What is the mechanism of Lambert-Eaton myasthenic syndrome (LEMS)?

Lambert-Eaton Myasthenic Syndrome: Pathophysiological Mechanism

Lambert-Eaton Myasthenic Syndrome (LEMS) is an autoimmune disorder characterized by antibodies targeting presynaptic voltage-gated calcium channels (VGCC), particularly P/Q-type, resulting in reduced acetylcholine release at the neuromuscular junction. 1

Pathophysiological Mechanism

Primary Autoimmune Process

• Antibody Target: Approximately 90% of LEMS patients have antibodies against P/Q-type voltage-gated calcium channels (VGCCs) located on presynaptic nerve terminals 2
• Functional Impact: These antibodies bind to and reduce the number of functional VGCCs at active zones of the motor nerve terminal 3
• Neurotransmitter Deficit: The reduction in calcium influx through these channels leads to decreased quantal release of acetylcholine at the neuromuscular junction 3

Disease Variants

1. Paraneoplastic LEMS (P-LEMS):

   • Associated with malignancy in 50-60% of cases
   • Most commonly linked to small cell lung cancer (SCLC) 4
   • Tumor cells express the same VGCCs that become targets of the autoimmune response 3

2. Autoimmune LEMS (A-LEMS):

   • Not associated with cancer
   • Often related to other autoimmune disorders 2

Electrophysiological Consequences

• Reduced CMAP: Compound muscle action potentials are reduced at baseline 2
• Decremental Response: Significant decrements in response to low-frequency stimulation
• Incremental Response: Characteristic incremental response (>60% increase) after brief exercise or high-frequency stimulation 3
• Synaptic Disruption: The autoimmune attack not only reduces calcium channels but also disorganizes transmitter release sites 5
• Homeostatic Changes: The body attempts to compensate by upregulating other calcium channel types 5

Pathophysiological Differences from Myasthenia Gravis

• LEMS: Presynaptic disorder affecting calcium channels and acetylcholine release
• Myasthenia Gravis: Postsynaptic disorder with antibodies targeting acetylcholine receptors 1

Molecular and Cellular Changes

• Active Zone Disruption: Disorganization of transmitter release sites at the presynaptic membrane 5
• Reduced Release Probability: Each synapse has hundreds of transmitter release sites, but LEMS further reduces the already low probability of release at each site 5
• Calcium Channel Reduction: The number of functional P/Q-type VGCCs is significantly decreased 3

Clinical Manifestations Related to Pathophysiology

• Proximal Muscle Weakness: Due to insufficient acetylcholine release at neuromuscular junctions
• Autonomic Dysfunction: Caused by impaired neurotransmission at autonomic synapses
• Hyporeflexia/Areflexia: Results from reduced neuromuscular transmission
• Post-Exercise Facilitation: Brief improvement in strength after exercise due to calcium accumulation in the nerve terminal, temporarily enhancing acetylcholine release 1

Understanding this pathophysiological mechanism is crucial for diagnosis and treatment, as it explains the characteristic electrophysiological findings and forms the basis for symptomatic treatments like 3,4-diaminopyridine, which prolongs the action potential to allow more time for calcium influx through remaining channels 5.