Lambert-Eaton Myasthenic Syndrome (LEMS)
- Author: David E Stickler, MD; Chief Editor: Nicholas Lorenzo, MD, MHA, CPE more...
Lambert-Eaton myasthenic syndrome (LEMS) is a rare presynaptic disorder of neuromuscular transmission in which quantal release of acetylcholine (ACh) is impaired, causing a unique set of clinical characteristics, which include proximal muscle weakness, depressed tendon reflexes, posttetanic potentiation, and autonomic changes. The initial presentation can be similar to that of myasthenia gravis (MG), but the progressions of the 2 diseases have some important differences.
LEMS disrupts the normally reliable neurotransmission at the neuromuscular junction (NMJ). This disruption is thought to result from an autoantibody-mediated removal of a subset of the P/Q-type Ca2+ channels involved with neurotransmitter release.
In 40% of patients with LEMS, cancer is present when the weakness begins or is found later. This is usually a small cell lung cancer (SCLC), although LEMS has also been associated with non-SCLC, lymphosarcoma, malignant thymoma, or carcinoma of the breast, stomach, colon, prostate, bladder, kidney, or gallbladder.
Clinical manifestations frequently precede cancer identification. In most cases, the cancer is discovered within the first 2 years after onset of LEMS and, in virtually all cases, within 4 years.
Physiologic studies of neuromuscular transmission demonstrate that ACh release from the motor nerve terminal is impaired in the LEMS muscle. An autoimmune attack directed against the voltage-gated calcium channels (VGCCs) on the presynaptic motor nerve terminal results in a loss of functional VGCCs at the motor nerve terminals.
The number of quanta released by a nerve impulse is diminished. However, because presynaptic stores of ACh and the postsynaptic response to ACh remain intact, rapid repetitive stimulation or voluntary activation that aids in the release of quanta will raise the endplate potential above threshold and permit generation of muscle action potential.
As neuromuscular transmission is completed at additional neuromuscular junctions, a transient increase will occur in the strength of the muscle. Parasympathetic, sympathetic, and enteric neurons are all affected. Clinically, this phenomenon is noted by the appearance of previously absent tendon reflexes following a short period of strong muscle contraction by the patient.
For many years, clinical observations suggested an autoimmune etiology for LEMS. Such observations included the following:
LEMS is frequently associated with known autoimmune diseases
Prednisone, plasma exchange (PEX), and intravenous immunoglobulin (IVIg) are effective treatments
Patients with LEMS but without cancer frequently have elevated serum levels of organ-specific autoantibodies
More direct evidence has been accumulated supporting the autoimmune etiology of LEMS. Active zone particles (AZPs), which represent the VGCCs, are normally arranged in regular parallel arrays on the presynaptic muscle membrane. In patients with LEMS and in mice injected with LEMS immunoglobulin G (IgG), divalent antibodies against the VGCC cross-link the calcium channels, disrupting the parallel arrays. Ultimately, the AZPs cluster and decrease in number.
SCLC cells originate from neuroectoderm, share a number of antigens with peripheral nervous system tissue, and contain high concentrations of VGCCs. Calcium influx into these cells is inhibited by LEMS IgG. Antibodies to VGCCs are found in the serum of most LEMS patients. These observations suggest that VGCC antibodies downregulate VGCCs in LEMS.
In patients with LEMS who have SCLC or other cancer, cancer cells presumably contain antigens that mimic VGCCs and induce production of VGCC antibodies. In patients with LEMS but no cancer, VGCC antibodies are probably produced as part of a more general autoimmune state. In patients who have LEMS without cancer, an antibody response to domain IV of the 1A subunit of P/Q-type VGCCs is more common than in patients who have LEMS with cancer.
VGCC antibody levels do not correlate with disease severity among patients with LEMS. However, antibody levels do fall in individual patients if the disease improves after cancer therapy or immunosuppression.
All patients with LEMS who have associated SCLC have a history of long-term smoking. Only half of patients with autoimmune LEMS are long-term smokers.
United States statistics
The true incidence of LEMS is unknown. An estimated 3% of patients with SCLC have LEMS. The prevalence of SCLC is 5 cases per million population in the United States. Because only 50-70% of patients with LEMS have an identifiable cancer and because LEMS goes undiagnosed in many patients, the true total prevalence of LEMS may be considerably higher.
The overwhelming majority of cancers associated with LEMS are SCLC. However, many different malignancies may be involved. A partial list includes non-SCLC; neuroendocrine carcinomas; lymphosarcoma; malignant thymoma; cancers of the breast, stomach, colon, prostate, bladder, kidney, gallbladder, and rectum; basal cell carcinoma; leukemia; lymphoproliferative disorders such as Castleman syndrome; and Hodgkin lymphoma.
According to one estimate, there are approximately 400 cases in the United States at any given time. However, this estimate does not take into account the number of patients with LEMS who do not have SCLC or any other identifiable malignancy.
Age- and sex-related demographics
LEMS usually begins in later adulthood and is primarily a disease of middle-aged and older people. The most common age for the appearance of symptoms is 60 years. It is rare in children; however, at least 7 children younger than 17 years are reported to have had LEMS.
In earlier reports, LEMS occurred in males more frequently than females, by a ratio of almost 2:1. However, current reports note almost equal frequency in men and women.
The prognosis is often difficult to assess. It is largely determined by the presence and type of any underlying cancer, the presence and severity of any associated autoimmune disease, and the severity and distribution of weakness. In addition, patients with rapidly progressive symptoms usually have more severe disease.
The main problem created by LEMS is the progressive weakness that affects everyday activities and general quality of life. LEMS does not seem to affect the respiratory system as significantly as MG does. In most patients, weakness does not severely affect vital muscles. Maximum severity usually becomes established within several months of symptom onset.
In most cases, therapy with agents such as 3,4-diaminopyridine (DAP) may help to relieve symptoms partially, but usually symptoms progress over time. Without treatment, weakness and dysfunction do not usually vary. Exceptions are during periods of exacerbation induced by intercurrent illness or by medications that impair neuromuscular transmission.
Eventually, the weakness caused by LEMS can have profound consequences. However, death often results from the underlying malignancy. The diagnosis of LEMS frequently heralds cancer. This association is important in overall morbidity, since there is a very short survival time with SCLC.
Because LEMS may lead to early detection of SCLC, prognosis of SCLC in patients with SCLC-LEMS is better than in SCLC without LEMS. Patients with SCLC who develop LEMS possibly have a more effective immunologic response to the cancer, which results in improved survival. A more rapid clinical course is more frequent in patients with SCLC-LEMS.
When LEMS has been symptomatic for at least 2 years and no underlying cancer has been demonstrated, the LEMS was probably caused by an autoimmune process. At that point, prognosis is determined by severity of dysfunction and the presence and severity of other autoimmune conditions.
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