Lambert-Eaton Syndrome

Clemens Gödel is a freelancer for the medical team.

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Lambert-Eaton syndrome (Lambert-Eaton myasthenia syndrome) is a rare disease in which the signal transmission of the nerves is disturbed. The main symptoms of Lambert-Eaton syndrome are muscle weakness, reflex failures and impaired regulation of various body functions. In about 60 percent of cases, Lambert-Eaton syndrome occurs in the context of cancer. It is particularly typical in so-called small cell lung cancer. Therapeutically, the cancer must first and foremost be combated and the symptoms treated. Read everything about symptoms, diagnosis and therapy here.

ICD codes for this disease: ICD codes are internationally recognized codes for medical diagnoses. They can be found, for example, in doctor's letters or on certificates of incapacity for work. G70

Lambert-Eaton syndrome: description

Lambert-Eaton syndrome (LES) is one of the so-called myasthenias. The main symptom of myasthenia is muscle weakness. The best-known disease in this group is myasthenia gravis, which is much more common and usually does not occur in connection with cancer. However, myasthenia gravis and Lambert-Eaton syndrome are very similar in terms of symptoms. In both diseases, the signal transmission from the nerve endbones to the muscle fibers is disturbed. As a result, both diseases typically lead to a noticeable fatigue and weakness of the muscles. Signal transmission by nerves, which regulate various basic functions of the body, is also affected.

Basically, two groups must be distinguished in Lambert-Eaton syndrome: First, those cases in which Lambert-Eaton syndrome occurs without an identifiable cause (idiopathic Lambert-Eaton syndrome, about 40 percent). Second, those cases of Lambert-Eaton syndrome that arise in the context of cancer (paraneoplastic Lambert-Eaton syndrome, about 60 percent). The two variants cannot be differentiated based on the symptoms. For this reason, when diagnosing Lambert-Eaton syndrome, tumors must always be looked for as possible triggers.

The idiopathic Lambert-Eaton syndrome occurs in a quarter of all cases together with other autoaggressive diseases, such as lupus erythematosus. In paraneoplastic Lambert-Eaton syndrome, a certain type of lung cancer, small cell lung cancer, is responsible for the development in about 80 percent of cases. The symptoms of Lambert-Eaton syndrome often precede the tumor by up to five years.

Lambert-Eaton syndrome is extremely rare. According to the German Society for Muscle Sick People, around five in one million people are affected in Germany. This means that only several hundred people (around 400 mathematically) are affected. Most of those affected are over 40 years old. The average age at the onset of the disease is around 60 years. Patients with idiopathic Lambert-Eaton syndrome usually have an earlier onset of the disease, which is often less than 40 years of age. Men are more likely to have Lambert-Eaton syndrome. This is probably due to the fact that they smoke a little more often overall and thus more often develop airway tumors such as small-cell lung cancer.

Lambert-Eaton syndrome: symptoms

The main characteristics of Lambert-Eaton syndrome are rapid fatigue of the muscles, weakening or loss of reflexes and impairment of the so-called autonomic nervous system. Symptoms typically worsen with vigorous activity, hot weather, or even a hot bath.

Muscle weakness

The so-called limb girdle muscles are particularly affected by the weakness or paralysis of the muscles. These are the muscles of the shoulder and pelvic area. The muscle weakness usually begins close to the thigh and spreads up and down as the disease progresses. These muscle dysfunction can lead to gait disorders. In addition, muscle pain and cramps also occur. When a muscle is very active, the force can be stronger for a few seconds. After that, however, it drops significantly. This rapid exhaustion is very typical of the Lambert-Eaton syndrome. The reason for this is that the activation of the calcium channels increases the release of messenger substances in the short term (see causes and risk factors).

