Bilateral Sequential Inferior Petrosal Sinus Sampling with Corticotrophin-Releasing Hormone Stimulation in the Diagnosis of Cushing’S Disease

European Journal of Endocrinology (1998) 139 161–166 ISSN 0804-4643

Bilateral sequential inferior petrosal sinus sampling with corticotrophin-releasing hormone stimulation in the diagnosis of Cushing’s disease

S J Padayatty1,3, S M Orme1, M Nelson1,2, J T Lamb2 and P E Belchetz1 1Department of Endocrinology and 2Department of Neuroradiology, The General Inﬁrmary at Leeds, Leeds LS13EX, UK and 3Division of Endocrinology, Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA (Correspondence should be addressed to S J Padayatty, Payson House #14C, 435 East 70th Street, Manhattan, New York, New York 10021 USA)

Abstract Objective: The demonstration of a central to peripheral ACTH gradient in a hypercortisolaemic patient is diagnostic of Cushing’s disease. We tried to determine whether single blood samples for ACTH obtained sequentially from each of the inferior petrosal sinuses following human corticotrophin-releasing hormone (hCRH) stimulation can reliably establish such a gradient. Design: Prospective study. Patients: Seventeen patients with clinical and biochemical features of Cushing’s syndrome. Methods: After the administration of hCRH, the patients underwent bilateral sequential inferior petrosal sinus sampling, with a single blood sample obtained from each of the inferior petrosal sinuses sequentially, along with a peripheral venous sample. The petrosal sinus catheter was withdrawn immediately after obtaining a blood sample. Patients did not require indwelling catheters in the petrosal sinuses, nor heparinisation. Results: Bilateral sequential inferior petrosal sinus sampling correctly identiﬁed a pituitary source of ACTH, as shown by a central to peripheral ACTH ratio >2, in all patients in whom the procedure was successfully carried out. All patients underwent transsphenoidal pituitary surgery resulting in remission. Conclusions: The simpliﬁed method of inferior petrosal sinus sampling, using a single sequential sample from each of the inferior petrosal sinuses, following initial hCRH stimulation, is as accurate as the more complex test using multiple bilateral simultaneous inferior petrosal sinus samples. It avoids the use of indwelling cerebral venous catheters and is therefore unlikely to cause brain stem damage.

European Journal of Endocrinlogy 139 161–166

Introduction sampling (BSimIPSS) as presently carried out is technically demanding in time and materials and The differential diagnosis of Cushing’s syndrome, in carries a small risk. Cavernous sinus sampling (2, 3), particular the differentiation of pituitary-dependent developed to improve diagnostic accuracy, is even more adrenocorticotrophin (ACTH) hypersecretion from ecto- invasive and complex but provides no advantage over pic ACTH secretion, is often difficult. Pituitary imaging inferior petrosal sinus sampling (4). Jugular venous with computed tomography or magnetic resonance sampling is less invasive but also less sensitive (5). We scanning sometimes identifies an adenoma but the have simplified inferior petrosal sinus sampling to make results may be misleading due to high false positive and it easier, cheaper and potentially a safer procedure, false negative results. Identifying an ACTH gradient without any loss in diagnostic accuracy. between inferior petrosal sinuses and the peripheral blood is at present the most accurate method of identifying a pituitary source of ACTH hypersecretion (1). This is done by sampling both inferior petrosal Patients and methods sinuses simultaneously for ACTH, using pre-placed catheters, before and after the administration of Patients corticotrophin-releasing hormone (CRH). The demon- Seventeen consecutive patients referred to the endo- stration of a central to peripheral gradient in the crine service were studied prospectively. There were 4 concentration of ACTH in a hypercortisolaemic patient males and 13 females with a mean age of 38 years is diagnostic of a pituitary source of ACTH hypersecre- (range 22–73) (Table 1). The patients had history and tion. Bilateral simultaneous inferior petrosal sinus clinical findings typical of Cushing’s syndrome. After 2

᭧ 1998 Society of the European Journal of Endocrinology

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Table 1 Patient details with the results of BSeqIPSS following the i.v. administration of 100 mg hCRH. Bold numbers show the higher of the two central to peripheral ratios. Inter-sinus ratio is the ratio of the right and left central to peripheral ratios.

