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Year : 2002  |  Volume : 12  |  Issue : 1  |  Page : 13-20
Rationale and technique of inferior petrosal venous sinus sampling in ACTH dependent cushings syndrome - a pictorial essay

Department of radiology, Amrita Institute of Medical Sciences, Amrita Lane, Elamakkara, Cochin-682026, Kerala, India

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Keywords: Cushings Syndrome, Adrenocorticotrophic hormone (ACTH), Inferior Petrosal Sinus Sampling, Corticotrophin Releaving Hormone (CRH)

How to cite this article:
Prabhu N K, Moorthy S, Sreekumar K P, Nair V, Kumar H, Pillai A K. Rationale and technique of inferior petrosal venous sinus sampling in ACTH dependent cushings syndrome - a pictorial essay. Indian J Radiol Imaging 2002;12:13-20

How to cite this URL:
Prabhu N K, Moorthy S, Sreekumar K P, Nair V, Kumar H, Pillai A K. Rationale and technique of inferior petrosal venous sinus sampling in ACTH dependent cushings syndrome - a pictorial essay. Indian J Radiol Imaging [serial online] 2002 [cited 2021 Jan 26];12:13-20. Available from:

   Introduction Top

More than any other area in clinical endocrinology, the diagnosis, differential diagnosis and management of Cushing's syndrome continues to challenge physicians and causes considerable controversy[1]. The clinical spectrum in Cushing's syndrome is wide. 3-4% of individuals with poorly controlled Diabetes mellitus and an obese phenotype, may have this condition. The etiology may be due to Adrenocorticotropic hormone (ACTH) dependent causes like excessive ACTH production from the pituitary, ectopic ACTH secretion by a non-pituitary tumour, or ACTH independent excessive autonomous secretion of cortisol from a hyperfunctioning adrenocortical tumour. Rarer miscellaneous conditions like ectopic Corticotrophin release hormone (CRH) secretion, primary bilateral pigmented nodular adrenal hyperplasia, macronodular adrenal hyperplasia, ectopic actions of gastric inhibitory peptides and other syndromes like McCune - Albright's and Carneys also produce Cushing's Syndrome. Pseudo Cushing's states with similar clinical presentations may be found in depression and alcohol dependence. Cushingoid features may be found in simple obesity.

The most common cause of Cushing's syndrome is ACTH secreting pituitary microadenoma - termed Cushing's disease. However, differentiation of Cushing's disease from ectopic ACTH secretion (from a non-pituitary source) is often difficult. Though ectopic ACTH secretion accounts for less than 10% of ACTH dependent Cushing's syndrome, the treatment is radically different and differentiation is important.

Diagnosis is complicated by cyclical and intermittent secretion by ACTH secreting tumours. Moreover, different biochemical tests have varying sensitivities and specificities. The value of cross-sectional imaging in ACTH dependent Cushing's syndrome is also restricted, in view of the presence of small nonfunctioning 'incidentalomas' in upto 10% of MRI done in normal young people. The poor sensitivity of imaging for microadenomas of the pituitary is a further problem[1]. In this scenario, bilateral inferior petrosal sinus sampling (BIPSS) has a role in differentiating with confidence, Cushing's disease from ectopic ACTH secreting tumours producing Cushing's syndrome.

   Biochemical Tests Top

The diagnosis of Cushing's syndrome is established by the biochemical confirmation of a hypercortisolemic state - marked by high urine free Cortisol, inadequate suppression of serum cortisol after Low dose dexamethasone suppression test, and dampening of the normal circadian rhythm. In view of the often cyclic nature of the disease, documentation of hypercortisolism is vital, since subsequent biochemical tests for differentiating the causes are accurate only during periods of active and sustained hypercortisolism[1].

The next step is in differentiating ACTH dependent Cushings from ACTH independent causes like primary adrenal tumours. This is accomplished by ACTH assays, which show extremely low levels in adrenal causes of hypercortisolism[1].

