Lambert-Eaton myasthenic syndrome

Definition

Lambert-Eaton myasthenic syndrome is an autoimmune disease that causes muscle weakness and easy fatigability, particularly in the pelvic muscles and thighs.

Description

In order to understand Lambert-Eaton myasthenic syndrome, it's important to have some understanding of the basics of nerve transmission and stimulation of muscle movement. Nerve impulses in the body are electrical and chemical currents that travel down a nerve fiber. When they reach the end of that nerve fiber, they trigger the release of the neurotransmitter chemical acetylcholine. Acetycholine must cross a tiny gap called the synapse in order to stimulate the muscle to contract. The nerves leading to the synapse or synaptic junction are called the presynaptic nerves.

In the case of Lambert-Eaton myasthenic syndrome, the body's immune system accidentally treats specialized areas (called calcium channels) along the presynaptic nerve as if they were foreign. These calcium channels are vital to the presynaptic nerve's ability to release acetylcholine into the synaptic junction. The immune cells attack the calcium channels as they would attack an invader such as a virus or bacteria. When the calcium channels are damaged, the release of acetylcholine into the synapse is compromised, resulting in less acetycholine being available to stimulate the muscle.

Lambert-Eaton myasthenic syndrome has a very strong association with cancer, particularly small-cell lung cancer. The symptoms of Lambert-Eaton myasthenic syndrome often occur prior to diagnosis with lung cancer. In fact, about two-thirds of all people with Lambert-Eaton myasthenic syndrome will be diagnosed with some type of cancer, usually small-cell lung cancer, within two to three years of the onset of their initial symptoms of Lambert-Eaton myasthenic syndrome. Other types of cancer associated with Lambert-Eaton myasthenic syndrome include non-small-cell lung cancer; lymphosarcoma; malignant thymoma; and carcinoma of the breast, stomach, colon, prostate, bladder, kidney, or gallbladder.

Because of the strong connection between Lambert-Eaton myasthenic syndrome and cancer, it is sometimes considered to be a paraneoplastic syndrome (a syndrome in which substances produced by cancer cells prompt abnormalities in the body at a distance from the actual site of the malignancy). In the case of Lambert-Eaton myasthenic syndrome, it is thought that the immune system produces immune cells in response to the presence of early cancer cells. These immune cells cross-react with the calcium channels on nerve cells, resulting in the symptoms of Lambert-Eaton myasthenic syndrome.

Demographics

Lambert-Eaton myasthenic syndrome is very rare, only striking about five people per every one million annually. At any one time, there are thought to be about 400 people in the United States suffering from Lambert-Eaton myasthenic syndrome. Twice as many men than women are affected, and the average age at diagnosis is about 60 years of age. Family history of Lambert-Eaton myasthenic syndrome is a known risk factor for development of the disease, as is a personal history of smoking.

Causes and symptoms

In Lambert-Eaton myasthenic syndrome, the immune system accidentally attacks the calcium channels of the presynaptic nerve cells, preventing normal release of the neurotransmitter acetylcholine into the synaptic junction, and compromising the flow of nervous information between the presynaptic and postsynaptic nerves.

Symptoms of Lambert-Eaton myasthenic syndrome begin with weakness and some achiness and tenderness in the thigh and pelvic muscles. The upper arms may also exhibit some weakness. Due to the weak thigh and upper arm muscles, the patient's walk may have a waddling appearance, and it may be difficult for the patient to lift his or her arms above the head. Exercise may initially improve the weakness, but the weakness may become more pronounced as exercise continues. Eyelids may droop (ptosis). Many patients notice uncomfortably dry eyes, mouth, and skin. Patients may develop difficulty chewing, swallowing, and/or speaking, as well as constipation, sudden drops in blood pressure when rising from lying down to sitting or standing, abnormalities of sweating, and erectile problems in men.

