General Description

Inferior petrosal sinus (IPS) sampling is an endovascular procedure used for the evaluation of patients with Cushing’s disease (CD). In the setting of hypercortisolemia, the procedure is performed to differentiate a pituitary from an ectopic source of the adrenocorticotropic hormone (ACTH). It can also be used to localize a patient’s pituitary microadenoma (i.e., midline or right or left of midline) with an average accuracy of 78% (range 50%–90%).

ACTH levels obtained from venous drainage in proximity to the pituitary gland are compared to peripheral blood levels before and after corticotropin-releasing hormone (CRH) stimulation. ACTH is expected to be found at a higher concentration close to the gland with respect to distant location. Therefore, an ACTH gradient indicates pituitary CD, whereas the absence suggests ectopic CD. In the setting of CD, pituitary release of ACTH is increased in response to intravenous administration of CRH. ACTH is released from the anterior pituitary gland; it drains into the cavernous sinus and jugular venous system via the IPS.

The IPS sampling procedure was introduced in 1977 in a unilateral form and was adopted for diagnostic evaluation of Cushing’s syndrome in 1991. Currently, bilateral IPS sampling is the closest procedure to a reference standard for differential diagnosis of CD and is more accurate than clinical, biochemical, and imaging analyses, with a sensitivity and specificity of 88%–100% and 67%–100%, respectively, that increase to 96%–100%, respectively, after CRH stimulation. Successful bilateral sampling is usually achieved in more than 90% of cases with false-negative rates ranging from 1% to 10%.

Indications

Bilateral IPS sampling should be reserved for

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  Patients with clinical and biochemical evidence of CD and negative or equivocal magnetic resonance imaging (MRI) findings (no discrete pituitary lesion on MRI).

  
  
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  Patients with equivocal responses to hormone testing or in cases of discrepancies between biochemistry and imaging findings.

  
  
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  Persistence of Cushing’s syndrome after previous unsuccessful pituitary surgery, to confirm the CD diagnosis.

  
  
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  Patients with an ACTH or cortisol response to the CRH test not consistent with CD, independently from the response to a high-dose dexamethasone suppression test, unless the MRI finding shows clear evidence of pituitary adenoma.

Bilateral IPS sampling should not be performed in the following circumstances:

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  A positive response to the CRH test, especially in the case of a consistent response to the dexamethasone suppression test, even in the absence of MRI evidence of pituitary adenoma.

  
  
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  Bleeding diathesis or disorders.

  
  
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  Allergy to contrast material.

Neuroendovascular Anatomy

Understanding the venous anatomy is crucial to the success of the procedure. Blood from the anterior lobe of the pituitary gland flows through the hypophyseal veins into a network of veins overlying the anterior pituitary surface, which drains laterally into the cavernous sinuses, and from here into the IPSs, which course posteriorly and caudally passes through the anterior jugular foramen, at the skull base. The cavernous sinuses are lateral to the pituitary fossa and are interconnected by the anterior and posterior intercavernous sinuses, which run in front of and behind the pituitary gland, by the inferior intercavernous sinus coursing along the sellar floor between the anterior and posterior pituitary lobes, and by the basilar plexus, which is located along the dorsum sellae. As the IPS courses through the dura, it receives tributaries from the dura, pons, medulla, internal auditory meatus, and the anterior condylar vein (ACV), which communicates with the plexus surrounding the 12th cranial nerve in the hypoglossal canal. Pituitary venous drainage is normally unilateral, thus allowing the lateralization of ACTH-secreting adenomas through bilateral IPS sampling.

Approximately 75% of patients have large, bilaterally symmetrical IPSs; 18% have asymmetrical IPSs with one smaller than the contralateral; and in 7%, the petrosal sinuses are bilaterally small. The IPS typically joins the internal jugular vein at the level of the inferior margin of the jugular foramen, approximately 6 mm below its entry into the foramen, although in some cases, the junction may be extracranial or intracranial or it may drain directly into the sigmoid sinus.

Anatomic variants are not uncommon and can cause an alternative venous drainage. They are categorized into four groups. In type I (45%), the IPS drains directly into the internal jugular bulb with absent or nearly absent communication with the ACV. In type II (24%), the IPS anastomoses with the ACV before draining into the internal jugular vein. In type III (24%), the IPS drains into the internal jugular vein as a plexus of veins rather than as a single vein. In type IV, the IPS drains solely or predominantly into the vertebral venous plexus by way of the ACV, without a connection between the IPS and the jugular vein. This configuration is present in 1%–7% of patients. In the case of hypoplastic IPS, bilateral IPS sampling yields false-negative results in approximatively 1% of cases.

Procedural Preparation

The procedure, including ACTH sampling after CRH stimulation, usually lasts for 60–90 min and is performed under conscious sedation. The suppression of normal corticotrophs by long-standing hypercortisolemia is crucial for the diagnostic accuracy of bilateral IPS sampling, because it ensures that any ACTH measured is secreted by tumor tissue (pituitary or ectopic). As ACTH secretion is intermittent and blood samples obtained between two ACTH secretory episodes might result in a false-negative ratio (central vs. peripheral ACTH blood concentration); the procedure is performed under CRH stimulation to increase diagnostic sensitivity. We routinely administer systemic heparin to an activated coagulation time of 250–300 s.