Myasthenia gravis

Overview

Myasthenia gravis is a disorder that causes weakness of the skeletal muscles, which are muscles that the body uses for movement. The weakness most often starts in the muscles around the eyes, causing drooping of the eyelids (ptosis) and difficulty coordinating eye movements, which results in blurred or double vision. In a form of the disorder called ocular myasthenia, the weakness remains confined to the eye muscles. In most people with myasthenia gravis, however, additional muscles in the face and neck are affected. Affected individuals may have unusual facial expressions, difficulty holding up the head, speech impairment (dysarthria), and chewing and swallowing problems (dysphagia) that may lead to choking, gagging, or drooling.

Other muscles in the body are also affected in some people with myasthenia gravis. The muscles of the arms and legs may be involved, causing affected individuals to have changes in their gait or trouble with lifting objects, rising from a seated position, or climbing stairs. The muscle weakness tends to fluctuate over time; it typically worsens with activity and improves with rest.

Weakness of the muscles in the chest wall and the muscle that separates the abdomen from the chest cavity (the diaphragm) can cause breathing problems in some people with myasthenia gravis. About 10 percent of people with this disorder experience a potentially life-threatening complication in which these respiratory muscles weaken to the point that breathing is dangerously impaired, and the affected individual requires ventilation assistance. This respiratory failure, called a myasthenic crisis, may be triggered by stresses such as infections or reactions to medications.

People can develop myasthenia gravis at any age. For reasons that are unknown, it is most commonly diagnosed in women younger than age 40 and men older than age 60. It is uncommon in children, but some infants born to women with myasthenia gravis show signs and symptoms of the disorder for the first few days or weeks of life. This temporary occurrence of symptoms is called transient neonatal myasthenia gravis.

Symptoms

Myasthenia gravis can affect any voluntary muscle. Voluntary muscles are the muscles that we directly control to make our body do things like walk, run, write, throw, lift, smile, and chew. In myasthenia gravis the most commonly affected muscles are the muscles that control eye and eyelid movement, facial expression, and swallowing. The degree of muscle weakness varies from person to person. People with more severe disease may have many muscles affected, including the muscles that control breathing. People with mild disease may have only one muscle group involved, such as the eye muscles.

In general, signs and symptoms of myasthenia gravis may include a drooping of one or both eyelids (ptosis); blurred or double vision (diplopia); unstable or waddling gait; weakness in the arms, hands, fingers, legs, and neck; a change in facial expression; difficulty in swallowing and shortness of breath; and impaired speech (dysarthria).

People can develop myasthenia gravis at any age. For unknown reasons, it is most commonly diagnosed in women younger than age 40 and men older than age 60. It is uncommon in children, but some infants born to women with myasthenia gravis have signs and symptoms of the condition for the first few days or weeks of life. This temporary occurrence of symptoms is called transient neonatal myasthenia gravis.

Eye muscles:

In more than half the people who develop myasthenia gravis, their first signs and symptoms involve eye problems, such as:

  • Drooping of one or both eyelids (ptosis).
  • Double vision (diplopia), which may be horizontal or vertical, and improves or resolves when one eye is closed.

Face and throat muscles:

In about 15 percent of people with myasthenia gravis, the first symptoms involve face and throat muscles, which can cause:

  • Altered speaking. Your speech may sound very soft or nasal, depending upon which muscles have been affected.
  • Difficulty swallowing. You may choke very easily, which makes it difficult to eat, drink or take pills. In some cases, liquids you're trying to swallow may come out your nose.
  • Problems chewing. The muscles used for chewing may wear out halfway through a meal, particularly if you've been eating something hard to chew, such as steak.
  • Limited facial expressions. Your family members may comment that you've "lost your smile" if the muscles that control your facial expressions have been affected.

Neck and limb muscles:

Myasthenia gravis can cause weakness in your neck, arms and legs, but this usually happens along with muscle weakness in other parts of your body, such as your eyes, face or throat.

The disorder usually affects arms more often than legs. However, if it affects your legs, you may waddle when you walk. If your neck is weak, it may be hard to hold up your head.

Causes

Myasthenia gravis is not directly inherited, nor is it contagious. However, a genetic predisposition to autoimmune disease can run in families. Occasionally, myasthenia gravis may occur in more than one member of the same family.

The exact cause of myasthenia gravis is unknown, but it is likely that many factors contribute to the risk of developing this disorder.

Myasthenia gravis is a type of autoimmune disorder. Autoimmune disorders occur when the immune system mistakenly attacks healthy tissue. In myasthenia gravis, the body produces antibodies that block the muscle cells that receive messages (neurotransmitters) from the nerve cells.

