Diagnosis Of Cushing's Disease Research Articles

PMON152 In Patients with Cushing's Disease and a Visible Tumor on MRI, IPSS does not Add to the Accuracy of Predicting Tumor Lateralization

Abstract Introduction There is controversy surrounding the value of bilateral inferior petrosal sinus sampling (BIPSS) for tumor lateralization in Cushing's disease (CD). We compare lateralization results between BIPSS and pituitary imaging against gold-standard surgical localization. Methods A retrospective chart review was conducted in patients with pathology-confirmed CD, visible tumor on MRI (with and without contrast), and who underwent BIPSS at our institution between 2003-2020. An inferior petrosal sinus to peripheral (IPS/P) prolactin ratio >1.8 was used to confirm appropriate IPS sampling. An inter-sinus ACTH gradient ratio greater than 1.4, adjusted for prolactin where available, was used to determine lateralization. In each case, the neurosurgeon performed a full pituitary gland exploration to avoid missing any tumors despite visible tumor on MRI. Descriptive statistics were used. Results Of 32 patients with CD, visible tumor on MRI, and BIPSS testing, 27 (84%) patients had technically successful bilateral IPSS catheterization and are the subjects of this study. All 27 of these patients had IPS/P ACTH ratio greater than 2 at baseline or 3 after CRH stimulation, consistent with CD, and all 27 lateralized. The median age at diagnosis was 42 years (range 21-69 years) and 85% were female (N=23). The median tumor size on MRI was 5 mm (range 3-8 mm). In 22/27 (81%) patients, the result of the IPSS lateralization was concordant with MRI findings. When MRI and BIPSS lateralization agreed, 21/22 (95%) were confirmed by surgical pathology. Of the 5 cases where MRI and BIPSS disagreed on laterality, the operative report was consistent with MRI lateralization in 3/5 cases, and bilateral disease in the remaining 2 cases. There were no cases where BIPSS lateralization was correct when MRI lateralization was incorrect. Overall, MRI correctly lateralized 26/27 cases (96%), whereas BIPSS correctly lateralized 23/27 (85%). In the subset of 13 patients with tumors measuring <6mm on MRI, MRI imaging lateralization was correct in all 13 (100%) cases and BIPSS lateralization was correct in 11/13 (85%). Adverse events associated with BIPSS were noted in 4 patients (15%) ranging from hematoma to headache. Among the 5 patients who did not have successful BIPSS cannulization, one experienced the adverse effect of transient severe headache. There were no serious complications. The surgeons performed bilateral sellar exploration in all cases regardless of BIPSS or MRI lateralization results. Conclusion When a tumor is visible on MRI, regardless of its size (≥ 3mm), BIPSS does not add to the accuracy of determining tumor lateralization. BIPSS may best be reserved for situations where the diagnosis of CD is in question. Further studies are required to determine the value of BIPSS in lateralizing the source of CD in patients without visible tumor. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

