Major Diagnostic Advance: Bilateral Inferior
Petrosal Sinus Sampling in Cushing's Syndrome
Cushing's syndrome, with its high
morbidity and mortality, requires a diagnostic workup which includes
verifying the patient's cortisol excess, then documenting the
site of hormone overproduction. ACTH-dependent causes include
pituitary tumors (Cushing's disease) and ectopic ACTH-secreting
(or rarely CRH-secreting) tumors, while ACTH-independent Cushing's
is due to a primary adrenal lesion (Figure 1, below).
The most common cause of Cushing's syndrome is Cushing's disease,
but 15% of all cases are due to ectopic production of ACTH (and
rarely CRH). The classical ectopic Cushing's syndrome cases,
usually due to small cell carcinoma of the lung, are easy to
distinguish from pituitary Cushing's because of markedly elevated
ACTH and failure to suppress urine cortisol and its metabolites
with high dose dexamethasone. However, many patients are being
recognized as having benign occult ectopic Cushing's, most commonly
due to carcinoid tumors, with bronchial carcinoid being the
most frequent subtype. A recent series has shown that in most
patients with bronchial carcinoid, the clinical features are
typical of pituitary Cushing's, the tumor is occult in about
two-thirds of the patients, and the clinical course is often
prolonged, with a delay in diagnosis of up to 18 years. Most
patients with this disorder have normal to mildly elevated ACTH
levels, and more than half have dexamethasone suppressability,
traditionally believed to be diagnostic of pituitary Cushing's.
Therefore, bronchial carcinoid may produce a clinical and biochemical
pattern identical to that seen in pituitary Cushing's. This
presents a serious diagnostic dilemma in determining whether
the patient should have pituitary or chest surgery.
Figure 1 From Schteingart DE: Cushing's syndrome in EndocrinoIogy and Metabolisrn Clinics of North America Barkan AL (ed), Vol. 18, No. 2, June 1989; with permission.
Figure 2 Reprinted, by permission of The New England Journal of Medicine Vol. 312 p. 101, 1985.
BIPSS Technique - The most important recent advance in the diagnostic evaluation of patients with Cushing's syndrome has been the use of bilateral inferior petrosal sinus sampling (BIPSS) for ACTH The inferior petrosal sinuses receive drainage from the pituitary gland without mixture of blood from other sources. Therefore, if the patient has pituitary Cushing's, the ACTH levels in the IPS are high compared to an ACTH drawn in the periphery. In contrast, in ectopic Cushing's, the ACTH in the IPS and the periphery should be equivalent because the tumor is located elsewhere. The test is usually performed by vascular radiologists on an outpatient basis. With local anesthesia, femoral catheters are advanced bilaterally up to the inferior petrosal sinuses (Figure 2). After confirmation of catheter location by fluoroscopy, several ACTH samples are drawn simultaneously from the right and left at the same time that a peripheral level is being drawn from an arm vein. CRH can also be injected to provoke ACTH release. Samples are then assayed for ACTH, and the pituitary-to-peripheral ratios are calculated.
Localization - If the pituitary-to-peripheral ratio is greater than 2 (greater than 3 if CRH was given) the patient has Cushing's disease, with a sensitivity and specificity of 100% if CR14 is used. If the pituitary-to-peripheral ratio is less than 1.5 to I (less than 3 if CRH was given) the patient has ectopic Cushing's. This test, therefore, allows certainty as to the location of Cushing's syndrome, thereby directing the correct surgical approach
Lateralization - A feature of pituitary anatomy is that each half of the pituitary drains into the ipsilateral IPS, often making it possible to localize the tumor to the pituitary gland and to determine which side it is located on (to lateralize it). In 20% of patients the neurosurgeon is not able to locate the pituitary tumor intraoperatively. Now, if sampling data suggest lateralization, the neurosurgeon can explore that side. The IPSS is correct in predicting tumor location in approximately two-thirds of cases. However, because it is not always correct, it is important that the neurosurgeon explore the other side if no tumor is found on the predicted side. Shown above are results of BPSS in an individual patient. There were five ACTH samples drawn q 5 minutes. As can be seen, all of the samples show a pituitary-to-peripheral ratio greater than 2, confirming a pituitary source of the Cushing's. In addition, all the samples show a right-to-left gradient of greater than 1.4 to 1, documenting that the tumor is likely to be on the right side. This patient did have a right-side pituitary microadenoma and was cured following pituitary surgery at the Massachusetts General Hospital.
Some rare difficulties in ability to localize and lateralize
Failure to Localize
Failure to Lateralize
1. Inability to Catheterize
1. Incorrect Catheter Placement
2. Incorrect Catheter Placement
2. Sample Withdrawal was too
3. Anomalous Venous Drainage
3. Midline Microadenoma
4. Hypercortisolemia Not Present
medical therapy, s/p adrenalectomy, periodic hormonogeneis
4. Prior Transsphenoidal Surgery
5. Ectopic Tumor Secreting
5. Ectopic Tumor Secreting
Complications - Complications are infrequent, with the most common being a hematoma at the groin site and transient ear pain. The NIH recently published data on four patients who had neurologic complications following the BIPSS in a total series of 500 patients. In all four patients, a catheter design developed at the NIH was used and all four patients experienced neurologic symptoms during the procedure. In the two cases where the patients were reassured and the procedure continued, permanent neurologic damage ensued. In the two cases where the procedure was stopped immediately after development of symptoms, all neurologic problems resolved within 48 hours
Summary - In summary, BIPSS offers a major advance in establishing the correct location of hormone excess in patients with Cushing's syndrome. In many centers, it is performed in all patients who do not have a definite macroadenoma seen on MRI. This test should eliminate completely those "surgical failures" which were actually diagnostic failures, and thereby provide better treatment for patients with Cushing's syndrome.
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