Differential diagnosis of ACTH dependent Cushing's syndrome is difficult. Both pituitary microadenomas and non-pituitary tumours secreting ACTH are small and difficult to visualize and heavy reliance is placed on biochemical testing to direct imaging of the appropriate site. The widely used High dose dexamethasone test, relies on the fact that the ACTH secreting cells in pituitary microadenomas retain some responsiveness to the negative feedback effects of glucocorticoids while tumours producing ectopic ACTH do not. It has been largely superseded by the more accurate CRH test - an IV injection produces an excessive rise in plasma ACTH and cortisol in patients with pituitary adenomas, while such an effect is seen only rarely in patients with ectopic ACTH production. However between 7-14% of patients with Cushing's due to pituitary microadenomas, fail to respond to CRH testing[1].

   Rationale of BIPSS Top

Since ACTH dependent Cushing's syndrome is secondary to a pituitary microadenoma in over 90% of patients, the pretest probability of Cushing's disease is 90% [1,2]. Any test which attempts to discriminate between Cushing's disease and ectopic ACTH production must have accuracy significantly above 90% to be useful. None of the biochemical tests described above have a diagnostic accuracy of near 100%[1],[2].

Detection of a pituitary microadenoma on MR does not confirm functionality of the adenoma, since 10% of the general population harbors incidentalomas. Moreover, in 40-50% of cases of Cushing's disease, no abnormality is disclosed on pituitary imaging[1]. The reported sensitivity of MRI for pituitary microadenomas quoted in other series, varies between 69-90%[2].

Bilateral simultaneous venous sampling from the inferior petrosal sinuses after peripheral injection of CRH can confirm or refute a central (pituitary) source of ACTH, by detecting a significant gradient between the pituitary (central) and peripheral values of plasma ACTH, and thus confirm Cushing's disease. The sensitivity and specificity of this procedure is 96-100% in various series[3]. The positive predictive value of this test is high, since there are virtually no false positives, while false negative are uncommon. To some extent, it can even lateralize the site of the pituitary tumour to guide microsurgery.

   Indications Top

In Cushing's syndrome, with hypercortisolemia, and biochemical evidence of ACTH dependent disease, BIPSS is indicated if there is a difficulty in differentiating a pituitary source of ACTH secretion from an ectopic non-pituitary source, i.e. when[2],

1. No discrete pituitary lesion is identified by imaging, or equivocal results

2. Discrete pituitary lesion identified, but peripheral ACTH results are equivocal after CRH stimulation

3. Persistent Cushing's syndrome after transsphenoidal surgery

4. Clinical need to resolve discrepancy between clinical, biochemical and imaging tests

   Technique Top

MR scans [Figure - 1] and relevant Biochemical tests [Table - 1] are reviewed with the endocrinologist. Informed consent is taken after explanation of the possible risks and complications. The patient is kept fasting overnight and sedated with Diazepam 10mg orally before the procedure. The Lab is informed on the previous day; Lavender top collection tubes on dry ice (for serum ACTH) and Red top collection tubes (for serum cortisol) are kept ready for blood samples.

Both Femoral veins are catheterized, with a 7F and 6F Terumo Sheath (Terumo Corporation, Tokyo). The larger sheath helps in simultaneous collection of peripheral venous blood around the diagnostic catheter. 5000 IU of Heparin is injected intravenously. The right femoral sheath is intended for right jugular catherisation, and left femoral sheath for left jugular catheterization, to prevent confusion during sample collection.

Using a 5F Multipurpose catheter and straight Terumo guide wire (Terumo Corporation, Tokyo), the right atrium is crossed, the superior Vena Cava is entered and the catheter manipulated into the left brachiocephalic vein [Figure - 2]. The head of the clavicle marks the left internal jugular vein entry into the brachiocephalic vein. Entry into the left internal jugular is often difficult, because of a valve at the inferior jugular bulb [Figure - 3]. Probing with a multipurpose catheter and straight or angled Terumo wire, during phases of deep inspiration may help, since the valve opens at this time. A head down position may distend the internal jugular vein. Frequently the catheter may enter the external jugular or the vertebral vein [Figure - 4], and detecting the ostium of the internal jugular vein may be difficult. In contrast, the ostium of the right internal jugular vein is often in a straight line with the SVC, and presents no difficulty in catheterisation [Figure - 2]. Rarely the right internal jugular ostium may be slightly lateral. On both sides, the external jugular opening is lateral to the internal jugular ostium. If all methods fail, a direct puncture of the internal jugular vein can be done with ultrasound guidance.