ODP304 Cyclic Cushing Disease: A Diagnostic Challenge

Abstract Background Cyclic Cushing syndrome is a clinical challenging diagnosis due to an unpredictable duration of periodic hypercortisolemia shifting with normocortisolemia periods. Only small proportion of such cases are due to a corticotroph pituitary adenoma with cyclic activity. Clinical case: 27-year-old after she stopped nursing her baby, she had no resumption of menses. She then developed mild headache and weight gain of 20kg throughout 3 months. She also developed facial hair, acne, easy bruising and striae. She was evaluated by a local physician where Cushing syndrome (CS) was suspected. Local testing showed the following results: UFC: 1117 and 1572 mcg/24h (<403mcg/24h), low dose DST of 595.8 nmol/l (<50nmol/l) and ACTH 60 pg/mL (10-100pg/mL). An MRI identified a 6 mm pituitary adenoma. The patient was sent to our pituitary clinic under the diagnosis of Cushing disease (CD). Upon examination at our institution, the patient reported asthenia, mood changes, depression and hirsutism. The physical examination revealed classical signs of CS. No other comorbidities were detected. A seven-hour 7mg dex infusion testwas performed (1), with basal cortisol of 187.5 nmol/l, early suppression of 12.6 nmol/l and late suppression of 27.5 nmol/l which is negative for hypercortisolism. As the high suspicion of CS, the patient was followed monthly with UFC and serum cortisol. During this normocortisolemia period the patient lost 10kg of weight, recovered its menses and coloration changes of striae. Laboratory follow up UFC of 67, 71 mcg/24h and serum cortisol of 124, 270, 103.4, 358.6 and 413 nmol/l ACTH 20, 21, 23, 28, 25 pg/mL. After 6 months of no clinical sign of hypercortisolism the patient reached to us as she noticed her striae changed, started gaining weight, lost menses and changed headache frequency. Laboratories revealed UFC was 754.6 mcg/24h and low dose DST was 751.1 nmol/l and ACTH of 70 pg/mL. We conducted another continuous 7mg dex infusion for seven hours with basal cortisol of 669.2 nmol/l, early suppression of 90.2 nmol/l (>50% suppression) and late suppression of 691.5 nmol/l which was compatible with CD. Additional testing was performed, with a 18F-NOTA-Octreotide and a full body CT that did not reveal an ectopic ACTH producing tumor neither an adrenal mass. Patient underwent a transsphenoidal surgery and reached remission of her hypercortisolism. Conclusion CD may be difficult to be confirmed but also it is important to consider that some cases showed cyclic activity. As far as we could acknowledged, this is the first case showing a 6-month period of normocortisolemia in a cyclic ACTH-secreting pituitary adenoma. Bibliography Biemond P, de Jong FH, Lamberts SW. Continuous dexamethasone infusion for seven hours in patients with the Cushing syndrome. A superior differential diagnostic test. Ann Intern Med. 1990 May 15;112(10): 738–42. Presentation: No date and time listed

PSAT002 Unilateral Adrenalectomy as a Treatment Option in Patient with Cyclical Cushing's Syndrome

Abstract Background Patients with Cyclical Cushing`s Syndrome (CSS) are at risk for a lengthy timeline of living with the untreated disease. Continual increased amounts of cortisol can lead to increased morbidity and mortality in these patients and finding effective treatments is of the utmost importance. Here we present a treatment course of the patient with CCS who eventually underwent unilateral adrenalectomy, resulting in marked improvements in excessive cortisol- mediated metabolic derangements. Clinical Case In 2014, a 51-yo female with hypertension (HTN), hyperlipidemia (HLD), and type 2 diabetes (T2D) presented to VA endocrinology clinic for the evaluation of incidentally found bilateral adrenal nodules. Based on the extensive biochemical evaluation, the patient was diagnosed with ACTH-dependent Cushing's disease (CD). In the setting of newly diagnosed CD and complex metabolic co-morbidities, in 09/2016 she underwent pituitary resection. However, she remained hypercortisolemic and in 12/2016 she had a second hypophysectomy. Despite surgical efforts, hypercortisolemia persisted. Neuroendocrine imaging studies and chest computed tomography excluded non-pituitary etiology of CD. She was subsequently started on ketoconazole but it was stopped due to side effects. Other CD-directed agents were not approved, so we continued routine management of T2D, HTN, and HLD. In 2018, the patient developed acute coronary syndrome and received percutaneous intervention despite therapy with statin and ezetimibe. Further, since her second hypophysectomy she required sequential addition of hypoglycemic agents and by the end of 2020, exenatide weekly, empagliflozin, and pioglitazone were added to her escalating basal-bolus insulin therapy due to persistent A1C elevation >10%. Continuous evaluation of her hypercortisolemia post-hypophysectomy suggested presence of CCS. To alleviate the metabolic burden of hypercortisolemia, the patient was offered unilateral adrenalectomy which she underwent in 03/2021. Within 6 months after the surgery, she has had unintentional 22-lb weight loss and we stopped both of her anti-HTN medications, discontinued weekly exenatide, and gradually de-escalated her initial daily insulin regimen of approximately 1.0 u/kg to an only basal insulin at 0.15 u/kg dose achieving A1C of 6.5%. There was no biochemical evidence of adrenal insufficiency since adrenalectomy was performed. Conclusion The patient with initial diagnosis of CD, which we later proved being CCS, underwent a unilateral adrenalectomy with the goal of reduction of cortisol burden. This decision was taken with the consideration that this would likely not be curative but intended to improve the course of her metabolic conditions. The 6-month observation following adrenalectomy has proven that we were able to in large extend achieve our goals. Therefore, this treatment approach should be considered for patients with CSS or CD. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Presurgical predictive factors of surgical remission in Cushing's disease. Study of 32 cases

