A 54-year-old previously healthy man comes to the office due to progressive fatigue and weakness for the past 2 months. His weakness predominantly involves the lower extremities, causing him to have difficulty rising from a chair. The patient also has a persistent cough and unintentional 7-kg (15.4-lb) weight loss during the same period. He has a 30-pack-year smoking history and drinks alcohol occasionally. Physical examination shows bilaterally decreased strength in the proximal muscles of the lower extremities with normal bulk and tone. Quadriceps tendon reflexes are diminished bilaterally. Chest x-ray reveals a hilar mass, biopsy of which demonstrates small cells that stain positive for chromogranin and synaptophysin. Which of the following is the most likely cause of this patient's muscle weakness?

Question

A 54-year-old previously healthy man comes to the office due to progressive fatigue and weakness for the past 2 months.  His weakness predominantly involves the lower extremities, causing him to have difficulty rising from a chair.  The patient also has a persistent cough and unintentional 7-kg (15.4-lb) weight loss during the same period.  He has a 30-pack-year smoking history and drinks alcohol occasionally.  Physical examination shows bilaterally decreased strength in the proximal muscles of the lower extremities with normal bulk and tone.  Quadriceps tendon reflexes are diminished bilaterally.  Chest x-ray reveals a hilar mass, biopsy of which demonstrates small cells that stain positive for chromogranin and synaptophysin.  Which of the following is the most likely cause of this patient's muscle weakness?

Quizplus · Accepted Answer

11ec160b_39bb_e8d5_9249_b7f881cae169_MD0001_00 This patient with small cell lung cancer (small cells with neuroendocrine differentiation) has progressive proximal muscle weakness and diminished reflexes in the lower extremities, suggestive of paraneoplastic Lambert-Eaton myasthenic syndrome (LEMS). LEMS is an autoimmune disorder characterized by antibodies against presynaptic voltage-gated calcium channels at the neuromuscular junction. Normally, these calcium channels open in response to a presynaptic action potential, leading to an influx of calcium ions that cause synaptic vesicle fusion and acetylcholine release. LEMS-associated autoantibodies inhibit calcium influx, resulting in reduced acetylcholine release and failure to provoke muscular contractions. Muscular weakness in LEMS is progressive and predominantly involves the proximal muscles; it typically affects the lower limbs (eg, difficulty rising from a chair or climbing stairs) before the upper limbs (eg, raising arms above the head). Deep tendon reflexes are typically diminished or absent. Both strength and reflexes improve transiently with isometric muscular contractions in a phenomenon known as postexercise facilitation, likely due to a buildup of intracellular calcium with repetitive stimuli. Approximately 50% of patients have an underlying malignancy, most commonly small cell lung cancer. (Choice B) Autoantibodies against postsynaptic nicotinic acetylcholine receptors cause myasthenia gravis (MG), another immune-mediated neuromuscular disorder. MG typically involves the extraocular (eg, ptosis, diplopia) and bulbar (eg, dysphonia, dysphagia) muscles before affecting the limbs, and reflexes typically remain intact. (Choice C) Guillain-Barré syndrome occurs due to immune-mediated, segmental axonal demyelination; however, it typically occurs after an upper respiratory or gastrointestinal (eg, Campylobacter) infection. Rapidly progressive ascending paralysis (distal prior to proximal muscle involvement) is characteristic. (Choice D) Metastatic disease within the epidural space can cause spinal cord compression. Patients typically develop spastic paraparesis below the level of involvement. Hyperreflexia is common, and urine and stool retention may be seen (depending on the level of involvement). (Choice E) Protein degradation in cancer cachexia is associated with activation of the ubiquitin-proteasome system. Cancer cachexia causes muscle and fat loss, but weakness would be expected to affect proximal and distal muscles equally and reflexes are preserved. Educational objective: Lambert-Eaton myasthenic syndrome is characterized by antibodies against presynaptic voltage-gated calcium channels. Patients develop progressive proximal muscle weakness with reduced/absent reflexes that predominantly involves the lower extremities. The syndrome is often associated with malignancy, particularly small cell lung cancer.

A 54-Year-Old Previously Healthy Man Comes to the Office Due