The muscles around the eyes can also be affected. While the involvement of the eye muscles in myasthenia gravis is an early sign of the disease, it rarely occurs in Lambert-Eaton syndrome. A failure of the eye muscles leads to double vision due to the impaired movements of the eyeball. The muscles in the eyelids can also be affected, so that those affected notice drooping eyelids (ptosis) that cannot be opened or at least cannot be opened completely. In pronounced cases, the respiratory muscles in Lambert-Eaton syndrome can also be affected by muscle weakness. Fortunately, this potentially life-threatening complication is very rare. The muscles responsible for speaking and swallowing can also be affected by muscle weakness.

Weakened or extinguished reflexes

As part of the Lambert-Eaton syndrome, various reflexes can also be weakened or completely extinguished. Those affected hardly notice this themselves, but for the doctor it is an important sign of the disease that is easy to check. Disturbed reflexes are not specific to Lambert-Eaton syndrome, but can occur in a variety of other neurological diseases.

Impairment of the autonomic nervous system

The nerves of the so-called autonomic nervous system are important for the unconscious control of important basic functions of the body. These functions include the regulation of salivary glands, gastrointestinal activity, the urinary bladder and other unconsciously controlled processes in the body. For this reason, those affected by Lambert-Eaton syndrome suffer from symptoms such as dry mouth, constipation, erectile dysfunction, as well as impaired focusing while seeing. Furthermore, the emptying of the bladder can be disturbed.

Lambert-Eaton syndrome: causes and risk factors

With regard to the causes of Lambert-Eaton syndrome, a distinction is made between two groups of patients: On the one hand, Lambert-Eaton syndrome occurs in around 40 percent of cases without an identifiable cause (idiopathic). On the other hand, it occurs in around 60 percent of cases in connection with cancer (paraneoplastic) - especially small cell lung cancer. Lambert-Eaton syndrome can also occur in blood cancers such as leukemia. The diagnosis of Lambert-Eaton syndrome can sometimes precede the diagnosis of cancer by months or even years. In individual cases, the cancer was not found until five years later.

Antibodies interfere with the transmission of signals from the nerves to the muscles

In order for a muscle to contract (contract), an electrochemical signal must be transmitted from a nerve to the muscle. This takes place at the so-called motor end plate (synapse). When an electrical stimulus reaches the nerve endings at the synapse, calcium flows into the nerves through certain calcium channels. This influx of calcium into the nerve endings causes the neurotransmitter acetylcholine to be released. The acetylcholine passes through the gap between the nerve endings and the muscle (synaptic gap) and activates special docking points on the muscle cell membrane. In Lambert-Eaton syndrome, this transmission of signals from a nerve to the muscle is disturbed.

This is because people with Lambert-Eaton syndrome have certain antibodies circulating in the blood. These antibodies destroy some of the calcium channels mentioned above. This results in a reduced influx of calcium and thus a reduced release of the messenger substance acetylcholine. Normal signal transmission is thus weakened. However, since not all calcium channels are destroyed, the contact between the nervous system and muscles is not completely interrupted, but rather significantly disturbed.

Paraneoplastic Lambert-Eaton Syndrome: Cancer cells form calcium channels

Why it comes to the formation of the autoaggressive antibodies against the calcium channels has not yet been clarified with certainty. What is certain, however, is that cancer cells also have calcium channels on their surface. Exactly the same channels were found on cancer cells of small cell bronchial carcinoma as are also found on the motor endplate. For this reason, scientists believe that the immune system makes antibodies against these calcium channels in order to defend itself against the cancer. However, since these channels also occur in the area of the motor endplate, the above-described disturbance of signal transmission can occur in cancer diseases through the immune defense. This hypothesis could also explain that a successful fight against cancer at the same time significantly improves the course of Lambert-Eaton syndrome.

Idiopathic Lambert-Eaton Syndrome: Dysregulated immune system

It is still unclear why Lambert-Eaton syndrome can occur independently of cancer (and therefore without an identifiable cause). Scientists suspect that the immune system is generally dysregulated in people with idiopathic Lambert-Eaton syndrome. This theory is supported by the fact that people with idiopathic Lambert-Eaton syndrome often also develop other autoaggressive antibodies and thereby develop so-called autoimmune diseases. These diseases, which often occur with Lambert-Eaton syndrome, include Hashimoto's thyroiditis (an autoimmune inflammation of the thyroid gland, lupus erythematosus and rheumatoid arthritis.