PurposeIdentify presurgical factors associated with surgical remission in Cushing's disease (CD). MethodsAll the patients with ACTH-dependent Cushing's Syndrome in follow-up at our centre between 2014–2021 (n=40) were identified. Those patients with CD diagnosis who underwent transsphenoidal surgery by the same neurosurgeon (n=32) were included. Surgical remission was defined as plasma cortisol <1.8μg/dl and normal or low urinary free cortisol (UFC) after surgery. ResultsSixty-three per cent (n=20) were women, and the mean age at diagnosis was 42.3±17.9 years. Six patients had macroadenomas, 17 had microadenomas, and in the other 9 patients, no pituitary lesion was identified on the MRI. Seven patients were previously operated on in another centre. Surgical remission was achieved in 75% (n=24). Only three patients experienced recurrence. No association between pre-surgical demographic (age, sex, comorbidities) or hormonal (UFC, ACTH, late-night salivary cortisol levels) characteristics and the probability of surgical remission was observed. The only variable associated with a greater chance of remission was the presurgical visualisation of the adenoma on MRI (OR 8.3, P=0.02). It was also observed that patients with a history of a previous pituitary surgery had a lower tendency to achieve remission, although statistical significance was not reached (OR 0.17, P=0.09). ConclusionsIn our experience, 75% of patients with CD achieved biochemical cure after the intervention. Surgical remission was up to eight times more frequent in those patients in whom the adenoma was visualised before the intervention, but no other presurgical predictive factors of cure were identified.

Diagnostic Power of Bilateral Inferior Petrosal Sinus Sampling with Desmopressin in Paediatric Cushing’s Disease

Objective:The aim of this study was to evaluate the diagnostic accuracy of bilateral inferior petrosal sinus sampling (BIPSS) with desmopressin for pediatric Cushing’s disease (CD).Methods:We reviewed studies performed in children that evaluated the accuracy of BIPSS with desmopressin.Results:All included studies were case series of children with adrenocorticotropin hormone (ACTH)-dependent Cushing’s syndrome. The overall accuracy of BIPSS before stimulation was 84.1% (37/44), and after stimulation it was 92.3% (36/39). The overall lateralizing accuracy of BIPSS was 50.0%.Conclusion:Considering that available evidence is limited, it appears that BIPSS with desmopressin stimulation is accurate for the diagnosis of pediatric CD, but its lateralizing accuracy is probably not suitable for pediatric clinical practice.

A noninvasive scoring model for the differential diagnosis of ACTH-dependent Cushing's syndrome: a retrospective analysis of 311 patients based on easy-to-use parameters.

The differential diagnosis of ACTH-dependent Cushing's disease (CS) is challenging. The gold standard approach bilateral inferior petrosal sinus sampling (BIPSS) is expensive and invasive, while other noninvasive tests, like the high-dose dexamethasone suppression test (HDDST), provide unsatisfactory diagnostic accuracy. This study aimed to find a new noninvasive practical approach with higher diagnostic accuracy to differently diagnose ACTH-dependent CS, which can be used in centers where BIPSS cannot be applied. 264 Cushing's disease (CD) patients and 47 ectopic ACTH secretion syndrome (EAS) patients were analyzed in this single-center retrospective study (2011-2021). The multivariate logistic model was used to construct the scoring model. Female (adjusted OR 3.030, 95%CI 1.229-7.471), hypokalemia (0.209, 0.076-0.576), ACTH (0.988, 0.982-0.994), MRI pituitary lesion positive (8.671, 3.521-21.352), and HDDST positive (2.768, 1.139-6.726) have a strong association with the differential diagnosis of ACTH-dependent CS and were included in the final multivariable logistic regression model. A -14-to-14-point noninvasive scoring model was built on the model. The AUC of the noninvasive scoring model was 0.915 (95% CI 0.869-0.960), significantly higher than the AUC of HDDST (0.756, 95% CI 0.685-0.825, P = 0.004). The optimal cutoff of the model was ≥0 to diagnose CD. The sensitivity of the noninvasive scoring model was 91.3% (95% CI 87.3%-94.1%), and the specificity was 80.9% (95% CI 67.5%-89.6%). When the model's sensitivity was 100.0%, the cutoff was ≥ -10 with a specificity of 19.2%; when the model's specificity was 100.0%, the cutoff was ≥ 13 with a sensitivity of 22.7%. We developed a noninvasive scoring model to distinguish CD and EAS in ACTH-dependent CS patients with higher diagnostic utility than HDDST in the same cohort. The noninvasive scoring model might be applied in areas where BIPSS is unavailable, the CRH is hard to obtain, or the desmopressin stimulation is not widely applied. It also provided a triage tool for selecting patients that might benefit the most from a further BIPSS test.

