Etiology

Cancer is found either at disease onset or subsequently in around 50% of patients with Lambert-Eaton myasthenic syndrome (LEMS).[2][8][9]​​ In cancer-associated LEMS, small cell lung cancer (SCLC) is the most commonly associated cancer, although an association with lymphoproliferative disorders has also been described.[3] SCLC cells contain high concentrations of voltage-gated calcium channels (VGCCs) that presumably induce production of VGCC antibodies.

In autoimmune or nonparaneoplastic LEMS (NCA-LEMS), anti-VGCC antibodies are produced as part of a more general autoimmune state. The provoking factor is unknown, but associations with HLA-B8, -A1, and -DR3 are strong, and associated autoimmune diseases are common; 27% of patients with NCA-LEMS exhibit evidence of an additional organ-specific autoimmune disorder.[10][11][12]​ Of these, autoimmune thyroid disease is the most common; vitamin B12 deficiency, rheumatoid arthritis, inflammatory myopathy, and systemic vasculitis have also been reported.

Pathophysiology

The fundamental pathology is disruption of neurotransmission due to depletion of VGCCs. In normal neurotransmission, depolarization of the presynaptic nerve terminal triggers calcium influx at VGCC that ultimately results in quantal release of acetylcholine (ACh) into the synaptic cleft. This produces localized depolarization of the adjacent periendplate muscle membrane. The amplitude of the resulting miniature endplate potentials reflects the size of each ACh quantum, as well as the responsiveness of the postsynaptic muscle membrane to ACh. Microphysiologic studies demonstrate that miniature endplate potential amplitude is normal in the muscle of patients with LEMS, but fewer quanta are released by each nerve depolarization.[13] This has been further illustrated microstructurally using immunoelectron microscopy.[14] VGCC are normally arranged in regular parallel arrays on the presynaptic nerve terminal membrane. In LEMS, this pattern is lost and the VGCCs become clustered and reduced in number.[15] Studies of mice treated with LEMS immunoglobulins have revealed that the quantal content of the endplate potential is reduced and that presynaptic membranes of the treated mice display the same VGCC clustering and numeric depletion as that observed in humans.[14][16]

Several lines of evidence support an autoimmune etiology for LEMS. First, immunomodulation with prednisone, plasma exchange, or intravenous immune globulin improves weakness in many patients with LEMS.[9]​​​[17][18]​​​​ Second, passive transfer of immunoglobulins from patients with LEMS to mice causes electrophysiologic and morphologic changes in the neuromuscular junction similar to the changes seen in patients with LEMS.[15][16][19]​​​ Finally, P/Q VGCCs have been shown to be the target of pathogenic LEMS antibodies that downregulate VGCC expression by antigenic modulation.[14] Antibodies against the P/Q VGCC have been demonstrated in serum of 90% of nonimmunosuppressed patients with LEMS.[20]

Classification

Clinical classification[1]

In association with cancer (CA-LEMS)

  • Small cell lung cancer is the most commonly associated cancer, although an association with lymphoproliferative disorders has also been described.

In association with an organ-specific autoimmune disorder without cancer (NCA-LEMS)

  • Autoimmune thyroid disease is the most common; vitamin B12 deficiency, rheumatoid arthritis, inflammatory myopathy, and systemic vasculitis are also observed.

Use of this content is subject to our disclaimer