Myasthenia Gravis

Myasthenia Gravis

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Myasthenia Gravis is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • MG

Disorder Subdivisions

  • congenital myasthenia
  • familial infantile (congenital) myasthenia gravis
  • generalized myasthenia gravis
  • ocular myasthenia gravis
  • transient neonatal myasthenia gravis

General Discussion

Myasthenia gravis is a neuromuscular disorder primarily characterized by muscle weakness and muscle fatigue. Although the disorder usually becomes apparent during adulthood, symptom onset may occur at any age. The condition may be restricted to certain muscle groups, particularly those of the eyes (ocular myasthenia gravis), or may become more generalized (generalized myasthenia gravis), involving multiple muscle groups.



Most individuals with myasthenia gravis develop weakness and drooping of the eyelids (ptosis); weakness of eye muscles, resulting in double vision (diplopia); and excessive muscle fatigue following activity. Additional features commonly include weakness of facial muscles; impaired articulation of speech (dysarthria); difficulties chewing and swallowing (dysphagia); and weakness of the upper arms and legs (proximal limb weakness). In addition, in about 10 percent of cases, affected individuals may develop potentially life-threatening complications due to severe involvement of muscles used during breathing (myasthenic crisis).



Myasthenia gravis results from an abnormal immune reaction in which the body's natural immune defenses (i.e., antibodies) inappropriately attack and gradually destroy certain receptors in muscles that receive nerve impulses (antibody-mediated autoimmune response).

Symptoms

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 initially characterized by weakness of muscles controlling the eyes, resulting in drooping of the upper eyelids (ptosis) and double vision (diplopia). Affected 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 unusually 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 weakness and easy fatigability of arm and leg muscles. In approximately 10 percent of cases, affected individuals may develop myasthenic crisis or sudden severe weakness of the jaw and throat (oropharyngeal) or respiratory muscles, requiring respiratory assistance. It may appear to be triggered by respiratory infection, stress, surgery, or a change in medication.



In individuals with myasthenia gravis, the course of the disorder may be variable. For example, the degree of muscle weakness may vary over hours, from day to day, or over longer periods, tending to increase with repeated muscle use and to improve with sleep or 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, emotional upset, menstruation, and/or pregnancy.



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 also exists and is not caused by an abnormal immune system, but rather genetic defects of muscle and nerve communication (neuromuscular transmission). This condition usually occurs in infants but may become evident in adulthood. Associated features may vary in severity from case to case. Such abnormalities may include feeding difficulties, sudden episodes in which there is absence of spontaneous breathing (apnea), failure to grow and gain weight at the expected rate, muscle weakness and fatigue, weakness or paralysis of eye muscles (ophthalmoplegia), and/or other abnormalities.

Causes

In most individuals with myasthenia gravis (MG), there is 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 an unknown trigger from the environment to cause the disease.



In most instances, myasthenia gravis is thought to be 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 certain 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. 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 those with myasthenia gravis remains 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 certain "muscle-like" (myoid) cells in the thymus may stimulate the production of antibodies that improperly 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.)



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 gravis can be 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.



All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.



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 MG 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.

Affected Populations

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.



Autoimmune myasthenia gravis more frequently affects females than males. Associated symptoms may become apparent at any age; however, reports indicate that symptom onset most commonly peaks in women during their 20s or 30s and in men who are in their 50s or 60s.

Standard Therapies

Diagnosis

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.



Specialized blood studies are also conducted to detect the presence of antibodies to the acetylcholine receptor or muscle specific kinase. Such 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.



Additional diagnostic studies may include electromyography (EMG), a test that records electrical activity in skeletal muscles. 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.



Treatment

Some individuals with mild myasthenia gravis rarely do not require treatment. Decisions concerning whether treatment is necessary and what measures should be used will be made based upon the specifics of each patient's case. Recommended treatments for myasthenia gravis may include various measures that may alleviate symptoms, including anticholinesterase drugs (cholinesterase inhibitors), and/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. Such medications include neostigmine or pyridostigmine by mouth (orally).



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 gravis.



In many individuals with autoimmune myasthenia gravis, 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 more rapid improvement than other immunosuppressive agents. 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 typically includes surgical removal of the thymus (thymectomy). In addition, thymectomy is recommended for most younger individuals with generalized myasthenia gravis. Evidence indicates that, in those without thymoma, thymectomy alleviates symptoms in many patients. Physicians are continuing to study which patients are best treated by thymectomy. 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 months to years.



Experts indicate that randomized controlled clinical trials are necessary to objectively evaluate the long-term effectiveness of thymectomy in those with myasthenia gravis. However, based upon available evidence, it is generally recommended that thymectomy should be considered for most individuals with generalized disease between the ages of puberty to middle age (up to at least age 55). Decisions must be individualized for those who have localized involvement of eye muscles, are older than 55 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 should be treated as 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; plasmapheresis; intravenous immunoglobulin and/or other appropriate therapies



Plasmapheresis may also 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 the fluid portion of the blood (intravenous immunoglobulin IVIG) may also be provided as a temporary therapy for some affected individuals 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. Certain 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.



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.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.



For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:



Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov



For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com

References

TEXTBOOKS

Christadoss P. Myasthenia Gravis: Disease Mechanisms and Immune Intervention. Deer Park, NY: Linus Publications; 2010.



Kaminski HJ, Myasthenia Gravis and Related Disorders, Totowa, NJ: 2nd Edition, Humana Press; 2009.



Behrman RE, et al., eds. Nelson Textbook of Pediatrics. 16th ed. Philadelphia, Pa: W.B. Saunders Company; 2000:1885-87.



Beers MH, et al., eds. The Merck Manual. 17th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1999:1497-99.



