Myasthenia Gravis

There are two main types of myasthenia gravis (MG); generalized and ocular, with multiple subtypes of each. Ocular MG affects the eye and eyelid muscles, causing double vision, drooping eyelids and difficulty focusing. Generalized MG is a chronic autoimmune, neuromuscular disease that causes weakness in the skeletal muscles that connect to your bones and contract to allow body movement in the arms and legs, and allow for breathing.

All neuromuscular disorders are caused by a range of deficiencies and disorders, including:

• Genetic mutation
• Viral infection
• Autoimmune disorder
• Hormonal disorder
• Metabolic disorder
• Dietary deficiency
• Certain drugs and poisons

Myasthenia gravis (MG) is caused by an error in how nerve signals are transmitted to muscles. It occurs when communication between the nerve and muscle is interrupted at the neuromuscular junction—the place where nerve cells connect with the muscles they control.

Neurotransmitters are chemicals that neurons, or brain cells, use to communicate information. When electrical signals or impulses travel down a motor nerve, the nerve endings release a neurotransmitter called acetylcholine that binds to sites called acetylcholine receptors on the muscle. The binding of acetylcholine to its receptor activates the muscle and causes a muscle contraction.

In MG, antibodies (immune proteins produced by the body’s immune system) block, alter or destroy the receptors for acetylcholine at the neuromuscular junction, which prevents the muscle from contracting. This is most often caused by antibodies to the acetylcholine receptor itself, but antibodies to other proteins, such as MuSK (Muscle-Specific Kinase) protein, can also impair transmission at the neuromuscular junction. The thymus gland controls immune function and may be associated with myasthenia gravis. It grows gradually until puberty and then gets smaller until it is replaced by fat. Throughout childhood, the thymus plays an important role in the development of the immune system because it is responsible for producing T-lymphocytes or T-cells, a specific type of white blood cell that protects the body from viruses and infections.

In many adults with MG, the thymus gland remains large. People with the disease typically have clusters of immune cells in their thymus gland and may develop thymomas (tumors of the thymus gland). Thymomas are most often harmless, but they can become cancerous. Scientists believe the thymus gland may give incorrect instructions to developing immune cells, ultimately causing the immune system to attack its own cells and tissues and produce acetylcholine receptor antibodies—setting the stage for the attack on neuromuscular transmission.

A myasthenic crisis is a medical emergency that occurs when the muscles that control breathing weaken to the point where a ventilator is required to breathe. It may be triggered by infection, stress, surgery or an adverse reaction to medication. Approximately 15 to 20 percent of people with myasthenia gravis experience at least one myasthenic crisis, and up to 50 percent may have no obvious cause for their myasthenic crisis. Certain medications have been shown to cause myasthenia gravis; however, these medications may still be used if it is more important to treat an underlying condition.

Many neuromuscular disorders are inherited, passed from generation to generation through genetic code, though sometimes they are a result of spontaneous gene mutation. There are links to NDs and immune system disorders, but each condition has its unique causes.

Myasthenia gravis, similar to other autoimmune disorders, occurs in genetically susceptible individuals. Precipitating factors include conditions like infections, immunization, surgeries and drugs.

Myasthenia gravis affects both males and females and occurs across all racial and ethnic groups. It most commonly impacts young adult females (under 40) and older males (over 60), but it can occur at any age, including childhood. Myasthenia gravis is not inherited, nor is it contagious. Occasionally, the disease may occur in more than one member of the same family.

Although myasthenia gravis is rarely seen in infants, the fetus may acquire antibodies from a female parent—a condition called neonatal myasthenia. Neonatal myasthenia gravis is generally temporary, and the child’s symptoms usually disappear within two to three months after birth. Rarely, children of a healthy female parent may develop congenital myasthenia. This is not an autoimmune disorder but is caused by defective genes that produce abnormal proteins in the connection between the end of a nerve that carries signals from brain to a muscle (the neuromuscular junction) and can cause similar symptoms to myasthenia gravis.

Muscle response and neuronal-electrical activity can be tested using electromyography (EMG). These diagnostic tools stimulate muscles and help neurologists detect abnormalities in responses.

