Introduction

Lambert-Eaton Myasthenic syndrome (LEMS) is a rare autoimmune disease that is caused by antibody action on the neuromuscular junction (NMJ).¹ Autoimmune diseases occur when the body’s immune system starts to attack its own cells, often causing severe harm. The NMJ is where the nerves relay signals to the muscles for them to contract or relax, allowing for movement. If the NMJ is damaged, muscle weakness and paralysis ensues.¹

To analyze where these antibodies attack the NMJ, it is necessary to understand how nerves communicate with muscles. Neurons use electrical impulses to communicate; these impulses are controlled by the opening and closing of channels on the neurons’ surfaces, which allow charged ions to enter and exit. ¹ The movement of charged ions is similar to electricity, and causes the transmission of signals to the muscles. When the channels that these ions use are blocked or damaged, the electrical impulses cannot occur, and the neurons cannot send signals. At the NMJ, this would be indicated by muscle weakness or paralysis. See Figure 1 for a detailed depiction of the innervated NMJ. ¹

Figure 1: A detailed diagram of the neuromuscular junction or NMJ. The nerve axon terminal comes close to, but does not touch the muscle fibre or sarcolemma. At the synaptic cleft, in the bottom left, it releases neurotransmitters that then bind to the receptor channels in the muscle to generate an effect. Note the importance of the channels at the site where the nerve and muscle meet.

In LEMS, the NMJ is damaged as a result of autoantibodies targeting the P/Q-type voltage-gated calcium channels (VGCC). ³ There are multiple types of LEMS, but the two that are the most common are: LEMS with small cell lung cancer (SCLC) and LEMS that is not present with any cancer. The other types include LEMS that occurs alongside prostate carcinoma, thymoma, and lymphoproliferative disorders (caused by the uncontrolled production of a type of white blood cell). ³

Around 60% of patients with LEMS also have SCLC, and LEMS can even be treated as a sign that this particular cancer may be present.¹ It is important to note that there is no current definitive cure for LEMS, and treatments usually focus on alleviating its symptoms, such as muscle paralysis, instead of treating the underlying cause. However, many drugs are being researched for their effectiveness at treating LEMS.³

Etiology and Pathology
Both the apparent pathophysiology of LEMS and its potential genetic basis will be discussed. As mentioned earlier, autoantibodies attack the VGCC, especially at the NMJ, causing the connection between nerves and muscles to be severed, leading to eventual muscle paralysis.¹ In SCLC, cancer cells have been found to have higher concentrations of P/Q-type VGCC, which are then attacked by the body’s immune system to defend against the cancer. The body produces antibodies against the VGCC, but these antibodies inadvertently attack normal cells as well, leading to LEMS.⁴ Further studies indicate that in some cases, LEMS can be caused by autoantibodies attacking sodium channels as well. ⁵ Sodium channels cause neurons to fire signals, so if they are destroyed, the neuron cannot communicate with other cells.⁵ As apparent, LEMS can involve serious damage to the various ion channels of the body.

The pathophysiology of VGCC in patients with LEMS is also unique; the channels can be observed using immunoelectron microscopy. Normally, calcium channels are arranged in regular arrays, but in this condition, they are arranged in a clustered fashion.⁴ It is unknown whether this has a significant effect on the development of the disease.

Not only does LEMS pathophysiology affect the NMJ, but it also frequently affects the autonomic nervous system. The autonomic nervous system is responsible for involuntary nerve control in the body; this includes heart rate, digestion, sweating, pupil dilation, and so on. ⁴ All connections in this nervous system rely on acetylcholine, which is a neurotransmitter released in the body through calcium channels. Hence, individuals with this condition may also experience autonomic dysfunction symptoms like constipation or a dry mouth.⁴ More information is described in the “Symptoms & Diagnosis” section below.

Finally, a potential genetic basis for LEMS is being thoroughly researched. One gene of particular interest has been the CACNB2 gene, which programs the calcium voltage-gated channel auxiliary subunit beta 2. This is where the autoantibodies have been found to bind in order to disable the VGCC.⁶ No particular disorders with this subunit have been found, but they are an area of active research. Some genetic connections have been made between patients with SCLC and LEMS and genes encoding human leukocyte antigen (HLA) proteins, which are markers in the body that alert the immune response. It is unknown what exactly goes wrong with these molecules and their exact connection with LEMS, but similarities have been observed across patients with the condition.¹

Therefore, the underlying causes of LEMS remain elusive, as research is being done to find treatments that target the immune system dysfunction rather than simply diminish the symptoms. More information regarding the management of this condition is discussed in the “Prognosis” section.

Symptoms & Diagnosis
LEMS is associated with muscle weakness and paralysis, particularly in the extremities. As the disease progresses over months, the mouth, eyes, speech, and other muscles are affected in the same manner. Weight loss occurs, and tendon reflexes are weak. As mentioned above, autonomic dysfunction is frequently present.¹ Some of these autonomic symptoms include dry mouth, dry eyes, blurred vision, poor pupillary adaptation (inability to dilate or constrict the pupil when responding to changes in incoming light), difficulty swallowing, early satiety, and more. Surprisingly, despite the fact that the autonomic nervous system heavily controls breathing, respiration is not usually affected in LEMS patients. The underlying reason for this is still being investigated.⁷ The VGCC and neurons of LEMS patients can also be investigated to examine symptoms, as shown below in Figure 2. Figure 2 examines the differences in membrane potential and neuron firing rates in individuals with or without LEMS. The graphed experiment shown is a definitive test for the diagnosis of this condition.

