Lambert Eaton Myasthenic Syndrome (LEMS): An Autoimmune Syndrome Causing Muscle Weakness

Lambert Eaton Myasthenic Syndrome belongs to the class of disorders referred to as neuromuscular transmission disorders. That is to say, that this group of diseases affects the ability of the nerves to communicate with the muscles and thus leads to muscle weakness.

Lambert Eaton Myasthenic Syndrome (LEMS) is also an autoimmune disorder because it is a product of the body that is acting to cause the disorder. In other words, the body is acting against itself to cause disease.

Finally, LEMS is often a paraneoplastic disorder. The term paraneoplastic refers to a disease that is indirectly caused by a neoplasm or cancer. While we will discuss LEMS in detail, it is important to know that a variety of paraneoplastic syndromes exist and can be the first signs of a malignancy.

PATHOPHYSIOLOGY

In order to understand LEMS, it is necessary to first understand how muscles are made to work. We will take a look at the transmission of information from the brain to the muscles and analyze the steps that allow this remarkable process to occur.

One of the first things that occurs when a person wants to make a voluntary movement (i.e. a movement that the individual decides to make and not a reflex) is that the frontal lobe will communicate the intention to the parietal lobe on the appropriate side of the brain. Remember that the left side of the brain controls motor movement on the right side of the body and vice versa. While there are a few minor exceptions to this rule, this holds for nearly all muscle actions and certainly those that we are interested in.

The parietal lobes around found on both sides of the brain and are located above the ears. Each lobe is divided into specific segments that are responsible for controlling different muscles in the body. When one of these segments fires an impulse (electrical), it travels down nerve fibers on its way to the appropriate muscle. Nerves from the brain carry information down the spinal cord to the appropriate level where they make a connection to another nerve. The location where two nerves meet once another is referred to as a neural synapse.

At a synapse, nerves do not directly touch one another. Instead, they only come close to touching. The space between the end of one nerve and the beginning of the next is referred to as the synaptic cleft. The cleft is just a tiny space between nerves. Communication between nerves occurs through the release of chemicals, usually acetylcholine, that travel from the end of the first nerve (called the axon) to the beginning of the next nerve (called the dendrite) by diffusing across the very tiny synaptic cleft.

Once the chemical signal reaches the next nerve, it is converted back into an electrical signal and continues its journey toward the muscle. When the electrical impulse reaches the end of this second nerve, it is again converted into a chemical signal at another cleft. This cleft is referred to as a neuromuscular junction and deserves some special attention.

When an electrical impulse reaches the end of a nerve at a neuromuscular junction, several special things happen. First, the depolarization caused by the presence of the electrical action potential causes specialized calcium gates on the surface of the nerve ending to open. These specialized calcium gates are referred to as voltage gated calcium channels and when they open, they allow calcium to enter the axon of the nerve. High levels of calcium inside the axon cause special packages of chemicals (called vesicles) to hook to the surface of the nerve and release their chemicals into the cleft between nerve and muscle.

The chemical that is release is acetylcholine and it diffuses across the cleft from the nerve axon to the muscle where it binds to special receptors on the muscle. When it binds to these receptors, sodium and potassium (salts) are allowed into the muscle cell. This causes depolarization of the muscle cell, which allows calcium to enter that cell and bind to specialized proteins that allow the muscle to contract. As long as acetylcholine (ACh) is present, the muscle cell will remain depolarized. In order to stop the process and allow the muscle to relax, special enzymes called cholinesterases break down the ACh. These enzymes will become important later when we discuss the diagnosis and treatment of LEMS (1).

This is a basic overview of how the brain tells a muscle to contract and move. The most important part of this process in regard to LEMS is the neuromuscular junction. In particular, acetylcholine and the calcium channels are important. In LEMS, the calcium channels are prevented from working properly by the presence of antibodies against these channels. Without proper functioning of the calcium channels in the neuron (nerve), calcium cannot enter the axon and trigger the release of ACh and thus depolarization of the muscle fiber cannot occur. The result is muscle weakness.

The development of autoantibodies in LEMS is poorly understood. In fact, the antibodies can arise through a variety of mechanisms and even though LEMS can be its own, free-standing autoimmune disease, it is often associated with cancer. Estimates vary, but it is generally accepted that 50 - 70% of LEMS cases are the result of an underlying malignancy (2). That is to say, in the majority of cases auntoantibodies arise as the result of a cancer. Most often, the cancer is small cell lung cancer (SMLC), but lymphoma, non-small cell lung cancer, prostate cancer and bladder cancer have also been implicated in LEMS (3).

SYMPTOMS

Often, the symptoms of LEMS develop before the presence of a malignancy is known. Thus, it is important to recognize and correctly diagnose the condition so that an evaluation of an occult cancer can be performed.

The major symptom of LEMS is muscle weakness. Usually the proximal muscles of the lower legs are most commonly affected (2). This means that the thigh muscles and hamstrings become weak. Patients will not difficulty climbing stairs, rising from a chair, or lifting their legs. The weakness is generally insidious in onset and progressive over time. This means that the weakness is usually mild to begin with, but becomes more severe over weeks or months (4).

Any other muscle can be affected, but the proximal legs are most common while muscles of the face and eyes are affected in up to 70% of patients (2). Symptoms due to affects of the facial muscles include ptosis (inability to open the eyelids), facial drooping, and difficulty swallowing (5). When the muscles of the eye are affected, double vision (diplopia) is the major symptom because the muscles are unable to keep both eyes pointing in the same direction.

