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The author: Professor Yasser Metwally

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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. Recent work demonstrates that 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 also has been associated with non-SCLC lung cancer, lymphosarcoma, malignant thymoma, or carcinoma of 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 frequently is associated with known autoimmune diseases. Prednisone, plasma exchange (PEX), and intravenous hyperimmune human gamma globulin (IVIg) are effective treatments. LEMS patients without cancer frequently have elevated serum levels of organ-specific autoantibodies.

Recently, more direct evidence has been accumulated supporting the autoimmune etiology of LEMS. Active zone particles (AZP), which represent the VGCCs, normally are 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 downregulate 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 probably are produced as part of a more general autoimmune state.

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:

• In the US: An estimated 3% of patients with SCLC have LEMS. SCLC has a prevalence of 5 per million in the US. Since only half of patients with LEMS have a tumor, total prevalence is at least double this figure (1 per 100,000). Since many patients with LEMS are undiagnosed, the true incidence is probably higher.

Mortality/Morbidity: This correlates with the morbidity/mortality of the underlying SCLC.

Sex: In earlier reports, males outnumbered females by almost 2:1. However, more recent studies show that the gender incidence is almost equal.

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

CLINICAL PICTURE

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

  • Respiratory muscles usually are not 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 complain of 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 LEMS patients.

  • 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 probably has underlying lung cancer.

Physical: Weakness is usually mild compared to the patient’s complaints.

• Strength usually is 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.

• Deep tendon reflexes are reduced or absent, but frequently they can 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.

WORKUP

Lab Studies:

• Voltage-gated calcium channel antibodies

  • VGCC antibodies have been reported in 75-100% of patients with LEMS who have SCLC and in 50-90% of patients with LEMS without underlying cancer.

  • They also are found in fewer than 5% of patients with MG, in up to 25% of patients with lung cancer without LEMS, and in some patients who do not have LEMS but have high levels of circulating immunoglobulins (eg, systemic lupus erythematosus, rheumatoid arthritis).

  • Sensitivity and specificity of the VGCC assay are affected by the source of antigen and the specific laboratory measuring the antibody.

Imaging Studies:

• CT scan or MRI of chest

  • SCLC is the malignancy most frequently associated with LEMS.

  • In all adult patients with LEMS, imaging studies of the chest for cancer detection should be performed. If imaging findings are negative in a patient with a substantial risk of having lung cancer, bronchoscopy should be performed. If both imaging and bronchoscopy are initially negative and risk factors for lung cancer are present, periodic reassessment thereafter is indicated.

Other Tests:

• Acetylcholine receptor antibodies

  • ACh receptor (AchR) antibodies most commonly are associated with MG.

  • AChR antibodies are found occasionally in low titers in LEMS.

Procedures:

• Repetitive nerve stimulation studies

  • These studies confirm the LEMS diagnosis by demonstrating characteristic findings on electrodiagnostic studies. Compound muscle action potentials (CMAPs) recorded with surface electrodes are small, often less than 10% of normal, and fall during 1-5 Hz repetitive nerve stimulation (RNS).

  • During stimulation at 20-50 Hz, the CMAP increases in size (ie, facilitation) and characteristically becomes at least twice the size of the initial response.

  • A similar increase in CMAP size is seen immediately after the patient voluntarily contracts the muscle maximally for several seconds.

  • In virtually all patients with LEMS, a decremental response to low-frequency nerve stimulation is observed in the hand muscles. This finding is not specific to LEMS and can be seen in MG and other neuromuscular diseases.

  • In LEMS, the CMAP amplitude is low in most muscles tested. This finding is also nonspecific and is seen commonly in other neuromuscular diseases.

  • Facilitation greater than 100% is seen in some but not all muscles (or in all patients) with LEMS. Facilitation greater than 50% in any muscle suggests LEMS. However, these findings also might suggest MG. If facilitation is greater than 100% in most muscles tested or greater than 400% in any muscle, the patient almost certainly has LEMS. If facilitation is less than 50% in all muscles tested, the patient still may have LEMS, especially if weakness has been present for only a short time or the patient has been treated partially.

  • When LEMS is mild, the electromyography (EMG) findings may resemble those of MG, including normal CMAP amplitudes, decremental response to RNS at low rates, and little facilitation. One helpful feature is that in LEMS, the EMG findings are usually more severe than the clinical findings would suggest. The opposite is frequently true in MG.

• Needle electromyography: Conventional needle EMG in LEMS demonstrates markedly unstable motor unit action potentials, which vary in shape during voluntary activation.

• Single-fiber electromyography

  • The jitter and blocking measured by single-fiber EMG is increased markedly in LEMS, frequently out of proportion to the severity of weakness.

  • In many endplates, jitter and blocking decrease as the firing rate increases. This pattern is not seen in all endplates or in all patients with LEMS.

  • Because jitter and blocking also may decrease at higher firing rates in some endplates of patients with MG, this pattern does not confirm a LEMS diagnosis unless it is dramatic and seen in most muscles.

• Bronchoscopy: If risk of lung cancer is substantial and imaging studies are normal, perform bronchoscopy to detect SCLC.

MANAGEMENT

Medical Care:

• Individually tailor therapy on the basis of severity of weakness, underlying disease(s), life expectancy, and response to previous treatment.

