Petrosal Sinus Sampling
Inferior petrosal sinus sampling (IPSS) is an invasive procedure in which adrenocorticotropic hormone (ACTH) levels are sampled from the veins that drain the pituitary gland; these levels are then compared with the ACTH levels in the peripheral blood to determine whether a pituitary tumor (as opposed to an ectopic source of ACTH) is responsible for ACTH-dependent Cushing syndrome. IPSS can also be used to establish on which side of the pituitary gland the tumor is located.
Cushing disease results from excessive cortisol production due to elevated ACTH levels produced by a pituitary tumor. In contrast, Cushing syndrome includes all conditions of hypercortisolism due to either ACTH-dependent causes (eg, Cushing disease or ectopic ACTH secretion by a nonpituitary tumor) or ACTH-independent causes (eg, excessive autonomous secretion of cortisol from a hyperfunctioning adrenocortical tumor).
Other and rarer conditions that can lead to Cushing syndrome include ectopic corticotrophin-releasing hormone (CRH) secretion, primary bilateral pigmented nodular adrenal hyperplasia, macronodular adrenal hyperplasia, ectopic actions of gastric inhibitory peptides, and other syndromes, such as McCune-Albright syndrome and Carney syndrome. Pseudo-Cushing states with similar clinical presentations may be found in depression and alcohol dependence. Cushingoid features may also be found in obesity.
Differentiating ACTH-dependent from ACTH-independent Cushing disease is often straightforward, but it can be difficult to differentiate Cushing disease from hypercortisolism caused by ectopic ACTH secretion (ie, from a nonpituitary source) owing to the cyclical and intermittent secretion by ACTH-secreting tumors and the varying sensitivities and specificities of the various biochemical tests. [1, 2] According to Prabhu et al (2002), the value of cross-sectional imaging in ACTH-dependent Cushing syndrome is also restricted because small nonfunctioning pituitary incidentalomas are present in up to 10% of MRI scans performed in healthy young people. 
The poor sensitivity of imaging for microadenomas of the pituitary is another problem.  ACTH-secreting pituitary adenomas are difficult to identify on standard 1.5T or 3T MRI as well as with dynamic contrast imaging.  In the majority of cases, routine thin slice contrast-enhanced T1-weighted MRI is able to provide anatomic detail and help identify the IPS drainage pattern. In some cases, when the drainage pattern cannot be identified, even spatial resolution does not help portray the complex anatomy.  In such a situation, IPSS alone helps to differentiate Cushing disease from Cushing syndrome due to ectopic ACTH-secreting tumors  and is therefore still the gold standard for diagnosis of ACTH-secreting pituitary adenomas. [5, 8] It is well established that IPSS can accurately diagnose Cushing disease and it is also known that MRI provides greater accuracy in localizing the site of the adenoma.  Kakade et al.  have suggested that in case of equivocal MRI pituitary findings, prior IPSS can avoid unnecessary transsphenoidal surgery. One study reports that 7T MRI may help to detect standard 1.5T and 3T MRI-negative Cushing disease and may preempt IPSS in the future. 
IPSS was introduced in 1977 by Corrigan et al, who reported the use of unilateral selective catheterization and venous sampling to localize ACTH secretion in a patient with a perplexing clinical and laboratory picture compatible with either ectopic ACTH secretion or pituitary-dependent Cushing syndrome. Later, it was established that the ACTH levels in the pituitary venous drainage may be asymmetric, owing either to the location of the corticotroph adenoma or asymmetric variations in venous anatomy.
Pituitary venous drainage is usually ipsilateral, so the venous drainage on the contralateral side relative to the adenoma does not often have a high concentration of ACTH. Doppman et al (1984) suggested simultaneous sampling from both inferior petrosal sinuses (IPSs) to avoid false-negative results in the presence of a pituitary corticotroph adenoma. This procedure was termed bilateral inferior petrosal sinus sampling (BIPSS). 
Many corticotroph adenomas are susceptible to stimulation by exogenously administered CRH, as was first described in 1991 by Oldfield et al to increase the sensitivity of BIPSS.  Two different forms of CRH have been used in the various studies reported: ovine CRH (oCRH) and human CRH (hCRH). Nieman et al (1989) have reported that the peripheral ACTH and cortisol responses to oCRH were significantly higher than with human CRH. 