In addition, studies have found that certain genetic factors also play a role in people with idiopathic Lambert-Eaton syndrome. For example, the genetic traits HLA-B8, HLA-DR3 and the DQ2 gene occur more frequently. These genes are found in many diseases that are caused by autoaggressive processes in the immune system (autoimmunity). So the explanation for autoimmune diseases such as Lambert-Eaton syndrome seems to lie in the genetic makeup of those affected.

Drug interactions

Medicines may also have an influence on the development and severity of the symptoms in Lambert-Eaton syndrome: A number of drugs, some of which are frequently used, lead to the worsening of the symptoms of Lambert-Eaton syndrome. These include drugs that are used for anesthesia, but also some antibiotics and benzodiazepines such as diazepam. For this reason, every use of medication in people with Lambert-Eaton syndrome must be carefully checked. Every attending physician should be informed about the presence of the disease.

Lambert-Eaton Syndrome: Investigations and Diagnosis

The right person to contact if you suspect Lambert-Eaton syndrome is a specialist in neurology. For clarification, further doctors can be involved in the diagnosis and treatment, including radiologists and oncologists. At the doctor's appointment, a precise description of the symptoms can provide important clues for Lambert-Eaton syndrome. The neurologist could ask the following questions during the anamnesis interview:

Have you noticed that your muscles tire quickly, for example when climbing stairs or walking long distances?
Are you having problems urinating, bowel movements, or sexual activity?
Do you have a noticeably dry mouth?
Do you suffer from visual disturbances (e.g. double vision) or have you noticed droopy eyelids?
Do you or your loved ones have any known cancer or autoimmune diseases?
What medications are you taking?

This is followed by the physical examination, during which neurological findings in particular are collected. . This means that the doctor uses various tests to check the functioning of the nervous system. This test includes, among other things, the examination of muscle strength and reflexes.

To test muscle strength, the doctor will ask the patient to briefly contract a muscle with maximum force. The tension in the Lambert-Eaton syndrome shows a brief improvement in muscle strength for 10 to 15 seconds. However, if the muscle tension persists, this decreases significantly. This is an important clue about Lambert-Eaton syndrome. In addition, getting up from a crouch is checked. This is usually made difficult or even impossible by the affected thigh muscles.

During the examination, the doctor will examine important reflexes. This includes the well-known blow under the kneecap to trigger the patellar tendon reflex (PSR). In Lambert-Eaton syndrome, the reflexes are typically only weakly triggered or completely extinguished. However, this is not a specific sign of Lambert-Eaton syndrome, but can also occur in the context of other diseases. However, the check is very important because it is very easy to draw conclusions about the general functionality of the nervous system.

Further investigations

Weakened muscle strength and extinguished reflexes already indicate a neurological disease. However, further examinations are always necessary to diagnose Lambert-Eaton syndrome. The examinations include electrophysiological tests, a blood test and, if necessary, imaging tests to detect cancer:

Electrophysiological studies

This includes various tests that can be used to check the normal function of nerves and muscles. If Lambert-Eaton syndrome is suspected, electrical muscle activity is measured using an electromyogram (EMG), for example. From this, conclusions can be drawn as to whether a muscle weakness is primarily due to nerve damage or a muscle disorder: With the help of electrodes, a muscle can be stimulated and the electrical activity recorded. With repeated high-frequency stimulation with very low current surges, the activity of the muscle improves briefly in Lambert-Eaton syndrome. The increase in muscle activity from repeated stimulation is typical of Lambert-Eaton syndrome and is known as an increment. The course of the Lambert-Eaton syndrome can also be monitored with the help of the electromyogram.

Blood test

In 90 percent of those affected, various antibodies can be detected in the blood that are typical for the disease. The therapy can reduce the antibody concentration in the blood. In addition to the reduction in symptoms, this can be used to measure the success of the treatment.

