What are the diagnostic criteria and treatment options for Eaton-Lambert syndrome (Lambert-Eaton myasthenic syndrome, LEMS)?

Diagnosis of Lambert-Eaton Myasthenic Syndrome (LEMS)

LEMS diagnosis is established through a threefold approach: characteristic clinical features (proximal muscle weakness, areflexia, autonomic dysfunction), electromyography showing low-amplitude compound motor action potentials with incremental response to high-frequency stimulation or post-exercise facilitation, and detection of anti-voltage-gated calcium channel (VGCC) antibodies, specifically P/Q-type. 1, 2, 3, 4

Clinical Diagnostic Criteria

The clinical presentation follows a characteristic pattern that should immediately raise suspicion:

• Proximal muscle weakness predominantly affecting hip girdle and shoulder muscles in a craniocaudally progressive pattern 1, 3, 5
• Areflexia or reduced muscle stretch reflexes 3, 5
• Autonomic dysfunction including dry mouth, orthostatic hypotension, erectile dysfunction, and constipation 3, 4, 5
• Ocular and oropharyngeal muscles may be affected to a lesser extent 5

Important caveat: The absence of clinical features of LEMS means routine measurement of VGCC antibodies is not recommended—clinical suspicion must drive testing. 1

Electromyographic Findings (Key Confirmatory Criteria)

Electrodiagnostic testing provides definitive confirmation and reflects the presynaptic transmission defect:

• Low-amplitude compound motor action potentials (CMAPs) at baseline 3, 5
• Significant decrements (>10%) in response to low-frequency (2-3 Hz) repetitive nerve stimulation 3
• Incremental responses of >100% (often dramatic increases of 200-400%) after brief maximal voluntary exercise (10-15 seconds) or high-frequency (20-50 Hz) repetitive stimulation 3, 5

This incremental pattern distinguishes LEMS from myasthenia gravis, which shows decremental responses without post-exercise facilitation. 3, 4

Serological Testing

• Anti-VGCC antibodies (P/Q-type) are present in more than 90% of LEMS patients 1, 2, 3
• These antibodies are pathogenic and directly cause disease by blocking calcium channel function and reducing acetylcholine release 1, 2
• Critical interpretation point: VGCC antibodies should be carefully interpreted in the absence of characteristic clinical or electrodiagnostic features—they are supportive but not diagnostic in isolation 3

Malignancy Screening (Essential Step)

Once LEMS is diagnosed, immediately initiate rigorous oncological screening and surveillance, as 50-60% of cases are paraneoplastic, most commonly associated with small cell lung cancer (SCLC). 1, 3, 4, 5, 6

• The prevalence of LEMS in SCLC is 1-1.6% 1
• LEMS is a clinically important early indicator of possible cancer 4
• Paraneoplastic LEMS (P-LEMS) causes more severe, progressive disease and shorter survival than non-tumor LEMS (NT-LEMS) 6
• Screening should be particularly intensive in older patients with smoking history 5
• Younger, nonsmoking patients are more likely to have autoimmune (idiopathic) LEMS associated with other dysimmune diseases 3, 5

Treatment Approach

First-Line Symptomatic Treatment

Initiate 3,4-diaminopyridine (amifampridine/FIRDAPSE) as first-line symptomatic treatment, which improves neurotransmission by blocking presynaptic potassium channels. 7, 4, 5

• FDA-approved for LEMS in adults and pediatric patients ≥6 years 7
• More than 85% of patients have clinically significant benefit, with marked improvement in over half 5
• Dosing for adults and pediatric patients ≥45 kg: Start 15-30 mg daily in divided doses (3-5 times daily), increase by 5 mg every 3-4 days, maximum single dose 20 mg, maximum daily dose 100 mg 7
• Dosing for pediatric patients <45 kg: Start 5-15 mg daily in divided doses, increase by 2.5 mg every 3-4 days, maximum single dose 10 mg, maximum daily dose 50 mg 7
• Absolute contraindication: History of seizures 7

Immunotherapy (For Inadequate Response)

For patients with inadequate response to 3,4-diaminopyridine or more severe disease, add immunosuppressive therapy. 2

• Intravenous immunoglobulin (IVIg): Should be administered within 1 month of symptom onset for optimal response and can stabilize neurologic symptoms 1, 2
• Plasma exchange: Leads to clear clinical benefit and induces transient improvement in many patients 2, 5
• Chronic immunosuppression: Combinations of prednisone plus azathioprine have been used, though improvement occurs only after many months and requires chronic administration 5, 8

Paraneoplastic LEMS Management

For paraneoplastic LEMS associated with SCLC, tumor therapy is essential and the first priority, as response to cancer therapy favorably affects the course of LEMS. 2

• Successful treatment of underlying cancer leads to improvement in many patients 5
• Long-term prognosis is determined by tumor progression in SCLC-LEMS 4
• NT-LEMS does not reduce life expectancy 4

Common Diagnostic Pitfalls

• Misdiagnosis as myasthenia gravis: LEMS symptoms overlap with myasthenia gravis, but the incremental EMG response and predominant proximal/lower limb weakness distinguish LEMS 3, 4
• Delayed diagnosis: Requires high index of suspicion—consider LEMS in any patient with proximal weakness, reduced reflexes, and dry mouth 5
• Over-reliance on antibody testing: Do not screen with VGCC antibodies without clinical suspicion, and do not diagnose based on antibodies alone without supportive clinical and EMG findings 1, 3