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A 61-year-old man is evaluated in the office for a 6-month history of progressive weakness of the lower extremities. He says he has difficulty rising from a seated position and walking up stairs and also has episodes of dry eyes, dry mouth, and erectile dysfunction. The patient reports no ptosis, diplopia, dysphagia, or dyspnea. He has a 15-year history of hypertension and a 42 pack-year smoking history. Family history is unremarkable. His only medication is hydrochlorothiazide.
On physical examination, vital signs are normal. Manual muscle strength testing shows weakness in the proximal upper and lower limb muscles. Deep tendon reflexes are absent diffusely. Plantar responses are flexor. A sensory examination shows no abnormalities, and cranial nerve function is normal.
Laboratory studies show normal serum levels of sodium, potassium, calcium, creatinine, glucose, and creatine kinase. Results of liver chemistry studies are also normal.
Which of the following is the best diagnostic test for this patient?
A) Measurement of acetylcholine receptor antibody level
B) Measurement of parathyroid hormone level
C) Measurement of voltage-gated P/Q-type calcium channel antibody level
D) Muscle biopsy
Answer and Critique
The correct answer is C) Measurement of voltage-gated P/Q-type calcium channel antibody level. This item is available to MKSAP 15 subscribers as item 10 in the Neurology section.
This patient most likely has Lambert-Eaton myasthenic syndrome, as suggested by his history of proximal upper and lower limb weakness, the presence of autonomic symptoms (dry eyes/mouth, erectile dysfunction), and the finding of absent deep tendon reflexes on examination. These are characteristic signs and symptoms of the syndrome. Lambert-Eaton myasthenic syndrome is a neuromuscular junction disorder caused by disordered calcium channel function on the presynaptic nerve terminal. In most patients with this disorder, antibodies to voltage-gated P/Q-type calcium channel receptors exist. Lambert-Eaton myasthenic syndrome is typically a paraneoplastic syndrome, caused by or associated with an underlying malignancy, particularly small cell lung cancer. The diagnosis of Lambert-Eaton myasthenic syndrome precedes the clinical diagnosis of cancer in up to 50% of affected patients; therefore, in patients with newly diagnosed Lambert-Eaton myasthenic syndrome, a thorough search for an underlying cancer should be performed. If no evidence of malignancy is found, these patients should be evaluated serially for occult malignancy. In addition to elevated levels of voltage-gated P/Q-type calcium channel antibodies, the diagnosis can be confirmed through electrodiagnostic studies, particularly repetitive nerve stimulation studies, which show an increase in the muscle action potential (increment) after brief exercise.
Elevated levels of antibodies against acetylcholine receptors are present in 90% of patients with generalized myasthenia gravis. Myasthenia gravis is an autoimmune disorder that results in neuromuscular transmission failure, causing weakness of limb and cranial muscles. The diagnosis is confirmed through electrodiagnostic testing, including repetitive nerve stimulation studies and, in some patients, single-fiber electromyography. The presence of an elevated acetylcholine receptor antibody level may provide additional confirmatory evidence supporting the diagnosis of myasthenia gravis. In this patient, the absence of any bulbar signs or symptoms, such as ptosis, visual symptoms (blurred vision or diplopia), or dysphagia, in conjunction with absent deep tendon reflexes, would argue against myasthenia gravis.
Hyperparathyroidism, either primary or secondary, can result in proximal limb weakness. The normal calcium level in this patient would argue against a significant parathyroid disorder. Additionally, absent deep tendon reflexes would not be expected in a patient with hyperparathyroidism. Measurement of the parathyroid hormone level is therefore not indicated.
Muscle biopsy is not likely to offer any additional diagnostic information in this patient with normal serum creatine kinase levels. Muscle biopsy is indicated primarily in patients with suspected inflammatory myopathies, such as polymyositis, dermatomyositis, or inclusion body myositis, and in certain hereditary myopathic disorders. Symptom onset in the seventh decade argues against a hereditary myopathy, as does the normal creatine kinase level. Although serum creatine kinase levels can be normal in patients with inclusion body myositis, deep tendon reflexes are typically normal, and weakness is most prominent in quadriceps and deep finger flexor muscles.
Key Point
- The diagnosis of Lambert-Eaton myasthenic syndrome, a neuromuscular junction disorder that causes progressive proximal muscle weakness and areflexia, precedes the clinical recognition of cancer in up to 50% of patients.
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