Tumor search

Since Lambert-Eaton syndrome occurs in the majority of cases in the context of an underlying cancer, the examination must be intensively searched for a cancer.For this purpose, imaging methods such as computed tomography (CT), magnetic resonance tomography (MRT) or positron emission tomography (PET) are primarily used. If the examination was inconspicuous, it should be repeated closely, as recommended by the attending physician, so that no tumor growth is overlooked. If so-called SOX1 antibodies can be detected in the blood, cancer is likely to be the cause of Lambert-Eaton syndrome, even if a tumor has not yet been detected.

Lambert-Eaton Syndrome: Treatment

The cornerstone of therapy for Lambert-Eaton syndrome is the fight against the cancer, which is often the underlying disease. If the tumor is reduced in size or, in the best case, completely removed with chemotherapy, radiation or surgery, the symptoms of Lambert-Eaton syndrome also disappear. The exact course of treatment depends on whether you have paraneoplastic or idiopathic Lambert-Eaton syndrome (see “Description”). The therapy of the Lambert-Eaton syndrome aims on the one hand to reduce the symptoms and on the other hand to dampen the malfunctioning immune system (immune modulation).

Symptomatic therapy

The most important drugs in the symptomatic therapy of Lambert-Eaton syndrome are the substances amifampridine and 3,4-diaminopyridine. These drugs block channels that allow potassium to leak out of nerve cells. In this way, the reduced influx of calcium can be compensated for. The electrical voltage that leads to the release of the messenger substance can thus be maintained longer. As a result, the still functional calcium channels remain open longer and can thus replace the failed channels. The drugs can therefore improve muscle strength and correct disorders of the autonomic nervous system.

The additional administration of pyridostigmine for the treatment of Lambert-Eaton syndrome has not yet been adequately scientifically proven. However, some experts use this drug. This drug inhibits the breakdown of the messenger substance (acetylcholine), which means that it can work longer on the muscle after it has been released.

Immune modulation

If the symptoms of idopathic Lambert-Eaton syndrome cannot be sufficiently relieved by amifampridine or 3,4-diaminopyridine, drugs that slow the immune system (immunosuppression) should be used. At the beginning, the use of cortisone (prednisolone) and the active ingredient azathioprine is recommended. If it is not sufficiently effective, other immunosuppressive drugs can be used. In the case of paraneoplastic Lambert-Eaton syndrome, however, treatment that suppresses the immune system does not make sense, as the immune system is urgently needed to fight cancer cells and a drug weakening of the immune system would promote cancer growth.

In acute cases, the pathological antibodies can be intercepted with the help of artificial antibodies (intravenous immunoglobulins). These artificial antibodies are given into the blood through the vein under medical supervision. The effect of these antibodies reaches its maximum after about two to four weeks and lasts for four weeks.

The so-called plasma exchange (plasmapheresis) can also be carried out in severe cases. Similar to dialysis, the blood is conducted past a membrane. As a result, components of the immune system, especially antibodies, are retained. The effect of repeated plasma exchanges lasts for two to six weeks.

Lambert-Eaton syndrome: disease course and prognosis

Overall, the typical symptoms often increase in the course of the disease. For example, while at the beginning of the Lambert-Eaton syndrome only the muscle groups near the body (thighs, upper arm) are often affected, the muscle weakness can spread further away from the body (feet, fingers) and to the face. Symptomatic therapy can largely alleviate the symptoms. The prognosis depends on whether it is a cancer-associated (paraneoplastic) or idiopathic form of the disease.

The course of the paraneoplastic Lambert-Eaton syndrome depends heavily on the success of the cancer therapy. If this is the case, the symptoms improve, while the Lambert-Eaton syndrome also worsens with cancer relapses.

In contrast, the prognosis for idiopathic Lambert-Eaton syndrome is overall better. Muscle strength improves in around 88 percent of cases with an average duration of immunosuppression of six years. However, only a few patients with Lambert-Eaton syndrome manage without long-term treatment.

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