AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

INTRODUCTION

Section 2 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Background

Lambert-Eaton myasthenic syndrome (LEMS) is a rare disorder of neuromuscular transmission. It is a 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, but the progressions of the two diseases have some important differences.

In 1953, Anderson and others reported abnormal neuromuscular transmission in a 47-year-old man with oat cell lung cancer. In 1966, Lambert, Eaton, and Rooke described the clinical and electrophysiological findings in an additional group of 6 patients.

For many years, clinical observations suggested an autoimmune etiology for the disease. This was further suggested in the 1980s when mouse studies demonstrated that LEMS immunoglobulin G (IgG) depleted the presynaptic calcium channels involved in the release of ACh.

Pathophysiology

LEMS results from an autoimmune attack directed against the voltage-gated calcium channels (VGCCs) on the presynaptic motor nerve terminal. This 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.

Frequency

United States

The true incidence of LEMS is unknown. Approximately 3% of patients with small-cell lung cancer (SCLC) are believed to be affected, or an estimated 4 per 1 million people in the United States. Most figures estimate that between 50% and 70% of patients with LEMS have an identifiable cancer, with the overwhelming majority associated with SCLC. However, many different malignancies may be involved. A partial list includes non–small-cell lung cancer; neuroendocrine carcinomas; lymphosarcoma; malignant thymoma; cancers of the breast, stomach, colon, prostate, bladder, kidney, gallbladder, and rectum; basal cell carcinoma; leukemia; lymphoproliferative disorders such Castleman syndrome; and Hodgkin lymphoma. Some figures estimate approximately 400 cases in the United States at any one time. This estimate does not consider the number of patients with LEMS who do not have small-cell lung carcinoma or any identifiable malignancy.

Mortality/Morbidity

• The main problem created by LEMS is progressive weakness that affects everyday activities and general quality of life. LEMS does not seem to affect the respiratory system as significantly as myasthenia gravis.
• Eventually, the weakness 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.

Sex

Current reports note almost equal frequency in men and women.

Age

LEMS is primarily a disease of middle-aged and older people. However, at least 7 children younger than 17 years have been reported to have had LEMS. The most common age for the appearance of symptoms is 60 years.

CLINICAL

Section 3 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

History

• Cancer is present or subsequently discovered in 50-70% of patients with LEMS. In the case of lung cancer, the clinical symptoms of LEMS may precede detection of the underlying disease.
• The main symptom of LEMS is muscle weakness.
• • Lower extremity proximal muscles are affected predominantly. Therefore, patients typically have difficulty rising from a chair, climbing stairs, and walking.
  • Symptoms usually are insidious over months or years before the diagnosis is made.
• The oropharyngeal and ocular muscles are affected in about one quarter of cases of LEMS with symptoms including ptosis, diplopia, and dysarthria but usually not to the same extent or severity as in myasthenia gravis. Differentiation between the two diseases may be difficult.
• • A recent study looked at the localization of the initial muscle weakness and at the time of maximum severity in patients with myasthenia gravis and LEMS. The results showed that patients with myasthenia gravis had initial muscle weakness involving the extraocular muscles (59% of patients) and bulbar muscles (29% of patients). Conversely, LEMS never presented initially with ocular weakness, and 5% of patients with LEMS presented with bulbar weakness and 95% presented with limb weakness. In fact, almost all patients with LEMS with oculobulbar or proximal upper extremity weakness also have proximal lower extremity weakness.
  • In contrast, a significant portion of patients with myasthenia gravis never progress past weakness in the extraocular muscles. At the point of maximum weakness, 25% of patients with myasthenia gravis had purely ocular involvement, and there were no patients with LEMS who had only ocular involvement.
• Facilitation (strength improvement after exercise) is common in LEMS. This also can occur in the proximal muscles of patients with myasthenia gravis. However, repeated testing of many separate muscle groups may differentiate the two diseases.
• Many patients have some degree of autonomic dysfunction, usually characterized by dry mouth. This may be the initial presenting symptom.
• While respiratory muscle function often is involved, the involvement is usually not as severe as with myasthenia gravis. However, respiratory failure has been reported in patients with LEMS.
• Symptoms of the underlying cancer, as well as the "B" symptoms of cancer, may be present.

Physical

• Ptosis and diplopia are seen in about 25% of patients with LEMS.
• Autonomic dysfunction, including dysphagia, constipation, urinary retention, pupillary constriction, sweating, lacrimation and salivation abnormalities, postural hypotension, and respiratory muscle weakness may be present.
• Clinical manifestations of underlying malignancy, such as cachexia, may be present.
• Reflexes usually are reduced or absent in LEMS. They can be elicited by the patient actively contracting the muscle group in question for 10 seconds prior to reflex testing. An increase in reflex activity after contraction is a hallmark of LEMS.
• Fasciculations, common in diseases of the anterior horn cell, such as amyotrophic lateral sclerosis (ALS), are absent in LEMS.
• Proximal muscle weakness is noted on examination, especially in the thighs and the hips.