Normally when impulses travel down the nerve, the nerve endings release a neurotransmitter substance called acetylcholine. Acetylcholine travels from the neuromuscular junction - the place where nerve cells connect with the muscles they control - and binds to acetylcholine receptors which are activated and generate a muscle contraction. In myasthenia gravis, antibodies block, alter, or destroy the receptors for acetylcholine at the neuromuscular junction,which prevents the muscle contraction from occurring. These antibodies are produced by the body's own immune system.

In some cases, myasthenia gravis it is linked to tumors or other abnormalities of the thymus (a gland the plays an important role in the immune system). Researchers also believe that variations in particular unidentified genes may increase the risk to develop myasthenia gravis. Ultimately, many factors likely contribute to the risk of developing this complex disorder.

Antibodies:

Your nerves communicate with your muscles by releasing chemicals (neurotransmitters) that fit precisely into receptor sites on the muscle cells at the nerve-muscular junction.

In myasthenia gravis, your immune system produces antibodies that block or destroy many of your muscles' receptor sites for a neurotransmitter called acetylcholine (as-uh-teel-KOH-leen). With fewer receptor sites available, your muscles receive fewer nerve signals, resulting in weakness.

Antibodies may also block the function of a protein called a muscle-specific receptor tyrosine kinase (TIE-roh-seen KIE-nays). This protein is involved in forming the nerve-muscular junction. When antibodies block the function of this protein, it may lead to myasthenia gravis. Research continues to study how the antibodies inhibiting this protein are related to the development of myasthenia gravis.

Thymus gland:

Researchers believe that the thymus gland, a part of your immune system situated in the upper chest beneath your breastbone, may trigger or maintain the production of the antibodies that block acetylcholine.

Large in infancy, the thymus is small in healthy adults. In some adults with myasthenia gravis, however, the thymus is abnormally large. Some people with myasthenia gravis also have tumors of the thymus (thymomas). Usually, thymomas aren't cancerous (malignant).

Other causes:

Some people may have myasthenia gravis that isn't caused by antibodies blocking acetylcholine or the muscle-specific receptor tyrosine kinase. This type of myasthenia gravis is called antibody-negative myasthenia gravis. Antibodies against another protein, called lipoprotein-related protein 4, may play a part in the development of this condition.

Genetic factors also may be associated with myasthenia gravis:

Rarely, mothers with myasthenia gravis have children who are born with myasthenia gravis (neonatal myasthenia gravis). If treated promptly, children generally recover within two months after birth.

Some children are born with a rare, hereditary form of myasthenia, called congenital myasthenic syndrome.

Factors that can worsen myasthenia gravis:

  • Fatigue
  • Illness
  • Stress
  • Some medications — such as beta blockers, quinidine gluconate, quinidine sulfate, quinine (Qualaquin), phenytoin (Dilantin), certain anesthetics and some antibiotics

Prevention

Myasthenia gravis cannot be prevented.

Diagnosis

Neurological examination:

  • Reflexes
  • Muscle strength
  • Muscle tone
  • Senses of touch and sight
  • Coordination
  • Balance

The key sign that points to the possibility of myasthenia gravis is muscle weakness that improves with rest.

Tests to help confirm the diagnosis may include:

Edrophonium test:

Injection of the chemical edrophonium chloride (Tensilon) may result in a sudden, although temporary, improvement in your muscle strength. This is an indication that you may have myasthenia gravis.

Edrophonium chloride blocks an enzyme that breaks down acetylcholine, the chemical that transmits signals from your nerve endings to your muscle receptor sites.

Ice pack test:

If you have a droopy eyelid, your doctor may conduct an ice pack test. In this test, a doctor places a bag filled with ice on your eyelid. After two minutes, your doctor removes the bag and analyzes your droopy eyelid for signs of improvement. Doctors may conduct this test instead of the edrophonium test.

Blood analysis:

A blood test may reveal the presence of abnormal antibodies that disrupt the receptor sites where nerve impulses signal your muscles to move.

Repetitive nerve stimulation:

In this nerve conduction study, doctors attach electrodes to your skin over the muscles to be tested. Doctors send small pulses of electricity through the electrodes to measure the nerve's ability to send a signal to your muscle.

To diagnose myasthenia gravis, doctors will test the nerve many times to see if its ability to send signals worsens with fatigue.

Single-fiber electromyography (EMG):

Electromyography (EMG) measures the electrical activity traveling between your brain and your muscle. It involves inserting a fine wire electrode through your skin and into a muscle to test a single muscle fiber.

Imaging scans:

A CT scan or an MRI to check if there's a tumor or other abnormality in your thymus.

Pulmonary function tests:

To evaluate whether your condition is affecting your breathing.

