SUN-013 - A Small Tumor with A Big Impact: Neuropsychiatric Presentation of Cushing Disease

Introduction:
Cushing disease is most commonly recognized by its metabolic and physical stigmata. However, in some patients, neuropsychiatric symptoms may be the dominant presenting feature.

Case Presentation:
A 38-year-old woman with recently diagnosed diabetes and hypertension presented with one month of progressive cognitive impairment characterized by intermittent confusion, disorientation, and slowed responsiveness. She also reported two years of amenorrhea. On exam she was periodically oriented only to self, and was noted to have proximal muscle weakness and hirsutism. Abdominal striae, dorsocervical fat pad, facial plethora and central obesity were absent. Laboratory evaluation demonstrated hypokalemia to 2.3 mmol/L (3.5–5.1), HbA1c 13%, low free T4 of 0.47 ng/dL (0.8–1.8) with inappropriately normal TSH, and suppressed gonadotropins. Urine toxicology was negative. Head CT as well as subsequent MRI were unremarkable. Given hypertension and hypokalemia, primary hyperaldosteronism was initially considered but excluded by normal plasma aldosterone, renin, and angiotensin II levels. In the setting of persistent confusion and metabolic derangements, evaluation for hypercortisolism was pursued. Morning cortisol was elevated at 29 μg/dL (5–25) with non-suppressed ACTH of 31 pg/mL (10–50). 24-hour urine free cortisol was elevated at 126 μg/24 h ( < 45). Low-dose dexamethasone suppression testing showed persistently elevated cortisol of 16.75 μg/dL, while high-dose dexamethasone resulted in suppression to 5.54 μg/dL (>50% decrease), with adequate dexamethasone levels and elevated late-night salivary cortisol of 241 μg/dL ( < 100), consistent with ACTH-dependent Cushing disease. Dedicated pituitary MRI finally revealed a 6 × 6 × 10 mm adenoma.

Discussion:
ACTH-producing pituitary adenomas frequently evade detection on routine imaging due to their small size, hence the reliance on biochemical evaluation and clinical judgment for their diagnosis. In this case, the patient’s atypical presentation with altered mental status and absence of classic cushingoid features contributed to diagnostic uncertainty. Neuropsychiatric manifestations of Cushing disease are thought to result from chronic hypercortisolism inducing structural and functional brain changes in regions rich in glucocorticoid receptors, particularly the hippocampus, amygdala, and prefrontal cortex. Atrophy in these regions may be irreversible, and neurologic symptoms can persist even after surgical resection of the adenoma.

Conclusion:
Progressive neuropsychiatric symptoms accompanied by unexplained metabolic derangements should prompt evaluation for hypercortisolism, even in the absence of classic cushingoid features. Early use of structured dexamethasone suppression testing can identify radiographically subtle pituitary adenomas and prevent diagnostic delay.

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