Lambert-Eaton syndrome

Lambert-Eaton syndrome: description

The Lambert-Eaton syndrome (LES) belongs to the so-called myasthenia. The main symptom of myasthenia is muscle weakness. The most well-known disease of this group is myasthenia gravis, which is much more common and mostly unrelated to cancer. However, myasthenia gravis and Lambert-Eaton syndrome are very similar in symptoms. In both diseases, signal transmission from the nerve end button to the muscle fibers is disturbed. As a result, in both diseases typically a striking fatigue and weakness of the muscles occurs. In addition, signal transmission is affected by nerves that regulate various basic functions of the body.

Basically, Lambert-Eaton syndrome has to be divided into two groups: First, those cases where Lambert-Eaton syndrome occurs without apparent cause (idiopathic Lambert-Eaton syndrome, about 40 percent). Second, those cases of Lambert-Eaton syndrome that develop in the context of cancer (paraneoplastic Lambert-Eaton syndrome, about 60 percent). The two variants can not be distinguished on the basis of the symptoms. For this reason, when diagnosing a Lambert-Eaton syndrome, it is always necessary to search for tumors as possible triggers.

The idiopathic Lambert-Eaton syndrome occurs in a quarter of cases along with other autoaggressive diseases, such as lupus erythematosus. In the paraneoplastic Lambert-Eaton syndrome, in about 80 percent of cases, a specific type of lung cancer, small cell lung cancer, is responsible for its development. Often, the symptoms of Lambert-Eaton syndrome are up to five years ahead of the disease.

Lambert-Eaton syndrome is extremely rare. In Germany, according to the German Society of Muscular Diseases, about five out of every one million people are affected. Thus, only several hundred people (arithmetically about 400) are affected. Most sufferers are over 40 years old. The average age at onset of illness is around 60 years. Patients with idiopathic Lambert-Eaton syndrome usually have an earlier onset, often less than 40 years old. Men are more likely to be affected by Lambert-Eaton syndrome. This is probably due to the fact that they generally smoke a little more frequently and thus more frequently develop respiratory tumors such as small cell lung cancer.

Lambert-Eaton syndrome: symptoms

The main hallmarks of the Lambert-Eaton syndrome are rapid fatigue of the muscles, a weakening or loss of reflexes and an impairment of the so-called autonomic nervous system. The symptoms typically increase in heavy activity, hot weather or even a hot bath.

muscle weakness

Especially the so-called Girdle musculature is affected by the weakness or paralysis of the muscles. This is the musculature of the shoulder and pelvic area. The muscle weakness usually begins close to the thigh and spreads in the course of the disease up and down. Due to these muscle dysfunctions, gait disorders can occur. In addition, muscle aches and cramps also occur. With strong activity of a muscle, the force can be stronger in the short term for a few seconds. After that, however, it drops significantly. This rapid fatigue is very typical of the Lambert-Eaton syndrome. This is due to the fact 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 disease, Lambert-Eaton syndrome is rare. A failure of the eye muscles leads due to the impaired eyeball movements to double images. In addition, the muscles in the eyelids may also be affected, so that affected persons notice hanging eyelids (ptosis), which can not be opened or at least not fully opened. In severe cases, the respiratory muscles in Lambert-Eaton syndrome may be affected by muscle weakness. Fortunately, this potentially life-threatening complication is very rare. The muscles responsible for speaking and swallowing may also be affected by muscle weakness.

Attenuated or extinguished reflexes

As part of the Lambert-Eaton syndrome also various reflexes may be attenuated or completely extinguished. This is hardly noticeable to sufferers, but for the doctor it is an easily verifiable, important sign of the disease. Disturbed reflexes, however, are not specific to the Lambert-Eaton syndrome, but can occur in a variety of other neurological disorders.

Impairment of the autonomic nervous system

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

Lambert-Eaton syndrome: causes and risk factors

There are two groups of patients regarding the causes of Lambert-Eaton syndrome: On the one hand, Lambert-Eaton syndrome occurs in about 40 percent of cases with no identifiable cause (idiopathic). On the other hand, in about 60% of cases, it is associated with cancer (paraneoplastic) – especially small cell bronchial carcinoma. Likewise, the Lambert-Eaton syndrome can occur in cancers of the blood, such as leukemia. The diagnosis of Lambert-Eaton syndrome may precede the diagnosis of cancer by months or even years. In isolated cases, the cancer was found only five years later.