Treatment of recurrent and persistent Cushing's disease after first transsphenoidal surgery: lessons learned from an international meta-analysis.

Transsphenoidal surgery (TSS) is the first-line treatment for patients with Cushing's Disease (CD). Recurrence rates after a first TSS range between 3 and 22% within 3years. Management of recurrent or persistent CD may include repeat TSS or stereotactic radiosurgery (SRS). We performed a meta-analysis to explore the overall efficacy of TSS and SRS for patients with CD after an initial surgical intervention. EMBASE, PubMed, SCOPUS, and Cochrane databases were searched from their dates-of-inception up to December 2021. Inclusion criteria were comprised of patients with an established diagnosis of CD who presented with persistent or biochemically recurrent disease after a first TSS for tumor resection and were treated with a second TSS or SRS. Search criteria yielded 2,116 studies of which 37 articles from 15 countries were included for analysis. Mean age ranged between 29.9 and 47.9years, and mean follow-up was 11-104months. TSS was used in 669 (67.7%) patients, while SRS was used in 320 (32.4%) patients, and remission rates for CD were 59% (95%CI 0.49-0.68) and 74% (95%CI 0.54-0.88), respectively. There was no statistically significant difference in the remission rate between TSS and SRS (P = 0.15). The remission rate of patients with recurrent CD undergoing TSS was 53% (95%CI 0.32-0.73), and for persistent CD was 41% (95%CI 0.28-0.56) (P = 0.36). Both TSS and SRS are possible approaches for the treatment of recurrent or persistent CD after a first TSS. Our data show that either TSS or SRS represent viable treatment options to achieve remission for this subset of patients.

Cushing’s disease recurrence in two patients in the postpartum period: A case report

Introduction: Few reports are available on Cushing’s Disease (CD) occurrence in pregnancy. We report two cases of pituitary macroadenoma with initial remission, who experienced uneventful pregnancies in the setting of CD recurrence in the postpartum period. Case presentation: The cases were two women in their 30s with irregular menses, weight gain, and other CD symptoms. The laboratory and imaging workups indicated the diagnosis of CD, and subsequently, the patients were treated with Endoscopic Transsphenoidal Surgery (ETSS). After one and four years of remission, the patients became pregnant, and no signs or symptoms of CD were present in the meantime; 5-6 months after the delivery of healthy babies, the patients attended our clinic with complaints of weight gain and abnormal menstrual patterns. Findings from the workups confirmed CD recurrence. The patients underwent surgery and are now in the phase of remission. Conclusion: Overall, patients in remission seem to have a higher risk of CD recurrence in gestation and the postpartum period. This may raise the hypothesis that hypothalamic-pituitaryadrenal axis hyperactivity and hypercortisolism result in ACTH pituitary adenoma during pregnancy. Regarding negative results for estrogen receptors in the patients’ pathology, the association of hyperestrogenemia with hypercortisolism tends is questioned. Thus, the precise mechanism of CD recurrence in pregnancy is unknown, and further studies need to be performed.

Cushing's disease

Cushing's disease (CD) is the most prevalent cause of endogenous hypercortisolism. CD is responsible for multiple co-morbidities and increased mortality. Accurate and prompt diagnosis and optimal treatment are essential to improve the prognosis of CD. However, the diagnosis of CD is probably one of the most difficult in endocrinology and, therefore, diagnostic workup should be performed in an experienced center. Transsphenoidal surgery performed by an expert surgeon is the only therapeutic option that can offer definitive cure and remains the first-line treatment in most patients. Second-line treatments include pharmacotherapy, pituitary radiotherapy and bilateral adrenalectomy. The second-line therapeutic strategy is complex, must be individualized and performed in a multidisciplinary expert center. Symptomatic treatments of persisting co-morbidities after remission, which are responsible for increased mortality and impaired quality of life is an important part of medical management.

