Lambert-Eaton Myasthenic Syndrome (LEMS)
Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder characterized by antibodies targeting presynaptic voltage-gated calcium channels (VGCC), resulting in reduced acetylcholine release at the neuromuscular junction, causing muscle weakness, autonomic dysfunction, and areflexia. 1, 2
Pathophysiology
- LEMS is caused by autoantibodies that target P/Q-type voltage-gated calcium channels (VGCC) at presynaptic nerve terminals, inhibiting acetylcholine release and disrupting neuromuscular transmission 1, 2
- These antibodies are directly implicated in the pathophysiology of the disorder, causing reduced acetylcholine release at nerve terminals and consequently leading to muscle weakness 1
- The antibodies also inhibit transmitter release from parasympathetic, sympathetic, and enteric neurons, explaining the widespread autonomic dysfunction seen in LEMS 3
Clinical Presentation
- Proximal muscle weakness is the hallmark symptom, typically affecting the lower limbs first and progressing upward 1, 2
- Autonomic dysfunction manifests as dry mouth, constipation, impaired sweating, erectile dysfunction, and other dysautonomic features 3, 2
- Areflexia or diminished deep tendon reflexes are characteristic findings 4, 5
- Unlike myasthenia gravis, muscle strength in LEMS typically improves with repeated or sustained muscle contraction 1
- Symptoms often develop gradually and progressively worsen over time 2
Types of LEMS
- Paraneoplastic LEMS (P-LEMS): Associated with malignancy in approximately 60% of cases, most commonly small cell lung cancer (SCLC) 1, 2
- Autoimmune LEMS (A-LEMS): Non-tumor related, often associated with other autoimmune disorders 1, 2
- Rare associations with other malignancies have been reported, including non-Hodgkin lymphoma 4
Diagnosis
- Diagnosis is confirmed through a three-pronged approach: clinical features, electromyography, and anti-VGCC antibody testing 1, 2
- Electromyography typically shows:
- Reduced compound motor action potentials (CMAPs)
- Decremental responses to low-frequency stimulation
- Incremental responses after brief exercise or high-frequency stimulation 1
- Approximately 90% of LEMS patients have detectable P/Q-type VGCC antibodies 1
- A thorough search for underlying malignancy is essential, particularly SCLC, as LEMS can be an early indicator of cancer 2
Treatment
- FDA-approved treatment for LEMS includes 3,4-diaminopyridine (Firdapse), a potassium channel blocker that enhances acetylcholine release at the neuromuscular junction 6
- Immunosuppressive therapy with prednisone and azathioprine is often used for patients with persistent symptoms 2, 5
- In paraneoplastic LEMS, treatment of the underlying malignancy is the priority and can improve neurological symptoms 2, 4
- Symptomatic treatment significantly improves neurologic symptoms and quality of life 1
Prognosis
- Prognosis is related to the presence of cancer or autoimmune disease and the severity/distribution of muscle weakness 2
- In paraneoplastic LEMS, mortality is typically due to tumor progression 2
- Non-tumor LEMS generally does not reduce life expectancy 2
- Early diagnosis and treatment are crucial for improving outcomes 1
Differential Diagnosis
- Myasthenia gravis is the most common condition confused with LEMS due to overlapping symptoms 2
- Other conditions in the differential diagnosis include Lambert-Eaton myasthenic syndrome, myopathies, motor neuron disease, and other neuromuscular disorders 7
- LEMS should be distinguished from other causes of muscle weakness and autonomic dysfunction 7
Key Considerations
- LEMS is a clinically important early indicator of possible cancer; therefore, diagnosis should immediately prompt rigorous oncological screening and surveillance 2
- Patients with LEMS may have altered sensitivity to certain medications, particularly neuromuscular blocking agents used in anesthesia 8
- The impact of LEMS on quality of life is significant and warrants timely diagnosis and appropriate treatment 2