Central to ACTH (ng/ml) peripheral ratio Patient no. Sex/age Right IPS Peripheral Left IPS Peripheral Right Left Inter-sinus ratio

1 F/49 86 82 117* 114 1.05 1.01* 1.04* 2 M/22 177 162 2087 166 1.09 12.55 11.51 3 F/39 2225 184 1987 270 12.2 7.36 1.66 4 F/49 32 35 91 32 0.94 2.08 2.21 5 F/60 279 78 63 60 3.58 1.04 3.44 6 M/26 117 121 683 114 0.96 5.96 6.21 7 F/34 1118 119 69 71 9.04 0.97 9.32 8 F/33 315 201 1000 199 1.57 5.03 3.2 9 F/44 870 194 577 177 4.48 3.26 1.38 10 M/31 1849 179 279 315 10.31 0.88 11.72 11 F/32 1231 84 110 91 14.62 1.21 12.08 12 M/27 4000 720 3970 780 5.56 5.1 1.09 13 F/24 320 167 530 149 1.9 3.56 1.88

* Represents a jugular sample as the left inferior petrosal sinus could not be catheterised. IPS ¼ inferior petrosal sinus. days of familiarisation with the metabolic ward and venous anatomy was defined at this stage to avoid before the initiation of any treatment, they underwent inadvertent sampling of a large clival vein. The catheter biochemical and dynamic tests as in-patients. This was then withdrawn into the superior vena cava and included the measurement of 24 h urinary cortisol, a the procedure repeated on the left side. Finally the dexamethasone suppression test, a CRH test, and catheter was withdrawn and firm pressure applied at pituitary and/or adrenal imaging studies. All patients the groin puncture site. A peripheral blood sample was were hypercortisolaemic for at least 2 days preceding taken each time an inferior petrosal sinus was sampled. petrosal sinus sampling. One patient was excluded as BSimIPSS was carried out in a similar way but hCRH she had no detectable ACTH. Three patients underwent was given only after both inferior petrosal sinus BSimIPSS as previously described (1) and were sampled sampling catheters were in place. Samples were taken for 1 h. Thirteen patients underwent bilateral sequential simultaneously from both inferior petrosal sinus sampling inferior petrosal sinus sampling (BSeqIPSS) with human and a peripheral vein at 0, 2, 5, 10, 20, 40 and 60 min. CRH (hCRH) stimulation. All patients were subse- quently shown to have pituitary-dependent ACTH ACTH assay Samples for ACTH were collected in EDTA hypersecretion, as shown by cure or remission following tubes on ice, and plasma separated by centrifugation pituitary surgery. within 30 min and stored at ¹20 ЊC until assayed. The ACTH assay used was a pre-extracted radioimmuno- assay with an inter- and intra-assay coefficient of Methods variation of 15–19% and 7.5%, using National Institute Inferior petrosal sinus sampling BSeqIPSS was for Biological Standards and Control (London, UK) carried out in the neuro–angiographic suite with ACTH standard 74/555. minimal or no sedation. hCRH (100 mg) was adminis- tered through an indwelling cannula in an antecubital vein at the beginning of the procedure (i.e. at the time of Results femoral puncture). Under local anaesthesia, a standard Both inferior petrosal sinuses were successfully sampled femoral vein puncture was made. A 5 French catheter in all but one patient. All had a central to peripheral with guide wire was advanced into the right inferior gradient of >2.0, and went into remission following petrosal sinus, guided by digital subtraction imaging transsphenoidal pituitary surgery. Eight out of thirteen with the injection of small quantities of non-ionic water patients in whom a central to peripheral gradient was soluble contrast (Lopamidol or Lohexol). Prior to demonstrated had a ratio of central to peripheral <2 in sampling, a venogram was done with gentle injection one of the petrosal sinuses (Table 1). Patient No. 1 was a of contrast material taking particular care to avoid technical failure because it was not possible to reflux of contrast as far as the cavernous sinus. Blood catheterise her left inferior petrosal sinus. Samples (4–6 ml) was withdrawn from the petrosal sinus. A were obtained from the left jugular bulb and the right check venogram was then done, this time including the inferior petrosal sinus, neither of which showed a ipsilateral cavernous sinus but avoiding the contra- central to peripheral gradient. She underwent pituitary lateral cavernous sinus if it had yet to be sampled. The surgery resulting in cure of her Cushing’s disease.