Antibodies disrupt the transmission of signals from the nerves to the muscles

For a muscle to contract (contract), an electrochemical signal must be transmitted from a nerve to the muscle. This happens at the so-called motor end plate (Synapse). When an electrical stimulus reaches the nerve end at the synapse, calcium flows over certain calcium channels in the nerves. This calcium influx into the nerve endings causes the release of the messenger acetylcholine from the nerve. Acetylcholine travels through the gap between the nerve endings and the muscle (synaptic cleft) and activates special docking sites on the muscle cell membrane. In Lambert-Eaton syndrome, this transmission of signals from a nerve to the muscle is disturbed.

The reason for this is that in people with Lambert-Eaton syndrome certain antibodies circulate in the blood. These antibodies destroy part of the calcium channels mentioned above. This results in a reduced calcium influx and thus a reduced release of the messenger acetylcholine. Thus, the normal signal transmission is attenuated. Since not all calcium channels are destroyed, the contact between the nervous system and the muscles is not completely interrupted, but decisively disturbed.

Paraneoplastic Lambert-Eaton syndrome: cancer cells form calcium channels

The reason for the formation of the autoaggressive antibodies against the calcium channels has not yet been clarified. However, it is clear that cancer cells also have calcium channels on their surface. On cancerous cells of small cell bronchial carcinoma, the exact same channels were found as they also occur at the motor end plate. For this reason, scientists assume that the immune system produces antibodies against these calcium channels to defend against cancer. However, as these channels also occur in the area of ​​the motor end plate, the immune deficiency can cause the above-described disruption of signal transmission in the case of cancers. This hypothesis could also explain that a successful fight against the cancer at the same time significantly improves the course of Lambert-Eaton syndrome.

Idiopathic Lambert-Eaton syndrome: maladjusted immune system

It is still unclear why it can also occur regardless of cancer (and thus no apparent cause) to a Lambert-Eaton syndrome. Scientists suspect that in those with idiopathic Lambert-Eaton syndrome, the immune system is generally dysregulated. This theory is underpinned by the fact that in other people with idiopathic Lambert-Eaton syndrome, other autoaggressive antibodies are frequently formed, resulting in so-called autoimmune diseases. These diseases commonly associated with Lambert-Eaton syndrome include Hashimoto’s thyroiditis (autoimmune thyroiditis, lupus erythematosus and rheumatoid arthritis).

In addition, studies have found that certain genetic factors also play a role in those with idiopathic Lambert-Eaton syndrome. For example, the genetic features HLA-B8, HLA-DR3 and the gene DQ2 are more abundant. These genes are found in many diseases that are caused by autoaggressive processes of the immune system (autoimmunity). The explanation for autoimmune diseases, such as Lambert-Eaton syndrome, may therefore be in the genetic makeup of those affected.

Interactions with drugs

Medication may also affect the onset and severity of Lambert-Eaton syndrome: A number of commonly used medications may worsen the symptoms of Lambert-Eaton syndrome. These include drugs that are used in anesthesia, but also some antibiotics and benzodiazepines such as diazepam. For this reason, every use of medication in patients with Lambert-Eaton syndrome must be checked carefully. Every attending physician should be informed about the presence of the disease.

Lambert-Eaton syndrome: examinations and diagnosis

The right contact for suspected Lambert-Eaton syndrome is a specialist in neurology. For clarification, other doctors can be involved in the diagnosis and treatment, including radiologists and oncologists. At the doctor’s appointment, the exact description of the symptoms can already provide important information on a Lambert-Eaton syndrome. The neurologist could ask the following questions during an anamnesis interview:

• Have you noticed a rapid fatigability of the muscles, for example when climbing stairs or longer walking distances?
• Do you have problems with urination, bowel movements or sexual activity?
• Do you have a noticeably dry mouth?
• Do you suffer from visual disturbances (for example double vision) or have you noticed hanging eyelids?
• Is there a cancer or autoimmune disease known to you or your family?
• Which medications do you take?

This is followed by a physical examination in which, in particular, neurological findings are recorded. , This means that the doctor checks the function of the nervous system with various tests. Among other things, this examination includes the investigation of muscle strength and reflexes.

To test muscle strength, the doctor will ask the patient to briefly tense a muscle with maximum force. The tension in the Lambert-Eaton syndrome shows a brief improvement in muscle strength for 10 to 15 seconds. With prolonged muscle tension, however, this decreases significantly. This is an important indication of the Lambert-Eaton syndrome. In addition, getting up from the squat is checked. This is usually complicated by the affected thigh muscles or even impossible.

