Diagnostic challenges in cyclic Cushing's syndrome: a systematic review.

Cyclic Cushing's syndrome is a subentity of Cushing's syndrome in which phases of biochemical hypercortisolism (peaks) are followed by spontaneous periods of physiological or even hypocortisolaemic cortisol secretion (troughs). To identify common features of cyclic Cushing's syndrome, we systematically reviewed single case reports and case series in MEDLINE from database inception to Oct 10, 2022, and identified 707 articles, of which 149 articles were assessed for eligibility and 118 articles (covering 212 cases) were included in the analysis. Pituitary tumours accounted for 67% of cases of cyclic Cushing's syndrome (n=143), ectopic tumours for 17% (n=36), and adrenal tumours for 11% (n=23). Occult tumours accounted for 2% of cases (n=4), and 3% of cases were unclassified (n=6). We compared the clinical symptoms and comorbidities of patients with cyclic Cushing's syndrome with those of patients with non-cyclic Cushing's syndrome and observed no major difference. In adrenocorticotropic hormone (ACTH)-dependent cyclic Cushing's syndrome, bilateral inferior petrosal sinus sampling had a positive (ie, true pituitary) and negative (ie, true ectopic) predictive value of 100% when performed during periods of hypercortisolism, versus a positive predictive value of 73% and a negative predictive value of 86% when performed, irrespective of cortisolaemic status. Overall, 6% of patients (n=12) with cyclic Cushing's syndrome had unnecessary surgery due to misclassification. Remission rates were significantly lower and the time to remission significantly longer in patients with cyclic Cushing's syndrome compared with patients with non-cyclic Cushing's syndrome (p<0·001). Variations in biochemical test results due to unpredictable cycle duration and frequency might cause diagnostic challenges resulting in misdiagnoses and missed diagnoses.

Approach to the Patient: Diagnosis of Cushing Syndrome.

Cushing syndrome results from supraphysiological exposure to glucocorticoids and is associated with significant morbidity and mortality. The pathogenesis includes administration of corticosteroids (exogenous Cushing syndrome) or autonomous cortisol overproduction, whether or not ACTH-dependent (endogenous Cushing syndrome). An early diagnosis of Cushing syndrome is warranted; however, in clinical practice, it is very challenging partly because of resemblance with other common conditions (ie, pseudo-Cushing syndrome). Initial workup should start with excluding local and systemic corticosteroid use. First-line screening tests including the 1-mg dexamethasone suppression test, 24-hour urinary free cortisol excretion, and late-night salivary cortisol measurement should be performed to screen for endogenous Cushing syndrome. Scalp-hair cortisol/cortisone analysis helps in the assessment of long-term glucocorticoid exposure as well as in detection of transient periods of hypercortisolism as observed in cyclical Cushing syndrome. Interpretation of results can be difficult because of individual patient characteristics and hence requires awareness of test limitations. Once endogenous Cushing syndrome is established, measurement of plasma ACTH concentrations differentiates between ACTH-dependent (80%-85%) or ACTH-independent (15%-20%) causes. Further assessment with different imaging modalities and dynamic biochemical testing including bilateral inferior petrosal sinus sampling helps further pinpoint the cause of Cushing's syndrome. In this issue of "Approach to the patient," the diagnostic workup of Cushing syndrome is discussed with answering the questions when to screen, how to screen, and how to differentiate the different causes. In this respect, the latest developments in biochemical and imaging techniques are discussed as well.

The Effects of Sampling Lateralization on Bilateral Inferior Petrosal Sinus Sampling for Pediatric Cushing's Disease-A Single Endocrinology Centre Experience and Review of the Literature.

