What is myasthenia gravis?

Causes and Symptoms

Myasthenia gravis is a neuromuscular disorder characterized by weakness of skeletal muscles

following repeated use. The prevalence of the disease in the United States is approximately 14 in 100,000. It occurs in both genders of all ethnic groups, and the average age of onset is under forty for women and over sixty for men.

Normally, body movements result from the contraction of skeletal muscles, which are voluntary muscles attached to bone. These muscles are stimulated to contract by motor neurons in the brain and spinal cord. Nerve impulses travel down the motor neurons to their terminals, where a small amount of a substance known as a neurotransmitter is released onto the muscle’s surface. In this case, the neurotransmitter is the chemical acetylcholine. When acetylcholine binds to specific receptors on the muscle surface, contraction results.

In myasthenia gravis, an autoimmune disease, the patient’s immune system fails to recognize the acetylcholine receptors on skeletal muscle as part of “self”; thus, antibodies are erroneously produced against these receptors. Antibody binding to acetylcholine receptors causes the total number of functional receptors to be reduced because they are internalized and degraded by the muscle cells. With fewer remaining receptors, the muscle’s contractile response is weakened.

The root cause of this aberrant immune response remains unknown. The thymus, a gland involved in immune function, is abnormal in about 75 percent of patients with the disease. Two distinct thymic anomalies may occur in myasthenia gravis: One of these is thymic hyperplasia (an increase in the number of certain immune cells in the thymus) or thymoma (a thymic tumor). In some late-onset cases of myasthenia gravis, however, the thymus appears normal or even shrunken—yet these cases are also accompanied by elevated levels of antibodies recognizing acetylcholine receptors. Such inconsistencies are part of the reason that the relationship between the thymus and myasthenia gravis is not fully understood.

Skeletal muscle weakness is a symptom common to all forms of myasthenia gravis. Because this weakness is exacerbated with muscle use, it is not surprising that the first muscles to be affected are those used most often. Thus, the earliest signs of the disease often involve the muscles of the eye, including drooping of the eyelids and double vision. As other muscle groups become affected, advancing symptoms may include difficulty in chewing and swallowing, slurred speech, limb weakness, and breathing difficulties. Although symptoms are highly variable from patient to patient, they often fluctuate in severity with a similar daily pattern: Weakness is usually more pronounced in the evening than in the morning. Factors other than exertion that can provoke symptoms include viral illness, excitement, elevated temperature, menses, and pregnancy.

Although the long-term course of the disease can vary, it is usually progressive. In a minority of patients, weakness affects only the eye muscles. In other cases, progression is often most rapid within the first three years and may be punctuated with spontaneous temporary remissions. Treatment can help keep the symptoms under control.

Early symptoms are not always recognized as being linked to myasthenia gravis. A definitive diagnosis includes testing for the presence of antibodies that bind acetylcholine receptors. In addition, impaired nerve-muscle communication should be demonstrated in the form of specific muscle weakness elicited by repetitive nerve stimulation. Finally, it should be shown that muscle weakness is briefly relieved following the administration of edrophonium. This drug blocks the breakdown of acetylcholine, temporarily increasing the amount of the neurotransmitter available to act on muscle receptors.

Treatment and Therapy

Several treatment options have been developed with the goal of symptomatic control of myasthenia gravis. Treatment must be individually tailored depending on disease history and severity. Therapies include medications, surgery, and plasma exchange.

To improve neuromuscular transmission, drugs can be given to inhibit the action of acetylcholinesterase, the naturally occurring enzyme that degrades acetylcholine, thus prolonging the availability of acetylcholine so that its contractile effect is enhanced. Such drugs include neostigmine. Another pharmacological approach is to suppress the immune system with drugs such as prednisone and azathioprine; as a result, the production of abnormal antibodies is reduced.

Thymectomy, the surgical removal of the thymus, is commonly recommended as a treatment for myasthenia gravis. In general, this procedure is considered the most effective approach for obtaining sustained relief or remission. Maximum postsurgical improvement may take several years to occur, and results are usually best in younger patients early in their disease.

Plasma exchange is used as an immediate intervention to combat the sudden onset of severe symptoms such as respiratory failure, or in cases where the patient has not responded to other treatments. In this procedure, abnormal antibodies are removed from the blood plasma.

Perspective and Prospects

Myasthenia gravis was first described by the British physician Thomas Willis in 1685. Although relatively rare, it was the first neurological disease to be identified as having an autoimmune basis. The understanding of the disease was aided by converging research among neurophysiologists, neurologists, and immunologists; as such, these combined approaches have helped to elucidate other autoimmune diseases.

Although patients undergoing treatment for myasthenia gravis can expect a normal life span marked by significant improvement of their symptoms, as of 2013 there was no cure for the disease. Research is aimed at gaining a better understanding of the factors triggering the autoimmune response in myasthenia gravis, elucidating the relationship between the thymus and the disease, and fully understanding the molecular basis of normal and aberrant nerve-muscle transmission. This research should guide developments in treatment strategy, with a key goal being to cure the immune abnormality that underlies the disease.

Bibliography

Carson-DeWitt, Rosalyn. "Myasthenia Gravis (MG)." Health Library, September 10, 2012.

Kaminski, Henry J., ed. Myasthenia Gravis and Related Disorders. 2d ed. New York: Humana Press, 2010.

Kasper, Dennis L., et al., eds. Harrison’s Principles of Internal Medicine. 16th ed. New York: McGraw-Hill, 2005.

MedlinePlus. "Myasthenia Gravis." MedlinePlus, April 19, 2013.

National Institute of Neurological Disorders and Stroke. "NINDS Myasthenia Gravis Information Page." NINDS, December 4, 2012.

Parker, James N. and Philip M. Parker. Myasthenia Gravis: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References. San Diego, Calif.: ICON Health Publications, 2004.

Vincent, Angela. “Unravelling the Pathogenesis of Myasthenia Gravis.” Nature Reviews Immunology 2 (October, 2002): 797–804.