Information on the following diseases can be found in the Related Disorders section of this report:

• Myasthenia Gravis
• Guillain-Barre Syndrome

LEMS is characterized by weakness and fatigue especially of the pelvic and thigh muscles. Onset is gradual, typically taking place over several weeks to many months. The disease may affect the patient's ability to engage in strenuous exercise and may make such activities as climbing stairs or walking up a steep walkway difficult. Some LEMS patients also exhibit the following symptoms in a mild to moderate degree: dry mouth, difficulty swallowing, difficulty in articulation of speech, constipation, impotence, decreased sweating, and drooping of the upper eyelids. LEMS patients with or without cancer may also undergo significant weight loss. Other symptoms may include a pricking, tingling or creeping feeling on the skin (paresthesias) around the affected areas, double-vision (diplopia), and low blood pressure when in an upright position (orthostatic hypotension). Deep-tendon reflexes may be reduced or absent in LEMS patients, and lower limbs are affected more often than upper limbs.

LEMS is an autoimmune disorder. Autoimmune disorders are caused when the body's natural defenses against "foreign" or invading organisms (e.g., antibodies) begin to attack healthy tissue for unknown reasons. LEMS occurs because autoantibodies damage the "voltage-gated calcium channels (VGCC)" on the motor nerve membrane at the neuromuscular junction. These channels normally conduct calcium into the nerve resulting in release of a chemical known as acetylcholine. Acetylcholine helps in the communication between nerve cells and muscles and is one of a group of chemicals known as neurotransmitters, which help to transmit nerve impulses. The autoantibodies attack the VGCC resulting in less acetylcholine release.

In LEMS cases associated with cancer, it is believed that autoantibodies created against the VGCC on the small-cell lung tumor damage the VGCC on the nerve. It is unknown what causes autoantibody production in cases not associated with cancer.

In LEMS cases associated with cancer, affected individuals nearly always have a long smoking history.

There are approximately 400 known cases of Lambert-Eaton myasthenic syndrome in the United States. These include both males and females, but when LEMS is associated with cancer, as it is approximately 60 percent of the time, the patients tend to be older and are more likely to be men than women. Of LEMS patients over the age of 40, 70% of men and 30% of women will have a malignant tumor. The tumor is usually a small cell carcinoma of the lung. LEMS may occur up to five years (or even longer) before a tumor is detected. However, when LEMS is not related to cancer, the syndrome may occur at any age.

Symptoms of the following disorders can be similar to those of Lambert-Eaton Myasthenic Syndrome. Comparisons may be useful for a differential diagnosis:

Myasthenia Gravis (MG) is a chronic neuromuscular disease characterized by weakness and abnormally rapid fatigue of the voluntary muscles, with improvement following rest. Any group of muscles may be affected, but those around the eyes and the muscles used for swallowing are the most commonly involved. In LEMS, these head and neck muscles are usually not affected. Weakness of the limbs is a frequent characteristic of MG and is most pronounced at the end of the day and also after exercise. However, in patients with LEMS, muscle strength tends to improve after exercising the muscle. (For more information on this disorder, choose "Myasthenia" as your search term in the Rare Disease Database.)

Guillain-Barre Syndrome is an autoimmune disease which occurs when the body's defense system attacks the nerves, damaging the nerve's myelin and axon. Nerve signals are delayed and altered, causing weakness and paralysis of the muscles of the legs, arms, and other parts of the body. Abnormal sensations such as numbness or tingling also occur. If muscle nerves are damaged, the patient experiences aching and weak muscles, shortness of breath, and difficulty in swallowing. If the autonomic nervous system is damaged, the patient may experience alterations of blood pressure, heart rate, vision, body temperature, bladder function, and blood chemistries. (For more information on this disorder, choose "Guillain" as your search term in the Rare Disease Database.)

Diagnosis
Diagnosis of Lambert-Eaton myasthenic syndrome may be confirmed by an electromyogram (EMG), which provides a record of electrical activity in the muscles, or by measuring VGCC antibodies in the blood. The EMG initially shows a small amount of electrical activity in the muscle. After stimulation or exercise, there is increased activity in the muscle.

Treatment
Treatment of LEMS may vary depending upon the individual's age, general health, and the presence of associated cancer to autoimmune disorder. If cancer is present, treatment of Lambert-Eaton myasthenic syndrome first involves treatment directed at the cancer. This may result in relief of LEMS symptoms.

