NORD gratefully acknowledges Henry J. Kaminski, MD, Professor of Neurology, Chairman, Department of Neurology, George Washington University, for assistance in the preparation of this report.
Symptoms may be variable, with disease involvement potentially localized to certain muscles or affecting multiple muscle groups. In some affected individuals, the disease process may be limited to certain eye muscles, which is often described as “ocular myasthenia gravis.” In those with more generalized disease or “generalized myasthenia gravis,” affected muscles may include those of the eyes, face, jaw, and throat region; arm and leg (limb) muscles; and muscles involved in breathing (respiratory muscles).
The disorder is often begins with weakness of muscles controlling the eyes, resulting in drooping of the upper eyelids (ptosis), double vision (diplopia), or both. Individuals may also develop weakness of muscles of the face, jaw, and throat. In such cases, associated symptoms may include difficulties speaking (dysarthria), causing the voice to sound weak, hoarse, or “nasally,” and increasing chewing and swallowing difficulties (dysphagia) during the course of meals, leading to choking, coughing, or inhalation (aspiration) of food or liquids. Some individuals may also develop limb weakness and easy fatigability of arm and leg muscles. In approximately 10 percent of patients, myasthenic crisis or sudden severe weakness of the jaw and throat (oropharyngeal) or respiratory muscles occurs, requiring respiratory assistance. Sudden worsening of weakness may be triggered by infections, severe stress, surgery, or a reduction or sudden increase of prednisone. Patients with antibodies to MuSK may develop muscle atrophy, in particular of facial and tongue muscles.
The course of the myasthenia gravis is highly variable. For example, the degree of muscle weakness may vary over hours, from day to day, or over weeks and months, tending to increase with repeated muscle use and to improve with rest. In addition, particularly during the first years after disease onset, some affected individuals may experience alternating periods in which symptoms temporarily subside or worsen (remissions and exacerbations). A short-term aggravation of symptoms may be triggered by a variety of factors, including infection, excessive physical activity, menstruation, and after delivery of a child.
Infants of mothers who have myasthenia gravis may develop a temporary (transient) form of the disorder beginning within approximately 48 hours after birth. Known as transient neonatal myasthenia gravis, the condition may be characterized by generalized muscle weakness and low muscle tone (hypotonia); impaired sucking or swallowing; a weak cry; respiratory insufficiency; and/or little spontaneous movement. Such abnormalities may be present for days to weeks, after which affected infants have normal muscle strength.
Congenital myasthenia is caused by genetic defects of muscle and nerve communication (neuromuscular transmission), and not an abnormal immune system. Congenital myasthenia usually occurs in infants but may become evident in adulthood. Other features may vary in severity among patients. Such abnormalities may include feeding difficulties, sudden episodes of reduced breathing (apnea), failure to grow and gain weight at an expected rate, muscle weakness and fatigue, weakness or paralysis of eye muscles (ophthalmoplegia), and other abnormalities.
Most individuals with myasthenia gravis (MG) have no family history of MG and the disorder appears to occur spontaneously (sporadically) for unknown reasons. However, 3-5 percent of patients may have family members with MG or other autoimmune disorders. Individuals with MG have an increased frequency of certain genetically determined “human leukocyte antigens” (HLAs), suggesting that genetic predisposition may play some role. (HLAs are proteins that play an important role in the body’s immune system; they influence the outcome of transplantation and appear to affect an individual’s predisposition to certain diseases.) Other autoimmune diseases also appear to occur with increased frequency in individuals with MG, including thyroid disorders and systemic lupus erythematosus. These observations suggest that there is some genetic predisposition to MG which requires a trigger from the environment to cause the disease.
Myasthenia gravis is caused by an abnormal immune reaction (antibody-mediated autoimmune response) in which the body’s immune defenses (i.e., antibodies) inappropriately attack certain receptors in muscles that receive nerve impulses. The areas of contact between nerve endings and skeletal muscle fibers are known as neuromuscular junctions. Nerve endings release a chemical (the neurotransmitter acetylcholine) that transmits impulses to muscle fibers, ultimately resulting in their contraction. However, in individuals with myasthenia gravis, antibodies are inappropriately directed against sites (receptors) on the surface of certain muscle cells that bind with the neurotransmitter acetylcholine (acetylcholine receptors). (These antibodies are known as “anti-acetylcholine receptor antibodies [anti-AChR].) The abnormal autoimmune response results in a decreased number of acetylcholine receptors, causing failed nerve transmission at certain neuromuscular junctions and associated deficiency or weakness of muscle contractions. Another antibody was identified that attacks the muscle specific kinase protein (MuSK). These anti-MuSK antibodies also lead to a decrease in the number of acetylcholine receptors. Recently, antibodies to LRP-4 (lipoprotein receptor protein 4) were identified in patients without antibodies to MuSK or AChR. Whether these antibodies cause disease has not been absolutely confirmed. In five to eight percent of patients an antibody in the blood cannot be identified but patients have other tests consistent with myasthenia gravis.