As part of the examination, the doctor will check important reflexes. These include, among other things, the known impact below the kneecap to trigger the patellar tendon reflex (PSR). In the Lambert-Eaton syndrome, the reflexes are typically only weakly triggered or completely extinguished. However, this is not a specific sign for the Lambert-Eaton syndrome, but can also occur in the context of other diseases. Nevertheless, the review is very important, as it can be very easily conclusions about the gross functioning of the nervous system can be obtained.

Further investigations

Weakened muscular strength and extinguished reflexes already indicate a neurological disease. For the diagnosis of Lambert-Eaton syndrome, however, more and more examinations are necessary. The examinations include electrophysiological tests, a blood test and, if necessary, imaging tests for the discovery of a cancer:

Electrophysiological examinations

These include various tests that can be used to check the normal function of nerves and muscles. For example, if a Lambert-Eaton syndrome is suspected, electrical muscle activity is measured using an electromyogram (EMG). From this, conclusions can be drawn as to whether muscle weakness arises primarily as a result of nerve damage or a disorder of the muscle: electrodes can be used to stimulate a muscle and record the electrical activity. With repetitive high-frequency irritation with very low power surges, the muscle activity of the Lambert-Eaton syndrome improves in the short term. The increase in muscle activity due to repeated irritation is typical of Lambert-Eaton syndrome and is referred to as increment. With the help of the electromyogram, the course of the Lambert-Eaton syndrome can be monitored.

blood test

In 90 percent of those affected can detect in the blood different antibodies that are typical of the disease. The therapy can lower the concentration of antibodies in the blood. This can be measured in addition to the reduction of symptoms, a treatment success.

tumor search

Since Lambert-Eaton syndrome occurs in the majority of cases in the context of an underlying cancer, the investigation must be intensively searched for a cancer. These are primarily imaging techniques such as computed tomography (CT), magnetic resonance imaging (MRI) or positron emission tomography (PET). If the examination was inconspicuous, it should be repeated as recommended by the treating physician so as not to overlook any tumor growth. 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 the treatment of Lambert-Eaton syndrome is the fight against the often underlying cancer. If chemotherapy, radiation or surgery shrinks the tumor or, in the best case, completely removes it, the symptoms of Lambert-Eaton syndrome disappear. The exact course of treatment depends on whether there is paraneoplastic or idiopathic Lambert-Eaton syndrome (see “Description”). The therapy of the Lambert Eaton syndrome aims on the one hand at the reduction of the symptoms and on the other hand at an attenuation of the misguided immune system (immunomodulation).

Symptomatic therapy

The most important drug in the symptomatic treatment of Lambert-Eaton syndrome are the substances amifampridine and 3,4-diaminopyridine, These drugs block channels through which potassium escapes from the nerve cells. Thus, the reduced influx of calcium can be compensated. The electrical voltage, which leads to the release of the messenger, can be kept longer. As a result, the still functioning calcium channels remain open longer and can thus replace the failed channels. The drugs can thus improve muscle strength and repair disorders of the autonomic nervous system.

So far not sufficiently scientifically proven is the additional administration of pyridostigmine for the treatment of the Lambert Eaton syndrome. However, some experts use this drug. This drug inhibits the breakdown of the messenger substance (acetylcholine), so that it can act on the muscle after release more.

immunomodulation

If amidopridine or 3,4-diaminopyridine can not sufficiently alleviate the symptoms of Lambert-Eaton syndrome, medications 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 sufficient efficacy is not achieved, additional immunosuppressive drugs may be used. In contrast, in a paraneoplastic Lambert-Eaton syndrome, immunosuppressive treatment does not make sense, as the immune system is urgently needed to fight cancer cells, and drug-induced weakening of the immune system would promote cancer growth.

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

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

Lambert-Eaton syndrome: disease course and prognosis

Overall, the typical symptoms in the course of the disease often increase. While at the beginning of the Lambert-Eaton syndrome, for example, often only the proximal muscle groups (thighs, upper arm) are affected, the muscle weakness in the further course can also extend to the body (feet, fingers) and to the face. The symptomatic therapy can alleviate the symptoms for the most part. 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 cancer therapy. If this is the case, the symptoms improve, while the Lambert-Eaton syndrome also deteriorates in cancer recurrence.

In contrast, the prognosis of the idiopathic Lambert-Eaton syndrome is better overall. In about 88 percent of cases, muscular strength improves with an average duration of six years’ immunosuppression. Without permanent treatment, however, only a few patients come along Lambert-Eaton syndrome out.