Lambert-Eaton Myasthenic Syndrome

What is Lambert-Eaton Myasthenic Syndrome?

Lambert-Eaton myasthenic syndrome (LEMS) is a disorder related to the connection between nerves and muscles, which can be due to a bigger medical issue, called a paraneoplastic syndrome, or it can be a primary autoimmune disorder where the body’s immune system mistakenly attacks itself. Many cases are linked with a specific type of lung cancer known as small-cell lung cancer.

The main sign of LEMS is muscle weakness. The scientific reason behind it involves the development of specific antibodies – proteins in your blood produced in reaction to harmful substances. Here, these antibodies mistakenly target parts of the nerve cells responsible for the regulation of calcium, named voltage-gated calcium channels (VGCCs), located on the nerve endings. This results in a decrease in the release of acetylcholine, a chemical that helps transmit signals in the nervous system. Understanding both the cause behind LEMS, how it’s diagnosed, and how it’s treated, is important to manage this condition effectively.

What Causes Lambert-Eaton Myasthenic Syndrome?

LEMS, or Lambert-Eaton Myasthenic Syndrome, is a condition that can be linked to cancer (paraneoplastic) or not linked to cancer (non-paraneoplastic or NT-LEMS). Non-tumor LEMS is defined by not having any connection with cancer. In fact, about 60% of people with LEMS have a cancerous tumor, most commonly a type of lung cancer known as Small Cell Lung Cancer (SCLC).

Aside from SCLC, LEMS can also be connected with other types of cancers like other lung cancers, prostate cancer, thymoma (cancer of the thymus gland), and lymphoproliferative disorders (conditions where lymph cells are produced in excessive amounts). Studies have shown that a person can be diagnosed with LEMS up to 5 to 6 years before they are diagnosed with SCLC. Also, a significant risk factor for developing LEMS is a history of smoking. There is also a genetic link, as about 65% of younger patients with Non-Tumor LEMS have a certain genetic profile known as the HLA–B8–DR3 haplotype.

Risk Factors and Frequency for Lambert-Eaton Myasthenic Syndrome

Lambert-Eaton myasthenic syndrome (LEMS) is a rare condition that affects the nerves and muscles. It is 46 times less common than myasthenia gravis (MG), another similar disease. However, it’s worth noting that the annual rate of new cases of LEMS is only 10 to 14 times lower than MG, highlighting the severe nature of LEMS, particularly if associated with a type of lung cancer known as SCLC.

The majority, or about 60% to 75% of LEMS patients are male, whereas MG is usually more common in females. The typical age of people with LEMS linked to cancer is around 58. However, for LEMS cases that are not related to any form of cancer, the patient’s age and gender distribution are similar to those of MG, with two peak ages at 35 and 60. LEMS that is not associated with cancer often has a survival rate close to normal, indicating a more promising prognosis.

LEMS is a rare nerve and muscle disorder that is 46 times less common than MG.
The annual rate of new LEMS cases is only 10 to 14 times less than MG.
About 60% to 75% of LEMS patients are male.
The average age for LEMS linked with cancer is 58.
For LEMS cases not linked to cancer, the age and gender distribution are similar to those of MG, with two peak ages at 35 and 60.
Lems not associated with cancer generally has a relatively normal survival rate, giving a brighter outlook.

Signs and Symptoms of Lambert-Eaton Myasthenic Syndrome

Lambert-Eaton myasthenic syndrome (LEMS) is a medical condition that mainly shows up in three ways: weakness in the muscles, issues with body functions controlled by the nervous system (autonomic dysfunction), and a decrease or absence of deep tendon reflexes. Symptoms of LEMS usually start quietly and can become worse quickly, especially if it’s associated with a type of lung cancer known as small cell lung cancer (SCLC-LEMS).

The muscle weakness typically affects the thighs and hips first, making it difficult for people to stand up from sitting. This weakness usually starts near the center of the body and moves out towards the hands and feet, and from the bottom to the top of the body. Eventually, it can reach the muscles that control eye movement and swallowing. Patients often feel a dull ache or stiffness in their muscles. Even though the muscles are weak, they don’t usually shrink significantly. After exercising a muscle, it often temporarily becomes stronger and its reflexes improve. This is a unique feature of LEMS called post-exercise facilitation.
Problems with the cranial nerves, which control the eyes, face, throat, and neck, happen in about 70% of people with LEMS. These can include droopy eyelids, double vision, trouble swallowing, and slurred speech. These tend to appear later in the course of the disease.
Autonomic dysfunction, or problems with body functions unconsciously controlled by the nervous system, affect 80% to 96% of people with LEMS. The most common symptom is dry mouth. Men can have erectile dysfunction, and people may experience constipation, low blood pressure when standing up, and changes in sweating.
It’s relatively rare, but in advanced stages of the disease, LEMS can cause respiratory failure, where the lungs aren’t able to provide the body with enough oxygen or remove enough carbon dioxide.