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Table 2 Results of BSimIPSS (ACTH ng/ml) in individual patients following the i.v. administration of 100 mg hCRH at time 0.

Time after hCRH (min)

Sex/age Site 0 2 5 10204060

F/73 Right IPS 680 1230 1510 1600 940 590 370 Left IPS 59 75 246 174 80 81 88 Peripheral 39 43 47 63 82 58 42 F/32 Right IPS 36 50 56 28 24 26 Left IPS 189 780 490 360 232 247 272 Peripheral 46 39 48 37 26 25 27 F/34 Right IPS 940 2900 5400 5100 3600 4900 2090 Left IPS 830 1980 3500 5400 4300 3300 2130 Peripheral 39 58 61 217 120 265 109

IPS ¼ inferior petrosal sinus.

BSimIPSS showed that there was a central to peripheral After the administration of hCRH, it took a mean time gradient at baseline and throughout the procedure of 23 min (range 8–32 min) to obtain a sample from the which peaked at 2 to 10 min after hCRH (Table 2 and right inferior petrosal sinus, and a mean time of 50 min Fig. 1). (range 30–94 min) to sample the left.

Lateralisation of the source of ACTH Discussion A direct inter-petrosal sinus ratio could not be Our results show that high central to peripheral ACTH determined due to the time interval between collection ratios are seen at baseline and throughout the sampling of the two samples. Instead, a ratio between the right period, making it feasible to sample the inferior petrosal inferior petrosal sinus to peripheral, and the left inferior sinuses sequentially and demonstrate a central to petrosal sinus to peripheral gradient was calculated, peripheral gradient. This was conﬁrmed in every patient and this showed a gradient >1.38 in all cases. The studied with BSeqIPSS. accuracy and usefulness of such lateralisation in this The differential diagnosis of Cushing’s syndrome is series could not be determined due to the inability to often difﬁcult and selective venous sampling to detect a localise or detect an ACTH-secreting adenoma during source of ACTH hypersecretion has been employed for surgery or on histological examination of the excised many years. The earliest attempts at sampling were pituitary tissue in 6 out of 17 patients. made by obtaining blood from the jugular vein (6–8) to

Figure 1 Ratio of right (R) and left (L) inferior petrosal sinus to peripheral venous ACTH concentrations following the i.v. administration of 100 mg hCRH at time 0. A ratio of 2 or more was considered to indicate a pituitary source of ACTH.