Indication to dynamic and invasive testing in Cushing\u2019s disease according to different neuroradiological findings

PurposeDynamic testing represents the mainstay in the differential diagnosis of ACTH-dependent Cushing’s syndrome. However, in case of undetectable or detectable lesion < 6 mm on MRI, bilateral inferior petrosal sinus sampling (BIPSS) is suggested by current guidelines. Aim of this study was to analyze the performance of CRH, desmopressin and high-dose dexamethasone suppression test (HDDST) in the differential diagnosis of ACTH-dependent Cushing’s syndrome as well as the impact of invasive and noninvasive tests on surgical outcome in patients affected by Cushing’s disease (CD).MethodsRetrospective analysis on 148 patients with CD and 26 patients with ectopic ACTH syndrome.ResultsAmong CD patients, negative MRI/lesion < 6 mm was detected in 97 patients (Group A); 29 had a 6–10 mm lesion (Group B) and 22 a macroadenoma (Group C). A positive response to CRH test, HDSST and desmopressin test was recorded in 89.4%, 91·4% and 70.1% of cases, respectively. Concordant positive response to both CRH/HDDST and CRH/desmopressin tests showed a positive predictive value of 100% for the diagnosis of CD. Among Group A patients with concordant CRH test and HDDST, no difference in surgical outcome was found between patients who performed BIPSS and those who did not (66.6% vs 70.4%, p = 0.78).ConclusionsCRH, desmopressin test and HDDST have high accuracy in the differential diagnosis of ACTH-dependent CS. In patients with microadenoma < 6 mm or non-visible lesion, a concordant positive response to noninvasive tests seems sufficient to diagnose CD, irrespective of MRI finding. In these patients, BIPSS should be reserved to discordant tests.

Utility of bilateral inferior petrosal sinus sampling for diagnosis and lateralization of Cushing's disease in the pediatric population: case series and review of the literature.

Cushing's disease (CD) is the most common cause of ACTH-dependent hypercortisolism in children age ≥ 7. The utility of bilateral inferior petrosal sinus sampling (BIPSS), an important test in adults, is less defined in children. We present a case series of children with ACTH-dependent hypercortisolemia and review the literature to assess the utility of BIPSS in the diagnosis and localization of CD. We performed an IRB-approved chart review of patients aged ≤ 18 with ACTH-dependent hypercortisolism at MGH between 2000 and 2019 and collected clinical, laboratory, radiographic, BIPSS, surgical, and outcomes data. In our cohort (n = 21), BIPSS had a sensitivity of 93% and specificity of 100% for diagnosis of CD. Compared to surgery, successful BIPSS correctly predicted adenoma laterality in 69% of cases vs. 70% by MRI. Among patients with lesions ≥ 4mm (n = 9), BIPSS correctly lateralized in 50% vs. 100% by MRI. In patients with subtle lesions (< 4mm, n = 7), BIPSS correctly lateralized in 80% vs. 71% by MRI. In patients (n = 4) with CD and negative MRIs, BIPSS correctly lateralized in 75% cases. Surgical cure was achieved in 90% of patients and 95% of patients had long-term disease control. In our cohort (n = 21; n = 20 CD, n = 1 ectopic ACTH secretion), BIPSS was sensitive and specific for the diagnosis of CD. Compared to MRI, BIPSS was not additionally helpful for lateralization in patients with lesions ≥ 4mm on MRI. BIPSS was helpful in guiding surgical exploration and achieving immediate postoperative remission among patients with subtle and negative MRI findings.

Presurgical predictive factors of surgical remission in Cushing's disease. Study of 32 cases

PurposeIdentify presurgical factors associated with surgical remission in Cushing's disease (CD). MethodsAll the patients with ACTH-dependent Cushing's Syndrome in follow-up at our centre between 2014–2021 (n=40) were identified. Those patients with CD diagnosis who underwent transsphenoidal surgery by the same neurosurgeon (n=32) were included. Surgical remission was defined as plasma cortisol <1.8μg/dl and normal or low urinary free cortisol (UFC) after surgery. ResultsSixty-three per cent (n=20) were women, and the mean age at diagnosis was 42.3±17.9 years. Six patients had macroadenomas, 17 had microadenomas, and in the other 9 patients, no pituitary lesion was identified on the MRI. Seven patients were previously operated on in another centre. Surgical remission was achieved in 75% (n=24). Only three patients experienced recurrence. No association between pre-surgical demographic (age, sex, comorbidities) or hormonal (UFC, ACTH, late-night salivary cortisol levels) characteristics and the probability of surgical remission was observed. The only variable associated with a greater chance of remission was the presurgical visualisation of the adenoma on MRI (OR 8.3, P=0.02). It was also observed that patients with a history of a previous pituitary surgery had a lower tendency to achieve remission, although statistical significance was not reached (OR 0.17, P=0.09). ConclusionsIn our experience, 75% of patients with CD achieved biochemical cure after the intervention. Surgical remission was up to eight times more frequent in those patients in whom the adenoma was visualised before the intervention, but no other presurgical predictive factors of cure were identified.