Testing for Lambert-Eaton Myasthenic Syndrome

If you experience symptoms like weakness in the upper body muscles, lack of reflexes, or issues with involuntary functions like heart rate or digestion, your doctor might suspect you have a condition known as Lambert-Eaton Myasthenic Syndrome (LEMS). To confirm this, they’ll likely carry out a few tests.

One of these is a blood test that looks for specific antibodies – proteins your immune system makes to fight infections – that target something called P/Q-type Voltage-Gated Calcium Channels (VGCC). These are found in roughly 85-95% of people with LEMS. However, these are not unique to LEMS and can also be found in people with various neurological and autoimmune disorders. So, it’s not a definitive test for LEMS.

LEMS patients may also have antibodies against N-type VGCC, but this is less common, and SOX1, a specific tumor indicator with a high degree of certainty. However, the latter is usually present in LEMS patients who also have a type of lung cancer called Small Cell Lung Cancer (SCLC).

Electrodiagnostic studies (EDS) are another test your doctor might use to diagnose LEMS. This involves using nerve conduction studies (NCS) and electromyography (EMG), two tests that measure the electrical activity in your muscles and nerves. Typically, these tests show normal results for sensory nerves (those that help you feel), but motor nerves (those that control muscle movement) usually show reduced functionality.

EDS also includes a test called Repetitive Nerve Stimulation (RNS). This is an important test for diagnosing LEMS and it usually shows a decrease in nerve function during low-frequency stimulation but an increase during high-frequency stimulation.

A test known as Single-Fiber EMG (SFEMG) is the most sensitive test for disorders affecting the junction between nerves and muscles. It often shows increased jitter (variability in nerve impulse timing) in patients with LEMS, which usually improves with higher rates of nerve firing. However, RNS is still a commonly used and valuable test because it can help differentiate LEMS from a similar condition called Myasthenia Gravis (MG).

If you are diagnosed with LEMS, your doctor will likely recommend screening for cancer, especially lung cancer. This involves taking images of your body using methods like computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET), to check for the presence of tumors. Without any signs of cancer initially, it is advisable to continue periodic cancer screening for at least 2 years due to LEMS’s connection to cancer.

Patients at a higher risk, particularly those with a specific score derived from factors such as age and smoking history, known as the Dutch-English LEMS Tumor Association Prediction (DELTA-P) score, or positive SOX antibodies associated with SCLC-LEMS, should undergo frequent screenings every 3 months.

Treatment Options for Lambert-Eaton Myasthenic Syndrome

In situations where a person has a condition called Lambert-Eaton Myasthenic Syndrome (LEMS), which is often linked with a type of lung cancer called small cell lung cancer (SCLC), it’s important to treat the cancer, as this is the primary cause of the condition. Besides treating the underlying cancer, managing the symptoms of LEMS is also crucial, and there’s a range of treatment options.

Treatment mainly aims at improving the release of acetylcholine (ACh), a chemical messenger that helps our muscles move, from the areas where our nerves meet our muscles. Here are some ways this can be achieved:

Amifampridine, also called 3,4-diaminopyridine (3,4-DAP), is a medication that helps increase the release of ACh. It does this by blocking certain channels in the nerves that carry electricity, leading to a longer surge of electrical activity in the nerves. This promotes the release of ACh from the nerves into the muscles. It’s often the first option for managing the symptoms of LEMS.

Acetylcholinesterase inhibitors, such as pyridostigmine, help enhance the action of ACh in the body and are used to manage muscle weakness. However, their effects may not be as significant as in patients with Myasthenia Gravis (MG), another neuromuscular disorder.

Guanidine is a substance that can also improve the release of ACh, but due to its potential for significant side effects and possible kidney damage, it’s typically only considered if amifampridine is not available.

Some patients may continue to experience symptoms even after the above treatments. In these situations, treatments that modulate (change) or suppress the body’s immune response, which is involved in the development of LEMS, may be considered.

Intravenous immune globulin (IVIG) is an option for patients who do not respond to initial treatments. It’s believed to work by neutralizing harmful antibodies and balancing immune cells.

Steroids and other agents that suppress the immune system, such as azathioprine, mycophenolate, and cyclosporine, may be considered, but they’re generally not as effective as IVIG. Also, they can cause significant side effects which might limit their use.