Background: This study aims to analyze the diagnostic accuracy of bilateral inferior petrosal sinus sampling (BIPSS), the gold standard test for the differential diagnosis of ACTH-dependent Cushing's syndrome (CS) in a group of pediatric patients with Cushing's disease (CD). Methods: This is a retrospective analysis which include 12 patients with hypercortisolemia and inconclusive pituitary MRI, who underwent bilateral inferior petrosal sinus sampling (BIPSS) and transsphenoidal surgery (TSS) from 2004 to 2020 in the Children's Memorial Health Institute (CMHI) Warsaw, Poland. Pituitary origin of ACTH secretion was considered if baseline central to peripheral (C/P) ACTH level ratio was ≥ 2 or C/P ratio was ≥ 3 after human corticotropin-releasing hormone (hCRH) stimulation. The diagnosis was histologically confirmed in almost all cases after TSS. Results: The diagnostic accuracy of BIPSS reached 75% at baseline and 83.3% after CRH stimulation. The compatibility of localization of a microadenoma by BIPSS with the surgical location was 66.7%. Conclusions: Owing to its high diagnostic effectiveness, BIPSS remains the best test to differentiate CD from EAS. The indications for the procedure should be carefully considered, because EAS in the pediatric population, unlike in adults, is extremely rare. Moreover BIPSS has only limited value for indicating tumor localization.

Unusual ectopic ACTH syndrome in a patient with orbital neuroendocrine tumor, resulted false-positive outcome of BIPSS:a case report.

BACKGROUND: Cushing's syndrome has been described as a complex endocrine disorder characterized with high cortisol concentration. Correct and early diagnosis of Cushing's syndrome is challenging. According to the latest guideline, bilateral inferior petrosal sinus sampling (BIPSS) is considered to be the gold standard for the differential diagnosis. However, in some unusual cases, this method may be false positive. Here, we presented a rare case of orbital neuroendocrine tumor secreting adrenocorticotrophic hormone with false positive inferior petrosal sinus sampling. CASE PRESENTATION: A 48-year-old woman was admitted to West China Hospital of Sichuan University, presenting with fatigue, whole body edema for 1 year, alopecia and skin pigmentation for 5 months. Hormonal profiles including plasma cortisol and adrenocorticotrophic hormone (ACTH) measurements and low-dose dexamethasone inhibition test suggested that the patient had Cushing's syndrome. However, during tumor location phase, the results of high-dose dexamethasone inhibition test (HDDST) contradicted desmopressin (DDAVP) stimulation test. Thus, BIPSS was employed, and its results indicated a pituitary origin. Interestingly, MRI of sellar region showed an innocent pituitary but caught a serendipitous lesion in the lateral rectus muscle of left eye, which was later proved to be an orbital neuroendocrine tumor secreting ACTH by pathological and immunohistochemical results. ACTH level of the patients was < 0.1 ng/L and cortisol level was 51.61 nmol/L 1 week after surgery. At 24 months follow-up, the patient appeared stable with no complaints nor any symptoms of Cushing's syndrome, including moon face, purple striate and central obesity. The patient's life quality also improved significantly. CONCLUSION: We reported a rare case of endogenous Cushing's syndrome due to ectopic ACTH secreting from an orbital neuroendocrine tumor. This unique case of orbital EAS suggests that orbital venous blood backflow, owning to abnormal anatomic structures, may possibly lead to false positive BIPSS results.

Non-invasive Diagnostic Strategy in ACTH-dependent Cushing's Syndrome.