 

Prognosis

The prognosis of MG patients is generally good, as is quality of life, given very good treatment. In the early 1900s the mortality associated with MG was 70%; now that number is estimated to be around 3–5% which is attributed to increased awareness and medications to manage symptoms. Monitoring of a person with MG is very important as at least 20% of people diagnosed with it will experience a myasthenic crisis within two years of their diagnosis requiring emergent medical intervention. Generally, the most disabling period of MG might be years after the initial diagnosis.

Treatment

Treatment is by medication and/or surgery. Medication consists mainly of acetylcholinesterase inhibitors to directly improve muscle function and immunosuppressant drugs to reduce the autoimmune process. Thymectomy is a surgical method to treat MG.

Medications:

 

  • Cholinesterase inhibitors. Medications such as pyridostigmine (Mestinon) enhance communication between nerves and muscles. These medications don't cure the underlying condition, but they may improve muscle contraction and muscle strength. Possible side effects may include gastrointestinal upset, nausea, and excessive salivation and sweating.
  • Corticosteroids. Corticosteroids such as prednisone inhibit the immune system, limiting antibody production. Prolonged use of corticosteroids, however, can lead to serious side effects, such as bone thinning, weight gain, diabetes and increased risk of some infections.
  • Immunosuppressants. Your doctor may also prescribe other medications that alter your immune system, such as azathioprine (Imuran), mycophenolate mofetil (CellCept), cyclosporine (Sandimmune, Neoral), methotrexate (Trexall) or tacrolimus (Prograf). Side effects of immunosuppressants can be serious and may include nausea, vomiting, gastrointestinal upset, increased risk of infection, liver damage and kidney damage.

 

Intravenous therapy:

 

  • Plasmapheresis. This procedure uses a filtering process similar to dialysis. Your blood is routed through a machine that removes the antibodies that block transmission of signals from your nerve endings to your muscles' receptor sites. However, the beneficial effects usually last only a few weeks. After repeated treatments, it may be difficult for doctors to gain access to your vein. They may need to implant a long, flexible tube (catheter) into your chest to conduct the procedure. Other risks associated with plasmapheresis include a drop in blood pressure, bleeding, heart rhythm problems or muscle cramps. Some people may also develop an allergic reaction to the solutions used to replace the plasma.
  • Intravenous immunoglobulin (IVIg). This therapy provides your body with normal antibodies, which alters your immune system response. IVIg has a lower risk of side effects than do plasmapheresis and immune-suppressing therapy. However, it may take about a week to start working, and the benefits usually last no more than three to six weeks. Side effects, which usually are mild, may include chills, dizziness, headaches and fluid retention.
  • Monoclonal antibody. Rituximab (Rituxan) is an intravenous medication that is used in some cases of myasthenia gravis. This drug depletes certain white blood cells, altering the immune system and improving myasthenia gravis. Rituximab is usually given in infusions at an infusion center or done in a hospital on an outpatient basis. Repeat infusions are often done over a few weeks. Occasionally the infusions are repeated months later.

 

Surgery:

About 15 percent of the people with myasthenia gravis have a tumor in their thymus gland, a gland under the breastbone that is involved with the immune system. If you have a tumor, called a thymoma, doctors will conduct surgery to remove your thymus gland (thymectomy).

If you don't have a tumor in the thymus gland, surgery to remove the thymus gland may improve your myasthenia gravis symptoms. It may eliminate your symptoms, and you may be able to stop taking medications for your condition. However, you may not notice the benefits of a thymectomy for several years, if at all.

A thymectomy may be performed as an open surgery or as a minimally invasive surgery.

In an open surgery, your surgeon splits the central breast bone (sternum) to open your chest and remove your thymus gland.

Surgeons may perform minimally invasive surgery to remove the thymus gland, which uses smaller incisions. Minimally invasive thymectomy may include:

Video-assisted thymectomy. In one form of this surgery, surgeons make a small incision in your neck and use a long thin camera (video endoscope) and small instruments to visualize and remove the thymus gland through your neck. Alternatively, surgeons may make a few small incisions in the side of your chest. Doctors use a video scope and small instruments to conduct the procedure and remove the thymus gland through these incisions.

Robot-assisted thymectomy. In a robot-assisted thymectomy, surgeons make several small incisions in the side of your chest. Surgeons conduct the procedure to remove the thymus gland using a robotic system, which includes a camera arm and mechanical arms.

Benefits of these procedures may include less blood loss, less pain, lower mortality rates and shorter hospital stays compared with open surgery.

Physical measures:

Patients with MG should be educated regarding the fluctuating nature of their symptoms, including weakness and exercise-induced fatigue. Exercise participation should be encouraged with frequent rest. In people with generalized MG, some evidence indicates a partial home program including training in diaphragmatic breathing, pursed lip breathing, and interval-based muscle therapy may improve respiratory muscle strength, chest wall mobility, respiratory pattern, and respiratory endurance.

Resources

  • NIH
  • Mayo Clinic
  • Genetics Home Reference