Other Neuromuscular Transmission Disorders

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74 Other Neuromuscular Transmission Disorders

Ted M. Burns, H. Royden Jones, Jr.

Clinical Vignette

A 58-year-old woman presented with a 3-month history of progressive fatigue and lower extremity weakness, especially noticeable when she was walking up and down stairs or arising from a chair. Lately she had noted mildly slurred speech, transient double vision with eyelid droop, and dry mouth. Her past medical history was unremarkable. She had a 60-pack-year history of cigarette smoking. Examination was remarkable for mild weakness of orbicularis oculi, neck flexor, deltoid, triceps, and hip flexor and hip extensor muscles bilaterally. She had difficulty arising from a chair. Muscle stretch reflexes were absent on routine testing but elicitable after 10 seconds of isometric exercise.

Serum creatine kinase and acetylcholine (ACh) receptor antibody study results were normal. Nerve conduction studies (NCS) demonstrated low compound muscle action potentials (CMAPs) on most motor nerve conduction studies. A 15% decrement of CMAP amplitude was observed with 3-Hz repetitive motor nerve stimulation of the ulnar nerve. After 10 seconds of exercise, the ulnar CMAP amplitude facilitated approximately 300%, which is typical of a presynaptic neuromuscular transmission disorder. She was diagnosed with Lambert–Eaton myasthenic syndrome (LEMS). Serum voltage-gated P/Q calcium channel (VGCC) antibodies were later found to be elevated, consistent with LEMS.

A chest radiograph showed a right hilar mass; its biopsy revealed small cell lung cancer (SCLC). The patient received chemotherapy, as well as 3,4-diaminopyridine for symptomatic treatment of LEMS, resulting in some modest improvement in strength. She died 16 months later from complications of SCLC.

Lambert–Eaton Myasthenic Syndrome

Although rare, LEMS is the most frequently occurring presynaptic neuromuscular transmission disorder in adults. In approximately 50% of cases, LEMS is associated with cancer, especially SCLC. When LEMS is not associated with cancer, a primary autoimmune etiology is suspected. The paraneoplastic and nonparaneoplastic forms of LEMS share an autoimmune pathophysiologic mechanism. VGCC antibodies are detected in more than 90% of patients with either paraneoplastic or nonparaneoplastic LEMS. Antibodies to SOX1 have been identified in the majority of paraneoplastic LEMS patients but are not found in patients with nonparaneoplastic LEMS, and thus may prove valuable in evaluating for the presence or absence of cancer in a patient with LEMS. LEMS associated with lung cancer usually presents in past or present smokers, and clinical manifestations of LEMS often begin months to years before diagnosis of the malignancy. Therefore, a timely LEMS diagnosis may expedite the lung cancer diagnosis and influence treatment and prognosis. LEMS unassociated with cancer usually occurs in younger nonsmokers, especially women.

The vignette in this chapter illustrates cardinal LEMS symptoms and signs: proximal extremity weakness, reduced or absent muscle stretch reflexes, and complaints of fatigue and dry mouth, with milder symptoms of ocular and oropharyngeal weakness. Because of the patient’s history of cigarette smoking, paraneoplastic LEMS was the prime consideration. The muscle stretch reflexes demonstrated improvement after 10 seconds of exercise, indicative of a presynaptic neuromuscular junction transmission disorder, and this corresponded to the NCS of postexercise facilitation of the CMAP amplitude.

LEMS often provides an early diagnosis of SCLC because the immune response producing LEMS is believed to begin early in tumor evolution. However, by the time LEMS was diagnosed in the preceding vignette, the SCLC had metastasized and prognosis was poor.

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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