Fauci AS, et al., eds. Harrison's Principles of Internal Medicine, 14th Ed. New York, NY: McGraw-Hill, Inc; 1998:2469-72.



Adams, RD, et al., eds. Principles of Neurology. 6th ed. New York, NY: McGraw-Hill, Companies; 1997:1459-71.



Bennett JC, Plum F, eds. Cecil Textbook of Medicine. 20th ed. Philadelphia, Pa: W.B. Saunders Company; 1996:2171-73.



JOURNAL ARTICLES

Gronseth GS, et al. Practice parameter: thymectomy for autoimmune myasthenia gravis (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2000;55:7-15. Comment in: Neurology. 2000;55:3-4.



Jaretzki A, et al. Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America. Myasthenia gravis: recommendations for clinical research standards. Neurology. 2000;55:16-23. Comment in: Neurology. 2000;55:3-4.



Sasakura Y, et al. Myasthenia gravis associated with reduced masticatory function. Int J Oral Maxillofac Surg. 2000;29:381-83.



Paul RH, et al. Cognitive dysfunction in individuals with myasthenia gravis. J Neurol Sci. 2000;179:59-64.



Christiansen S, et al. Small thymomas and myasthenia gravis: a poorly understood association. Thorac Cardiovasc Surg. 2000;48:109-11.



Chiu HC, et al. The six year experience of plasmapheresis in patients with myasthenia gravis. Ther Apher. 2000;4:291-95.



Paul RH, et al. Fatigue and its impact on patients with myasthenia gravis. Muscle Nerve. 2000;23:1402-06.



Anlar B. Juvenile myasthenia: diagnosis and treatment. Paediatr Drugs. 2000;2:161-69.



Gerli R, et al. Long-term immunologic effects of thymectomy in patients with myasthenia gravis. J Allergy Clin Immunol. 1999;103:865-72.



Bach JF, et al. Are there unique autoantigens triggering autoimmune diseases? Immunol Rev. 1998;164:139-55.



Palace J, et al. A randomized double-blind trial of prednisolone alone or with azathioprine in myasthenia gravis. Neurology. 1998;50:1778-83.



de Carvalho MF, et al. Systemic lupus erythematous and myasthenia gravis: case report. Arq Neuropsiquiatr. 1998;56:137-40.



Yoshikawa H, et al. Acetylcholine receptor autoantibody secretion by thymocytes. Relationship to myasthenia gravis. Neurology. 1997;49:562-67.



Middleton LT. Congenital myasthenic syndromes. 34th ENMC International Workshop. Neuromuscul Disord. 1996;6:133-36.



Bain PG, et al. Effects of intravenous immunoglobulin on muscle weakness and calcium-channel autoantibodies in the Lambert-Eaton myasthenic syndrome. Neurology. 1996;47:678-83.



Phillips LH, et al. Epidemiologic evidence for a changing natural history of myasthenia gravis. Neurology. 1996;47:1233-38.



Merrill JE, et al. Autoimmune disease and the nervous system. Biochemical, molecular, and clinical update. West J Med. 1992;156:639-46.



Keys PA, et al. Therapeutic strategies for myasthenia gravis. DICP. 1991;25:1101-08.



Havard CW, et al. New treatment approaches to myasthenia gravis. Drugs. 1990;39:66-73.



FROM THE INTERNET

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Myasthenia Gravis; MG. Last Edited June 3, 2009. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed May 13, 2011.



Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Myasthenic Syndrome, Congenital, Associated with Episodic Apnea. Entry No: 254210. Last Edited June 3, 2009. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed May 13, 2011.

Resources

Myasthenia Gravis Foundation of America

355 Lexington Ave 15th Floor

New York, NY 10017-6603

Tel: (212)297-2156

Fax: (212)370-9047

Tel: (800)541-5454

Email: mgfa@myasthenia.org

Internet: http://www.myasthenia.org



American Autoimmune Related Diseases Association, Inc.

22100 Gratiot Ave.

Eastpointe, MI 48021

Tel: (586)776-3900

Fax: (586)776-3903

Tel: (800)598-4668

Email: aarda@aarda.org

Internet: http://www.aarda.org/



Muscular Dystrophy Association

3300 East Sunrise Drive

Tucson, AZ 85718-3208

USA

Tel: (520)529-2000

Fax: (520)529-5300

Tel: (800)572-1717

Email: mda@mdausa.org

Internet: http://www.mda.org/



NIH/National Institute of Neurological Disorders and Stroke

P.O. Box 5801

Bethesda, MD 20824

Tel: (301)496-5751

Fax: (301)402-2186

Tel: (800)352-9424

TDD: (301)468-5981

Internet: http://www.ninds.nih.gov/



Myasthenia Gravis Links

Web Site on the Internet

Email: stanley.way@prodigy.net

Internet: http://pages.prodigy.net/stanley.way/myasthenia/



New Horizons Un-Limited, Inc.

811 East Wisconsin Ave

P.O. Box 510034

Milwaukee, WI 53203

USA

Tel: (414)299-0124

Fax: (414)347-1977

Email: horizons@new-horizons.org

Internet: http://www.new-horizons.org



Genetic and Rare Diseases (GARD) Information Center

PO Box 8126

Gaithersburg, MD 20898-8126

Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/



Autoimmune Information Network, Inc.

PO Box 4121

Brick, NJ 08723

Fax: (732)543-7285

Email: autoimmunehelp@aol.com



European Society for Immunodeficiencies

1-3 rue de Chantepoulet

Geneva, CH 1211

Switzerland

Tel: 410229080484

Fax: 41229069140

Email: esid@kenes.com

Internet: http://www.esid.org



AutoImmunity Community

Email: moderator@autoimmunitycommunity.org

Internet: http://www.autoimmunitycommunity.org



For a Complete Report

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