In addition, drugs that suppress the activity of the immune system (immunosuppressive drugs) such as prednisone (alone or in conjuction with azathioprine or cyclosporin) may relieve symptoms. Other treatment is symptomatic and supportive.

Clinical trials are underway to study the orphan drug 3,4-diaminopyridine (3,4-DAP) for the treatment of LEMS. More studies are needed to determine the long-term safety and effectiveness of this treatment of Eaton Lambert Syndrome. For more information, contact:

Donald B. Sanders, MD
Box 3403
Duke University Medical Center
Durham, NC 27710
Tel: (919) 684-6078
Fax: (919) 660-3853
E-mail: sande007@mc.duke.edu

The orphan drug dynamine is being tested for treatment of LEMS. The drug is manufactured by Mayo Foundation, Rochester, MN.

Plasmapheresis may be of benefit in some cases of Lambert-Eaton myasthenic syndrome. This procedure is a method for removing unwanted substances (toxins, metabolic substances and plasma parts) from the blood. Blood is removed from the patient and blood cells are separated from plasma. The patient's plasma is then replaced with other human plasma and the blood is retransfused into the patient. More research is needed before plasmapheresis can be recommended for use in all but the most severe cases of LEMS.

The National Cancer Institute conducts clinical trials on new drugs being tested for lung cancer and other forms of cancer. To learn about locations of these investigations, contact the Cancer Information Service, 1-800-4- CANCER.
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

TEXTBOOKS
Parsons KT. Lambert-Eaton Myasthenic Syndrome. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:621.

Bennett JC, Plum F., eds. Cecil Textbook of Medicine. 20th ed. Philadelphia, PA: W.B. Saunders Co; 1996:1018.

Fauci AS, et al., eds. Harrison's Principles of Internal Medicine, 14th Ed. New York, NY: McGraw-Hill, Inc; 1998:2470.

Beers MH, Berkow R., eds. The Merck Manual, 17th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1999:1496-97.

JOURNAL ARTICLES
Van Petegem F, Clark KA, Chatelain FC, Minor DL Jr. Structure of complex between a voltage-gated calcium channel beta-subunit and an alpha-subunit. Nature. 2004;429:671-5.

Dalakas MC. Intravenous immunoglobulin in autoimmune neuromuscular diseases. JAMA. 2004;291:2367-75.

Newsom-Davis J. Lambert-Eaton myasthenic syndrome. Rev Neurol. 2004;160:177-80.

Sanders DB. Lambert-Eaton myasthenic syndrome: diagnosis and treatment. Ann N Y Acad Sci. 2003;1998:500-9.

Tim RW, et al. Lambert-Eaton myasthenic syndrome: Electrodiagnostic findings and response to treatment. Neurology. 2000; 54:2176-78.

Takamori M, Komai K, Iwasa K. Antibodies to calcium channel and synaptotagmin in Lambert-Eaton myasthenic syndrome. J Med Sci. 2000; 319(4):204-08.

Deneviratne U, de Silva R. Lambert-Eaton myasthenic syndrome. Postgrad Med J. 1999; 75(887):516-20.

Kumakura S, et al. Bone marrow necrosis and the Lambert-Eaton syndrome associated with interferon alfa treatment. New Eng J Med 1998; 338:199-200.

O'Suilleabhain P, et al. Autonomic dysfunction in the Lambert-Eaton myasthenic syndrome: serologic and clinical correlates. Neurology. 1998; 50:88-93.

Katz JS et al. Acetylcholine receptor antibodies in the Lambert-Eaton myasthenic syndrome. Neurology. 1998; 50:470-75.

Verschuuren JJ et al. Antibodies against the calcium chanel beta-subunit in Lambert-Eaton myasthenic syndrome. Neurology. 1998; 50:475-79.

McEvoy KM. 3,4 diaminopyridine in the treatment of Lambert-Eaton myasthenic syndrome. New Eng J Med 1989; 321:1567-71.

FROM THE INTERNET
Online Mendelian Inheritance in Man, OMIM (TM). Johns Hopkins University, Baltimore, MD. MIM Number: 600003:6/15/2004. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600003 Accessed on: July 5, 2004.

Sanders DB. Lambert-Eaton Myasthenic Syndrome. Emedicine. 2001. Available at: http://www.emedicine.com/neuro/topic181.htm Accessed on: July 5, 2004.

eMedicine-Lambert-Eaton Myasthenic Syndrome: Article by Paul Kleinschmidt, MD

http://www.emedicine.com/EMERG/topic292.htm