A 54-year-old woman comes to the office due to unsteady gait. The patient's legs have felt "rubbery," and she fell once while walking in the dark several weeks ago. She has had no headache, vision loss, focal weakness, or back pain. The patient has also had irritability and crying spells, which she attributes to menopause. She has a 6-year history of type 2 diabetes mellitus and takes metformin. The patient has had remarkable weight loss following various diets, and her hemoglobin A1c levels have been below 7% over the past year. Blood pressure is 124/68 mm Hg and pulse is 66/min with no orthostatic changes. BMI is 26 kg/m². Physical examination shows normal pupillary reflexes and funduscopy. Muscle strength in the lower extremities is normal. Bilateral plantar reflexes are upgoing. When the patient is instructed to stand with the feet together and eyes closed, she sways from side to side. Laboratory results are as follows: Which of the following is the best next step in management of this patient?

Question

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Explanation: This patient on chronic metformin therapy has neuropsychiatric manifestations (eg, irritability, crying spells), sensory ataxia (swaying when standing with eyes closed), and positive Babinski sign, raising strong suspicion for vitamin B₁₂ deficiency. Approximately 30% of patients on metformin develop clinically significant vitamin B₁₂ deficiency after ≥5 years of treatment. The mechanism is not entirely elucidated but may be in part due to metformin altering calcium homeostasis in the gastrointestinal tract, thereby impairing calcium-dependent vitamin B₁₂ absorption in the terminal ileum. ₁₂ ₁₂ terminal ileum Vitamin B₁₂ is required for DNA synthesis and myelin sheath formation; deficiency usually results in megaloblastic anemia (due to impaired hematopoiesis) and/or neurologic manifestations (due to myelin damage). A minority of patients have neurologic findings alone (as in this case); therefore, the lack of hematologic abnormalities (eg, macrocytosis) does not exclude the diagnosis. Neurologic abnormalities generally arise because of damage to the following: ₁₂ Dorsal columns, leading to impaired vibratory sensation/proprioception and sensory ataxia (gait impairment that worsens when the eyes are closed [positive Romberg sign]) Lateral corticospinal tracts, leading to positive Babinski sign Myelinated peripheral nerves, leading to lower extremity paresthesias Myelinated fibers in the brain, leading to neuropsychiatric manifestations (eg, irritation, mood changes) Workup begins with a serum vitamin B₁₂ level, but methylmalonic acid and homocysteine levels may be required if results are inconclusive. (Choice A) Lumbar spinal stenosis can be diagnosed with CT scan of the lumbosacral spine. This condition can cause positive Babinski sign due to compression of the corticospinal tracts, but most patients (>90%) have pain in the legs exacerbated by activity and weakness. (Choice B) Duloxetine can treat painful diabetic polyneuropathy. Most cases arise in patients with poorly controlled diabetes mellitus and generally present with loss of sensation in a stocking-glove pattern. Because this is a peripheral neuropathy, positive Babinski sign would not be seen. (Choice C) Contrast-enhanced MRI of the brain could aid in the diagnosis of demyelinating brain lesions (eg, multiple sclerosis), stroke, or brain neoplasm. Although brain lesions can cause positive Babinski sign, manifestations are usually unilateral; motor impairments are also commonly seen. A parasagittal meningioma could cause bilateral lower leg weakness but would not explain sensory ataxia. (Choice E) Hypothyroidism can cause peripheral polyneuropathy, which frequently presents with lower extremity paresthesia and sensory loss in a stocking-glove distribution. Although deep tendon reflexes may be diminished, Babinski sign would not be seen. Educational objective: Long-term (≥5 years) metformin therapy can cause vitamin B₁₂ deficiency due to alterations in calcium homeostasis, leading to impaired absorption of vitamin B₁₂ in the terminal ileum. Although megaloblastic anemia is often seen, a minority of patients have isolated neurologic findings (eg, paresthesias, sensory ataxia, neuropsychiatric changes). ₁₂ ₁₂

A 54-Year-Old Woman Comes to the Office Due to Unsteady