Some centers have reported improved accuracy and intrasellar localization with bilateral cavernous sinus sampling, [14, 15] but there is an increased risk of cranial nerve palsy,  so this technique has not yet gained popularity.
Internal jugular venous sampling (IJVS) has also been attempted as a technically easier alternative to BIPSS. Radvany et al. compared IJVS with IPSS in 30 consecutive patients with MRI-negative ACTH-dependent Cushing syndrome. Their results indicate that IJVS is not as helpful as IPSS in diagnosing the pituitary as the source of excessive ACTH.  Although IJVS has specificity similar to that of BIPSS, it has a lower sensitivity (83% versus 94%), according to Ilias et al. 
Using samples drawn from IPSS, Oklu et al  have identified 3 small compound potential biomarkers of Cushing disease (pyridoxate, deoxycholic acid, and trimethyl adipate). These may elucidate tumor biology and suggest, in the future, possible diagnostic molecular imaging probes and therapeutic targets in patients with recurrent disease after surgery.
A detailed description of the IPS anatomy has been provided by Miller and Doppman (1991) (see image below). 
In most individuals, the IPS narrows to become a single vein, emptying into the ipsilateral internal jugular vein (IJV). In about 25% of individuals, the IPS drainage forms a plexus of channels that empty into the IJV.  In 0.6%-7% of individuals, there is no connection between the IJV and the IPS, making standard sampling impossible. [19, 21]
In approximately 60% of individuals, pituitary venous drainage is symmetrical,  with most of the venous effluent from each side of the pituitary draining in to the ipsilateral IPS.  As a result, in most people, BIPSS can be an effective tool to lateralize corticotroph adenomas and to avoid false-negative results.
Doppman et al (1999) attributed the 0.8% prevalence of false-negative results to a hypoplastic or anomalous IPS.  Shiu et al (1968) first described a classification system for the IPS anatomic variants.  Bonelli et al (2000) have described a modification of Shiu et al’s classification system, as follows: 
Type I (see image below): An IPS anastomosing with the IJV; the anterior condylar vein is absent or joins the IPS at a defined origin; the short segment of the vein from the point of this anastomosis to the IJV is termed the inferior condylar confluence
Type II (see image below): A common origin of the IPS and anterior condylar vein with the IJV
Type III (see image below): An IPS consisting of several small channels communicating with the IJV
Type IV (see image below): An IPS that communicates with the anterior condylar vein and not the IJV
According to Bonelli et al (2000), BIPSS is indicated under the following conditions: 
No discrete pituitary lesion is identified on imaging, or results are equivocal
A discrete pituitary lesion is identified, but peripheral ACTH results are equivocal after CRH stimulation
Cushing syndrome persists after transsphenoidal surgery
There is clinical need to resolve discrepancy among clinical, biochemical, and imaging tests
Contraindications to IPSS include the following:
Bleeding diathesis or disorders
Allergies to dye contrast
Ischemic heart disease
This procedure should be performed at a center with interventional radiologists who have skill and experience in performing BIPSS.
Cushing disease is indicated by a significant gradient between the pituitary and peripheral venous values of plasma ACTH obtained by simultaneous sampling (basal ratio of the plasma ACTH values obtained from central and peripheral samples greater than 2). [4, 25] To increase the sensitivity, the sampling is repeated after peripheral administration of oCRH. Following this a peak central to peripheral plasma ACTH ratio of 3 or more [4, 25] occurring 3-5 minutes after oCRH stimulation is highly indicative of Cushing disease. An overall sensitivity of 96% and specificity of 100% in differentiating Cushing disease from ectopic ACTH secretion is reported using this method. [4, 12]
False-positive results are rare. False-negative results (4%) are likely to be multifactorial owing to abnormalities in petrosal sinus anatomy, technical reasons, or intrinsic properties of the tumor ACTH secretion.  According to Wind et al,  potential false-negative results are the most common type of diagnostic error with IPSS for the differential diagnosis of Cushing syndrome and can be identified by peak IPSS ACTH values of less than 400 pg/mL.
