Lambert Eaton myasthenic syndrome (LEMS)

What is Lambert Eaton myasthenic syndrome (LEMS)? 

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder of neuromuscular transmission caused by antibodies directed against presynaptic voltage-gated P/Q calcium channels on motor and autonomic nerve terminals.

There are two forms: Paraneoplastic (most common) and nonparaneoplastic (autoimmune).

Lambert Eaton myasthenic syndrome is an antibody-mediated autoimmune disease.

The target of the aberrant immune response is the presynaptic P/Q voltage-gated calcium channel (VGCC) at the neuromuscular junction.

The cardinal symptom of Lambert Eaton myasthenic syndrome is weakness, usually in the proximal muscles and more prominent in the lower extremities.

In about 50% to 60% of cases, the syndrome is paraneoplastic, associated mostly with small-cell lung cancer.

Onset of symptoms may precede detection of tumor by 1 to 4 years.

LEMS is frequently associated with autonomic symptoms, including dry mouth, impotence, and constipation.

Less common symptoms include orthostatic hypotension, micturition difficulties, dry eyes, and impaired sweating.

Variations in heart rate and blood pressure may occur with the Valsalva maneuver or deep breathing, and sweat tests also may be abnormal.

Synonyms

• Eaton-Lambert syndrome
• •LEMS

7 Interesting Facts of Lambert Eaton myasthenic syndrome

1. Some cases are associated with carcinoma, particularly small cell carcinoma of the lung; other cases are true autoimmune disorders
2. Weakness with diminished or absent muscle stretch reflexes
3. Proximal lower extremity muscles are affected most; ocular and bulbar muscles are mildly affected
4. Transient strength improvement with exercise
5. Poor response to pyridostigmine or other cholinesterase inhibitors
6. Autonomic dysfunction is possible
7. Differentiated with repetitive nerve stimulation studies that confirm diagnosis

Incidence

Uncertain; estimated at five cases per 1 million persons annually (in U.S.)

Prevalence

Uncertain; estimated at one per 100,000 (in U.S.). Up to 3% of small cell lung cancer (SCLC) patients are estimated to develop LEMS.

Predominant Sex

Male:female ratio of 2:1

Peak Incidence

Sixth decade

Physical Findings & Clinical Presentation

• •Weakness with diminished or absent muscle stretch reflexes
• •Proximal lower-extremity muscles affected most
• •Ocular and bulbar muscles less commonly affected
• •Transient strength improvement with brief exercise
• •Reflexes may be facilitated by repeatedly tapping the tendon or after brief exercise
• •Autonomic dysfunction common (dry mouth [75%], sexual dysfunction, blurred vision, constipation, orthostasis, etc.)

Etiology

• •Antibodies directed against presynaptic voltage-gated P/Q calcium channels are present in most patients. The reduction in calcium influx causes a reduction in presynaptic acetylcholine release at motor and autonomic nerve terminals.
• •Paraneoplastic forms, usually associated with SCLC, account for 50% to 70% of patients.
• •Autoimmune forms, usually in patients with other autoimmune diseases, occur in 10% to 30% of patients.

 Diagnosis

Differential Diagnosis

• •Myasthenia gravis: The clinical presentation of Lambert-Eaton myasthenic syndrome is similar to that of myasthenia gravis except that in LEMS, weakness improves with exercise, and hyporeflexia and dysautonomia are present
• •Polymyositis
• •Primary myopathies
• •Carcinomatous myopathies
• •Polymyalgia rheumatica
• •Botulism
• •Guillain-Barré syndrome

Workup

Diagnosis is confirmed on basis of characteristic electrodiagnostic (electromyography [EMG]/nerve conduction study [NCS]) findings and detection of serum anti-voltage-gated calcium channel antibodies (90%). EMG reveals: Reduced motor amplitudes with normal sensory studies; >10% decrement in motor amplitudes on slow repetitive nerve stimulation (RNS) at 2 to 5 Hz, with >100% increment on fast RNS (20 to 50 Hz) or immediately after 10 sec of maximum exercise (post-exercise facilitation).

