Inferior Petrosal Sinus Sampling (IPSS) is the Next Best Investigation
For a patient with biochemical features of Cushing's disease but normal pituitary MRI, bilateral inferior petrosal sinus sampling (IPSS) is the definitive next step to confirm a pituitary source of ACTH excess. 1, 2
Why IPSS is the Gold Standard in This Scenario
The diagnostic challenge here is clear: biochemical testing confirms ACTH-dependent Cushing's syndrome, but MRI fails to visualize a pituitary adenoma. This occurs frequently because:
- Microadenomas are often ≤2 mm in diameter, making them difficult or impossible to detect even on high-quality MRI 1
- MRI has only 63% sensitivity for detecting ACTH-secreting pituitary adenomas, meaning it misses approximately one-third of cases 1, 2
- Up to 40% of patients with surgically-confirmed Cushing's disease have negative or equivocal MRI findings 1, 3
The Diagnostic Algorithm
When pituitary MRI is normal or shows a lesion <6 mm, IPSS should be performed to definitively distinguish between pituitary Cushing's disease and ectopic ACTH syndrome 1, 2. The consensus guidelines are explicit:
- Lesions ≥10 mm on MRI: IPSS not necessary, proceed to surgery 1
- Lesions 6-9 mm on MRI: Expert opinion varies, but majority recommend IPSS 1
- Lesions <6 mm or negative MRI: IPSS is mandatory 1, 2
IPSS Diagnostic Criteria
The test confirms a pituitary source when the central-to-peripheral ACTH ratio is:
Diagnostic accuracy is excellent: sensitivity of 96-100% and specificity approaching 100% when performed correctly 4, 5, 3
Why Other Options Are Incorrect
A. Repeat MRI in 6 months - This delays definitive diagnosis and treatment unnecessarily. The sensitivity of MRI will not improve with time, and the patient continues to suffer morbidity from untreated hypercortisolism 1
B. CT abdomen - Only indicated if there is high clinical suspicion for ectopic ACTH syndrome (very high urinary free cortisol, profound hypokalemia, male patient) or if IPSS confirms an ectopic source 1, 2
D. High-dose dexamethasone test - This non-invasive test has limited diagnostic accuracy and is not recommended as a definitive test when IPSS is available. It may be considered only in specialized centers as part of a combined non-invasive approach, but this is not standard practice 1
E. Adrenal vein sampling - This is used for primary aldosteronism, not for ACTH-dependent Cushing's syndrome. The elevated ACTH confirms this is not an adrenal source 1, 2
Critical Technical Considerations
IPSS must be performed at a specialized center by an experienced interventional radiologist, as successful cannulation depends heavily on operator expertise 1, 4. Key technical points include:
- Confirm active hypercortisolism immediately before the procedure, especially in suspected cyclical Cushing's disease 2, 4
- Measure prolactin levels simultaneously from the petrosal sinuses to confirm adequate venous efflux and improve diagnostic accuracy 1, 4
- Stop steroidogenesis inhibitors before testing to allow accurate interpretation 2
- Successful bilateral cannulation rate should be >85% in experienced hands 5
Common Pitfalls to Avoid
Do not perform IPSS to diagnose Cushing's syndrome itself - ACTH-dependent hypercortisolism must be biochemically confirmed before the procedure 4, 5. IPSS only localizes the source of excess ACTH, it does not diagnose the syndrome 4
Beware of false negatives - These can occur with inadequate venous sampling, cyclical disease during a quiescent phase, or technical failure 4. Prolactin-adjusted ACTH ratios can help identify inadequate sampling 4
IPSS lateralization is less reliable than localization - While the test excellently confirms a pituitary source, predicting which side of the pituitary harbors the adenoma is less accurate (requires interpetrosal gradient ≥1.4) 2