Once both internal jugular veins are catherized, the multipurpose catheters are exchanged for a 5.5 H1 Headhunter catheter with an 038" lumen. These catheters act as guiding catheters for the Microcatheter - Microwire combination to enter the inferior petrosal sinus. A Multipurpose catheter with a 45 degree angle can also be tried as an alternative guiding catheter. At this point, another IU of Heparin is given intravenously.

Knowledge of the inferior petrosal venous anatomy is essential [6], since there are wide variations in the drainage of the sinus [Figure - 5]. The sinus may be hypoplastic or there may be multiple small channels instead of a single inferior petrosal vein. Rarely, the inferior petrosal vein may drain into the condylar vein, with no communication with the internal jugular - in which case the procedure is impossible. A hand injection in the superior jugular bulb, with 10 ml of contrast, during valsalva or compression of both internal jugular veins at the root of the neck, will usually opacify all the tributaries and the inferior petrosal sinuses [Figure - 6]. A road map can be acquired at this stage to mark the ostium of the inferior petrosal sinus. Lateral and anteroposterior views are acquired. A Tracker 10 or Tracker 18 microcatheter (Target Therapeutics, Freemont, CA) with a Seeker 10 or Seeker 16 wire (Target Therapeutics, Freemont, CA) is introduced thru the diagnostic catheter. The diagnostic catheter is gently manipulated to point anterolaterally, a cm or so below the superior jugular bulb, and gentle probing is carried out with the microwire, till the Inferior petrosal sinus is entered. The diagnostic catheter is never pushed into the sinus, but rests at the ostium [Figure - 7]. Once the microcatheter passes into the sinus [Figure - 8], the microwire is removed and a gentle diagnostic angiogram is done through the microcatheter, with a 2 cc Luer lock syringe. The purpose is to check position of the microcatheter tip, so that it is not engaged in a collateral vein, and to check communication with the cavernous sinus [Figure - 9]. Any sluggishness of flow of contrast may suggest that the sinus is hypoplastic. In such a case the catheter itself may be occluding the sinus, increasing the risk of complications, or the drainage of blood from the cavernous sinus may be diverted through other collaterals leading to false low values of ACTH in the sample.

The microcatheter position should be well in the inferior petrosal sinus (IPS) to prevent dislodgement, but deep catherisation, or cavernous sinus entry is not required[7] in most situations[Figure - 10]. Sampling can now start

Simultaneous sampling of the IPS and peripheral veins for plasma ACTH is performed 5 and 1 minute before ovine CRH stimulation. One microgram/Kg or a maximum of 100 microgram of ovine CRH (Ferring, Inc) is given intravenously in a peripheral vein and samples for plasma ACTH collected 2, 5 and 10 minutes after stimulation. Each sample requires 3 ml of blood and can be collected within 75 seconds through the microcatheters. With each ACTH sample, a peripheral sample for plasma cortisol is also taken. Catheter position is checked before collection of each sample.

During the procedure, signs of brain stem ischaemia viz. slurred speech, hemifacial paresthesias, sensation of enlarged tongue, perioral tingling and labile hypertension - are danger signs, and procedure should be terminated immediately. Sedation should not be deep for easy recognition of these signs.

   Interpretation of Results Top

A significant gradient between the pituitary (central) and peripheral venous values of plasma ACTH, obtained by simultaneous sampling, is indicative of Cushing's disease [Table - 2]. If the basal ratio of the plasma ACTH values obtained from central and peripheral samples is greater than 2, it is indicative of Cushing's disease [1],[4]. To increase the sensitivity, the sampling is repeated after peripheral administration of ovine CRH. A peak central to peripheral plasma ACTH ratio of 3 or more[1],[4], which usually occurs 3-5 minutes post oCRH stimulation is indicative of Cushing's disease. An overall sensitivity of 96% and specificity of 100% in differentiating Cushing's disease from ectopic ACTH secretion is reported by this method [1],[3]. False positive results are rare. False negatives are uncommon (4%) and occur due to abnormalities in petrosal sinus anatomy or other technical reasons [2].