The symptoms of LEMS are very similar to those of a related condition referred to as myasthenia gravis (MG), which also causes weakness of the muscles of the face and body. It is important to distinguish MG from LEMS as the treatments are different and the need to evaluate for occult malignancy is more urgent in LEMS. There are diagnostic tests that can be sued to separate the two conditions, but there are symptomatic differences as well.

One of the ways in which the symptoms of LEMS differ from those of MG is referred to as facilitation. In MG, use of the affected muscle in a repeated fashion leads to increased weakness. In LEMS, the opposite is true. Repeated use or stimulation of a muscle affected by LEMS will result in a decrease in weakness of the muscle. This phenomenon is referred to as facilitation.

Another group of symptoms present in LEMS that generally is not present in MG is autonomic dysfunction. That is, improper functioning of the nervous system responsible for all of the "automatic: functions in the body. This includes such things as sweating and heart beat. Patients with autonomic dysfunction will often experience dry mouth, dizziness when standing, impotence, and rapid fluctuations in blood pressure (5).

While specific symptoms of cancer may also be present, they usually are not. If present at all, symptoms of cancer in early LEMS generally fall into the category of "B" type symptoms and include such things as unintended weight loss, night sweats, fevers, and chills. Usually the symptoms of LEMS present before symptoms of the cancer do.

DIAGNOSIS

Diagnosis of LEMS depends on both physical exam findings and laboratory testing. We will focus on physical exam findings first.

Deep tendon reflexes are generally absent or diminished in a patient with LEMS. One helpful diagnostic maneuver involves having a patient contract a muscle for 10 seconds and testing for the reflex both before and after. The return of a previously absent reflex in this setting is characteristic of LEMS. An example would be the return of the knee reflex after prolonged contraction of the quadriceps muscles.

The tensilon test involves the administration of a cholinesterase inhibitor to help differentiate between LEMS and MG. A cholinesterase inhibitor prevent the enzyme that breaks down ACh from working, thus leading to an increased amount of ACh in the synaptic cleft and an increased strength in muscle contraction (please see above). Generally, this test works only in MG and not in LEMS. Thus, administration of a cholinesterase inhibitor followed by increased muscle strength is diagnostic of MG and not LEMS. Unfortunately, this test is not incredibly reliable and is generally not used any longer (4).

Direct measurement of antibodies against the calcium channels yields a definitive diagnosis of LEMS. However, antibodies are only present in 85% of cases, making this a specific, but not very sensitive test (2). The presence of antibodies makes the diagnosis, but their absence does not rule out LEMS. If LEMS is suspected, but the antibody testing is negative, one final test can be performed to make the clinical diagnosis of LEMS.

Electrodiagnostic studies involve the use of needles and mild electric shocks in order to stimulate individual muscles. The level of electrical shock need to stimulate a muscle and the movement obtained after a given shock can be used to diagnose LEMS and also to differentiate it from MG. In LEMS, the following things are found on electrodiagnostic testing:

- The amount of shock needed to stimulate a muscle is decreased after exercising. This is the opposite of what is found in MG.

- The gain following exercise rapidly diminishes

- Rapid repetition of the shock leads to enhanced muscle stimulation while slow repetition leads to decreased muscle stimulation.

This test can be painful, but the data obtained are often essential to diagnosis and to staging the severity of muscle involvement (4).

TREATMENT

The treatment of LEMs can be broken down into four categories as follows:

Emergency treatment - When the muscles responsible for breathing are affected in LEMS, supportive therapy is needed. This involves the use of supplemental oxygen and, in some cases, the use of a tube and respirator to do the breathing that a person cannot do on his or her own (4).

Medication - Cholinesterase inhibitors are used in LEMS, but generally do not result in significant improvement. Nevertheless, they are used. Generally, a small amount of benefit is obtained by combining a cholinesterase inhibitory with a potassium channel blocker. This second class of drugs works by preventing potassium channels from working properly at the end of the axon and thus allowing for a prolonged depolarization. The prolonged depolarization of the axon allows more calcium channels to open, more calcium to enter, and thus more ACh vesicles to release their ACh. The cholinesterase inhibitor then allows the ACh that is released to remain in the synapse longer, leading to a stronger depolarization of the muscle fiber and thus stronger muscle contraction. Potassium channel blockers, of which 3,4,-diaminopyridine is most effective, are very toxic and must be used carefully be physicians experienced in their administration (4).

Immune modulation - This refers to the use do of drugs and procedures designed to minimize the effectiveness of the autoantibodies or rid them from the body altogether. The administration of antibodies through IV (called IVIG) that are designed to bind to the autoantibodies and render them ineffective can be moderately effective in some patients. (4)

Treatment of the Cancer - If LEMS is the result of an underlying malignancy, the symptoms can be reduced or eradicated through treatment of the tumor. While complete removal of a tumor and cure of a cancer is always the ultimate goal, it is not necessary to remove the tumor in its entirety to treat LEMS. Often, simply shrinking the tumor through the use of chemotherapy or radiation is enough to decrease the level of circulating autoantibody and thus decrease the symptoms of LEMS.

PROGNOSIS

Despite these treatments, LEMS is generally progressive over time. Despite its progressive nature, LEMS is seldom accountable for death in patients who suffer from it. Usually, the underlying malignancy results in death before LEMS does.