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NORD is very grateful to Paul Gozzard, MRCP, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, UK, for assistance in the preparation of this report.
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.
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.
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 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.
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, eye muscle weakness, when present, tends to be mild and, unlike with MG, is almost never the only symptom of the disease. .Severe respiratory muscle weakness, which can be fatal in MG is rare in LEMS. On the other hand, the autonomic symptoms which affect most LEMS patients, are not present in MG. 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 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 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).
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.
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Report last updated: 2012/03/29 00:00:00 GMT+0