Myasthenia Gravis
Overview
Myasthenia gravis (MG) is a chronic autoimmune disorder that results in progressive skeletal muscle weakness. Skeletal muscles are primarily muscle fibers that contain bands or striations (striated muscles) that are connected to bone. MG causes rapid fatigue (fatigability) and loss of strength upon exertion that improves after rest.
In early stages, myasthenia gravis primarily affects muscles that control eye movement (extraocular muscles) and those that control facial expression, chewing, and swallowing. If untreated, the disorder may affect muscles that control breathing (respiration), causing acute respiratory failure.
Types
Myasthenia gravis can be classified according to which skeletal muscles are affected. Within a year of onset, approximately 85-90% of patients develop generalized myasthenia gravis, which is characterized by weakness in the trunk, arms, and legs.
About 10-15% of patients have weakness only in muscles that control eye movement. This type is called ocular myasthenia gravis.
Other types of MG include congenital, which is an inherited condition caused by genetic defect, and transient neonatal, which occurs in infants born to mothers who have MG. Congenital MG develops at or shortly after birth and causes generalized symptoms.
Transient neonatal MG is a temporary condition that develops in 10-20% of infants born to mothers who have MG. Transient neonatal MG is caused by circulation of the mother's antibodies through the placenta and it lasts as long as the mother's antibodies remain in the infant (usually a few weeks after birth).
Incidence and Prevalence
Myasthenia gravis affects approximately 2 out of every 100,000 people and can occur at any age. It is most common in women between the ages of 18 and 25. In men, the condition usually develops between 60 and 80 years of age.
Causes and Risk Factors
MG usually is caused by a malfunction of the immune system. The causative factor is unknown, but the disorder may have a genetic link. Causes include a genetic defect, which results in congenital MG, and the circulation of maternal antibodies through the placenta, which result in transient neonatal MG.
Acetylcholine (ACh) is a neurotransmitter that is involved in the transfer of information to muscle tissue. In myasthenia gravis, cells that bind to other cells to neutralize or destroy them (called antibodies) destroy acetylcholine receptor sites (AChR) in areas of muscle tissue that receive nerve impulses (called neuromuscular junctions), preventing nerve impulses from reaching the muscles. This results in weakness and rapid fatigue in affected muscles.
MG may be associated with other autoimmune diseases. Patients with family members who suffer from disorders such as rheumatoid arthritis, scleroderma, and lupus may have an increased risk for myasthenia gravis.
The thymus is an organ that produces cells involved in immune responses. It is located below the larynx and above the heart. Approximately 15% of MG patients have a tumor of the thymus (thymoma) and 60-80% have abnormal enlargement (hyperplasia) of the thymus.
Signs and Symptoms
Initial symptoms of MG may include difficulty speaking (dysarthria), difficulty swallowing (dysphagia), drooping eyelids (ptosis), and double vision (diplopia). Patients often have nasal-sounding speech and weak neck muscles that give the head a tendency to fall forward or backward. These symptoms occur in about 90% of MG cases, are usually intermittent (i.e., come and go), and may disappear for weeks and then recur.
Generalized weakness often develops in the trunk, arms, and legs within a year of onset. Arm muscles usually are affected most severely. Muscle weakness tends to worsen as the day progresses, especially after prolonged activity.
Pregnancy can improve, worsen, or have little effect on MG symptoms. Frequently, symptoms first occur during pregnancy or after delivery.
Complications
Myasthenic crisis is a medical emergency that develops when muscles that control breathing become severely weakened. This condition may lead to acute respiratory failure and patients often require a respirator to assist breathing during the crisis. Other complications that may develop include choking, food aspiration, and pneumonia.
Factors that can trigger complications in patients with myasthenia gravis include illness (e.g., viral respiratory infection), surgery, corticosteroid use that is tapered too quickly, overexertion (especially in hot weather), pregnancy, and emotional stress.
Diagnosis
Diagnosis of myasthenia gravis includes the following:
- Blood tests
- Clinical and neurological examination
- Imaging tests (e.g., x-ray, CT scan)
- Intravenous anticholinesterase or Tensilon test
- Medical history
- Neurological tests (e.g., electromyography)
Blood tests are performed to determine serum levels of certain antibodies (e.g., AChR-binding antibodies, AChR-modulating antibodies, antistriational antibodies). High levels of these antibodies may indicate MG.
Neurological examination involves testing muscles and reflexes. MG may cause abnormal eye movements, inability to move the eyes normally, and drooping eyelids. To test arm and leg muscles, the patient may be instructed to maintain a position against resistance for a period of time. Weakness that occurs during this test is called fatigability.
Chest x-ray and computed tomography (CT scan) may be performed to detect enlarged thymus (thymoma), which is common in MG.
The Tensilon test is often used to diagnose MG. The enzyme acetylcholinesterase breaks down acetylcholine (ACh) after the muscle is stimulated, preventing prolonged muscle response to a single nerve impulse. Edrophonium chloride (Tensilon) is a drug that temporarily blocks the action of acetylcholinesterase.