An Optimized Pathway for the Differential Diagnosis of ACTH-Dependent Cushing's Syndrome Based on Low-Dose Dexamethasone Suppression Test.

ContextTraditionally, low-dose dexamethasone suppression test (LDDST) was used to confirm the diagnosis of Cushing’s syndrome (CS), and high-dose dexamethasone suppression test (HDDST) was used to differentiate Cushing’s disease (CD) and ectopic adrenocorticotropin (ACTH) syndrome (EAS), but some studies suggested that HDDST might be replaced by LDDST. For the differential diagnosis of CS, dexamethasone suppression test was usually combined with other tests such as bilateral petrosal sinus sampling (BIPSS) and pituitary magnetic resonance imaging, but the optimal pathway to incorporate these tests is still controversial.ObjectivesTo develop an optimized pathway for the differential diagnosis of CD and EAS based on LDDST.Design and SettingSingle-center retrospective study (2011–2019).PatientsTwo hundred sixty-nine CD and 29 EAS patients with pathological diagnosis who underwent consecutive low- and high-dose DST.ResultsFor the differential diagnosis of CD and EAS, the area under curve (AUC) of LDDST using urine free cortisol (0.881) was higher than that using serum cortisol (0.685) (p < 0.001) in head-to-head comparison among a subgroup of 108 CD and 10 EAS. The AUC of LDDST (0.883) was higher than that of HDDST (0.834) among all the included patients. With the cutoff of <26%, the sensitivity and specificity of LDDST were 39.4% and 100%. We designed a new pathway in which BIPSS was only reserved for those patients with unsuppressed LDDST and adenoma <6mm, yielding an overall sensitivity of 97.7% and specificity of 86.7%.ConclusionLDDST had similar value to HDDST in differentiating CD and EAS using the specific cutoff point. The pathway that combined LDDST and BIPSS could differentiate CD and EAS accurately.

Paediatric patients with Cushing disease and negative pituitary MRI have a higher risk of nonremission after transsphenoidal surgery.

Diagnostic workup of Cushing disease (CD) involves imaging evaluation of the pituitary gland, but in many patients no tumour is visualised. The aim of this study is to describe the association of magnetic resonance imaging (MRI) findings with the postoperative course of paediatric and adolescent patients with CD. Patients with a diagnosis of CD at less than 21 years of age with MRI evaluation of the pituitary before first transsphenoidal surgery were included. Clinical, imaging and biochemical data were analysed. One hundred and eighty-six patients with paediatric or adolescent-onset CD were included in the study. Of all patients, 127 (68.3%) had MRI findings consistent with pituitary adenoma, while the remaining had negative or inconclusive MRI. Patients with negative MRI were younger in age and had lower morning cortisol and adrenocorticotropin levels. Of 181 patients with data on postoperative course, patients with negative MRI had higher odds of not achieving remission after the first surgery (odds ratio = 2.6, 95% confidence intervals [CIs] = 1.1-6.0) compared to those with positive MRI. In patients with remission after first transsphenoidal surgery, long-term recurrence risk was not associated with the detection of a pituitary adenoma in the preoperative MRI (hazard risk = 2.1, 95% CI = 0.7-5.8). Up to one-third of paediatric and adolescent patients with CD do not have a pituitary tumour visualised in MRI. A negative MRI is associated with higher odds of nonremission after surgery; however, if remission is achieved, long-term risk for recurrence is not associated with the preoperative MRI findings.

