Lambert-Eaton Myasthenic Syndrome

Lambert-Eaton Myasthenic Syndrome

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Lambert-Eaton Myasthenic Syndrome 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

  • Eaton-Lambert syndrome
  • Lambert-Eaton syndrome
  • LEMS
  • myasthenic syndrome of Lambert-Eaton

Disorder Subdivisions

  • None

General Discussion

Lambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder characterized by the gradual onset of muscle weakness, especially of the pelvic and thigh muscles. Approximately 60 percent of LEMS cases are associated with a small cell lung cancer (SCLC), and the onset of LEMS symptoms often precedes the detection of the cancer. The LEMS patients with cancer tend to be older and nearly always have a long history of smoking. In cases in which there is no associated cancer, disease onset can be at any age.

Symptoms

LEMS is characterized by weakness and fatigue especially of the pelvic and thigh muscles. 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. Onset is gradual, typically taking place over several weeks to many months. There is often a progression of symptoms whereby the shoulder muscles, muscles of the feet & hands, speech & swallowing muscles and eye muscles are affected in a stepwise fashion. The symptoms progress more quickly when LEMS is associated with cancer. Most LEMS patients also exhibit the following symptoms (sometimes called autonomic symptoms): dry mouth, , constipation, impotence and, decreased sweating,. LEMS patients with or without cancer may also undergo significant weight loss. The tendon reflexes are diminished or absent on examination. Hence, in summary, LEMS is often described as a clinical "triad" of proximal muscle weakness, autonomic symptoms and reduced tendon reflexes.

Causes

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.

Affected Populations

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 SCLC, the patients tend to be older and are more likely to be men than women. The average age of onset of SCLC is around 60 years. Around 3% of SCLC patients develop LEMS. Clinical symptoms of LEMS usually precede the SCLC diagnosis (sometimes by many years).When LEMS is not related to cancer, the syndrome may occur at any age.

Standard Therapies

Diagnosis

Diagnosis of LEMS is based on clinical symptoms and signs, electrophysiological studies, and antibody testing.



Electromyography initially shows a small amount of electrical activity in the muscle. After high frequency repetitive stimulation or exercise, there is increased activity in the muscle.



Anti-VGCC antibodies are detectable in around 85% of LEMS patients and when detected they are highly specific for the condition, or by measuring VGCC antibodies in the blood.



Screening for SCLC is a very important part of the diagnostic workup for LEMS. A chest CT (and sometimes FDG-PET) scan will usually form the basis of this screening. Depending on the risk profile, a negative initial screen will be repeated at suitable time intervals. A recently discovered tumor marker antibody directed against SOX, which is found in 65% of SCLC LEMS patients as opposed to only 5% of non-tumor LEMS patients may help guide clinical practice in the future.



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.



A recent Cochrane review concluded that limited evidence from two randomized controlled trials (RCTs) showed that 3,4-diaminopyridine (3,4,-DAP) improved muscle strength scores and compound muscle action potential amplitudes in patients with LEMS. Until recently, oral 3,4-DAP was only available as an unlicensed formulation as 3,4-diaminopyridine base, which was used in the RCTs. In November 2009, the FDA granted orphan drug status to BioMarin Pharmaceutical's Amifampridine, a phosphate salt formulation of oral 3,4-DAP. To date, there is no published evidence that the licensed product has improved clinical effectiveness over the 3,4-diaminopyridine base.



Some LEMS patients have reported benefits from adding pyridostigmine to 3,4-DAP but to date there have not been any clinical trials using this drug in LEMS.



In addition to symptomatic treatment, drugs that suppress the activity of the immune system (immunosuppressive drugs) are used in more severe cases of LEMS, e.g. prednisone (alone or in conjunction with azathioprine or cyclosporin).

Investigational Therapies

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

References

TEXTBOOKS

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



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



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



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



JOURNAL ARTICLES

Keogh M, Sedehizadeh S, Maddison P. Treatment for Lambert-Eaton myasthenic syndrome. Cochrane Database Syst Rev. 2011;(2):CD003279.



Titulaer MJ, Lang B, Verschuuren JJ. Lambert-Eaton myasthenic syndrome: from clinical characteristics to therapeutic strategies. Lancet Neurol. 2011;10(12):1098-107.



Titulaer MJ, Klooster R, Potman M et al. SOX antibodies in small-cell lung cancer and Lambert-Eaton myasthenic syndrome: frequency and relation with survival. J Clin Oncol. 2009;27(26):4260-7.



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.



INTERNET

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Calcium Channel, Voltage-Dependent, BETA-2 Subunit; CACNB2. Entry No: 600003. Last Edited December 15, 2011. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed February 23, 2012.



Stickler DE. Lambert-Eaton Myasthenic Syndrome. Emedicine. http://emedicine.medscape.com/article/1170810-overview. Updated June 29, 2011. Accessed February 23, 2012.

Resources

Myasthenia Gravis Foundation of America

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Muscular Dystrophy Association

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Genetic and Rare Diseases (GARD) Information Center

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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

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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



Child Neurology Foundation

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Tel: (952)641-6100

Fax: (952)881-6276

Tel: (877)263-5430

Email: jstone@childneurologyfoundation.org

Internet: http://www.childneurologyfoundation.org



For a Complete Report

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