A doctor may perform or order several tests to confirm a diagnosis of myasthenia gravis (MG):

• Physical and neurological examination: A doctor will review your medical history and conduct a physical examination. In a neurological examination, the physician will check:
  • Muscle strength and tone
  • Coordination
  • Sense of touch
  • Any impairment of eye movements
• Edrophonium test: This test is used to test eye muscle weakness and uses injections of edrophonium chloride to briefly relieve weakness. The drug blocks the breakdown of acetylcholine and temporarily increases the levels of acetylcholine at the neuromuscular junction.
• Blood test: People living with myasthenia gravis may have abnormally elevated levels of acetylcholine receptor antibodies. A second antibody called the anti-MuSK antibody has been found in about half of individuals with myasthenia gravis who do not have acetylcholine receptor antibodies. A blood test can also detect this antibody. However, in some individuals with myasthenia gravis, neither of these antibodies is present; this is called seronegative (negative antibody) myasthenia.
• Electrodiagnostics: Diagnostic tests include repetitive nerve stimulation, which repeatedly stimulates your nerves with small pulses of electricity to tire specific muscles. Muscle fibers in myasthenia gravis, as well as other neuromuscular disorders, do not respond as well to repeated electrical stimulation. Single-fiber electromyography (EMG), which is considered the most sensitive test for myasthenia gravis, detects impaired nerve-to-muscle transmission. EMG can be very helpful in diagnosing mild cases of myasthenia gravis when other tests fail to demonstrate abnormalities. 
• Diagnostic imaging: Diagnostic imaging of your chest using computed tomography (CT) or magnetic resonance imaging (MRI) may identify the presence of a thymoma.
• Pulmonary function testing: Measuring breathing strength can help predict if respiration may fail and lead to a myasthenic crisis.

Because weakness is a common symptom of many other disorders, the diagnosis of myasthenia gravis is often missed or delayed (sometimes up to two years) in people who have either mild weakness or in those individuals whose weakness is restricted to only a few muscles.

Doctors review an individual’s medical history and a complete family history to determine if the muscle disease is secondary to a disease affecting other tissues or organs or is an inherited condition. It is also important to rule out any muscle weakness resulting from prior surgery, exposure to toxins, or current medications that may affect the person’s functional status. Thorough clinical and neurological exams can help doctors do the following:

• Rule out disorders of the central and/or peripheral nervous systems
• Identify any patterns of muscle weakness and atrophy
• Test reflex responses and coordination
• Look for contractions

Symptoms of neuromuscular disorders include muscular weakness, wastage, cramps, spasticity (stiffness), which later causes joint or skeletal deformities, and muscle pain. Additional symptoms include breathing and swallowing difficulties.

The following symptoms are commonly associated with myasthenia gravis (MG):

• Weakness of the eye muscles (ocular myasthenia)
• Drooping of one or both eyelids (ptosis)
• Blurred or double vision (diplopia)
• Changes in facial expressions
• Difficulty swallowing
• Shortness of breath
• Impaired speech (dysarthria)

Neuromuscular disorders are determined through various tests that measure a body’s nerves ability to conduct electricity. Electromyography (EMG) tests can determine the health of a muscle. Additionally, doctors may use muscle biopsies, genetic testing and blood tests.

In diagnosing myasthenia gravis (MG), a doctor may perform or order several tests to confirm a diagnosis:

• Physical and neurological examination: A doctor will review your medical history and conduct a physical examination. In a neurological examination, the physician will check:
  • Muscle strength and tone
  • Coordination
  • Sense of touch
  • Any impairment of eye movements
• Edrophonium test: This test is used to test eye muscle weakness and uses injections of edrophonium chloride to briefly relieve weakness. The drug blocks the breakdown of acetylcholine and temporarily increases the levels of acetylcholine at the neuromuscular junction.
• Blood test: People living with myasthenia gravis may have abnormally elevated levels of acetylcholine receptor antibodies. A second antibody called the anti-MuSK antibody has been found in about half of individuals with myasthenia gravis who do not have acetylcholine receptor antibodies. A blood test can also detect this antibody. However, in some individuals with myasthenia gravis, neither of these antibodies is present; this is called seronegative (negative antibody) myasthenia.
• Electrodiagnostics: Diagnostic tests include repetitive nerve stimulation, which repeatedly stimulates your nerves with small pulses of electricity to tire specific muscles. Muscle fibers in myasthenia gravis, as well as other neuromuscular disorders, do not respond as well to repeated electrical stimulation. Single-fiber electromyography (EMG), which is considered the most sensitive test for myasthenia gravis, detects impaired nerve-to-muscle transmission. EMG can be very helpful in diagnosing mild cases of myasthenia gravis when other tests fail to demonstrate abnormalities. 
• Diagnostic imaging: Diagnostic imaging of your chest using computed tomography (CT) or magnetic resonance imaging (MRI) may identify the presence of a thymoma.
• Pulmonary function testing: Measuring breathing strength can help predict if respiration may fail and lead to a myasthenic crisis.