Rituximab is a type of drug that targets receptors found on B lymphocytes, a type of white blood cell involved in the immune response. It’s thought to be effective in treating disorders caused by B cells, including LEMS, but more research is needed to confirm its effectiveness.

Lastly, a procedure known as plasma exchange, in which the plasma component of the blood is replaced, could be beneficial in certain hard-to-treat cases.

When a doctor is trying to diagnose Lambert–Eaton syndrome (or LEMS), they might also need to rule out myasthenia gravis (MG). Some clues that it might be LEMS rather than MG are:

Lack of reflexes
Issues with the autonomic system, which controls things like heart rate and digestion
A specific reaction to exercise that is unique to LEMS

Muscle diseases (myopathies) also need to be considered during the diagnostic process. If a patient doesn’t have any sensory symptoms, then the doctor might be able to rule out certain nerve diseases (like polyneuropathy or polyradiculopathies).

What to expect with Lambert-Eaton Myasthenic Syndrome

Patients diagnosed with LEMS, or Lambert-Eaton Myasthenic Syndrome, often find that the condition negatively affects their quality of life due to symptoms like muscle weakness and other body system involvements. Some patients may also experience side effects from the treatments. The good news is that LEMS usually reacts well to treatment. In fact, about 60% of patients are able to maintain their daily activities and independence upon diagnosis. Moreover, within a year of treatment, this figure rises to 85%.

The life expectancy for LEMS patients can depend on the type of LEMS they have. If someone has NT-LEMS, or non-tumor related LEMS, their life expectancy is typically similar to that of the general population. However, with paraneoplastic LEMS, which is associated with cancer, the life expectancy often depends on the underlying cancer. Most commonly, this cancer is SCLC or small cell lung cancer. Interestingly, LEMS patients with SCLC often have better survival rates than those with SCLC who do not have LEMS. On average, they live 17 months as compared to the 7 months expected in non-LEMS SCLC patients.

Possible Complications When Diagnosed with Lambert-Eaton Myasthenic Syndrome

Problems related to LEMS (Lambert-Eaton Myasthenic Syndrome) fall into two categories – those caused by the disorder itself and those that arise from its treatment. The disorder itself can cause complications linked to weakness like injuries from falling, bone fractures, and a type of pneumonia that comes from inhaling food or saliva (aspiration pneumonia). It can also lead to issues due to the involvement of the body’s nervous system controlling involuntary actions (autonomic involvement), like having a dry mouth, constipation, difficulty swallowing (dysphagia), and erectile dysfunction. This could eventually lead to weight loss and ideally extreme thinness (emaciation).

Treatment for LEMS can also bring its own set of problems. These are largely due to the side effects of medications. An example is that certain symptoms like tingling sensations and numbness could be experienced when using 3,4-DAP (a medication for LEMS). Additionally, complications such as a decrease in blood cells (cytopenia) and infections could arise from the use of drugs that suppress the immune system (immunosuppressive drugs).

LEMS-associated complications include:

Falls from weakness
Bone fractures
Aspiration pneumonia
Dry mouth
Constipation
Difficulty swallowing
Erectile dysfunction
Weight loss and extreme thinness

On the other hand, treatment-related complications encompass:

Tingling sensation and numbness from use of 3,4-DAP
Decrease in blood cells from immunosuppressive drugs
Infections due to immunosuppressive drugs

Preventing Lambert-Eaton Myasthenic Syndrome

Lambert-Eaton myasthenic syndrome (LEMS) usually starts slowly and gets worse over time. Patients often feel extremely tired, even when they don’t seem very weak during a doctor’s check-up. It’s important for doctors to suspect this condition so that they can diagnose it quickly. They also need to look out for symptoms related to the body’s automatic functions, like a dry mouth which is the most common issue, followed by erectile dysfunction in men and difficulty passing stools.

Sometimes, doctors discover that a person has LEMS before they find out they have small-cell lung cancer (SCLC); this could be many years before. Doctors will use tests that measure the electrical activity in the muscles (electrophysiological testing), and checks for antibodies against voltage-gated calcium channels (VGCC antibody testing), which help them make a quick and accurate diagnosis. These tests also help them look for signs of hidden cancer.

It’s really important that patients understand their diagnosis, what treatments are available, what they can expect in terms of how their condition may progress, and possible side effects related to their treatment. This empowers patients and their families by giving them a thorough understanding of the disease and what to expect as they move forward.

Frequently asked questions

Lambert-Eaton Myasthenic Syndrome (LEMS) is a disorder related to the connection between nerves and muscles, which can be caused by a paraneoplastic syndrome or a primary autoimmune disorder. It is often associated with small-cell lung cancer.