Causes

LEMS is the result of an autoimmune process in which antibodies develop to the VGCCs and impair the release of ACh from the presynaptic terminal. The same calcium channels in cell lines are found in SCLC, and they are also inhibited by LEMS-IgG, in both tumor and nontumor cases. In tumor cases, a protein of the calcium channel particles may trigger the autoantibody response, but the stimulus in the nontumor cases is unknown.

DIFFERENTIALS

Section 4 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Other Problems to be Considered

Botulism
Paraneoplastic syndrome
Tick paralysis

WORKUP

Section 5 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Lab Studies

• Very few tests are of importance to the ED physician in regard to LEMS since the diagnosis is not made in the ED. It would be reasonable, however, to consider basic tests in any patient with cancer who reports weakness and dry mouth. These basic tests would include the following:
• • CBC
  • Basic chemistry
  • Pulse oximetry

Imaging Studies

• Chest radiography
• Chest CT if chest malignancy is suspected

Procedures

• Tensilon test
• • This test may be used to help differentiate LEMS and myasthenia gravis. However, the test is highly subjective, and it is of little value in the diagnosis of LEMS in the ED.
  • The test may produce an improvement in strength but rarely is the response in patients with LEMS as noticeable as the typical response in patients with myasthenia gravis.
• The only true methods of differentiating myasthenia gravis and LEMS are the detection of ACh receptor antibodies and the presence of underlying malignancy.
• Electrodiagnostic studies are critical to the clinical diagnosis. Criteria that are characteristic of LEMS include the following:
• • Low-amplitude CMAP after a single, supramaximal stimulus
  • Postexercise potentiation of CMAP
  • Rapid disappearance of postexercise increment
  • Decremental response at lower rates of stimulation after repetitive nerve stimulation and incremental response at higher rates of stimulation

TREATMENT

Section 6 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Prehospital Care

• In the rare case of respiratory distress or failure, treat as in any other patient: initiate supplemental oxygen; secure intravenous access; and intubate, if indicated.

Emergency Department Care

• In the ED setting, the most serious threat to life in these patients is the rare cases of respiratory failure.
• If necessary to intubate, the use of neuromuscular blocking agents may further exacerbate the weakness and have prolonged effects.
• If possible, avoid the following medications, which may cause acute or subacute worsening of weakness:
• • Any neuromuscular blocking agent
  • Aminoglycoside antibiotics
  • Magnesium and/or iodinated intravenous contrast agents
  • Calcium channel blockers

Consultations

• In patients with chronic weakness, a consultation with a neurologist for electromyographic testing, further workup, and initiation of pharmacotherapy may be indicated. The diagnosis may be suspected clinically but must be confirmed by electrodiagnostic testing. In addition, many of the medications and therapies that have been shown to produce clinical improvement are not appropriate for the emergency department. Most notably, in addition to pharmacotherapy, IVIG has been shown in the last few years to have significant results.

MEDICATION

Section 7 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Therapy seldom is started in the ED. In general, before medical therapy begins, myasthenia gravis must be excluded. If the diagnosis is in any doubt, further workup or therapy for myasthenia gravis should be considered. Medical therapy is tailored for each patient and might include various combinations of the drugs listed below. Therapy is best coordinated with the primary care physician and appropriate consultants.

Typical treatments for the patients with SCLC as the cause of their LEMS would include combination therapy with cisplatin and etoposide. Through both tumor modulation and its direct immunosuppressive properties, chemotherapy does seem to improve the symptoms of LEMS.

Drug Category: Cholinesterase inhibitors

These agents act by inhibiting the breakdown of ACh, which is intended to help compensate for the relative lack of ACh quanta release in LEMS. They usually do not provide a significant improvement; however, a few patients with mild disease may note some difference.

Drug Name	Guanidine hydrochloride
Description	Thought to act by increasing free intracellular calcium concentrations through inhibition of mitochondrial respiration. Inhibits respiration by blocking potassium channels and thus prolonging the nerve terminal action potential. This increases release of ACh after nerve impulse and may decrease rates of repolarization and depolarization of muscle cell membranes. Primarily cited in case reports and has not been studied in randomized trials.
Adult Dose	Start 5-10 mg/kg/d PO divided during waking hours depending on response; not to exceed 30 mg/kg/d Side effects are what normally limit use of the drug and are mostly described as gastrointestinal plus distal paraesthesias.
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Pyridostigmine enhances response, allowing dose of each drug to be reduced
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	May have adverse effect on renal function; monitor renal function with regular urine examinations and serum creatinine determinations; may cause bone marrow suppression; atrial fibrillation and hypotension have been reported

Drug Category: Potassium channel blockers

Aminopyridines block potassium channels in membranes and facilitate chemical synaptic transmission at autonomic, neuromuscular, and central synapses. Both 4-aminopyridine and 3,4-diaminopyridine have been used, but 4-AP is thought to be less effective and is almost twice as toxic, with many neurologic effects reported.