Diagnosis

Lambert-Eaton myasthenic syndrome may be diagnosed by demonstrating the presence of specific antibodies in the blood that are directed against aspects of the presynaptic nerve, such as the calcium channels. Studies of nerve conduction and muscle function will reveal a variety of abnormalities. When Lambert-Eaton myasthenic syndrome is diagnosed, a search should also be done for the presence of a previously undiagnosed cancer, especially small-cell lung cancer.

Treatment team

Patients with Lambert-Eaton myasthenic syndrome should be examined and then treated by both a neurologist and an appropriate cancer specialist (oncologist).

Treatment

When a cancer is identified, the first concern should be the appropriate treatment of that malignancy. Secondarily, treatment of Lambert-Eaton myasthenic syndrome may include medications to improve transmission of nerve impulses across the synaptic junction (such as pyridostigmine bromide) as well as immunosuppressant agents (such as corticosteroids, azathioprine, cyclosporine, or intra-venous immungoglobulin) to decrease the immune system's ability to further damage the presynaptic nerves. A treatment called plasmapheresis may help remove damaging immune cells from the blood.

Prognosis

The prognosis of individuals with Lambert-Eaton myasthenic syndrome varies widely. In fact, the most important element of prognosis involves the prognosis associated with any existing cancer.

Special concerns

Patients who develop Lambert-Eaton myasthenic syndrome should be thoroughly screened for the presence of a previously undetected cancer. If none is found, the patient should undergo regularly scheduled surveillance to monitor for the subsequent development of a malignancy.

Resources

BOOKS

Al-Losi, Muhammad, and Alan Pestronk. "Paraneoplastic Neurologic Syndromes." Harrison's Principles of Internal Medicine, edited by Eugene Braunwald, et al. New York: McGraw-Hill Professional, 2001.

Gruenthal, Michael. "Lambert-Eaton Myasthenic Syndrome." Ferri's Clinical Advisor: Instant Diagnosis and Treatment, edited by Fred F. Ferri. St. Louis: Mosby, 2004.

Posner, Jerome B. "Nonmetastatic Effects of Cancer: The Nervous System." Cecil Textbook of Internal Medicine, edited by Lee Goldman, et al. Philadelphia: W.B. Saunders Company, 2000.

PERIODICALS

Bataller, L. "Paraneoplastic neurologic syndromes. " In Neurologic Clinics 21(1)(February 1, 2003): 221–247

WEBSITES

Lambert-Eaton Myasthenic Syndrome Fact Sheet. National Institute of Neurological Disorders and Stroke (NINDS). Bethesda, MD: NINDS, 2003.

Rosalyn Carson-DeWitt, MD

Key Terms: Autoimmune reaction, Neurotransmitter.

Description

Eaton-Lambert syndrome, also called Lambert-Eaton myasthenic syndrome (LEMS), is a rare disorder affecting the muscles and nerves. LEMS is known to be associated with small cell lung cancer. It may also be associated with cancers such as lymphoma, non-Hodgkin's lymphoma, T-cell leukemia, non-small cell lung cancer, prostate cancer, and thymoma.

The primary symptom of LEMS is muscular weakness or paralysis that varies in intensity and location throughout the body. Other symptoms of LEMS include tingling sensations on the skin, double vision, difficulty maintaining a steady gaze, and dry mouth or difficulty in swallowing.

The first signs of LEMS tend to be:

• changes in vision
• decreased posture and muscle tone
• difficulty in chewing or swallowing
• difficulty in climbing stairs
• difficulty in lifting simple objects
• speech impairment
• a drooping head
• fatigue
• and/or a need to use hands to get up from a sitting or lying position

LEMS is often misdiagnosed as myasthenia gravis because of the similarities between the symptoms of these two disorders.

Causes

The symptoms of LEMS are the result of an insufficient release of neurotransmitter by nerve cells. Neurotransmitter is a chemical which passes signals from the nerve cells to the muscles in order for the muscles to move. The decreased level of neurotransmitter causes a muscle reaction to the nerve signal that is lower than normal. The underlying cause of the lower-than-normal neurotransmitter release seen in LEMS patients is believed to be related to a malfunction of the patient's own immune system (an autoimmune reaction).

