very small doses, the toxin can be used to relieve muscle spasms and to reduce wrinkles.

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. Spores can also enter the body through the eyes or a break in the skin.

There are several different forms of botulism.

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. Other 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). Less commonly, beef, milk products, pork, poultry, and other foods cause botulism.

Wound botulism occurs when Clostridium botulinum contaminates a wound or is introduced into other tissues. Inside the wound, the bacteria produce toxins that are absorbed into the bloodstream. Injecting drugs with needles that are not sterilized can cause this type of botulism, as can injecting contaminated heroin into a muscle or under the skin (skin popping).

Infant botulism develops in infants who eat food containing spores of the bacteria rather than toxins. The spores then grow in the infant's intestine, where they 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 younger than 6 months.

Did You Know... The toxin that causes botulism is used to treat uncontrollable muscle spasms and to reduce wrinkles. Injecting illicit drugs increases the risk of botulism.

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 people become 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. Muscle tone in the face may be lost. Speaking and swallowing become difficult. Because swallowing is difficult, food or saliva is often inhaled (aspirated) into the lungs, causing choking or gagging and increasing the risk of pneumonia. Some people become constipated. 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 90% 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. Eyelids droop, crying is weak, infants are less able to suck, and their face loses its expression. Problems range from being tired and feeding slowly to losing a substantial amount of muscle tone and having difficulty breathing. When infants lose muscle tone, they may feel abnormally limp.

Diagnosis

Doctors suspect botulism based on symptoms. However, other disorders can cause similar symptoms, so additional information is needed.

Electromyography (stimulating muscles and recording their electrical activity—see Diagnosis of Brain, Spinal Cord, and Nerve Disorders: Electromyography and Nerve Conduction Studies) may be useful. In most cases of botulism, it shows abnormal muscle responses after electrical stimulation.

For foodborne botulism, a likely food source provides a 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 blood or when the bacteria are detected in a culture of stool. Toxins may also be identified in food that the person ate.

For wound botulism, doctors ask whether people have had an injury that broke the skin. Doctors may inspect the skin for puncture marks suggesting use of an illicit drug. The diagnosis 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.

Sometimes determining whether botulism developed from a wound or from food is impossible.

Prevention

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. 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, so refrigerating food does not automatically make it safe.

The following measures can help prevent foodborne botulism:

• Cooking food at 176° F (79.9° C) for 30 minutes, which almost always destroys toxins
• Boiling home-canned food for 10 minutes, which destroys the toxins
• Discarding canned foods that are discolored or smell spoiled
• Discarding cans that are swollen or leaking
• Refrigerating oils infused with garlic or herbs
• Keeping potatoes that have been baked in aluminum foil hot until served
• Not feeding children younger than 2 years honey, which may contain Clostridium botulinum spores

If people are unsure whether a can should be discarded, they can check it when they start to open it. Before making the first puncture, they can place a few drops of water in the spot to be punctured. If water is expelled rather than sucked into the can when the can is punctured, the can is contaminated and should be discarded.

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 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.

Researchers and other people who work with the bacteria or its toxin are immunized.

Did You Know... ·Infants should not be fed honey.

Treatment

People who may have botulism should go to the hospital immediately. Laboratory tests to confirm the diagnosis are done, but treatment often cannot be delayed until the results are known. To help eliminate any unabsorbed toxin, doctors may give activated charcoal by mouth or through a tube inserted into the stomach.

Vital signs (pulse, breathing rate, blood pressure, and temperature) are measured often. If breathing problems begin, people are 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. Also, some people have a serious allergic (anaphylactic) reaction to the antitoxin, which is derived from horse serum, or develop serum sickness (see Bites and Stings: What Is Serum Sickness?). The antitoxin is not recommended for infant botulism, but use of a botulism immune globulin (derived from the blood of people immunized against botulism) in infants is being studied. People 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 disorder that causes weakness.

Eaton-Lambert syndrome is caused by antibodies that interfere with the release of acetylcholine rather than attack acetylcholine receptors (as occurs in myasthenia gravis—see Peripheral Nerve Disorders: Myasthenia Gravis). Eaton-Lambert syndrome usually precedes, occurs with, or develops after certain cancers, especially lung cancer.

Eaton-Lambert syndrome causes muscle weakness, but persistent use of a muscle causes an increase rather than a decrease in strength (as occurs in myasthenia gravis). People also tire easily. The mouth is dry, the eyelid droops, and the upper arms and thighs are painful. Men may have erectile dysfunction.

Symptoms suggest the diagnosis, but electromyography (stimulating muscles, then recording their electrical activity) is needed to confirm the diagnosis.

Treating cancer, if present, sometimes relieves symptoms due to Eaton-Lambert syndrome. Guanidine, a drug that increases the release of acetylcholine, often lessens symptoms but may inhibit the bone marrow's production of blood cells and impair liver function. Corticosteroids and plasmapheresis (filtering of toxic substances, including abnormal antibodies, from the blood) help some people.

Last full review/revision February 2008 by Michael Rubin, MD