The specific cause of abnormal autoimmune responses in patients with myasthenia gravis is unknown. However, researchers suggest that the thymus has some role in this process. According to reports in the medical literature, up to approximately 75 percent of individuals with myasthenia gravis have distinctive abnormalities of the thymus. In most cases, there are increased numbers of cells in the thymus (hyperplasia). In addition, in about 10 percent of affected individuals, the thymus contains tumors (thymomas) that are typically noncancerous (benign). However, the tumors may be malignant. Researchers suggest that the thymus of MG patients does not appropriately eliminate cells that produce antibodies that attack body tissues. In the case of MG antibodies are produced that react against acetylcholine receptors, triggering the abnormal autoimmune response within the thymus. (A lymphoid tissue organ located behind the breastbone, the thymus plays an important role in the immune system beginning during early fetal development until puberty. It is important in the maturation of certain specialized white blood cells [T lymphocytes] that have several functions, including assisting in the recognition of certain foreign proteins [antigens] or binding to cells invaded by microorganisms and destroying them.) The abnormalities that lead to production of anti-MuSK antibodies is poorly understood and appears not to involve the thymus.
Some infants born to mothers with myasthenia gravis may develop temporary muscle weakness and associated findings (i.e., transient neonatal myasthenia gravis). This condition results from the passage of anti-acetylcholine receptor antibodies through the placenta to the unborn child during pregnancy.
Congenital myasthenia is an inherited as an autosomal recessive, or more rarely, an autosomal dominant condition. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
Congenital myasthenia is not an autoimmune disease and therefore anti-acetylcholine receptor or anti-MuSK antibodies are not present. This group of disorders may result from various changes (mutations) in genes involved in nerve-muscle communication, with some involving abnormalities of the acetylcholine receptor.
Autoimmune myasthenia gravis has a prevalence of approximately 14-40 per 100,000 individuals in the United States. Reports indicate that the frequency of the disorder has appeared to increase over the last several decades. This may be because of better identification of patients, but also autoimmune disorders in general are increasing in frequency across the world.
Autoimmune myasthenia gravis more frequently affects females than males. Associated symptoms may become apparent at any age; however, symptom onset most commonly peaks in women during their 20s or 30s and in men in their 50s or 60s.
Myasthenia gravis is diagnosed based upon a thorough clinical evaluation, detection of characteristic symptoms and physical findings, a detailed patient history, and a variety of specialized tests. The diagnosis is suspected based on a characteristic distribution of muscle weakness and fatigue, without impairment other of neurologic function. Diagnostic studies include the intravenous injection of a drug that rapidly inhibits the action of an enzyme involved in breaking down acetylcholine, allowing the neurotransmitter to repeatedly interact with available acetylcholine receptors (edrophonium or Tensilon test). In those with the disorder, anticholinesterase testing of weak muscle groups temporarily restores muscle strength. The drugs edrophonium or neostigmine may be used during such testing. The Ice Pack Test involves placing a cold pack across the eyes for 10 minutes and then determining if eye lid droop has significantly improved. The Rest Test involves a patient closing their eyelids for 30 minutes and again assessment for improved lid position or eye movement is made. For all these tests there can be “false negatives” in which a patient with disease does not show improvement with the testing.
Specialized blood studies are also conducted to detect the presence of antibodies to the acetylcholine receptor or muscle specific kinase. Acetylcholine receptor antibodies may be detected in up to 90 percent of affected individuals with generalized disease and up to 50 percent of those with the ocular form. Muscle specific kinase antibodies are found in about 3-6 percent of patients.
Additional diagnostic studies may include electromyography (EMG), a test that records electrical activity in skeletal muscles. A specialized test usually performed only at academic medical centers called a single fiber exam is highly sensitive for detecting the abnormalities of MG. In addition, advanced imaging techniques may be conducted to help detect tumors of the thymus. Such studies may include computed tomography (CT) scanning or magnetic resonance imaging (MRI) of the mediastinum, which is the space between the lungs that contains the thymus and several other bodily structures. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of internal structures. During MRI, a magnetic field and radio waves create detailed cross-sectional images of certain organs and tissues.