Diagnostic Value of Bilateral Petrosal Sinus Sampling in Children with Cushing Disease: A Multi-center Study

Objective:Although the sensitivity and specificity of bilateral inferior petrosal sinus sampling (BIPSS) were shown to be quite high in adult patients, pediatric studies are limited in number and have conflicting results, since BIPSS is much less commonly performed in children. The aim of this study was to assess the role of BIPSS in the detection and accuracy of lateralization of pituitary adenomas in pediatric patients with Cushing disease (CD) and its possible advantage over other diagnostic methods.Methods:This was a multicenter, nationwide, web-based study. The diagnostic value of BIPSS in 16 patients, aged between four and 16.5 years with a confirmed diagnosis of CD, was evaluated retrospectively. The sensitivity and specificity of BIPSS and magnetic resonance imaging (MRI) were calculated, and compared statistically.Results:Standard tests, except for morning cortisol level, were effective in proving the presence of Cushing syndrome. While MRI findings were consistent with microadenoma in eight cases (50%), CD presence and lateralization was successfully predicted in 14 of 16 patients using BIPSS. BIPSS compared with MRI examination was significantly more accurate, both in pre-stimulation and post-stimulation results (p=0.047 and p=0.041, respectively). BIPSS showed a significantly higher sensitivity (92.8%) than MRI in detecting the pituitary source of adrenocorticotropic hormone secretion.Conclusion:These results suggest that BIPSS is superior to MRI for diagnostic work-up to confirm the diagnosis of CD. Moreover, in line with previous studies, BIPSS was shown to provide better information about adenoma location, which is vital for possible surgical intervention.

Inferior petrosal sinus sampling and stimulation with CRH: 15 years of experience in a tertiary hospital

BackgroundInferior petrosal sinus sampling (IPSS) is indicated in the diagnosis of adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome (CS), especially when the results of the initial diagnostic tests are discordant. ObjectiveTo describe the patients who underwent this invasive functional test in a tertiary hospital. MethodsThis was an observational study of a retrospective cohort of patients with ACTH-dependent CS and IPSS between 2004 and 2019. We determined their epidemiological, hormonal, radiological and functional characteristics, and evaluated their diagnostic capacity and optimal cut-off points to differentiate between Cushing's disease (CD) and ectopic Cushing's syndrome (ECS). Results23 patients were evaluated, of which 65.2% were women with the average age of 42 (36–62) years. ACTH secretion of pituitary origin was evident in 82.6% of the patients and of ectopic origin in 17.4%. Plasma cortisol, urinary free cortisol, and ACTH levels were higher in patients with ECS. Regarding IPSS, the baseline central/peripheral ACTH gradient detected 89.5% of patients with CD and after stimulation with CRH, 100%. The optimal cut-off points in the diagnosis of CD were 2.06 at baseline and 2.49 after CRH stimulation. ConclusionIPSS with CRH stimulation is a test with a high diagnostic accuracy for correctly classifying patients with CD and ECS. The cut-off points of the gradients may be different from the classic ones. Therefore, we recommend that each center perform its own evaluation.

Is there a common cause for paediatric Cushing's disease?

According to recent literature, somatic mutations in the ubiquitin-specific protease 8 (USP8) gene are the most common changes in patients with Cushing's disease (CD). Data on the frequency of these mutations in the paediatric population are limited. The aim of the presented study was to determine the frequency of the USP8 gene mutations in a group of paediatric patients with CD treated at the Children's Memorial Health Institute (CMHI). Eighteen patients (nine females) with CD were treated at CMHI, Warsaw, Poland between 1993 and 2019. All patients underwent transsphenoidal surgery (TSS) as a primary treatment for CD. The average age of all patients at TSS was 13.10 years (5.42-17.25). DNA was extracted from formalin-fixed paraffin-embedded resected tumour tissue. Sanger sequencing was performed on DNA sequence corresponding to the exon 14 of USP8 gene. The mean age at diagnosis of CD was 13.08 years, and the average duration of symptoms before diagnosis was 2.96 years. All patients were operated at CMHI by the same neurosurgeon. Fifteen out of 18 patients (83.33%) had initial biochemical remission after a single TSS procedure (post-operative serum cortisol < 1.8 μg/dL). The result of genetic testing was negative for all samples at the hotspot area of the USP8 gene. The current retrospective study demonstrates that mutations in the USP8 gene may not be as common a cause of paediatric Cushing's disease, as previously reported.