CONTEXT: Inferior petrosal sinus sampling (IPSS) is used to diagnose Cushing's disease (CD) when dexamethasone-suppression and CRH tests, and pituitary magnetic resonance imaging (MRI), are negative or give discordant results. However, IPSS is an invasive procedure and its availability is limited. OBJECTIVE: To test a noninvasive diagnostic strategy associated with 100% positive predictive value (PPV) for CD. DESIGN: Retrospective study. SETTING: Two university hospitals. PATIENTS: A total of 167 patients with CD and 27 patients with ectopic ACTH-syndrome investigated between 2001 and 2016. MAIN OUTCOME MEASURE(S): Performance of a strategy involving the CRH and desmopressin tests with pituitary MRI followed by thin-slice whole-body computed tomography (CT) scan in patients with inconclusive results. RESULTS: Using thresholds of a cortisol increase > 17% with an ACTH increase > 37% during the CRH test and a cortisol increase > 18% with an ACTH increase > 33% during the desmopressin test, the combination of both tests gave 73% sensitivity and 98% PPV of CD. The sensitivity and PPV for pituitary MRI were 71% and 99%, respectively. CT scan identified 67% EAS at presentation with no false-positives. The PPV for CD was 100% in patients with positive responses to both tests, with negative pituitary MRI and CT scan. The Negative Predictive Value was 100% in patients with negative responses to both tests, with negative pituitary MRI and positive CT scan. Using this strategy, IPPS could have been avoided in 47% of patients in whom it is currently recommended. CONCLUSIONS: In conjunction with expert radiologic interpretation, the non-invasive algorithm studied significantly reduces the need for IPSS in the investigation of ACTH-dependent Cushing's syndrome.

Role of bilateral inferior petrosal sinus sampling (BIPSS) in the diagnosis of Cushing's disease in a patient with double superior vena cava.

Cushing's syndrome is known to have a wide spectrum of clinical presentation with debilitating consequences and morbidity if not diagnosed and treated in time. Sometimes the diagnosis of Cushing's syndrome can be challenging to the endocrinologist, especially when the usual battery of biochemical tests and advanced cross-sectional imaging is negative or inconclusive. We described a case in which the use of bilateral inferior petrosal sinus sampling (BIPSS) was conclusive albeit being technically challenging (due to a rare incidental finding of double superior vena cava) and invasive in nature.

Bilateral inferior petrosal sinus sampling with desmopressin.

In this technical note, the use of desmopressin to stimulate pituitary adrenocorticotropic hormone secretion in place of the commercially available corticotropin releasing hormone (CRH) in bilateral inferior petrosal sinus sampling is described. Although the use of CRH is the standard of practice, it is currently unavailable in the USA and desmopressin provides reliable results with no additional observed side effects.

Bilateral inferior petrosal sinus sampling.

Bilateral inferior petrosal sinus sampling, the gold standard assay in diagnosing pituitary secretion of adrenocorticotropic hormone in Cushing disease, is highly accurate and safe when performed by experienced interventionalists. We review the anatomic and technical considerations essential for safe and reliable practice.

Inferior petrosal sinus sampling in the diagnosis of sellar neuropathology.

Because no single test is definitive for Cushing's disease (CD), establishing the diagnosis has remained a challenge that relies on building a critical mass of evidence. The differential diagnosis of corticotropin (ACTH)-dependent Cushing's syndrome (CS) traditionally has rested on noninvasive biochemical and radiologic testing. Bilateral inferior petrosal sinus sampling (BIPSS) is an invasive procedure that has become part of the diagnostic armamentarium surrounding CD. When used appropriately-that is, for patients who have biochemically confirmed ACTH-dependent CS but discordant biochemical or radiologic studies-BIPSS is the reference standard confirmatory test for CD.

Neurologic complications of inferior petrosal sinus sampling.

BACKGROUND AND PURPOSE: Inferior petrosal sinus sampling (IPSS) is a useful diagnostic technique in adrenocorticotropic hormone (ACTH)-dependent hypercortisolism with normal or equivocal MR imaging. The procedure is believed to be safe, with mostly minor complications. However, there are rare, but severe, neurologic complications that need to be considered. MATERIALS AND METHODS: We performed an institutional review board-approved retrospective review of our institutional IPSS experience from July 2001 to January 2007. IPSS was performed for the evaluation of Cushing disease. The end points of particular interest were the indications for IPSS and the incidence of associated complications. RESULTS: During the study period of 5(1/2) years, 44 patients underwent IPSS for evaluation of Cushing disease. There were 33 women and 11 men with a mean age of 43.1 years. Because of equivocal imaging and endocrine testing, 36 of 44 patients underwent IPSS, and 8 of 44 underwent IPSS after failed transsphenoidal exploration. The only complication was injury to the brain stem that occurred after an unremarkable procedure in a 42-year-old woman. She developed clinical evidence of pontomedullary dysfunction with MR imaging consistent with brain stem infarction. The cause of this injury is unclear, but a venous variant leading to transient venous hypertension or thrombosis is suspected. CONCLUSION: Neurologic injury is a rare but serious complication associated with IPSS. Despite this, if performed under a strict paradigm, IPSS is both accurate and safe and can be very useful in the management of Cushing disease.

