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Lambert-Eaton Myasthenic Syndrome (LEMS)

  • Author: David E Stickler, MD; Chief Editor: Nicholas Lorenzo, MD, MHA, CPE  more...
 
Updated: May 06, 2016
 

Background

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.[1]

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.[1]

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.

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Pathophysiology

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.

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Etiology

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.

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Epidemiology

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.

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Prognosis

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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Contributor Information and Disclosures
Author

David E Stickler, MD Assistant Professor, Department of Neurosciences, Director of Electromyography Laboratory, Director of MDA Clinic, Director of Neuromuscular Service, Director of ALS Clinic, Medical University of South Carolina

David E Stickler, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine

Disclosure: Nothing to disclose.

Chief Editor

Nicholas Lorenzo, MD, MHA, CPE Founding Editor-in-Chief, eMedicine Neurology; Founder and CEO/CMO, PHLT Consultants; Chief Medical Officer, MeMD Inc

Nicholas Lorenzo, MD, MHA, CPE is a member of the following medical societies: Alpha Omega Alpha, American Association for Physician Leadership, American Academy of Neurology

Disclosure: Nothing to disclose.

Acknowledgements

Paul E Barkhaus, MD Professor, Department of Neurology, Medical College of Wisconsin; Director of Neuromuscular Diseases, Milwaukee Veterans Affairs Medical Center

Paul E Barkhaus, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Neurological Association

Disclosure: Nothing to disclose.

Neil A Busis, MD Chief, Division of Neurology, Department of Medicine, Head, Clinical Neurophysiology Laboratory, University of Pittsburgh Medical Center-Shadyside

Neil A Busis, MD is a member of the following medical societies: American Academy of Neurology and American Association of Neuromuscular and Electrodiagnostic Medicine

Disclosure: Nothing to disclose.

Pamela L Dyne, MD Professor of Clinical Medicine/Emergency Medicine, University of California, Los Angeles, David Geffen School of Medicine; Attending Physician, Department of Emergency Medicine, Olive View-UCLA Medical Center

Pamela L Dyne, MD is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

J Stephen Huff, MD Associate Professor of Emergency Medicine and Neurology, Department of Emergency Medicine, University of Virginia School of Medicine

J Stephen Huff, MD is a member of the following medical societies: American Academy of Emergency Medicine, American Academy of Neurology, American College of Emergency Physicians, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Paul Kleinschmidt, MD Consulting Staff, Department of Emergency Medicine, Womack Army Medical Center

Paul Kleinschmidt, MD is a member of the following medical societies: American Academy of Emergency Medicine

Disclosure: ScrubCast, INC Ownership interest Other

Donald B Sanders, MD EMG Laboratory Director, Professor of Medicine (Neurology), Division of Neurology, Duke University Medical Center

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

References
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  3. Wirtz PW, Sotodeh M, Nijnuis M, Van Doorn PA, Van Engelen BG, Hintzen RQ, et al. Difference in distribution of muscle weakness between myasthenia gravis and the Lambert-Eaton myasthenic syndrome. J Neurol Neurosurg Psychiatry. 2002 Dec. 73(6):766-8. [Medline]. [Full Text].

  4. Sabater L, Titulaer M, Saiz A, Verschuuren J, Güre AO, Graus F. SOX1 antibodies are markers of paraneoplastic Lambert-Eaton myasthenic syndrome. Neurology. 2008 Mar 18. 70(12):924-8. [Medline].

  5. Titulaer MJ, Wirtz PW, Willems LN, van Kralingen KW, Smitt PA, Verschuuren JJ. Screening for small-cell lung cancer: a follow-up study of patients with Lambert-Eaton myasthenic syndrome. J Clin Oncol. 2008 Sep 10. 26(26):4276-81. [Medline].

  6. Keogh M, Sedehizadeh S, Maddison P. Treatment for Lambert-Eaton myasthenic syndrome. Cochrane Database Syst Rev. 2011 Feb 16. 2:CD003279. [Medline].

  7. Tarr TB, Lacomis D, Reddel SW, Liang M, Valdomir G, Frasso M, et al. Complete reversal of Lambert-Eaton myasthenic syndrome synaptic impairment by the combined use of a K+ channel blocker and a Ca2+ channel agonist. J Physiol. 2014 Aug 15. 592:3687-96. [Medline].

  8. Maddison P, Newsom-Davis J. Treatment for Lambert-Eaton myasthenic syndrome. Cochrane Database Syst Rev. 2005 Apr 18. CD003279. [Medline].

  9. Illa I. IVIg in myasthenia gravis, Lambert Eaton myasthenic syndrome and inflammatory myopathies: current status. J Neurol. 2005 May. 252 Suppl 1:I14-8. [Medline].

 
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Characteristic responses to repetitive nerve stimulation in patient with Lambert-Eaton myasthenic syndrome. (A) Responses elicited from hand muscle by stimulation of nerve at 3 Hz. Amplitude of initial response is less than normal, and response is decremental. (B) Responses as in A, immediately after voluntary activation of muscle for 10 seconds. Amplitude has increased. (C) Responses in hand muscle elicited by 20-Hz stimulation of nerve for 10 seconds. Response amplitude is less than normal initially, falls further during first few stimuli, then increases and ultimately becomes more than twice initial value.
Compound muscle action potentials elicited from hand muscle before and immediately after maximal voluntary activation of muscle for 10 seconds. Amplitude is small initially, increasing almost 10 times after activation.
 
 
 
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