Case series: Point-of-Care Ultrasound Conducted by Medical Students During their First Clinical Rotation Changes Patients’ Primary Diagnosis and Management

Background: As point-of-care ultrasound (POCUS) becomes a standard of care procedure, medical schools around the world have started to seek the integration of POCUS courses into their curricula. This puts medical students in a unique position as they are trained in an area in which many physicians lack knowledge. This case series provides a glimpse into the capabilities of POCUS even when used by medical students.&#x0D; Methods: Fourth-year medical students at Ben-Gurion University of the Negev performed numerous POCUS exams during their first clinical rotation at Soroka University Medical Center in Israel. All students completed a course in basic POCUS training and were evaluated in a brief practical exam before entering their first clinical rotation. Four of the cases in which the students took part are presented in this case series.&#x0D; Results: The POCUS exam in the first case discovered pulmonary embolism in addition to the diagnosis of Cushing disease. In the second case, endocarditis could have been diagnosed three days earlier had a POCUS exam been performed. Case 3 demonstrates the additional contribution of POCUS to the decision-making process carried out by physicians and its superiority in quantifying and diagnosing pleural effusion compared to chest X-Ray. Case 4 indicated that POCUS is preferable over chest X-ray and auscultation for the diagnosis of pulmonary edema.&#x0D; Conclusion: This case series may emphasize the capabilities POCUS has when utilized in the standard physical examination and the importance of incorporating POCUS instruction in medical schools for new physicians to acquire this skill.

Cateterismo de senos petrosos inferiores y estimulación con CRH: 15 años de experiencia en un hospital de tercer nivel

BackgroundInferior petrosal sinus sampling (IPSS) is indicated in the diagnosis of adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome (CS), especially when the results of the initial diagnostic tests are discordant. ObjectiveTo describe the patients who underwent this invasive functional test in a tertiary hospital. MethodsThis was an observational study of a retrospective cohort of patients with ACTH-dependent CS and IPSS between 2004 and 2019. We determined their epidemiological, hormonal, radiological and functional characteristics, and evaluated their diagnostic capacity and optimal cut-off points to differentiate between Cushing's disease (CD) and ectopic Cushing's syndrome (ECS). Results23 patients were evaluated, of which 65.2% were women with the average age of 42 (36-62) years. ACTH secretion of pituitary origin was evident in 82.6% of the patients and of ectopic origin in 17.4%. Plasma cortisol, urinary free cortisol, and ACTH levels were higher in patients with ECS. Regarding IPSS, the baseline central/peripheral ACTH gradient detected 89.5% of patients with CD and after stimulation with CRH, 100%. The optimal cut-off points in the diagnosis of CD were 2.06 at baseline and 2.49 after CRH stimulation. ConclusiónIPSS with CRH stimulation is a test with a high diagnostic accuracy for correctly classifying patients with CD and ECS. The cut-off points of the gradients may be different from the classic ones. Therefore, we recommend that each center perform its own evaluation.

Psychotropic Drugs in Patients with Cushing's Disease Before Diagnosis and at Long-Term Follow-Up: A Nationwide Study.

ContextPsychiatric symptoms are common in Cushing’s disease (CD) and seem only partly reversible following treatment.ObjectiveTo investigate drug dispenses associated to psychiatric morbidity in CD patients before treatment and during long-term follow-up.DesignNationwide longitudinal register-based study.SettingUniversity Hospitals in Sweden.SubjectsCD patients diagnosed between 1990 and 2018 (N = 372) were identified in the Swedish Pituitary Register. Longitudinal data was collected from 5 years before, at diagnosis, and during follow-up. Four matched controls per patient were included. Cross-sectional subgroup analysis of 76 patients in sustained remission was also performed.Main outcome measuresData from the Swedish Prescribed Drug Register and the Patient Register.ResultsIn the 5-year period before and at diagnosis, use of antidepressants (odds ratio [OR] 2.2 [95% confidence interval (CI) 1.3-3.7]) and 2.3 [1.6-3.5]), anxiolytics [2.9 (1.6-5.3) and 3.9 (2.3-6.6)], and sleeping pills [2.1 (1.2-3.7) and 3.8 (2.4-5.9)] was more common in CD than controls. ORs remained elevated at 5-year follow-up for antidepressants [2.4 (1.5-3.9)] and sleeping pills [3.1 (1.9-5.3)]. Proportions of CD patients using antidepressants (26%) and sleeping pills (22%) were unchanged at diagnosis and 5-year follow-up, whereas drugs for hypertension and diabetes decreased. Patients in sustained remission for median 9.3 years (interquartile range 8.1-10.4) had higher use of antidepressants [OR 2.0 (1.1-3.8)] and sleeping pills [2.4 (1.3-4.7)], but not of drugs for hypertension.ConclusionsIncreased use of psychotropic drugs in CD was observed before diagnosis and remained elevated regardless of remission status, suggesting persisting negative effects on mental health. The study highlights the importance of early diagnosis of CD, and the need for long-term monitoring of mental health.