What is the general diagnostic approach to Lambert-Eaton Myasthenic Syndrome (LEMS)?

Diagnostic Approach to Lambert-Eaton Myasthenic Syndrome (LEMS)

The diagnosis of Lambert-Eaton Myasthenic Syndrome (LEMS) requires a threefold approach including clinical features assessment, electromyography with characteristic findings, and anti-voltage-gated calcium channel (VGCC) antibody testing. 1

Clinical Presentation

• LEMS typically presents with progressive proximal muscle weakness, often accompanied by general fatigue and autonomic symptoms 1
• Characteristic pattern of weakness predominantly affects hip and shoulder muscles, with less involvement of ocular and oropharyngeal muscles 2
• Reduced or absent muscle stretch reflexes are a hallmark finding 2
• Autonomic symptoms including dry mouth are common and should raise suspicion for LEMS 2
• Symptoms may overlap with other myasthenic syndromes, particularly myasthenia gravis, contributing to misdiagnosis or delayed diagnosis 1

Diagnostic Algorithm

Step 1: Clinical Evaluation

• Perform detailed neurological examination focusing on:
  • Pattern of muscle weakness (proximal > distal)
  • Reflexes (typically reduced or absent)
  • Autonomic symptoms (dry mouth, constipation, etc.) 1, 2
• Document whether weakness improves with brief exercise, which is characteristic of LEMS 3

Step 2: Electrodiagnostic Testing

• Electromyography (EMG) is essential and shows three characteristic findings:
  • Low-amplitude compound muscle action potentials (CMAPs) at rest 3, 2
  • Significant decrements in responses to low-frequency (2-3 Hz) repetitive nerve stimulation 3
  • Incremental responses (facilitation) after brief exercise or high-frequency stimulation (>20 Hz) 3, 2
• These findings reflect the presynaptic neuromuscular transmission defect and are key confirmatory criteria 3

Step 3: Serological Testing

• Test for P/Q-type voltage-gated calcium channel (VGCC) antibodies 1, 3
• Approximately 90% of LEMS patients have positive anti-VGCC antibodies 3
• Antibody results should be interpreted in the context of clinical and electrodiagnostic findings 3

Step 4: Cancer Screening

• LEMS is a clinically important early indicator of possible cancer; therefore, rigorous oncological screening is mandatory 1
• Up to 60% of LEMS cases occur as a paraneoplastic disorder, most commonly associated with small cell lung cancer (SCLC) 1
• Cancer screening should be particularly thorough in older patients with a history of smoking 2
• Recommended screening includes:
  • Chest CT scan (high-resolution)
  • PET scan if initial screening is negative
  • Periodic surveillance for at least 2 years if initial screening is negative 1, 4

Classification of LEMS

• Paraneoplastic LEMS (P-LEMS): Associated with malignancy, most commonly small cell lung cancer 3
• Autoimmune LEMS (A-LEMS): Not associated with cancer but often related to other autoimmune diseases 3

Differential Diagnosis

• Myasthenia gravis (most common misdiagnosis) 1
• Botulism (another presynaptic disorder with similar features) 5
• Myopathies and motor neuron diseases 3

Treatment Considerations

• For paraneoplastic LEMS, oncological treatment should take priority 4
• Symptomatic treatment typically involves:
  • 3,4-diaminopyridine (amifampridine) as first-line therapy to improve neurotransmission 6, 1
  • Immunosuppressants (prednisone plus azathioprine) for persistent symptoms 1
• FDA-approved amifampridine has demonstrated significant improvement in muscle strength and quality of life in clinical trials 6

Prognosis

• Prognosis is related to the presence of cancer or autoimmune disease and the severity/distribution of muscle weakness 1
• In paraneoplastic LEMS, cause of death is typically tumor progression 1
• Non-tumor LEMS generally does not reduce life expectancy 1

Common Pitfalls and Caveats

• Delayed diagnosis is common due to the rarity of LEMS and overlap with other neuromuscular disorders 3
• Negative antibody testing does not exclude LEMS if clinical and electrodiagnostic features are characteristic 3
• Early diagnosis is crucial, particularly to detect underlying malignancy in paraneoplastic cases 3
• Improvement of weakness after brief exercise is a distinctive clinical feature that can help differentiate LEMS from myasthenia gravis 3, 2