A 65-year-old woman comes to the office with several months of progressive cough and generalized weakness. The patient has limited mobility and shortness of breath due to osteoarthritis and chronic obstructive pulmonary disease, respectively. She also has difficulty standing from a chair, combing her hair, and putting dishes in overhead cabinets. The patient's medical history includes hypertension and hyperlipidemia. She quit smoking cigarettes 2 years ago but previously smoked 3 packs daily since age 20. Blood pressure is 112/70 mm Hg, and pulse is 92/min. BMI is 17 kg/m². Physical examination shows moderate weakness in the proximal muscles of her upper and lower limbs and loss of deep tendon reflexes. CT scan of the chest is shown below. Which of the following is the most likely cause of this patient's weakness?

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11ec25c8_d480_55c2_bc81_d13c9875bdf7_MD0003_00 This patient's presentation is consistent with Lambert-Eaton myasthenic syndrome (LEMS), a neuromuscular disorder caused by autoantibodies against voltage-gated calcium channels in the presynaptic motor nerve terminal that leads to decreased acetylcholine release and subsequent weakness. Approximately 50% of cases are associated with an underlying malignancy, mostly small cell lung cancer. This patient's long smoking history and recent presentation with cough, weakness, low BMI, and a lung mass on chest CT scan are concerning for malignancy. lung mass Patients initially have progressive symmetric proximal limb muscle weakness (eg, standing from a chair, combing hair, putting dishes in overhead cabinets). Deep tendon reflexes are reduced/absent, although vigorous muscle activity can improve reflexes and muscle strength temporarily. Autonomic dysfunction (eg, dry mouth, erectile dysfunction) is also common. The diagnosis is confirmed by checking for autoantibodies against voltage-gated calcium channels and by electrophysiological studies. Patients should also be evaluated and treated for a primary underlying malignancy. Symptomatic therapy includes guanidine or 3,4-diaminopyridine to increase presynaptic acetylcholine levels. Refractory symptoms may respond to immunologic therapy with intravenous immunoglobulin or oral immunosuppressants (eg, corticosteroids, azathioprine). (Choice A) Acute inflammatory demyelinating polyneuropathy (Guillain-Barré syndrome) is characterized by acute ascending muscle weakness with areflexia. Most patients have a preceding viral illness. (Choice B) Myasthenia gravis is caused by autoantibodies against post-synaptic acetylcholine receptors in the neuromuscular junction. In contrast to LEMS, patients with myasthenia gravis typically present with fatigable ocular (eg, ptosis, diplopia) and bulbar (eg, dysarthria) muscle weakness, which are not seen in this patient. In addition, myasthenia gravis would not cause loss of reflexes. Finally, myasthenia gravis is classically associated with thymoma rather than lung mass. (Choice D) Immune-mediated muscle inflammation suggests polymyositis. This condition can present with proximal muscle weakness. However, reflexes are typically preserved and muscle enzymes (eg, creatine kinase) are usually elevated. (Choice E) Multicentric central nervous system inflammation and demyelination are indicative of multiple sclerosis, which typically presents in women age 15-50 with neurologic deficits disseminated in space and time (eg, optic neuritis, internuclear ophthalmoplegia). (Choice F) Upper and lower motor neuron degeneration is suggestive of amyotrophic lateral sclerosis. It generally presents with bulbar symptoms followed by limb weakness associated with upper (eg, hyperreflexia, spasticity) and lower (eg, muscle atrophy, fasciculations) motor neuron signs. Educational objective: Lambert-Eaton myasthenic syndrome is frequently associated with an underlying malignancy (eg, small cell lung cancer). It is caused by autoantibodies directed against the voltage-gated calcium channels in the presynaptic motor nerve terminal leading to symmetric proximal muscle weakness with depressed deep tendon reflexes. References: The Lambert-Eaton myasthenic syndrome 1988-2008: a clinical picture in 97 patients. (http://www.ncbi.nlm.nih.gov/pubmed/18644631) Difference in distribution of muscle weakness between myasthenia gravis and the Lambert-Eaton myasthenic syndrome. (http://www.ncbi.nlm.nih.gov/pubmed/12438488)

A 65-Year-Old Woman Comes to the Office with Several Months