Cushing syndrome presenting as persistent delirium

Discussion

Cushing syndrome refers to the constellation of signs and symptoms that result from chronic hypercortisolism, regardless of the underlying cause.³ The most common cause of hypercortisolism is exogenous glucocorticoid therapy; endogenous cortisol overproduction is much less frequent.³ Endogenous Cushing syndrome is categorized as either ACTH-dependent (approximately 80% of cases) or ACTH-independent (approximately 20% of cases).^3,4 ACTH-dependent causes include Cushing disease (pituitary adenoma secreting ACTH) and, less commonly, ectopic ACTH secretion from non-pituitary tumours or ectopic corticotropin-releasing hormone secreting tumours.^3,4 ACTH-independent causes most often involve adrenal adenomas; other rare causes include adrenal carcinomas, macronodular adrenal hyperplasia, and primary pigmented nodular adrenocortical disease.⁴

Patients with Cushing syndrome usually present with clinical features of varying severity including obesity, facial plethora, dorsocervical fat pad, ecchymoses, red and purple striae (stretch marks) greater than 1 cm in width, thin skin, poor skin healing, abdominal pain, proximal muscle weakness, hirsutism, lethargy, and edema.^3,5 Coexisting conditions may include hypertension, abnormal glucose tolerance, hypokalemia, reduced bone density, dyslipidemia, and infections.^3,5,6 Given many of these signs and symptoms are present in other, more common diseases, diagnosis of Cushing syndrome is often delayed.⁷ Signs and symptoms potentially related to Cushing syndrome in the patient in the above-described case included thin skin, abdominal pain, osteoporosis, and infections, as well as hypokalemia, hyperglycemia, and worsening edema that were resistant to standard therapy.

Cognitive or psychiatric changes that may present with Cushing syndrome are varied and can include depression, irritability, cognitive or memory deficits, changes to personality, anxiety, labile emotions, hyperphagia, hypersomnia or insomnia, posttraumatic stress disorder, and vivid dreams.^3-5,8,9 Mania and psychosis are also possible, but rare.⁸ The hippocampus, amygdala, and frontal cortex of the brain were found to be particularly affected by glucocorticoid excess⁶ and therefore patients often present with multidomain cognitive deficits.⁴ The patient in the case above presented with cognitive changes, labile emotions, hyperphagia, and symptoms consistent with mania. Katragadda and colleagues found that a higher level of serum cortisol and longer duration of uncontrolled Cushing syndrome were associated with greater cognitive impairment.¹⁰ Therefore, timely diagnosis and treatment of Cushing syndrome is important to maximize a patient’s chance of cognitive recovery.

Initial diagnostic investigation of Cushing syndrome involves confirming hypercortisolism and establishing the underlying cause.³ Screening tests for hypercortisolism include 24-hour urinary free cortisol, late-night salivary cortisol, and 1-mg overnight dexamethasone suppression tests.³ Ideally, 2 or more of these tests should be done to diagnose hypercortisolism.³ Once hypercortisolism is confirmed, a plasma ACTH test is required to help distinguish between ACTH-dependent and ACTH-independent causes.³ Further localization requires additional imaging, such as magnetic resonance imaging of the pituitary gland or computed tomography of the adrenal gland.³

Treatment of endogenous Cushing syndrome aims to address the underlying cause of glucocorticoid excess, usually by surgically removing a tumour.^3,6 In cases where surgery is not feasible or fails to achieve remission, medical therapy can be used.⁶ Options include steroidogenesis inhibitors, glucocorticoid receptor antagonists, and drugs targeting ACTH production.³ Radiation therapy may also be needed in some cases.³ Long-term follow-up is essential, as patients are at risk for adrenal insufficiency requiring glucocorticoid replacement and disease recurrence.³ The patient in the above case was not a candidate for surgery and was therefore treated with a steroidogenesis inhibitor (ketoconazole).

Reflecting on the case of the patient described above, we found her psychiatric and cognitive symptoms to be the most prominent and interesting. Her initial presentation was felt to be most in keeping with delirium secondary to uncontrolled diabetes, cellulitis, constipation, and urinary tract infection. After treating these conditions, the patient improved but not as quickly, or as much as expected, suggesting another contributing etiology. This additional etiology was found inadvertently when a computed tomography scan of the patient’s abdomen was ordered due to pain and ultimately revealed an adrenal mass.