A high ratio of central to peripheral plasma ACTH, after oCRH stimulation is virtually diagnostic of pituitary microadenoma - however a low ratio is not specific for ectopic ACTH secretion, and can occur uncommonly in pituitary ACTH secreting adenomas [2].

The use of BIPSS in lateralizing the pituitary adenoma is controversial [1],[4]. An intersinus gradient of greater than 2, favors the location on the side of maximum secretion. However the diagnostic accuracy in lateralizing is only 70%. This could be due to the predominant median location of the tumour, or anomalies in petrosal venous anatomy and drainage, or hypoplasia of the sinus.

   Complications Top

Complications are rare, occurring in 0.2% in large series. The incidence is related to entry of microcatheter - wire systems into the sinus, where the catheter could engage and temporarily occlude small bridging veins connecting the transverse pontine, lateral medullary and pontomedullary veins with the inferior petrosal vein [Figure 12]. This results in brain stem ischaemia and hemorrhages [8,p]. Injury to these veins could result in subarachnoid bleed. Early recognition of the characteristic signs of brain stem ischaemia and termination of the procedure prevents irreversible damage[9].

   References Top

1.Newell-Price J, Trainer P, Besser M, Grossman A. The diagnosis and differential diagnosis of Cushing's syndrome and Pseudocushings states. Endocrine Reviews 1998; 19(5): 647-672.  Back to cited text no. 1    
2.Bonelli FS, Huston J, Carpenter PC, Erickson D, Young WF, Meyer FB, Adrenocorticotropic hormone-dependent Cushing's Syndrome: Sensitivity and Specificity of Inferior Petrosal Sinus Sampling. AJNR Am J Neuroradiol 2000; 21: 690-696.  Back to cited text no. 2    
3.Oldfield E, Doppman JL, Nielman L et al. Petrosal sinus sampling with and without corticotrophin-releasing hormone for the differential diagnosis of Cushing's syndrome. N Engl J Med 1991; 325: 897-905.  Back to cited text no. 3    
4.Booth GL, Redelmeier DA, Grosman H, Kovacs K, Smyth HS, Ezzat S. Improved diagnostic accuracy of Inferior Petrosal Sinus Sampling over Imaging for localizing pituitary pathology in patients with Cushing's Disease. J Clin Endocrinol Metab 1998; 83: 2291-2295.  Back to cited text no. 4    
5.Miller DL, Doppman JL. Petrosal sinus sampling: technique and rationale. Radiology 1991; 178: 37-47.  Back to cited text no. 5    
6.Miller DL, Doppman JL, Chang R. Anatomy of the junction of the inferior petrosal sinus and the internal jugular vein. Am J Neuroradiol 1993; 14: 1075-1083.  Back to cited text no. 6    
7.Teramoto A, Niemoto S, Takakura K, Sasaki Y, Machida T. Selective venous sampling directly from cavernous sinus in Cushing's syndrome. J Clin Endocrinol Metab 1993; 76: 637-641.  Back to cited text no. 7    
8.Bonelli FS, Huston J, Meyer FB, Carpenter PC. Venous subarachanoid hemorrhage after Inferior Petrosal Sinus Sampling for Adrenocorticotropic Hormone. AJNR Am J Neuroradiol 1999; 20: 306-307.  Back to cited text no. 8    
9.Doppman JL. There is no simple answer to a rare complication of Inferior Petrosal Sinus Sampling. AJNR Am J of Neuroradiol 1999; 20: 191-19.  Back to cited text no. 9    

Correspondence Address:
N K Prabhu
Department of radiology, Amrita Institute of Medical Sciences, Amrita Lane, Elamakkara, Cochin-682026, Kerala
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Source of Support: None, Conflict of Interest: None

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[Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4], [Figure - 5], [Figure - 6], [Figure - 7], [Figure - 8], [Figure - 9], [Figure - 10]


[Table - 1], [Table - 2]

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