  • When the LEMS diagnosis is confirmed, extensively search for an underlying malignancy with x-ray and CT scan of the chest and bronchoscopy.

  • Initial treatment should be aimed at the neoplasm, since weakness frequently improves with effective cancer therapy. No further LEMS treatment may be necessary in some patients.

• If no tumor is found, periodically search again for occult malignancy. Frequency of these evaluations is determined by the patient’s risk of cancer.

  • Patients younger than 50 years without history of long-term smoking have a low risk of associated malignancy, especially if evidence of coexisting autoimmune disease is present. Extensive surveillance for cancer may not be necessary for such patients.

  • Patients older than 50 years with history of long-term smoking almost certainly have underlying SCLC.

• In patients with cancer, LEMS is usually not the major therapeutic concern. The initial concern is the cancer.

  • Immunotherapy of LEMS without effective treatment of the underlying cancer usually produces little or no improvement in strength. A theoretical concern is that the immunosuppression may reduce immunologic suppression of tumor growth.

  • In patients with LEMS who do not have cancer, aggressive immunotherapy is justified more readily.

Consultations: Appropriate consultations include neurology and may include oncology and physical medicine.

MANAGEMENT

The initial pharmacotherapy of LEMS is with agents that increase the transmission of ACh across the neuromuscular junction, either by increasing the release of ACh or by decreasing the action of acetylcholinesterase. Treatment of the associated cancer also may decrease the weakness and other symptoms.

If these treatments are not effective and the patient has relatively mild weakness, determine if aggressive immunotherapy is justified. When such therapy is warranted, PEX or high-dose IVIg may be used initially to induce rapid, albeit transitory, improvement. Immunosuppressants should be added for more sustained improvement, although a theoretical concern exists that immunologic suppression of tumor growth may thereby be reduced in paraneoplastic LEMS.

Prednisone and azathioprine, the most frequently used immunosuppressants, can be used alone or in combination. Cyclosporine may benefit patients with LEMS who are candidates for immunosuppression but cannot take or do not respond well to azathioprine. Improvement may be seen within 1-2 mo after beginning cyclosporine, while the maximum response usually is seen in 3-4 mo.

PEX produces improvement in many patients with LEMS. Improvement is temporary unless the patient also is receiving immunosuppression. Response to PEX in patients with LEMS is often more gradual than in those with MG. Maximal response may take several weeks. Repeated courses of PEX may be necessary to maintain improvement. PEX may be performed 4-6 times over 7-10 d, as described in standard protocols. Potential complications include autonomic instability, hypercalcemia, and bleeding due to depletion of clotting factors.

IVIg, given in a course of 2 g/kg over 2-5 d, also induces clinically significant, temporary improvement in many patients. The frequency of improvement in response to repeated courses of treatment has not been determined.

FOLLOW-UP

Prognosis:

• Prognosis is determined largely 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.

• Because LEMS may lead to early detection of SCLC, prognosis of SCLC in patients with SCLC-LEMS is better than in SCLC without LEMS. It is possible that patients with SCLC who develop LEMS have a more effective immunological response to the cancer, which results in improved survival.

• When LEMS has been symptomatic for at least 2 years and no underlying cancer has been demonstrated, the LEMS probably was caused by an autoimmune process. At that point, prognosis is determined by severity of dysfunction and the presence and severity of other autoimmune conditions.

• In most patients, weakness does not affect vital muscles severely.

  • Maximum severity usually becomes established within several months of symptom onset.

  • Without treatment, weakness and dysfunction usually do not vary. Exceptions are during periods of exacerbation induced by intercurrent illness or by medications that impair neuromuscular transmission.

Medical/Legal Pitfalls:

• To avoid possible medicolegal problems, a thorough search for an underlying SCLC should be performed. In addition, drugs that can exacerbate the condition should be avoided if possible.

Special Concerns:

• Drugs that may exacerbate weakness in LEMS

  • Drugs that compromise neuromuscular transmission frequently exacerbate weakness in LEMS. Competitive neuromuscular blocking agents, such as d-tubocurarine and pancuronium, have an exaggerated and prolonged effect in patients with LEMS.

  • Initial signs of possible LEMS include prolonged weakness or apnea following administration of neuromuscular blocking agents during anesthesia.

  • Some antibiotics, particularly aminoglycosides, fluoroquinolones (eg, ciprofloxacin), and erythromycin, have significant neuromuscular blocking effects. Some antiarrhythmics (eg, quinine, quinidine, procainamide) and beta-adrenergic blocking drugs also worsen myasthenic weakness.

  • Exacerbation of LEMS after administration of any of several other agents, including magnesium and intravenous iodinated radiographic contrast agents, has been reported in isolated cases. In general, patients with LEMS should be observed for clinical worsening after initiating any new medication.

  • Unless absolutely necessary, avoid drugs that are known to impair neuromuscular transmission. In such cases, a thorough knowledge of their potential deleterious effects is required.

• Elevated temperature

  • Weakness of LEMS may be worse when the ambient temperature increases or when the patient is febrile.

  • Patients should avoid hot showers or baths.

  • Systemic illness of any sort may cause transient worsening of weakness.

References

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