AUTHOR INFORMATION

Section 1 of 10

Authored by Paul Kleinschmidt, MD, Clinical staff and Education Director, Department of Emergency Medicine, Womack Army Medical Center

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

Edited by Jerome FX Naradzay, MD, FACEP, Emergency Services Medical Director, Department of Emergency Medicine, Maria Parham Medical Center; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; J Stephen Huff, MD, Associate Professor of Emergency Medicine and Neurology, Department of Emergency Medicine, University of Virginia Health System; John Halamka, MD, Chief Information Officer, CareGroup Healthcare System, Assistant Professor of Medicine, Department of Emergency Medicine, Beth Israel Deaconess Medical Center; Assistant Professor of Medicine, Harvard Medical School; and Pamela Dyne, MD, Program Director, Associate Professor, Department of Medicine, Division of Emergency Medicine, University of California at Los Angeles School of Medicine

Author's Email:	Paul Kleinschmidt, MD
Editor's Email:	Jerome FX Naradzay, MD, FACEP

eMedicine Journal, February 15 2007, VOLUME 8, Number 2

INTRODUCTION

Section 2 of 10

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:

• In the US: 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

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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

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Amyotrophic Lateral Sclerosis
Anemia, Acute
Anemia, Chronic
Hypocalcemia
Hypokalemia
Hypomagnesemia
Hyponatremia
Hypothyroidism and Myxedema Coma
Multiple Sclerosis
Myasthenia Gravis
Polymyalgia Rheumatica
Polymyositis

Other Problems to be Considered:

Botulism
Paraneoplastic syndrome
Tick paralysis

WORKUP

Section 5 of 10

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

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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

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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	Pyridostigmine (Mestinon) -- Blocks ACh hydrolysis by cholinesterase, resulting in ACh accumulation at synapses and increasing stimulation of cholinergic receptors at myoneural junction. Most of the literature seems to have consensus that monotherapy with a cholinesterase inhibitor is ineffective. It is in the combination therapy with drugs such as 3,4-DAP that it may have some slight benefit.
Adult Dose	30-60 mg PO q4-6h Alternatively, 2 mg IV/IM q2-3h or 1/30th the PO dose
Pediatric Dose	7 mg/kg/d PO in 5-6 divided doses 0.05-0.15 mg/kg/dose IM/IV
Contraindications	Documented hypersensitivity; GI or GU obstruction
Interactions	Increases effects of depolarizing neuromuscular blockers; increases toxicity of edrophonium
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in bronchial asthma and those receiving a cardiac glycoside Overdose may cause cholinergic crisis, which may be fatal; atropine IV should be readily available for treatment of cholinergic reactions

Drug Name	Guanidine hydrochloride -- 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 Name	3,4-diaminopyridine (DAP) -- Aminopyridines improve neuromuscular transmission by facilitating release of ACh from the motor nerve terminal. They act by presynaptic potassium channel blockade prolonging action potentials and extending activation of VGCC. For >20 y, has been used to improve strength and autonomic function in most patients. Effect begins about 20 min after an oral dose. Each dose lasts about 4 h, and maximum effect of a given dosage may not be seen for 2-3 d. Patients with or without underlying cancer benefit from DAP. In the authors’ experience, >80% of patients with LEMS have significant clinical benefit; in more than half of these, improvement is marked. Not approved for clinical use in the US but available on a compassionate-use basis for individual patients. In most patients, pyridostigmine enhances and prolongs duration of action, permitting lower doses. Obtain application process information from Jacobus Pharmaceutical Co, Inc, Princeton, NJ, fax (609) 799-1176.
Adult Dose	Optimal dose varies considerably among patients; tailor dose and dosing schedule for each patient as follows: 10 mg PO tid/qid initial dose; observe response for 2 wk, increase dose in 5-mg increments at 2-wk intervals until maximum benefit obtained; not to exceed 80 mg/d; add pyridostigmine, 30 or 60 mg tid, and note effect on maximum response and on duration of action of each DAP dose; reduce DAP dose in 5-mg decrements until lowest effective dose determined Optimal dose of DAP may change; periodically reassess response to medication by slowly reducing dose to redetermine minimum dose that produces maximum response; repeat this procedure at least q12mo
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; history of seizures
Interactions	In most patients, pyridostigmine enhances and prolongs DAP's duration of action and permits lower doses; DAP may increase adverse GI effects of pyridostigmine; if this occurs, reduce dose of pyridostigmine
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Adverse effects minimal, usually limited to brief perioral and digital paresthesias, if dose is >10 mg; GI hyperactivity with cramps and diarrhea may occur when DAP taken with pyridostigmine; minimize this effect by reducing pyridostigmine dose; seizures may occur at doses >100 mg/d; asthma attacks have been induced in patients with preexisting asthma; theoretically, DAP could cause cardiac arrhythmia, although no such effects have been reported; no known organ toxicity even in patients with LEMS who have taken aminopyridines for >10 y; because clinical experience with these agents is limited, periodically perform blood tests of liver and kidney and hematologic functions to detect adverse effects; liver function tests, BUN and creatinine levels, and CBC should be performed q3mo for first year, then q6-12mo