Assessment of bilateral inferior petrosal sinus sampling (BIPSS) in the diagnosis of Cushing's disease.

BACKGROUND: The differential diagnosis of adrenocorticotropin (ACTH)-dependent Cushing's syndrome (CS) remains a challenging issue for clinical endocrinologists. In this respect, bilateral inferior petrosal sinus sampling (BIPSS) appears to be the most sensitive and specific test. Here, we report our 15-year experience of analyzing the performance of BIPSS, both in the correct diagnosis and in the precise lateralization of tumors in patients with Cushing's disease (CD). METHODS: Between 1992 and 2006, 18 patients with CD (16 females, 2 males; age range, 14-56 years) were admitted to Taipei Veterans General Hospital and subjected to BIPSS plus ovine corticotropin-releasing hormone (oCRH) stimulation. Four of them had previously undergone transsphenoidal hypophysectomy (TSH) and had a recurrence thereafter. BIPSS was performed by inserting a catheter in the right and left inferior petrosal sinus for ACTH assay via a femoral vein puncture. An inferior petrosal sinus/peripheral ACTH ratio (C/P ratio) > or = 2 at baseline > or = 3 after oCRH injection indicated a pituitary origin of ACTH secretion, and an interpetrosal ACTH gradient (IPS ratio) > or = 1.4 at baseline or after oCRH indicated evidence of lateralization. RESULTS: Positive BIPSS results were found in 16 patients at baseline and in 17 patients after oCRH injection. In 17 out of 18 patients, TSH was subsequently carried out and a pituitary source was confirmed on histopathologic examination. The only 1 false-negative test result was noted in a patient who had undergone previous TSH. Thus, the sensitivities of BIPSS for the diagnosis of CD before and after oCRH stimulation were 89% and 94%, respectively. Moreover, using an IPS ratio > or = 1.4 as a criterion, BIPSS correctly lateralized the tumor in 9 of 17 and 10 of 17 patients at baseline and after oCRH stimulation, respectively, including in 2 patients who had a centrally located tumor and who had an IPS ratio < 1.4. Thus, the sensitivities of lateralization of BIPSS were 53% and 59%, respectively. None of the 4 patients who had previous TSH were precisely localized by BIPSS. If these 4 patients were excluded, the sensitivities of BIPSS for localizing in the patients who had not undergone previous operation increased to 70% (9/13) at baseline and 77% (10/13) after oCRH stimulation, respectively. CONCLUSION: BIPSS combined with oCRH stimulation is a safe and reliable examination both in the differential diagnosis of CD and in the correct lateralization of pituitary microadenoma in patients without previous pituitary surgery. Nevertheless, this procedure may provide misleading results in patients who have received previous pituitary surgery.

Venous thrombo-embolism following inferior petrosal sinus sampling in Cushing's disease.

Bilateral inferior petrosal sinus sampling for ACTH with corticotrophin releasing hormone stimulation has become an established test in differentiating pituitary Cushing's disease from Cushing's syndrome due to ectopic ACTH secretion. We report two patients with Cushing's disease who developed thromboembolic complications soon after inferior petrosal sinus sampling. We discuss the possible mechanisms leading to this complication in a syndrome in which thromboembolic complications are well recognized and highlight the need for consideration of prophylactic anticoagulation.