eMedicine Specialties > Neurology > Neuromuscular Diseases

Lambert-Eaton Myasthenic Syndrome

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
Coauthor(s): Donald B Sanders, MD, EMG Laboratory Director, Professor of Medicine (Neurology), Division of Neurology, Duke University Medical Center
Contributor Information and Disclosures

Updated: Jan 29, 2009

Introduction

Background

Lambert-Eaton myasthenic syndrome (LEMS) is a rare condition in which weakness results from an abnormality of acetylcholine (ACh) release at the neuromuscular junction. LEMS results from an autoimmune attack against voltage-gated calcium channels (VGCC) on the presynaptic motor nerve terminal.

Cancer is present when the weakness begins or is later found in 40% of patients with LEMS. 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.

Pathophysiology

Physiological studies of neuromuscular transmission demonstrate that ACh release from the motor nerve terminal is impaired in the LEMS muscle. The effect of ACh on the postsynaptic muscle membrane is normal.

The following clinical observations suggest autoimmune etiology: LEMS is frequently associated with known autoimmune diseases. Prednisone, plasma exchange (PEX), and intravenous hyperimmune human gamma globulin (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 (AZP), 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 VGCC. Calcium influx into these cells is inhibited by LEMS IgG. Antibodies to VGCC are found in the serum of most LEMS patients. These observations suggest that VGCC antibodies down-regulate VGCC in LEMS.

In patients with LEMS who have SCLC or other cancer, cancer cells presumably contain antigens that mimic VGCC 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 with LEMS without cancer, an antibody response to domain IV of the 1A subunit of P/Q-type VGCC is more common then in 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.

Frequency

United States

An estimated 3% of patients with SCLC have LEMS. The prevalence of SCLC is 5 cases per million population in the United States. Only half of patients with LEMS have a tumor, so total prevalence is at least double this figure (1 case per 100,000 population). Because in many patients LEMS is undiagnosed, the true incidence is probably higher.

Mortality/Morbidity

Morbidity and mortality correlate with the morbidity and mortality of the underlying SCLC.

Sex

In earlier reports, LEMS occurred in males more frequently than females by a ratio of almost 2:1. However, more recent studies show that the sex incidence is almost equal.

Age

LEMS usually begins in later adulthood; it can occur in children, but rarely.

Clinical

History

Symptoms usually begin insidiously. Many patients have symptoms for months or years before the diagnosis is made. Weakness is the major symptom, with proximal muscles more affected than distal muscles (especially in the lower limbs).

• The typical patient with LEMS presents with slowly progressive proximal leg weakness.
  • Weak muscles may ache and are occasionally tender.
  • Oropharyngeal and ocular muscles may be mildly affected.
  • Respiratory muscles are not usually affected, but cases with severe respiratory compromise have been reported.
• Most patients have a dry mouth, which frequently precedes other symptoms of LEMS. Many do not mention this unless specifically questioned.
  • Many patients report an unpleasant metallic taste.
  • Some patients have other manifestations of autonomic dysfunction, including impotence in males and postural hypotension.
• LEMS may be discovered first when prolonged paralysis follows the use of neuromuscular blocking agents during surgery.
• Exacerbation of weakness has been described following administration of aminoglycoside or fluoroquinolone antibiotics, magnesium, calcium channel blockers, and iodinated intravenous contrast agents.
• Relationship between cancer and LEMS
  • Smoking and age at onset are major risk factors for cancer in patients with LEMS.
  • Duration of symptoms is a factor.
  • If a tumor is not found within the first 2 years after symptom onset, cancer is unlikely. For example, a patient younger than 50 years at onset who does not have a tumor discovered after 2 years of close follow-up is unlikely to have an underlying cancer. On the other hand, a long-term smoker with LEMS onset after age 50 years probably has underlying lung cancer.

Physical

Weakness is usually mild compared to the patient's reports.

• Strength is usually reduced in proximal muscles of the legs and arms, producing a waddling gait and difficulty elevating the arms.
• Some degree of eyelid ptosis or diplopia, usually mild, is found in 25% of patients. Occasionally, difficulty chewing, dysphagia, or dysarthria is present.
• Most patients have a dry mouth, eyes, or skin.
• In some patients, strength may improve after exercise and then weaken as activity is sustained. This is demonstrable in approximately half of all patients with LEMS.
• Tendon reflexes are reduced or absent but can frequently be provoked or increased by activating the appropriate muscles or by repeatedly tapping the tendon.
• Sensory examination is normal unless a coincident peripheral neuropathy is present, which is not uncommon in patients with underlying cancer.
• Tensilon or pyridostigmine may improve strength, but this is rarely as dramatic as in myasthenia gravis (MG).

Causes

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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