In MG, there are few acetylcholine receptor sites (AChR) on the muscle and acetylcholine is broken down before it can fully stimulate the muscle, resulting in muscle weakness. By blocking the action of acetylcholinesterase, Tensilon prolongs muscle stimulation and temporarily improves strength.
In this test, Tensilon is administered intravenously (into a vein) and muscle response is evaluated. In cases of MG, muscle weakness improves within 1 minute. The Tensilon test is most effective when easily observed weakness is present, and is less useful for vague or fluctuating complaints. Side effects of the test include temporary abnormal heart rhythms such as rapid heart rate (atrial fibrillation) and slow heart rate (bradycardia).
Electromyography (EMG) uses electrodes to stimulate muscles and evaluate muscle function. Muscle contractions that become progressively weaker may indicate MG.
Differential Diagnosis
Disorders that may cause symptoms similar to MG include botulism and Lambert Eaton syndrome. Botulism results from Clostridium botulinum infection, which can also block AChR and cause muscle weakness.
Lambert Eaton syndrome is associated with certain types of lung cancer. This condition produces EMG results that are different than those produced by MG.
Medications can block the neuromuscular junction and cause symptoms similar to MG. These drugs include the following:
- Antibiotics (e.g., ciprofloxacin, erythromycin, ampicillin)
- Antispasmodic drugs (e.g., trihexyphenidyl; used to treat movement disorders)
- Beta-adrenergic receptor blocking agents (e.g., propranolol, timolol)
- Cardiac drugs (e.g., procainamide, verapamil, quinidine)
- Lithium (used to treat bipolar disorder)
- Penicillamine (penicillin product; used to treat metal poisoning)
Treatment
Myasthenia gravis is one of the most treatable neuromuscular disorders. The choice of treatment depends on several factors, including age, overall health, and severity of disease.
Medications
Anticholinesterase medications such as neostigmine (Prostigmin®) and pyridostigmine (Mestinon®) are usually prescribed. These drugs prevent ACh destruction and increase the accumulation of ACh at neuromuscular junctions, improving the ability of the muscles to contract.
Side effects include excessive salivation, involuntary muscle twitching (fasciculation), abdominal pain, nausea, and diarrhea. A drug called kaolin may be used with anticholinesterase medications to reduce gastrointestinal side effects.
Corticosteroids (e.g., prednisone) suppress the antibodies that block AChR at the neuromuscular junction and may be used in conjunction with anticholinesterase. Corticosteroids improve symptoms within a few weeks and once improvement stabilizes, the dose is slowly decreased.
A low dosage may be used indefinitely to treat MG; however, side effects such as gastric ulcers, osteoporosis (bone thinning), weight gain, high blood sugar (hyperglycemia), and increased risk for infection may develop over the long term.
Immunosuppressants such as azathioprine (Imuran®) and cyclophosphamide (Cytoxan®) are used to treat generalized MG when other medications fail to reduce symptoms. Side effects may be severe and include low white blood cell count (leukopenia), liver dysfunction, nausea, vomiting, and hair loss.
Immunosuppressants are not used to treat congenital MG because this condition is not the result of an immune system malfunction.
Other Treatments
Plasmapheresis, or plasma exchange, is used to modify the immune system malfunction. It can be used to treat severe worsening of symptoms (exacerbations) or in preparation for surgery (thymectomy).
In this procedure, blood is removed from the body and blood cells are separated from the liquid portion of the blood (plasma). Then, AChR antibodies are removed and blood cells are diluted with artificial plasma (usually a solution of saline and sterilized human albumin protein) and infused back into the body.
Typically, 2 to 3 liters of plasma is removed and replaced during a single treatment, which takes several hours. Most patients undergo several sessions over the course of 2 weeks or more. Plasmapheresis improves MG symptoms within days and improvement lasts 6-8 weeks.
Risks include low blood pressure, dizziness, blurred vision, and formation of blood clots (thrombosis).
Thymectomy is surgical removal of the thymus gland. It is usually performed on patients with a tumor of the thymus (thymoma) and patients younger than age 55 with generalized MG. Benefits of thymectomy develop gradually and most improvement occurs years after the procedure is performed.
Prognosis
Symptoms of myasthenia gravis usually progress to maximum severity within 3 years. After 3 years, patients usually stabilize or improve. Infants with transient neonatal MG may develop acute respiratory failure within a few weeks after birth.
Advances in medical care have reduced the mortality rate from respiratory failure in MG patients to approximately 3%. Patients over the age of 40, those with a short history of severe disease, and those with thymoma have a worse prognosis.
Prevention
Myasthenia gravis cannot be prevented, but avoiding the following triggers may help patients prevent exacerbations:
- Emotional stress
- Exposure to extreme temperatures
- Fever
- Illness (e.g., respiratory infection, pneumonia, tooth abscess)
- Low levels of potassium in the blood (hypokalemia; caused by diuretics, frequent vomiting)
- Medications (e.g., muscle relaxants, anticonvulsants, certain antibiotics)
- Overexertion