Sharma and Nieman  have suggested that prolactin measurement during IPSS can improve diagnostic accuracy and decrease false-negative results. According to them, baseline prolactin inferior petrosal sinus–to-peripheral (IPS/P) ratio (ipsilateral to the dominant post-CRH ACTH IPS/P ratio) of 1.8 or more suggests successful catheterization during IPSS and prolactin-normalized ACTH IPS/P ratios can then be used to differentiate between a pituitary and ectopic source of ACTH. Values of 0.7 or lower are suggestive of ectopic ACTH syndrome and those 1.3 or higher are indicative of Cushing disease. However, they were unable to explain the implication of values between 0.7 and 1.3 and recommend further studies.
Per Jarial et al.,BIPSS using either 5U or 10U human corticotrophin-releasing hormone (hCRH) or lysine vasopressin (LVP) was useful to confirm the source of excess ACTH in all their patients. Using 10U LVP helped to correctly localize the site of the adenoma in 75% of patients.  In countries where CRH is not easily available, vasopressin has been used with IPSS.  Feng et al., report that IPSS with desmopressin is an alternative to IPSS with CRH as it can also diagnose Cushing disease and can lateralize the tumor with moderate accuracy. 
When MRI is normal, IPSS can be used to guide surgical exploration; however, because of the limited accuracy of lateralization, thorough exploration of the pituitary gland is required when an adenoma is not readily discovered based on predicted location. 
IPS catheterization is technically demanding, and even experienced interventionists may fail in up to 15%-20% of cases.
Complications of IPSS are rare although it is an invasive procedure.  The most common complication is groin hematoma, occurring in 3%–4% of cases.  As iodinated contrast is injected during BIPSS, there is a risk of acute renal insufficiency, especially in patients with pre-existing renal failure or hypovolemia. 
Adverse events such as pulmonary thromboembolism, [32, 33] venous subarachnoid hemorrhage,  pontomedullary junction stroke,  brainstem infarction,  transient sixth cranial nerve palsy,  and obstructive hydrocephalus  have been reported. The incidence is related to the entry of microcatheter-wire systems into the sinus, where the catheter could engage and temporarily occlude small bridging veins that connect the transverse pontine, lateral medullary, and pontomedullary veins with the inferior petrosal vein, resulting in brainstem ischemia and hemorrhage.  Injury to these veins could result in subarachnoid hemorrhage.
Early recognition of the characteristic signs of brainstem ischemia and termination of the procedure prevents irreversible damage. 
In addition, there are risks of radiation exposure during fluoroscopy, heparin-induced thrombocytopenia, and catheter-related infections. Catheter placement–related discomfort, headache, otalgia, and tinnitus have also been reported by Utz et al (2007). 
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Gauri Mankekar, MBBS, PhD, MS, DNB Otorhinolaryngologist
Gauri Mankekar, MBBS, PhD, MS, DNB is a member of the following medical societies: Association of Medical Consultants of Mumbai, Association of Otolaryngologists of India, Cochlear Implant Group of India
Disclosure: Nothing to disclose.
Jonathan P Miller, MD Director, Functional and Restorative Neurosurgery, Director of Epilepsy Surgery, Attending Neurosurgeon, University Hospitals Cleveland Medical Center; Director, Functional and Restorative Neurosurgery Center, UH Cleveland Medical Center Neurological Institute; Associate Professor of Neurosurgery, Fellowship Director, Functional and Stereotactic Neurosurgery, Associate Residency Program Director, Department of Neurosurgery, Surgical Director, Neuromodulation Center, Case Western Reserve University School of Medicine
Jonathan P Miller, MD is a member of the following medical societies: Alpha Omega Alpha, American Association of Neurological Surgeons, American College of Surgeons, American Epilepsy Society, American Society for Stereotactic and Functional Neurosurgery, Congress of Neurological Surgeons, International Neuromodulation Society, North American Neuromodulation Society, Ohio State Neurosurgical Society, Society of Neurological Surgeons
Disclosure: Nothing to disclose.
The authors thank Dr. J. Modhe, Chief, Department of Radiology, PD Hinduja Hospital, Mahim, for reviewing this article.
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