Lambert Eaton myasthenic syndrome

This disorder is much less common than myasthenia gravis. It is characterized by proximal muscle weakness, depressed tendon reflexes, post-tetanic potentiation and autonomic changes, including dry mouth and constipation. Onset can be in adolescence, but is usually after 40 years of age. Other autoimmune diseases may associate, notably thyroid disease and vitiligo, and other autoantibodies occur at increased frequency.

About 60% of cases have associated small cell lung cancer (SCLC). The neurological disorder typically precedes radiological evidence of the tumor by up to 2 years, and exceptionally 4-5 years. Many of the remainder have been followed for 10 years or more, making an underlying tumor very unlikely.

The physiological abnormality is presynaptic, in contrast to myasthenia gravis. Quantal release of acetylcholine by the nerve impulse depends on the opening of voltage-gated Ca2 channels (VGC.'Cs) and the consequent local influx of Ca2f into the nerve terminal; in LEMS, the calcium-dependent release of transmitter is greatly reduced, and freeze-fracture electron microscopy shows loss of active zone particles that are thought to represent VGCCs. Postsynaptic AChRs are normal.

The disorder is caused by IgG autoantibodies that bind to VGCCs (or to structures closely associated with them). There are at least four subtypes of neuronal VGCCs (T-, L-, N-, P/Q-). Antibodies to P/Q-type VGCCs dominate the immune response, and can be detected by radioimmunoprecipitation assay using a cone snail neurotoxin ([125I]a>-conotoxin MVIIC) to label the VGCCs. Serum titers broadly correlate with disease severity in individual patients. LEMS IgG injected into mice transfers the physiological changes, i.e. reduced quantal release of acetylcholine and morphological changes such as clustering and reduction in the number of active zone particles. These effects appear to be dependent on antibody divalency, as Fab fragments are without effect, suggesting that loss of VGCCs may be brought about by cross-linking. Recent passive transfer studies to mice have shown that the autonomic changes may similarly be mediated by autoantibodies to P/Q-type and occasionally N-type VGCCs.

HLA-B8 and (less strongly) HLA-DR3 and Ig heavy chain markers associate with LEMS, both in its SCLC-associated and noncancer forms. SCLC patients without LEMS do not show these associations, implying that susceptibility to LEMS in SCLC cases is partly conferred by immune response genes.

SCLC is thought to be of neural crest origin. SCLC cell lines express VGCCs, as shown by depolarization-induced 45Ca2+ influx. LEMS IgG, both from SCLC and non-SCLC cases, causes a highly significant reduction of K+-stimulated 45Ca2+ flux into these cells compared with control IgG, and inhibition of flux correlates with an electromyographic measure of disease severity. These results suggest that the antibodies against VGCCs in SCLC cases are triggered by tumor VGCCs, and that the cross-reactivity with nerve terminal VGCCs leads to the neurological disorder. The immune response in these patients may be generated within the tumors as macrophage infiltration in LEMS-associated SCLC is greatly increased compared with non-LEMS cases.

Thus, in its cancer-associated form, LEMS provides the first clear evidence that a paraneoplastic neurological syndrome can be caused by an antibody-mediated autoimmune process. Consistent with this, treatment of the neoplasm by surgery, chemotherapy or deep X-ray is usually followed by improvement or remission of the neurological syndrome in those who survive the effects of the tumor. Many of the noncancer cases respond to immunosuppressive treatment (prednisolone and azathioprine), and short-term improvement may follow plasmapheresis or intravenous immunoglobulin.

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