Downloaded from Bioscientifica.com at 09/27/2021 08:03:16PM via free access 164 S J Padayatty and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (1998) 139 demonstrate a central to peripheral ACTH gradient. It heparinisation is unnecessary. It is of interest that was shown that there was no jugular vein to peripheral none of our patients developed groin haematomas, blood ACTH gradient in patients with ectopic ACTH unlike those in the reported series in which antico- production (9) in marked contrast to patients with agulation was used (1). Pulmonary embolism has been Addison’s disease or following adrenalectomy for reported after BSimIPSS (25) and this may be related to Cushing’s disease (10). Selective sampling of the jugular the development of an inguinal haematoma (26). Brain vein showed evidence of a pituitary source of ACTH in stem injuries that have occurred during BSimIPSS (27, 90% of patients with Cushing’s disease (5). Sampling 28) are thought to be due to localised venous from one or both inferior petrosal sinuses, but not the hypertension (27) resulting from the temporary jugular bulb, showed a gradient of >2.0 in all patients venous occlusion due to the indwelling catheter. These with Cushing’s disease but not in those with ectopic injuries include damage to the pons, IVth ventricle, ACTH secretion (11), thus allowing a clear distinction medulla (27) and the pontomedullary junction probably to be drawn between these two groups (12). However, due to venous infarction (29). Although uncommon, sampling from a single inferior petrosal sinus can be the risk of catastrophic brain stem damage cannot be misleading (13). Unilateral sampling in our series could justified for a procedure used to confirm Cushing’s have been misleading in 6 out of 13 patients. disease in a population in whom the prior probability of BSimIPSS avoids the problems associated with this diagnosis is very high, and it does not completely jugular vein or unilateral inferior petrosal sinus rule out a false positive (30) or negative result (31). sampling and invariably identifies a pituitary source of Further, in patients with early (32), mild, or pseudo ACTH when the procedure is technically successful Cushing’s (33), petrosal sinus sampling has poor (14–17). The petrosal sinus to peripheral gradient may diagnostic value. be increased by the administration of CRH (18–21). In a We could not determine the value of inter-sinus large series, a petrosal sinus to peripheral gradient of ACTH gradient in our series due to the inability to 3·0 after CRH administration showed a 100% sensitiv- identify and orientate accurately a pituitary adenoma ity and specificity in those patients in whom Cushing’s during surgery and on histology in some patients, a disease could be confirmed by surgery (1). problem encountered in other studies (34). Never- Using BSeqIPSS with hCRH, we were able to theless, all achieved remission. Several studies have demonstrate a pituitary source of ACTH (a central to shown that using BSimIPSS with CRH stimulation, peripheral ACTH ratio >2) in all patients where the lateralisation of the adenoma within the pituitary gland procedure was technically successful. In these cases, the may be achieved (1, 14, 16, 35) in some or all patients, BSimIPSS would have provided no further diagnostic and hemihypophysectomy of the suspected side has advantage. The three patients who had BSimIPSS had been advised if an adenoma cannot be identified during central to peripheral ACTH gradients diagnostic of surgical exploration. Others, however, have found Cushing’s disease at baseline and throughout the lateralisation by inferior petrosal sinus sampling to be sampling period, with a brief increment following CRH misleading (17, 21), and in one report the intra- administration. Sequential sampling at any of these operative measurement of ACTH in the peri-pituitary time periods would provide the same diagnostic blood was used to correct the misleading results from information. As this series did not include any patient inferior petrosal sinus sampling (36). The value of with ectopic ACTH syndrome, the specificity of the test inferior petrosal sinus sampling in the lateralisation of a could not be validated. pituitary source of ACTH is uncertain. It is likely to The technique of BSimIPSS is technically difficult and remain so due to the frequent asymmetry (seen in 35 to may be complicated by catheter displacement during 39%) of pituitary venous drainage (37–39), although the procedure, which can invalidate the test. This is this does not impede successful catheterisation (37). avoided in the modified sequential sampling method Further, lateralisation of secretion of ACTH, arginine described as the catheters are not left in situ. A serious vasopressin and oxytocin is seen in the petrosal sinus of potential complication of leaving a cannula in situ in normal volunteers. ACTH and arginine vasopressin both inferior petrosal sinuses is cavernous sinus responses to CRH were similarly lateralised, implying thrombosis, a condition which carries a high morbidity the normal occurrence of asymmetry in the concentra- and mortality (22, 23). Although BSimIPSS has been tions of ACTH in the petrosal sinus (40). Lateralisation performed without heparinisation (21), most groups may not be so important as the cure rate is unaffected use heparin to avoid this dangerous complication. by the nature and extent of the pituitary lesion or the However, heparinisation may itself be hazardous in surgical procedure used (41). hypercortisolaemic patients, and in the event of In summary, inferior petrosal sinus sampling can perforation of the petrosal sinus, a complication that identify a pituitary source of ACTH in patients with has occurred during petrosal sinus catheterisation (24) clear clinical and biochemical evidence of Cushing’s for other indications, anticoagulation may prove syndrome. Complications are infrequent but can catastrophic. Since BSeqIPSS does not require an produce crippling brain stem damage. BSeqIPSS with indwelling catheter in the inferior petrosal sinus, CRH stimulation is as effective as BSimIPSS in the

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