LEMS is a rare nerve and muscle disorder that is 46 times less common than MG.

Signs and symptoms of Lambert-Eaton Myasthenic Syndrome (LEMS) include: - Muscle weakness, particularly in the thighs and hips, making it difficult to stand up from sitting. This weakness starts in the center of the body and spreads towards the hands and feet, and from the bottom to the top of the body. Eventually, it can affect the muscles controlling eye movement and swallowing. Patients may experience a dull ache or stiffness in their muscles. Interestingly, after exercising a muscle, it often temporarily becomes stronger and its reflexes improve, a unique feature of LEMS known as post-exercise facilitation. - Problems with the cranial nerves, which control the eyes, face, throat, and neck, occur in around 70% of people with LEMS. These can manifest as droopy eyelids, double vision, difficulty swallowing, and slurred speech. These symptoms tend to appear later in the course of the disease. - Autonomic dysfunction, affecting 80% to 96% of individuals with LEMS, involves problems with body functions controlled unconsciously by the nervous system. Dry mouth is the most common symptom. Men may experience erectile dysfunction, and people may also have constipation, low blood pressure upon standing, and changes in sweating. - In advanced stages of the disease, LEMS can lead to respiratory failure, where the lungs are unable to provide sufficient oxygen or remove enough carbon dioxide. However, this is relatively rare.

LEMS can be linked to cancer (paraneoplastic) or not linked to cancer (non-paraneoplastic or NT-LEMS). Non-tumor LEMS is defined by not having any connection with cancer. In fact, about 60% of people with LEMS have a cancerous tumor, most commonly a type of lung cancer known as Small Cell Lung Cancer (SCLC).

Myasthenia gravis (MG) and muscle diseases (myopathies)

The types of tests that are needed for Lambert-Eaton Myasthenic Syndrome (LEMS) include: 1. Blood test: This test looks for specific antibodies that target P/Q-type Voltage-Gated Calcium Channels (VGCC), which are found in a majority of LEMS patients. However, this test is not definitive for LEMS as these antibodies can also be found in other neurological and autoimmune disorders. 2. Electrodiagnostic studies (EDS): This includes nerve conduction studies (NCS) and electromyography (EMG) to measure the electrical activity in muscles and nerves. EDS can show reduced functionality in motor nerves, which control muscle movement, in LEMS patients. 3. Repetitive Nerve Stimulation (RNS) test: This test is important for diagnosing LEMS and typically shows a decrease in nerve function during low-frequency stimulation but an increase during high-frequency stimulation. 4. Single-Fiber EMG (SFEMG): This is the most sensitive test for disorders affecting the junction between nerves and muscles. SFEMG often shows increased jitter in patients with LEMS, which improves with higher rates of nerve firing. In addition to these tests, screening for cancer, especially lung cancer, is recommended for LEMS patients using imaging methods like computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET).

Lambert-Eaton Myasthenic Syndrome (LEMS) is treated by managing the underlying cancer, as it is the primary cause of the condition. In addition to treating the cancer, there are various treatment options available to manage the symptoms of LEMS. These options include medications such as Amifampridine (3,4-DAP) and Acetylcholinesterase inhibitors like pyridostigmine, which help improve the release and action of acetylcholine (ACh) in the body. Guanidine can also be used to enhance ACh release, but it is typically considered only if Amifampridine is not available due to potential side effects. In cases where symptoms persist, treatments that modulate or suppress the immune response, such as Intravenous immune globulin (IVIG), steroids, and other immune-suppressing agents, may be considered. Rituximab, a drug that targets B lymphocytes, and plasma exchange may also be beneficial in certain cases.

When treating Lambert-Eaton Myasthenic Syndrome (LEMS), there can be side effects due to the medications used. Some of the side effects include: - Tingling sensations and numbness from the use of 3,4-DAP medication. - Decrease in blood cells (cytopenia) from immunosuppressive drugs. - Infections due to the use of immunosuppressive drugs.

The prognosis for Lambert-Eaton Myasthenic Syndrome (LEMS) depends on whether it is associated with cancer or not. LEMS that is not associated with cancer generally has a relatively normal survival rate, giving a brighter outlook. However, for LEMS cases that are associated with cancer, the life expectancy often depends on the underlying cancer. LEMS patients with small cell lung cancer (SCLC) often have better survival rates than those without LEMS, living an average of 17 months compared to 7 months for non-LEMS SCLC patients.

A neurologist.

Muscle Weakness Neurology