Because weakness is a common symptom of many other disorders, the diagnosis of myasthenia gravis is often missed or delayed (sometimes up to two years) in people who have either mild weakness or in those individuals whose weakness is restricted to only a few muscles.

Doctors review an individual’s medical history and a complete family history to determine if the muscle disease is secondary to a disease affecting other tissues or organs or is an inherited condition. It is also important to rule out any muscle weakness resulting from prior surgery, exposure to toxins, or current medications that may affect the person’s functional status. Thorough clinical and neurological exams can help doctors do the following:

• Rule out disorders of the central and/or peripheral nervous systems
• Identify any patterns of muscle weakness and atrophy
• Test reflex responses and coordination
• Look for contractions

Medical therapy, immunosuppressive drugs, assistive devices and pain management are all common treatment methods for neuromuscular disorders. Filtering out antibodies that are associated with the disease from the blood is an alternative treatment called apheresis.

Currently, there is no known cure for myasthenia gravis (MG). Available treatments can control symptoms and often allow you to have a relatively high quality of life. Most people with MG have an average life expectancy.

There are several therapies available to help reduce and improve muscle weakness:

• Thymectomy: An operation to remove the problematic thymus gland can reduce symptoms, possibly by rebalancing the immune system. A NINDS-funded study of 126 people with myasthenia gravis with thymoma and those with no visible thymoma found the surgery reduced muscle weakness and the need for immunosuppressive drugs. Stable, long-lasting complete remissions are the goal of thymectomy and may occur in about 50 percent of individuals who undergo this procedure.
• Monoclonal antibody: A treatment that targets the process by which acetylcholine antibodies injure the neuromuscular junction. The U.S. Food and Drug Administration (FDA) has approved the use of the medication eculizumab for the treatment of generalized myasthenia gravis in adults who test positive for the antiacetylcholine receptor (AchR) antibody.
• Anticholinesterase medications: Medications to treat myasthenia gravis include anticholinesterase agents such as mestinon or pyridostigmine, which slow the breakdown of acetylcholine at the neuromuscular junction and improve neuromuscular transmission and increase muscle strength.
• Immunosuppressive drugs: Group of drugs that improve muscle strength by suppressing the production of abnormal antibodies, such as prednisone, azathioprine, mycophenolate mofetil and tacrolimus. The drugs can cause significant side effects and must be carefully monitored by a physician.
• Plasmapheresis and intravenous immunoglobulin: Therapies that are used in severe cases of myasthenia gravis to remove destructive antibodies that attack the neuromuscular junction, although their effectiveness usually only lasts a few weeks or months.
  • Plasmapheresis is a procedure using a machine to remove harmful antibodies in plasma and replace them with good plasma or a plasma substitute.
  • Intravenous immunoglobulin is a highly concentrated injection of antibodies pooled from many healthy donors that temporarily changes the way the immune system operates. It works by binding to the antibodies that cause myasthenia gravis and removing them from circulation.

Some cases of myasthenia gravis may go into remission, either temporarily or permanently, and muscle weakness may disappear completely so that medications can be discontinued.

While many neuromuscular disorders have no cure and are progressive, treatments can increase mobility, diminish symptoms and lengthen life. Patients can reduce pain, increase muscle control and reduce muscle degeneration by exercising regularly.

Some people with myasthenia gravis (MG) do not respond well to available treatment options, which usually include long-term suppression of the immune system. New drugs are being tested, either alone or in combination with existing drug therapies, to see if they are more effective in targeting the causes of the disease.

NINDS-funded researchers are exploring the assembly and function of connections between nerves and muscle fibers to understand the fundamental processes in neuromuscular development, which could reveal new therapies for neuromuscular diseases like MG. Researchers are also exploring better ways to treat MG by developing new tools to diagnose people with undetectable antibodies and identify potential biomarkers (signs that can help diagnose or measure the progression of a disease) to predict an individual’s response to immunosuppressive drugs.

Findings from a NINDS-supported study yielded conclusive evidence about the benefits of surgery for individuals without thymoma, a subject that was debated for decades. Other studies will continue to examine different therapies to see if they are superior to standard care options. Additionally, assistive technologies, such as magnetic devices, may also help people with MG to control some symptoms of the disorder.