Drug Category: Immunosuppressants

If therapies already described are ineffective, more aggressive immunotherapy may be indicated. Therapy can take the form of plasma exchange or high dose IVIG, with the potential for more long-term immunosuppression, usually with prednisone or azathioprine.

Drug Name	Azathioprine (Imuran)
Description	Inhibits mitosis and cellular metabolism by antagonizing purine metabolism and inhibiting synthesis of DNA, RNA, and proteins. These effects may inhibit formation of immune cells, possibly reducing activity of immune system.
Adult Dose	50 mg/d PO; increase by 50 mg/d q3d to optimum therapeutic goal of 150-200 mg/d
Pediatric Dose	2-5 mg/kg/d PO/IV initially, followed by maintenance dose of 1-2 mg/kg/d
Contraindications	Documented hypersensitivity; low levels of serum TPMT
Interactions	Allopurinol increases toxicity; ACE inhibitors may induce severe leukopenia; may increase levels of methotrexate metabolites and decrease effects of anticoagulants, neuromuscular blockers, and cyclosporine
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Increases risk of neoplasia; caution with liver disease and renal impairment; hematologic toxic effects may occur; check TPMT level prior to therapy and monitor liver, renal, and hematologic functions; pancreatitis rarely associated

Drug Category: Blood products/immunomodulating agents

Agents in this category may be used to improve clinical and immunologic aspects of the disease. They may decrease autoantibody production and increase solubilization and removal of immune complexes.

FOLLOW-UP

Section 8 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Further Inpatient Care

• In patients in whom LEMS is suspected and history suggests acute worsening, admission for observation and testing is warranted.
• Patients experiencing acute exacerbations of weakness should be admitted for further testing and therapy that is best completed on an in-patient basis.
• Medical therapy, as previously mentioned, to include immunosuppression and plasmapheresis, may be indicated.

Further Outpatient Care

• Ideally, the patient's neurologist or primary care physician should coordinate all tests and procedures ordered on an outpatient basis.
• Physical therapy and exercise are important parts of the outpatient regimen to help maintain muscle tone and strength.

Deterrence/Prevention

• The ED physician should be aware of medications that can cause deterioration in the patient's condition. These include neuromuscular blocking agents, aminoglycosides, magnesium, iodinated intravenous contrast, and calcium channel blockers.

Complications

• The most significant complication, and the only one that applies to emergency medicine, is acute respiratory compromise. This is rare and usually is due to iatrogenic reasons (as already discussed).
• Increased temperatures from fever or the environment also may worsen the weakness.
• Patients may experience transient worsening following hot baths and showers or during systemic illnesses.

Prognosis

• The prognosis is difficult to determine since it often is linked with the progression of the underlying cancer.
• In most cases, therapy with agents such as DAP may help to relieve symptoms partially, but usually symptoms progress over time.

REFERENCES

Section 9 of 9

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

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• Buchwald B, Ahangari R, Weishaupt A, Toyka KV. Presynaptic effects of immunoglobulin G from patients with Lambert-Eaton myasthenic syndrome: their neutralization by intravenous immunoglobulins. Muscle Nerve. Apr 2005;31(4):487-94. [Medline].
• Collins DR, Connolly S, Burns M, et al. Lambert-eaton myasthenic syndrome in association with transitional cell carcinoma: a previously unrecognized association. Urology. Jul 1999;54(1):162. [Medline].
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• Smith AG, Wald J. Acute ventilatory failure in Lambert-Eaton myasthenic syndrome and its response to 3,4-diaminopyridine. Neurology. Apr 1996;46(4):1143-5. [Medline].
• Verschuuren JJ, Wirtz PW, Titulaer MJ, et al. Available treatment options for the management of Lambert-Eaton myasthenic syndrome. Expert Opin Pharmacother. Jul 2006;7(10):1323-36. [Medline].
• Wirtz PW, Sotodeh M, Nijnuis M, et al. Difference in distribution of muscle weakness between myasthenia gravis and the Lambert-Eaton myasthenic syndrome. J Neurol Neurosurg Psychiatry. Dec 2002;73(6):766-8. [Medline].

Article Last Updated: Feb 15, 2007