An instructive review of this disease by O’Neill and colleagues consisted of 50 well-studied cases, in which they described proximal leg weakness in all, arm weakness in 39, diplopia in 25, ptosis in 21, and dysarthria in 12. Symptoms were paresthesias, aching pain (suggesting arthritis), and a number of autonomic disturbances, such as dryness of the mouth, constipation, difficult micturition, and impotence. This latter group of symptoms gives the syndrome an unmistakable stamp as discussed further on under “Diagnosis.” One should not be surprised to find other neurologic manifestations of neoplasia (e.g., polyneuropathy, polymyositis or dermatomyositis, multifocal leukoencephalopathy, cerebellar degeneration, as discussed in Chap. 30).
The onset of weakness is subacute and the course, variably progressive. Males are affected far more often than females (5:1). The weakness may precede discovery of the tumor by months or years. Approximately 60 percent of cases are associated with small cell lung cancer, but small numbers have also occurred with carcinoma of the breast, prostate, stomach, and rectum, and with lymphomas; in about one-third of patients, no tumor is found. Some cases are associated with other autoimmune diseases, but most are paraneoplastic or idiopathic. The condition may occur in children, usually with no relation to tumor. In the tumor cases, death usually occurs in a few months or years from the effect of the neoplasm; the idiopathic ones fluctuate over years.
The response to neostigmine and pyridostigmine is poor or at least unpredictable, and this finding in a myasthenic patient should bring the diagnosis of Lambert-Eaton syndrome to mind. In contrast, d-tubocurarine, suxamethonium chloride, gallamine, and other muscle relaxants have a deleterious effect and may cause fatality, just as in myasthenia gravis.
Conventional electrodiagnostic studies show no abnormality in the peripheral nerves. A single stimulus of nerve may evoke a low-amplitude muscle action potential (in contrast to myasthenia gravis, in which it is normal or nearly so) whereas at fast rates of stimulation (50 per s as shown in Fig. 2-15B) or following strong voluntary contraction (for 15 s or longer) there is a marked increase in the amplitude of action potentials (incrementing response hence the term “inverse myasthenia,” which has been applied to Lambert-Eaton syndrome [LEMS]). Single-fiber recordings show an increase in “jitter” as in myasthenia gravis, as described in Chap. 2.
Elmquist and Lambert, from a series of studies of excised muscle, deduced that there is a defect in the release of ACh quanta from the presynaptic nerve terminals, akin to the effects of botulinum toxin, magnesium excess, and neomycin. The presynaptic vesicles themselves appear to be normal in morphology and content. Also in contrast to myasthenia gravis, the surface area of the postsynaptic receptor membrane in this syndrome is actually increased (A.G. Engel, 1976).
The physiologic mechanism in Lambert-Eaton myasthenic syndrome is a loss of voltage-gated calcium channels on the presynaptic motor nerve terminal. The calcium channels become cross-linked and aggregated by IgG autoantibodies, ultimately reducing the number of functioning channels (Fukunaga et al). These antibodies against a specific component of the presynaptic membrane have the effect of reducing the presynaptic release of ACh, virtually the opposite of myasthenia gravis.