Approximately 50% of LEMS patients have a small cell lung cancer (SCLC), often not clinically evident at the inception of neuromuscular symptoms. Presumably, the immune response leading to LEMS begins early in tumor evolution. SCLC is more likely in patients with weight loss greater than or equal to 5%, bulbar involvement, erectile dysfunction, in those older than 50 years, and in active smokers. Primary autoimmune, nonparaneoplastic LEMS occurs in younger adults and very rarely in children.
The initial LEMS clinical manifestations often begin months to a few years before SCLC is recognized. Sometimes, however, the cancer precedes LEMS. Classic symptoms include fatigue, proximal muscle weakness, dry mouth sometimes presenting as increased thirst, and, in men, erectile dysfunction. The motor components relate to autoimmune blockage of the nicotinic presynaptic NMJ calcium channels and muscarinic symptoms from similar effects on the acetylcholine-dependent autonomic nervous system receptors. Sometimes fatigue per se suggests to the unwary clinician that the younger patient most likely has emotional issues, particularly depression, or possibly is “hysterical.” Occasional patients observe their symptoms improve after brief exercise, as exemplified by experiencing increased strength near the top of stairs. Additional more subtle symptoms of LEMS patients mimic myasthenia gravis: mild diplopia, ptosis, difficulty chewing, dysphagia, and dysarthria secondary to oropharyngeal weakness.
Neurologic examination demonstrates proximal weakness; sometimes initially noted by the examining physician when the patient arises to greet her or him. Sometimes the weakness has a “give way component;” however, when LEMS patients are asked to contract the weakened muscle a few times, their initial weakness may totally, albeit briefly, improve, only to weaken once again. Similarly, muscle stretch reflexes (MSR) are initially diminished or absent. However, if the biceps or quadriceps muscle strength is tested and then immediately reexamined for their respective MSR, the examiner may detect facilitation and a normal reflex for a limited time. This is the clinical representation of postexercise facilitation typical for presynaptic NMTD disorders and representative of the classic electromyographic (EMG) facilitation. Some LEMS patients present with, or develop, a gait ataxia over and above their degree of weakness. Sometimes, this is the primary LEMS manifestation and may be secondary to severe most proximal muscle weakness, particularly the paraspinal muscles necessary to stabilize the spine. Ataxic gait may also suggest a primary cerebellar degeneration from a concomitant paraneoplastic disorder.
EMG provides a means to confirm a clinical diagnosis of LEMS. Motor nerve conduction demonstrates low-amplitude compound muscle action potentials (CMAPs) that demonstrate postexercise facilitation after 10 seconds voluntary exercise. With LEMS, the CMAP at least doubles in amplitude. There is also a significant decrement on repetitive motor nerve stimulation (RMNS) similar to MG.
Voltage-gated calcium channel antibodies are detected in 90% of patients with either paraneoplastic or primary autoimmune LEMS. Because SCLC is found in 50% of LEMS patients, chest computed tomography (CT) is required to search for an occult tumor, particularly in older adults who smoke cigarettes. A tumor is often not immediately apparent; therefore repeat studies are required biannually.
Primary treatment for LEMS-associated lung cancer may eventually lead to muscle strength improvement, presumably by removing the antigenic stimulus. Symptomatic treatment of LEMS per se aims to improve neuromuscular transmission (NMT). 3,4- Diaminopyridine promotes presynaptic ACh release. In addition, the anticholinesterase medication pyridostigmine can sometimes also improve NMT. Immune-modulating agents, such as prednisone or azathioprine, are indicated in primary autoimmune LEMS. Despite improvement in muscle strength, sometimes the gait ataxia does not improve.
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