Lambert-Eaton Myasthenic Syndrome (LEMS) is a rare, neuromuscular junction autoimmune disease. The immune system produces immunoglobulin G antibodies against voltage-gated calcium channels (VGCC) residing on the cell membrane of the presynaptic nerve ending.1,3,5,6 The etiology of LEMS is decreased exocytosis of the neurotransmitter acetylcholine from presynaptic neurons into the neuromuscular junction (NMJ) caused by autoantibodies attacking VGCCs.3,7.10 There are two distinct groups of LEMS patients: those with small cell lung carcinoma (SCLC) and those without SCLC. SCLS is the cause of LEMS in about 50% of SCLS-LEMS patients and treatment for these patients with the underlying paraneoplastic malignancy is cancer therapy. The SCLC-LEMS subgroup tends to be over the age of 50 with a male predilection and long-term smoking, reflecting smoking habits that may contribute to SCLC.3,7,10 In the remainder of LEMS patients who have no SCLC, the etiology is unknown and no cure exists, so treatment for these non-tumor LEMS (NT-LEMS) patients focus on resolution of symptoms.1,7 This NT-LEMS subgroup comprises all age groups with a female predilection.1 LEMS is caused by IgG autoantibodies that attack VGCCs, predominantly the P/Q-type calcium channels, which make up more than 95% of functional receptors at the NMJ.1,6,7 In the SCLC-LEMS group, the tumor is the agent that initiates LEMS.3 Expressed on the plasma membrane of SCLC cells, VGCCs are antigens that induce autoantibody production. Newly formed autoantibodies can also cross-react with VGCC self-antigens located on the presynaptic neuron.1,3 These sequential events and symptoms in SCLC-LEMS patients culminate from the buildup of autoimmunity that occurs in early tumor development prior to cancer detection.10 In the NT-LEMS group, no initiating event has yet been discovered to cause the production of autoantibodies. As a result of the autoantibody-antigen immune reaction in both LEMS groups, the signaling pathway of neurotransmitter release is disrupted. The reduction in the number of functional VGCCs leads to a decrease in the influx of calcium ions into the nerve terminal. Without this influx, the normal function of molecules involved in synaptic vesicle fusion and acetylcholine release, such as synaptotagmin, synaptobrevin, and SNAP-25, are inactive.3 If the release of packets or quanta of acetylcholine into the NMJ from pre-synaptic neuron to post-synaptic muscle fiber is disrupted and decreased, then the signal transduced to the muscle is below normal levels.5,7 Given the skeletal muscle fiber’s failure to depolarize and contract, this weak transduced signal is presented as muscle weakness in various parts of the body, especially in the proximal areas such as the upper and lower limbs.1,3,5,7 Dysfunctional and downregulated VGCCs in LEMS patients is the concentration of pathogenic change at the cellular level. VGCCs are ion channels that consist of 5 subunits, but autoantibodies in LEMS selectively targets only one of these subunits: the
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All LEMS patients are clinically diagnosed using a classical triad of symptoms, electrophysiological measurements, and antibody panels.7 The classical triad of symptoms in LEMS patients is muscle weakness of the limbs, commonly found in the legs, that advances distally, reduced tendon reflexes, and autonomic dysfunction.1,7 Clinicians use electrophysiological measurements in the form of repetitive nerve stimulation (RNS) in order to objectively test for signs of proximal weakness in rested muscle, which is observed in approximately 80% of all LEMS patients.1,3,7 American neurologists Lambert-Eaton first described six cases where an electrophysiological pattern was observed with RNS, so this pattern remains a hallmark for diagnosis.5 In RNS, LEMS patients exhibit an abnormal decrease in compound muscle action potential amplitude when low frequency stimulation of 2-5 Hz is used and an increase in compound muscle action potential amplitude after exercise or high frequency stimulation.5,7 This change in muscular strength is primarily due to the autoantibody-mediated attack on VGCCs, thereby mitigating the ability for acetylcholine to exit from presynaptic vesicles, to bind acetylcholine receptors of the post-synaptic muscle fiber, and to initiate an action potential and muscle contraction. These autoantibodies are highly sensitive and are detected in 85% of patients with LEMS, whose specificity for distinct muscle weakness is 100%.1,3 The second classical symptom, reduced tendon reflexes, is largely related to muscle weakness because these reflexes are typically hypoactive or absent in a LEMS patient upon clinical examination.1 In a high frequency stimulation, maximal isometric contraction of muscle fibers for a period of 10-15s can induce a tendon reflex that was previously diminished or absent. Called post-exercise facilitation, this
All LEMS patients are clinically diagnosed using a classical triad of symptoms, electrophysiological measurements, and antibody panels.7 The classical triad of symptoms in LEMS patients is muscle weakness of the limbs, commonly found in the legs, that advances distally, reduced tendon reflexes, and autonomic dysfunction.1,7 Clinicians use electrophysiological measurements in the form of repetitive nerve stimulation (RNS) in order to objectively test for signs of proximal weakness in rested muscle, which is observed in approximately 80% of all LEMS patients.1,3,7 American neurologists Lambert-Eaton first described six cases where an electrophysiological pattern was observed with RNS, so this pattern remains a hallmark for diagnosis.5 In RNS, LEMS patients exhibit an abnormal decrease in compound muscle action potential amplitude when low frequency stimulation of 2-5 Hz is used and an increase in compound muscle action potential amplitude after exercise or high frequency stimulation.5,7 This change in muscular strength is primarily due to the autoantibody-mediated attack on VGCCs, thereby mitigating the ability for acetylcholine to exit from presynaptic vesicles, to bind acetylcholine receptors of the post-synaptic muscle fiber, and to initiate an action potential and muscle contraction. These autoantibodies are highly sensitive and are detected in 85% of patients with LEMS, whose specificity for distinct muscle weakness is 100%.1,3 The second classical symptom, reduced tendon reflexes, is largely related to muscle weakness because these reflexes are typically hypoactive or absent in a LEMS patient upon clinical examination.1 In a high frequency stimulation, maximal isometric contraction of muscle fibers for a period of 10-15s can induce a tendon reflex that was previously diminished or absent. Called post-exercise facilitation, this