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	Prednisone (Deltasone, Orasone, Sterapred) -- Used as immunosuppressant in treatment of autoimmune disorders. Combination of corticosteroid therapy with azathioprine may be more effective than steroid monotherapy.
Adult Dose	60-80 mg/d PO qd maximum or divided bid/qid
Pediatric Dose	4-5 mg/m2/d PO; alternatively, 1-2 mg/kg PO qd
Contraindications	Documented hypersensitivity; connective tissue, fungal, tubercular skin, or viral infections; peptic ulcer disease; hepatic dysfunction; GI disease
Interactions	Estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Abrupt discontinuation may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur

Drug Name	Azathioprine (Imuran) -- 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.

Drug Name	Immune globulin intravenous (Gamimune, Gammagard, Sandoglobulin) -- Neutralize circulating myelin antibodies through anti-idiotypic antibodies; down regulates proinflammatory cytokines, including INF-gamma; blocks Fc receptors on macrophages; suppresses inducer T and B cells and augments suppressor T cells; blocks complement cascade; promotes remyelination; may increase CSF IgG (10%).
Adult Dose	2 g/kg IV over 2-5 d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; IgA deficiency
Interactions	Globulin preparation may interfere with immune response to live-virus vaccine (MMR) and reduce efficacy (do not administer within 3 mo of vaccine)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Check serum IgA level before IVIG (use an IgA-depleted product, eg, Gammagard S/D); infusions may increase serum viscosity and thromboembolic events; infusions may increase risk of migraine attacks, aseptic meningitis (10%), urticaria, pruritus, or petechiae (2-30 d postinfusion) Increases risk of renal tubular necrosis in elderly patients and in patients with diabetes, volume depletion, and preexisting kidney disease; laboratory result changes associated with infusions include elevated antiviral or antibacterial antibody titers for 1 mo, 6-fold increase in ESR for 2-3 wk, and apparent hyponatremia

FOLLOW-UP

Section 8 of 10

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.

TEST QUESTIONS

Section 9 of 10

CME Question 1: What percentage of people with Lambert-Eaton myasthenic syndrome (LEMS) have a documented malignancy?

A: 20-25%
B: 50-70%
C: 75%
D: Greater than 90%
E: Less than 20%

The correct answer is B: While the original cases of LEMS were documented in patients with malignancy, further investigation has demonstrated that approximately 50-70% of patients with LEMS also have a malignancy.

CME Question 2: Which of the following is most suggestive of Lambert-Eaton myasthenic syndrome (LEMS)?

A: Oropharyngeal and ocular muscle weakness
B: Proximal muscle weakness
C: Increase in strength with exercise
D: Complaint of a dry mouth
E: Increase in reflexes following maximal muscle contraction

The correct answer is E: While any of these may be noted in patients with LEMS, the hallmark of the condition is an increase in reflexes following maximal muscle contraction.

Pearl Question 1 (T/F): On initial ED evaluation, laboratory examination is crucial to making the diagnosis of Lambert-Eaton myasthenic syndrome (LEMS).

The correct answer is False: 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 cancer patient complaining of weakness and dry mouth. These would include a CBC, basic chemistries, and pulse oximetry.

Pearl Question 2 (T/F): If Lambert-Eaton myasthenic syndrome is suspected, the general rule is that therapy is to be started as soon as possible in the ED.

The correct answer is False: Therapy seldom is started in the ED. In general, before medical therapy begins, myasthenia gravis must be excluded. Medical therapy is tailored for each patient and might include various combinations of the recommended drugs. Therapy is best coordinated with the primary care physician and appropriate consultants.

Pearl Question 3 (T/F): Lambert-Eaton myasthenic syndrome (LEMS) is the result of an autoimmune process.

The correct answer is True: In a patient with LEMS, antibodies develop to the voltage-gated calcium channels and impair the release of acetylcholine from the presynaptic terminal. The important take home point is that it very often precedes the diagnosis of malignancy, and the patient should be assumed to have an undiagnosed cancer until fully evaluated.

Pearl Question 4 (T/F): Lambert-Eaton myasthenic syndrome (LEMS) may, on occasion, be found in children.

The correct answer is True: 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 LEMS.

BIBLIOGRAPHY

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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 2005 Apr; 31(4): 487-94[Medline].
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• 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 2002 Dec; 73(6): 766-8[Medline].

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