Laboratory Tests

Check P/Q calcium channel antibody titers (commercially available).

Imaging Studies

Screen for an underlying malignancy. Presentation with LEMS may precede diagnosis of SCLC by up to 5 yr; hence, CT of the chest or positron emission tomography (PET) scan may be required every 6 to 12 mo to evaluate for SCLC.

How is LEMS treated? 

When an underlying neoplasm is identified, removal or treatment of the tumor usually results in substantial improvement in all symptoms, including those of autonomic dysfunction.

In patients who do not have an underlying malignancy, the treatment is directed toward the enhancement of cholinergic function and immunosuppression.

The first treatment of choice is 3,4-diaminopyridine.

Previously, it was thought that blocking voltage-gated potassium channels, resulting in prolongation of action potential at the motor nerve junctions and lengthening the opening time of the VGCC, mediates this agent’s effect.

Recent studies show that it may also target the VGCC β-subunit directly and result in potentiating neuromuscular transmission.

In cases when this agent is not available, guanidine or pyridostigmine may provide benefit.

When the symptoms persist, immunosuppression with corticosteroids, azathioprine, or IVIG may be needed.

Treatment

• •Treatment consists of treating any underlying malignancy or immunosuppression, intravenous immunoglobulin (IVIG), or plasmapheresis when dealing with a purely autoimmune disease.
• •Amifampridine is the only FDA-approved treatment for symptomatic treatment of LEMS. Amifampridine works by blocking presynaptic potassium channels, thereby increasing presynaptic calcium concentrations and enhancing acetylcholine release.

Nonpharmacologic Therapy

Symptomatic treatment for autonomic dysfunction

Acute General Treatment

• •Amifampridine: Start 15 to 30 mg/day PO divided tid to qid and then increase by 5 mg/day every 3 to 4 days for a maximum of 20 mg per dose and 80 mg/day. This medication is contraindicated in patients with seizures.
• •Plasma exchange (200 to 250 ml/kg over 10 to 14 days) or IVIGs (2 g/kg divided over 2 to 5 days) often produces significant, temporary improvement.
• •Prednisone 1.0 to 1.5 mg/kg/day can be gradually tapered over months to minimal effective dose.
• •Azathioprine can be given alone or in combination with prednisone. Give up to 2.5 mg/kg/day. If patient is intolerant, can administer cyclosporine up to 3 mg/kg/day instead.

Chronic Treatment

Treat underlying malignancy if present

Amifampridine for symptoms of weakness

Disposition

• •Gradually progressive weakness leading to impaired mobility if untreated
• •Clinical remission may occur with chronic immunosuppressive therapy in 43% of cases
• •Possible substantial improvement with successful treatment of underlying malignancy

Referral

• •Referral to a neurologist is highly recommended because this is a rare disease requiring highly specialized treatment in the context of weighing risk vs. benefit of the different therapeutic options.
• •Surgical referral for tumor debulking in paraneoplastic forms necessary.

Pearls & Considerations

• •Prominent autonomic symptoms (dry eyes, dry mouth, impotence, orthostasis) are often clues to the diagnosis in the appropriate clinical context.
• •Many drugs may worsen weakness and should be used only if absolutely necessary. Included are succinylcholine, d-tubocurarine, quinine, quinidine, procainamide, aminoglycoside antibiotics, β-blockers, and calcium channel blockers.

Patient & Family Education

Document link available through www.lems.com/resources.

Suggested Readings

• Titulaer M.J., et al.: Lambert-Eaton myasthenic syndrome: from clinical characteristics to therapeutic strategies. Lancet Neurol 2011; 10 (12): pp. 1098-1107.
• U.S. National Library of Medicine: PubChem Compound Summary: 3,4-Diaminopyridine. Available at https://pubchem.ncbi.nlm.nih.gov/compound/3_4-diaminopyridine.