Decisions about specific treatment are based on specifics of each patient’s case. Recommended treatments for myasthenia gravis may include various measures that may alleviate symptoms, including anticholinesterase drugs (cholinesterase inhibitors) or alter the disease course, such as immunosuppressive drugs or surgery (thymectomy).
Initial treatment commonly includes the use of cholinesterase inhibitors, which increase muscle strength by preventing the normal breakdown of the neurotransmitter acetylcholine. Pyridostigmine by mouth (orally) is primarily used.
For infants with transient neonatal myasthenia gravis, therapy with cholinesterase inhibitors may be required for only a few days or weeks. In addition, in some cases, physicians may recommend therapy with cholinesterase inhibitors for infants with certain forms of congenital myasthenia.
In many individuals with autoimmune MG, therapy with medications that reduce activity of the immune system (immunosuppressive therapy) also results in improvement. Such agents, which may be combined with cholinesterase inhibitors, may include corticosteroids (e.g., prednisone) or certain other immunosuppressive drugs, particularly azathioprine, mycophenolate mofetil, tacrolimus, and cyclosporine. Generally, corticosteroids result in rapid improvement in the first 2 months of therapy while the other immunosuppressive drugs requiring many months to over a year to be effective. Patients receiving long-term therapy with such medications require ongoing monitoring to help prevent or appropriately treat adverse side effects.
In those with autoimmune myasthenia gravis associated with thymoma, recommended treatment is surgical removal of the tumor and the remaining thymus (thymectomy). In addition, thymectomy is recommended for younger individuals with generalized myasthenia gravis and acetylcholine receptor antibodies. Evidence indicates that, in those without thymoma, thymectomy reduces symptoms and need for prednisone in many patients. In addition, about 30 to 35 percent may eventually experience a complete cessation of symptoms without the use of medication (drug-free remission). Generally, observations suggest that such improvement occurs over a long period, with beneficial effects delayed for years.
Based on a randomized clinical trial of thymectomy plus prednisone plus prednisone alone, it is generally recommended that thymectomy should be considered for individuals with generalized disease between the ages of eighteen to 65 and have acetylcholine receptor antibodies. Decisions must be individualized for those who have localized involvement of eye muscles, are older than 65 years, or are children (i.e., with autoimmune myasthenia gravis). Thymectomy usually is not recommended for those with ocular myasthenia gravis unless thymoma is detected. Many physicians may recommend that thymectomy should be considered in appropriate cases for affected children with autoimmune myasthenia gravis. However, it is important to note that thymectomy is not effective in cases of Familial or congenital myasthenia gravis (which does not involve autoimmune abnormalities).
Myasthenic crisis is a medical emergency that requires management in an intensive care unit. Treatment may include emergency respiratory assistance (assisted ventilation); temporary cessation of anticholinesterase therapy to exclude excessive dosage as a possible cause; immediate treatment of possible causative infection with appropriate antibiotic medication or other therapy including plasmapheresis; intravenous immunoglobulin, high dose prednisone, and possibly other therapies.
Plasmapheresis may alleviate symptoms in individuals with autoimmune myasthenia gravis. During this procedure, which is also known as plasma exchange, damaging antibodies may be filtered from the blood. By providing a short-term reduction in the levels of anti-ACh receptor antibodies, plasmapheresis may be effective as a temporary therapy in those with severe symptoms or to help treat myasthenic crisis. In addition, plasmapheresis may be recommended to help improve an affected individual’s condition before undergoing surgical removal of the thymus.
Infusion of antibodies (immunoglobulins) obtained from thousands of blood donors and by purification of the fluid portion of the blood (intravenous immunoglobulin IVIG) may also be provided as a temporary therapy before surgical removal of the thymus or for those who experience periods of severe muscle weakness.
Individuals with myasthenia gravis may have increased sensitivity to the use of certain medications, such as particular anesthetics or muscle relaxants (e.g., succinylcholine, pancuronium). Therefore, this risk must be taken into consideration by surgeons, anesthesiologists, dentists, or other health care workers when making decisions concerning potential surgery and use of anesthetics. Other medications, such as particular antibiotics or antiarrhythmic agents, may also aggravate symptoms in individuals with myasthenia gravis and therefore should be avoided or used with caution. . Exacerbation of weakness may occur with various antibiotics, including aminoglycosides, macrolides, and some fluoroquinolones. Patients needing antibiotics should discuss this with their physicians. A complete list of medications to use with caution may be found at myasthenia.org
Physical therapy may also be recommended to help patients maintain muscle strength and range of motion, but must be performed in a manner to limit any over-exertion Additional treatment for the different forms of myasthenia gravis is symptomatic and supportive.
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