Figure 2: An examination of neurons in normal and LEMS cells, in mouse tissue. In the first graph, normal cells (control) can synapse and create a large increase in membrane potential. The cells with LEMS, however, do not show this stimulation at all. In the second graph, the control human tissues are compared with LEMS-1 and LEMS-2, two different patients with LEMS, and SN-LEMS, a patient with the symptoms but no autoantibodies detect in the blood. The LEMS channels can hardly fire as much as the control.

After a patient presents with the symptoms described, electrophysiology studies are conducted to measure muscle strength and responses. To detect the autoantibodies responsible, antibody testing is done. Most importantly, PET or CT scans of the body are done to detect any SCLC tumours that may be present with LEMS. ¹ One of the most important aspects of a LEMS diagnosis involves making sure that the patient does not have a similar condition, myasthenia gravis (MG), which also involves muscle weakness. The difference is usually within the eye muscles; MG eye muscle weakness is very common and the patient can hardly keep their eyes open, while this is not very noticeable in LEMS. LEMS is more defined by muscle weakness in the extremities. ¹

Prognosis

The prognosis of the condition is gradual muscle paralysis, which can occur throughout the body if left untreated; in patients who also have SCLC, the effects can be more severe and damaging due to the cancer cells taking metabolic resources away from normal cells. If LEMS presents with cancer, then the cancer is treated principally, as reducing it will cause the LEMS to recede. ¹ Various drugs are being researched and used to attempt to improve the quality of life of individuals with this condition. Amifampridine (also known as Firdapse or Ruzurgi) is the most common treatment used for LEMS. It is a potassium channel blocker that increases acetylcholine levels, stimulating the NMJ, and is quite effective in treating LEMS symptoms through long-term administration. ^1,3,8 Since voltage gated calcium channels can also cause autonomic functions to grow awry, mestinon is another drugused to treat autonomic dysfunction (particularly of the parasympathetic nervous system and sweat glands, both of which rely on acetylcholine function). Finally, immunosuppressants may be used as a last resort to block the action of the autoantibodies. ¹ It is pertinent to note that these treatments target the symptoms of this condition, not its cause.

Children
Children do not need to be screened or tested for LEMS, as patients with this condition are usually males around 40 years of age. The risk of developing LEMS increases in individuals who smoke, as this is linked to SCLC. ⁹ The condition is very rare in younger populations, with only 11 cases of children with the disease reported in scientific literature. ¹

Ayesha Umair

Current Research & Relevant Resources
Most of the current research being done on LEMS involves exploring the benefits of amifampridine. Amifampridine phosphate tablets have been found to be effective in treating LEMS symptoms, and might even be helpful in other diseases of the NMJ. ⁸ One of the main policy advancements in this area has been the 2019 FDA approval of amifampridine use against LEMS in children 6 to 17 years of age. ¹ However, this change is not entirely helpful, as children very rarely develop the disease. More trials on amifampridine, mestinon, immunosuppressants, and immunoglobulins are still being conducted.

Many support groups and organizations exist to help individuals with neuromuscular disorders cope with such conditions, and provide resources so that patients can better understand symptoms and treatments. These include, but are not limited to, the following:

Muscular Dystrophy Association - NORD
Myasthenia Gravis Foundation of America, Inc. - NORD
Genetic and Rare Diseases (GARD) Information Center - NORD
CORD Membership

Works Cited
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5. Blandino JK, Viglione MP, Bradley WA, Oie HK, Kim YI. Voltage-dependent sodium channels in human small-cell lung cancer cells: role in action potentials and inhibition by Lambert-Eaton syndrome. IgG. J Membr Biol. 1995;143(2):153-163. doi:10.1007/BF00234661
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7. Waterman SA. Autonomic dysfunction in Lambert-Eaton myasthenic syndrome. Clin Auton Res. 2001;11(3):145-154. doi:10.1007/BF02329922
8. Mantegazza R. Amifampridine tablets for the treatment of Lambert-Eaton myasthenic syndrome. Expert Rev Clin Pharmacol. 2019;12(11):1013-1018. doi:10.1080/17512433.2019.1681972
9. Gilhus NE. Lambert-eaton myasthenic syndrome; pathogenesis, diagnosis, and therapy. Autoimmune Dis. 2011;2011:973808. doi:10.4061/2011/973808
10. Lorenzoni PJ, Kay CSK, Werneck LC, Scola RH. Lambert-Eaton myasthenic syndrome: the 60th anniversary of Eaton and Lambert's pioneering article. Arq Neuropsiquiatr. 2018;76(2):124-126. doi:10.1590/0004-282X20170194 [0]: https://rarediseases.org/rare-diseases/lambert-eaton-myasthenic-syndrome/ [1]: https://courses.lumenlearning.com/ap1/chapter/skeletal-muscle/ [2]: https://www.ncbi.nlm.nih.gov/gene/783

Cite This Article:

Umair A., Zada D., & Chau J. Lambert-Eaton Myasthenic Syndrome: Treatments and Interactions with Cancer. Illustrated by S. Chen. Rare Disease Review. October 2021. DOI: 10.13140/RG.2.2.15153.51041