It is an autoimmune disease causing muscle weakness, and failure of autonomic nervous system. It is somewhat similar to Myasthenia Gravis but also quite different.

What are typical symptoms of LEMS?

Typically, patient may present with muscle weakness. The pattern of weakness is different from myasthenia gravis. Patient mainly complains of weakness in legs, and unsteadiness. Weakness of upper body can happen but is less common. Other symptoms include dizziness from low blood pressure, mouth dryness, constipation, metallic taste, and erectile dysfunction.

 

How common is LEMS?

It is one of the rare diseases, affecting about 2-5 people in a million.

 

What age group is affected?

Typical age group is 50-60s, and men are more affected than women.

 

What is the relationship between LEMS and cancer?

In about half of the cases, LEMS is associated with a hidden cancer. Small cell lung cancer is the most common association. If not already known, every case of LEMS requires a workup to rule out cancer.

 

What exactly is the problem in LEMS?

Similar to myasthenia gravis, LEMS is a problem with muscles. While it is a problem with muscles, it is not a problem of muscle cells. This means that muscles are affected but not because of a muscle disease. They are indirectly affected. Muscles are normally controlled through signals coming from brain. These electric signals are transmitted through nerves to each and every muscle. When these electrical signals reach a muscle, they do not directly reach a muscle cell as an electric charge. Instead, they pass through a complex process that converts the electrical signal to a biochemical one. This conversion takes place at tiny structures on the muscle fibers called neuromuscular junctions, which in a way are acting as transducers. LES is a defect of these microscopic transducers or neuromuscular junctions.

For anyone looking for more detail, here is more detail. The neuromuscular junction or the transducer has two ends, one on the nerve side and the other on the muscle, like a plug and a switch. LEMS is the problem on the nerve side of this structure, or the plug. There are tiny structures or sacs on that end filled with a chemical called acetylcholine. For the message to go through, some of these sacs have to open up and release acetylcholine. This process starts when the so-called voltage-gated calcium channels (VGCC) are open and release calcium inside the cell. A patient with LEMS has developed antibodies against these channels (specifically, against alpha1-subunit of the P/Q VGCC). With antibodies attached to these channels, they cannot function or open, and release calcium. With less calcium going in, vesicles full of acetylcholine do not release enough acetylcholine, which leads to less amount of signal passing through. After a while, these structures with their attached antibodies can be attacked by the body’s own immune system and destroyed. The whole process leads to decrease in number of these sacs, with decreased amount of acetylcholine release, and weakening of the overall neuromuscular junctions or the transducers. Without proper amount of signal going through, muscles do not function leading to weakness.

 

How is LEMS diagnosed?

Its diagnosis is little bit tricky. Clinically, it presents with proximal muscle weakness, autonomic dysfunction, and areflexia or hyporeflexia on examination. For confirmation, two methods are used:

A: Antibody testing: A particular antibody called voltage-gated calcium channel (VGCC P/Q and N) antibody level is high in LEMS, but is not completely specific to this condition, which means that a person may have high level of this antibody without LEMS. In suspected cases, levels of VGCC, acetylcholine receptor antibodies (blocking, modulating, and binging types), and a para-neoplastic antibody panel should be ordered. If diagnosis is confirmed, with no known h/o cancer, appropriate malignancy screening should be performed. If initially negative, cancer screening can be repeated after a few months.

B: Electrical testing: Both nerve conduction studies (NCS) and electromyogram (EMG) can be used to diagnose, but NCS is more useful than EMG. Finding on NCS are unique and if present, are diagnostic of LEMS. A specialized EMG test called single-fiber EMG can help, but is not available in every neurology office. Also, it is not specific and may not be required. Routine EMG is done to rule out other diseases of nerve and muscle that may also cause weakness, and may look like LEMS. NCS can check electrical potential passing through a nerve. A normal nerve has a particular shape and size of this potential. In LEMS, the size of the electrical potential is typically diminished. This test is done at rest and after exercising the muscle (10 seconds of maximum exercise on 2-Hz to 3-Hz repetitive nerve stimulation). In LEMS, the main finding is an increase in amplitude of action potentials after exercise, the so-called incremental response, or post-exercise facilitation.

 

How is LEMS treated?

Following are the treatment options:

A: 3,4 diaminopyridine (3,4-DAP) and amifampridine: These meds can help with symptoms but do not fix the problem. Each can be taken as a pill 5-20mg three times a day, and each dose lasts for a few hours. It is used with caution in patients with seizures. Otherwise, side effects are minimal, such as paresthesias.

B: Pyridostigmine: It can be used as an adjunct therapy with amifampridine.

C: Intravenous immunoglobulin (IVIg): Intravenous immunoglobulin (IVIg): This is the plasma part of blood, collected from the donated blood after red blood cells are separated. It is given as intravenous infusion. Common risks are allergies, kidney overload (due to high amount of protein), and headaches.

D: Plasmapheresis: This is a procedure similar to dialysis. Patient is attacked to a machine that draws patient’s blood, removes some of the antibodies from it, and delivers it back to the patient. The procedure is done in a hospital and a session may take hours. It is done to remove some antibodies that may be causing the disease.

E: Immune suppressing drugs: Before one considers an immune suppressing drug, it is important to make sure patient does not have a cancer. Otherwise, this kind of treatment may worsen the cancer. If it is found, treating the cancer is the best way forward. If cancer work-up is negative, and patient does not respond to the above treatments, drugs like prednisone or azathioprine can be considered.

F: Miscellaneous: Patient may also need treatment for low blood pressure, mouth dryness, and erectile difficulties.

 

What medicines should a patient with LEMS avoid?

More common are following:

Neuromuscular blockers

Macrolides

Quinolones

Immune checkpoint inhibitors.

 

Where can I find more information about LEMS?

American Academy of Neurology

American Society of Clinical Oncology