Etiology and Pathophysiology

Under normal conditions, neuronal depolarization opens VGCCs on the presynaptic axon terminal membrane, resulting in calcium influx within the nerve terminal. Intracellular calcium binds to calmodulin and mobilizes acetylcholine (ACh) vesicles that are released into the synaptic cleft (Fig. 74-1). The VGCCs are the primary site of immunopathology in LEMS. Divalent IgG autoantibodies cross-link the calcium channels, disrupting their function, resulting in inadequate release of presynaptic ACh vesicles from motor and autonomic cholinergic nerve terminals. The release of fewer ACh quanta at the neuromuscular junction decreases the probability of reaching the “all or none” depolarization threshold of a muscle fiber and thus the likelihood of the muscle fiber action potential (MFAP) generation. It is this drop out of a significant number of MFAP generation that results in low CMAPs on routine NCS.

Figure 74-1 Physiology of Neuromuscular Junction.

The VGCCs expressed on SCLC cells and other neoplasms provide the presumed antigenic stimulus for antibody production to VGCC in the paraneoplastic form of LEMS. The precise antigenic stimulus in the nonparaneoplastic varieties of LEMS remains to be identified. Muscle weakness, fatigue, and autonomic symptoms result because the VGCC antibodies reduce the ACh release at motor and autonomic nerve terminals, impairing synaptic transmission.

Clinical Presentation

The clinical presentation is similar in primary autoimmune and secondary paraneoplastic LEMS. Fatigue is a prominent and early symptom in LEMS patients. Patients with LEMS also complain of proximal weakness, especially lower extremity weakness, sometimes mimicking a myopathy. The complaints of fatigue and proximal weakness often may seem disproportionate to the objective examination findings. When patients with suspected LEMS do not have objective detectable weakness, it may be better appreciated by watching individuals rise from a chair or climb stairs (Fig. 74-2). Muscle stretch reflexes are typically reduced or absent and this finding can be an important clue to the diagnosis. Postexercise potentiation of depressed or absent muscle stretch reflexes and of muscle strength is often demonstrable and signifies a presynaptic neuromuscular junction transmission disorder.

Figure 74-2 Lambert–Eaton Syndrome.

Oculopharyngeal weakness in the form of diplopia, ptosis, dysphagia, and dysarthria is frequently reported but is usually relatively mild. Autonomic symptoms, including dry mouth or erectile dysfunction in men, should prompt clinicians to consider LEMS. In fact, it is unlikely—although not impossible—for a patient with LEMS to be without symptoms of dry mouth. Patients with LEMS also sometimes complain of vague sensory symptoms, such as tingling and numbness.

Diagnostic Approach

Appropriate NCS testing is crucial in the diagnosis of LEMS (Fig. 74-3

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