What is the diagnosis and recommended management for a patient presenting with symptoms suggestive of cyclical Cushing's syndrome, including variable vision problems, muscle fatigue, weight gain, sleep disturbances, anxiety, and mood swings?

Diagnosis: Cyclic Cushing's Syndrome

This patient's constellation of symptoms—including variable vision, muscle weakness, weight gain without caloric excess, buffalo hump, reversed sleep cycle, mood disturbances, and cognitive dysfunction—strongly suggests cyclic Cushing's syndrome, which requires multiple sequential screening tests over time rather than single-point testing to capture episodic hypercortisolism. 1, 2, 3

Diagnostic Strategy

Initial Screening Approach

• Perform 2-3 different screening tests initially: late-night salivary cortisol (LNSC), 24-hour urinary free cortisol (UFC), and overnight 1-mg dexamethasone suppression test (DST) 1, 4
• The overnight DST is positive when morning cortisol remains >1.8 μg/dL (50 nmol/L) after 1 mg dexamethasone given at bedtime 1, 4
• LNSC has the highest specificity among screening tests and should be collected at the patient's usual bedtime rather than strictly at midnight 1

Critical Consideration for Cyclic Disease

A single normal test does NOT exclude Cushing's syndrome in this patient. 2, 3 Research demonstrates that 65 of 66 patients with confirmed Cushing's syndrome had at least one normal test, with the probability of having Cushing's syndrome despite one negative test being 92% for salivary cortisol, 88% for UFC, and 86% for 17-hydroxycorticosteroids 2.

• Perform frequent sequential measurements over weeks to months using LNSC or UFC to capture cortisol peaks and troughs 1, 3
• Formal diagnosis of cyclic Cushing's requires demonstrating three peaks and two troughs of cortisol production 3
• Time testing to coincide with symptomatic periods when the patient experiences worsening of vision changes, muscle weakness, or mood symptoms 2, 3

Differential Diagnosis Workup

Once hypercortisolism is confirmed:

• Measure plasma ACTH to distinguish ACTH-dependent (normal/elevated ACTH) from ACTH-independent (suppressed ACTH) causes 1, 5
• If ACTH-dependent: obtain pituitary MRI and consider inferior petrosal sinus sampling (IPSS), particularly if imaging shows lesions <10 mm or is equivocal 1
• Cyclic Cushing's originates from pituitary adenoma in 54% of cases, ectopic ACTH-producing tumors in 26%, and adrenal tumors in 11% 3

Management Algorithm

First-Line Treatment

Surgical resection of the cortisol-producing source is the definitive first-line therapy regardless of etiology 4, 5, 6:

• Transsphenoidal surgery for pituitary adenoma (Cushing's disease)
• Unilateral adrenalectomy for adrenal adenoma
• Resection of ectopic ACTH-producing tumor when identified

Medical Management

For patients awaiting surgery, with persistent disease, or who are non-surgical candidates:

• Steroidogenesis inhibitors are the primary medical therapy 4, 5, 6:

  • Ketoconazole or metyrapone are typically first-line agents 1, 4
  • These medications block cortisol production at the adrenal level

• Hypertension management requires specific approach: Spironolactone or eplerenone should be first-line antihypertensives because they block mineralocorticoid receptors that mediate cortisol-induced hypertension 4

  • Conventional antihypertensives (ACE inhibitors, ARBs, calcium channel blockers) are often ineffective at achieving blood pressure targets in Cushing's syndrome 4

Second-Line Options

• Pituitary radiation therapy (with or without steroidogenesis inhibitors) for Cushing's disease 6
• Bilateral adrenalectomy for ACTH-dependent causes refractory to other treatments 5, 6
• Glucocorticoid receptor blockers as alternative medical therapy 5

Key Clinical Pitfalls

Testing Errors to Avoid

• Do not rely on single negative tests in patients with strong clinical suspicion—the episodic nature means normal results are common even in confirmed cases 2, 3
• Avoid LNSC testing in patients with disrupted day/night cycles (though this patient's reversed sleep cycle is likely a symptom of the disease itself) 1
• Be aware that DST false positives occur with CYP3A4 inducers, oral estrogens, or rapid dexamethasone metabolism 1
• Measure dexamethasone levels concomitantly with cortisol to reduce false-positive DST results 1

Symptom Recognition

The patient's "existential boredom," anhedonia, profound sadness, and cognitive difficulties ("struggle to follow plot lines") are neuropsychiatric manifestations of hypercortisolism, not primary psychiatric disease 5, 6. These symptoms should improve with successful treatment of the underlying Cushing's syndrome.

Monitoring During Treatment

• After successful surgery, monitor for adrenal insufficiency as cortisol production recovers over approximately 12 months 1
• Reassess for growth hormone deficiency 3-6 months postoperatively if applicable 1