This autoimmune reaction is caused by antibodies that a patient produces in response to small cell lung cancer, or one of the other cancers associated with LEMS.

Since continued use of the muscles may lead to a build-up of the neurotransmitter to normal levels, symptoms of LEMS can often be lessened or alleviated by use of the affected muscles. Myasthenia gravis, another disorder that has symptoms similar to LEMS, is caused by a blockage of neurotransmitters by antibodies. Symptoms of myasthenia gravis do not improve with continued muscle use. The improvement in symptoms that is observable in LEMS patients often helps to differentiate LEMS from myasthenia gravis.

LEMS is aggravated by neuromuscular blocking agents used during surgery; certain antibiotics, such as aminoglycoside and fluoroquinolone; magnesium; calcium channel blockers; and iodinated intravenous contrast agents used for medical imaging.

Treatments

The goal of treatment for LEMS patients is to improve muscle strength while also treating the cancer or other underlying disorder that is causing LEMS.

When possible, patients affected with LEMS should undergo a physical therapy program that is tailored to their health status and abilities. This may include stretching and flexibility manuevers as well as light strength and cardiovascular exercises. Symptoms of LEMS tend to be aggravated by prolonged exercise, so any physical therapy undertaken should be relatively short in duration.

Some LEMS patients are not able to undergo physical therapy because of their current state of health. In these cases, plasmapheresis (also called plasma exchange), a procedure in which blood plasma is removed from the patient and replaced, may be recommended. This procedure can be effective in a majority of LEMS patients.

Medications that suppress the immune response or that suppress the antibodies responsible for the weakness have also been shown to improve LEMS symptoms in some patients.

Alternative and Complementary Therapies

Yoga and other stretching exercises may be effective treatments for alleviating the physical symptoms of LEMS patients. Some LEMS patients also report improvement of symptoms after deep body massage or hydrotherapy.

Resources

Organizations

Muscular Dystrophy Association. 3300 E. Sunrise Dr., Tucson, AZ 85718. (800) 572-1717. .

Myasthenia Gravis Foundation of America, Inc. 5841 Cedar Lake Road, Suite 204, Minneapolis, MN 55416. (800) 541-5454. .

Other

"Calcium Channel Autoantibodies in the Diagnosis of the Lambert-Eaton Syndrome." Diagnostika GMBH June 2001. [cited June 28, 2001]. .

"Eaton Lambert Syndrome." Reader's Digest Health. 29 March 2001. [cited June 28, 2001]. .

"Lambert-Eaton Syndrome." Health Central June 2001. [cited June 28, 2001]. .

"Myasthenia Gravis Support and Community Forum." MGFriends.com 15 April 2001. [cited June 28, 2001]. .

"Myasthenic Syndrome (Lambert-Eaton; LEMS): Autoimmune." Neuromuscular Disease Center June 2001. [cited June 28, 2001]. .

—Paul A. Johnson, Ed.M.

Progressive proximal muscle weakness in individuals with carcinoma, in the absence of dermatomyositis or polymyositis. Also called carcinomatous myopathy, Eaton-Lambert syndrome.

Lambert-Eaton myasthenic syndrome
Classification and external resources
Detailed view of a neuromuscular junction: 1. Presynaptic terminal 2. Sarcolemma 3. Synaptic vesicle 4. Nicotinic acetylcholine receptor 5. Mitochondrion
ICD-10	G73.1
ICD-9	358.1
DiseasesDB	4030
MedlinePlus	000710
eMedicine	neuro/181 emerg/292
MeSH	D015624

Lambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder that affects voltage-gated calcium channels on the pre-synaptic membrane of the nerve-muscle (neuromuscular) junction. The inhibition of the voltage-gated calcium channels prevents acetylcholine from being released from the presynaptic terminal and the subsequent stimulation of the post-synaptic terminal which would lead to muscle contraction.^[1] The etiology of LEMS may resemble myasthenia gravis, but there are substantial differences between the clinical presentation and pathogenetic features of the two disorders.

