What is the best course of action for a 37-year-old woman with persistent anxiety, significant unintentional weight loss, paresthesias, and cognitive impairment, who has undergone extensive negative workup, including normal thyroid studies, vitamin B12 (385 pg/mL), pheochromocytoma and celiac screens, complete blood count (CBC), metabolic panel, antinuclear antibody (ANA) test, and computed tomography (CT) of the abdomen and pelvis, with mild inflammatory markers, elevated morning cortisol (29 mcg/dL) and normal adrenocorticotropic hormone (ACTH) levels, and a history of treatment with fluoxetine (Prozac), escitalopram (Lexapro), divalproex (Depakote), buspirone (Buspar), and dextroamphetamine-amphetamine (Adderall), and recently lybalvi?

Immediate Workup for ACTH-Dependent Hypercortisolism

This patient requires urgent evaluation for ACTH-dependent Cushing syndrome with a 24-hour urinary free cortisol test and dedicated pituitary imaging, as the elevated morning cortisol (29 mcg/dL) with normal ACTH indicates either pituitary adenoma or ectopic ACTH production—both potentially life-threatening conditions that explain her entire symptom complex. 1

Critical Diagnostic Algorithm

Step 1: Confirm Hypercortisolism

• Obtain 24-hour urinary free cortisol immediately to confirm true hypercortisolism rather than stress-related elevation 1, 2
• The combination of elevated cortisol with detectable (normal) ACTH definitively indicates ACTH-dependent Cushing syndrome 1
• Normal ACTH in the setting of hypercortisolism rules out primary adrenal causes, as adrenal tumors would suppress ACTH to undetectable levels 1, 2

Step 2: Localize the ACTH Source

• Order pituitary MRI with sellar cuts protocol as the first imaging study 1
• Pituitary adenomas are detected in only 63% of cases on MRI, so negative imaging does not exclude the diagnosis 1
• If pituitary MRI is negative or equivocal, proceed directly to bilateral inferior petrosal sinus sampling (BIPSS), which is the gold standard for confirming pituitary versus ectopic source 1
• A central-to-peripheral ACTH ratio ≥2:1 before CRH/desmopressin and ≥3:1 after stimulation confirms pituitary Cushing disease 1

Step 3: Rule Out Ectopic Sources

• If BIPSS suggests ectopic ACTH production, obtain chest/abdominal/pelvic CT or whole-body PET/CT to locate tumors in lung, thyroid, pancreas, or bowel 1
• Ectopic sources are the most likely alternative to pituitary adenoma when ACTH is detectable but not suppressed 1

Why This Explains Her Entire Clinical Picture

Weight Loss and Metabolic Dysfunction

• Cushing syndrome causes significant unintentional weight loss in some patients despite the classic teaching of weight gain 1
• Her impaired fasting glucose (116 mg/dL) and mild inflammatory markers (ESR 29, CRP 15) are consistent with hypercortisolism-induced hyperglycemia and inflammation 1, 2

Neuropsychiatric Symptoms

• Hypercortisolism directly causes anxiety, cognitive impairment, and psychiatric symptoms through HPA axis dysregulation 3
• Her persistent anxiety despite multiple SSRI trials strongly suggests an underlying endocrine cause rather than primary psychiatric disease 3
• The cognitive impairment following polypharmacy discontinuation may reflect unmasking of cortisol-induced neurotoxicity 3

Paresthesias

• While not classically associated with Cushing syndrome, the paresthesias warrant consideration of concurrent B12 deficiency (her level of 385 pg/mL is suboptimal, as levels <400 pg/mL can cause neurological symptoms despite being "normal") 4
• Hypercortisolism can also cause proximal muscle weakness and myopathy that may manifest as paresthesias 1, 2

Immediate Management Priorities

Before Definitive Treatment

• Monitor for adrenal crisis risk during BIPSS procedure—ensure adequate cortisol levels to avoid precipitating crisis 1
• Screen for hypertension, hypokalemia, and hyperglycemia as complications of hypercortisolism 1, 2

Definitive Treatment Based on Source

For Pituitary Cushing Disease:

• Transsphenoidal surgical resection is first-line treatment when adenoma is identified 1
• Postoperative corticosteroid supplementation is mandatory until HPA axis recovery 1, 2
• If surgery fails or is not feasible, ketoconazole 400-1200 mg/day is the preferred medical therapy due to relatively tolerable side effects 1

For Ectopic ACTH Production:

• Surgical removal of ectopic tumor if resectable 1
• If unresectable, consider bilateral laparoscopic adrenalectomy 1
• Medical management with ketoconazole or mitotane as alternatives 1

Critical Pitfalls to Avoid

• Do not attribute her symptoms to primary psychiatric disease when objective evidence of hypercortisolism exists—this delays life-saving diagnosis 1, 3
• Do not rely solely on pituitary MRI—37% of pituitary adenomas are not visible on imaging, requiring BIPSS for diagnosis 1
• Do not confuse pseudo-Cushing states (depression, alcoholism, obesity) with true Cushing syndrome—the 24-hour urinary free cortisol distinguishes these 1
• Do not delay workup for "psychiatric stabilization"—untreated Cushing syndrome causes progressive morbidity including cardiovascular disease, diabetes, and osteoporosis 1, 2

Monitoring During Workup

• Follow-up imaging and biomarkers every 3-6 months if treatment is delayed 1, 2
• Monitor for worsening hypertension, hyperglycemia, hypokalemia, and muscle atrophy 2
• Consider supplementing B12 to >400 pg/mL to address potential contribution to paresthesias 4