The disease is usually observed in middle aged and older individuals, although children and young adults may also be affected. The incidence of the disease is difficult to determine due to its low frequency.

Contents 1 History 2 Causes 3 Clinical findings 4 Diagnosis 5 Treatment 6 References

History

Anderson was the first person to mention a case with possible clinical findings of LEMS in 1953, but Lambert, Eaton and Rooke were the first physicians to substantially describe the clinical and electrophysiological findings of the disease in 1966.^[2][3]

It is usually associated with auto-immune self antibodies against the pre-synaptic voltage gated calcium channels,^[4] which leads to neuromuscular block.

Causes

While LEMS may be found as a solitary disease, 50% of cases have an associated small-cell lung cancer. Other malignancies associated with LEMS are extremely rare. The myasthenic syndrome associated with thymoma is actually true myasthenia gravis, where weakness worsens with repeated activity (as opposed to LEMS, where weakness improves with repeated activity).^[5]

Whether solitary or cancer-associated, the disease is believed to be of autoimmune origin. In 1989, the previously anticipated antibodies were demonstrated to be directed against presynaptic calcium channels, which are located in the neuromuscular junction (see synapse) and are responsible for the presynaptic release of acetylcholine. The calcium channel antibodies prevent the opening of calcium channels and thus prevent the release of acetylcholine.

There are some patients that do not carry these antibodies in their serum samples and the exact cause of disease in these cases still remains to be determined.^{[citation needed]} In cases with both LEMS and lung cancer (usually small cell type), the antibodies are suggested to be aimed at cancer cells and to bind and affect the antigens in neuromuscular junction accidentally.

Clinical findings

The major clinical finding is progressive weakness that does not usually involve the respiratory muscles and the muscles of face. In patients with affected ocular and respiratory muscles, the involvement is not as severe as myasthenia gravis. Also, in contrast to MG, symptoms of LEMS tend to be worse in the morning and improve with exercise and nerve stimulation. The proximal parts of the legs and arms are predominantly affected. Many patients have autonomic symptoms like dry mouth or impotence. Reflexes are usually reduced or absent.

Diagnosis

The diagnosis is established by clinical and laboratory findings (chest x-ray for a possible lung malignancy, antibodies to calcium channels, incremental response in repetitive nerve stimulation). Incremental response is an increased response of muscle fibers to very high frequencies of electrical stimulation. Observed increase in the response of muscle fibers proves that there is a difficulty with the release of acetylcholine and this difficulty can be overwhelmed by intensive stimulation.

Treatment

Corticosteroids, azathioprine and 3,4-diaminopyridine are used in treatment of LEMS with limited success. In some cases with a progressive and intractable course, plasma exchange or intravenous immunoglobulin can be tried.

3,4 diaminopyridine works by blocking K⁺ channel efflux in nerve terminals so that action potential duration is increased. Ca²⁺ channels thus remain open for a longer period of time, which allows greater acetylcholine release to stimulate the muscle at the end plate.

References

1. ^ Lambert-Eaton Myasthenic Syndrome, emedicine, 2009
2. ^ Lambert-Eaton-Rooke syndrome at Who Named It?
3. ^ E. H. Lambert, L. M. Eaton, E. D. Rooke. Defect of neuromuscular conduction associated with malignant neoplasms. American Journal of Physiology, Bethesda, Maryland, 1956, 187: 612-613.
4. ^ Newsom-Davis J (February 2004). "Lambert-Eaton myasthenic syndrome". Rev. Neurol. (Paris) 160 (2): 177–80. PMID 15034474. http://www.masson.fr/masson/MDOI-RN-02-2004-160-2-0035-3787-101019-ART04. 
5. ^ Monden et al. Ann Thoracic Surg, 1984:46-52.

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