Inferior Petrosal Research Articles

P-50 WE KNOW YOU ARE THERE: MISSING MASS

Abstract Introduction Diagnosing neoplastic Cushing's Syndrome (CS) can be quite challenging. Activation of the hypothalamic-pituitary-adrenal axis may also be influenced by various conditions such as psychiatric disorders, alcoholism, obesity, or polycystic ovary syndrome. Here we present a case where Cushing's Disease (CD) or CS is evident but the mass could not be identified. Clinical Case A 40-year-old female patient was evaluated for difficulty in weight loss and uncontrolled diabetes. She had bipolar disorder, type 2 diabetes mellitus, initially detected during pregnancy and continuing postpartum, and hypertriglyceridemia (HTG). Despite treatment with fenofibrate and omega-3, she experienced five episodes of pancreatitis. Lipopheresis was performed every 21 days, and attacks have not recurred. Genetic testing for HTG was negative. Due to worsening obesity, orlistat was added. She was receiving 107 units of insulin daily, along with lithium, oxcarbazepine, lamotrigine, quetiapine, aripiprazole, metformin. Family history was unremarkable, and she did not smoke or consume alcohol. Physical examination showed weight of 85 kg, height of 1.55 m, and Body Mass Index of 35.38 (second-degree obesity). She had male-pattern hair loss and abdominal obesity. There was no purple striae. Buffalo hump, moon face, plethora, and supraclavicular fat pads were observed. (Figure-1) Laboratory evaluation showed 1 mg Dexamethasone Suppression Test at 7.5 ng/dl and 2.2 ng/dl (<1.8), HbA1c was 8.2% (4-5.6), triglycerides were 2000 mg/dl (<150), and microalbuminuria was 57 mg/day. Additional results included 24-hour urine cortisol of 203, 288, and 255 nmol/day, midnight cortisol levels of 14.3 ng/dl and 8.6 ng/dl, and ACTH levels of 12.5 pg/ml, 29 pg/ml, 70 pg/ml. Imaging revealed osteoporosis (L1-4 Z-score: -2.6, 0.764), and pituitary Magnetic Resonance Imaging (MRI) (3 Tesla) showed no mass lesion. Abdominal Computed Tomography indicated no adrenal mass lesion. Intravenous Desmopressin stimulation test (Inferior Petrosal Sinus Sampling-IPSS) was administered to differentiate CD from ectopic CS. IPSS showed CD. Despite controlled psychiatric periods, she had a 10-year history of hypercortisolism symptoms. Elevated midnight cortisol and high urine cortisol confirmed CD through IPSS. No additional evaluation for pseudo-cushing was deemed necessary. Metyrapone 2x250 mg was initiated, with pituitary MRI monitoring every six months. HTG treatment was adjusted to include gemfibrozil, omega-3, and medium-chain fatty acids. With dietary changes, triglyceride levels dropped to 300 mg/dl, and the patient lost 12 kg, aiding in managing triglycerides and diabetes. Ramipril was started for microalbuminuria, and atorvastatin was planned. During follow-up, 24-hour urine cortisol was 18.7 and 17.7 nmol/day. Conclusion In the case of a mass in CD that cannot be detected despite investigations, as in this patient, Metyrapone can be an option that saves time and helps reduce the patient’s complaints.Figure 1:Abdominal obesity, buffalo hump, moon face, plethora, and supraclavicular fat pads Table 1:IPSS results of the patient

O-06 CUSHING’S SYNDROME DUE TO BILATERAL IMMUNHISTOCHEMICALLY-PROVEN ACTH POSITIVE ADRENAL NEOPLASMS

Abstract Introduction Ectopic ACTH secretion is a rare cause of endogenous hypercortisolism. Herein, a case of Cushing’s syndrome due to bilateral immunhistochemically-proven ACTH positive adrenal neoplasms is presented. Clinical Case A 60 year old women was admitted with acute-onset severe hypokalemia and hyperglycemia. She had severe metabolic alkalosis and her serum K levels kept being below 1.5 mmol/L, if left untreated. Physical examination demonstrated facial and upper body flushing, but was otherwise normal. Laboratory analyses were; early morning plasma ACTH: 211 pg/ml, early morning serum cortisol: 88.9 mcg/dl, late night serum cortisol: 58.8 mcg/dl, late night plasma ACTH:42.3 pg/ml, total testosterone: 1.79 ng/ml (0.120-0.350), DHEAS: 377.8 mcg/dl (29.7-182.2), 24 H urine free cortisol (UFC): 6696 mcg/24 h (urinary volume:2.7L), plazma aldosterone: 1.43 ng/dl, PRA<0.1 ng/ml/saat, 17-OH-progesterone: 2.91 ng/ml, calcitonin <2.0 pg/ml. Relying on rapid-onset of severe findings and very high UFC, our prediagnosis was Ectopic ACTH Syndrome. Thorax CT, 18-FDG-PET and Ga-68-PET scans did not exhibit any source. Abdominal CT scan revealed diffuse enlargement of both adrenal glands. Then Desmopressin test was performed and demonstrated central gradient (Table 1). However, pituitary MRI demonstrated no lesion, but thinning of the global gland. Accordingly inferior petrosal sinus sampling (IPSS) was compatible with ectopic ACTH syndrome (Table 2). Due to life-threatening hypercortisolemia of unknown origin, a decision was made in favor of bilateral adrenalectomy. Fluconazole 2x200mg/day iv was started, and after 48 hours, serum cortisol dropped significantly. The operation was performed safely, the patient’s general condition and serum potassium improved rapidly. Pathological specimen was reported as bilateral adrenocortical oncocytic neoplasms, and Ki-67 index was <1%. Immunohistochemistry (IHC) showed strong staining for ACTH in both lesions (Figure). Conclusion Although very rare, adrenals should be kept in mind as a source of ectopic ACTH syndrome.Figure:Immunohistochemical (IHC) staining demonstrating ACTH-secreting adrenal tumors (original magnification x100) Table 1:Plasma ACTH levels following 10 mcg desmopressin given intravenously Table 2:Plasma ACTH levels during Inferior Petrosal Sinus Sampling test performed with desmopressin

Abstract 333: Multiple Dural AV fistulas ‐ patient tailored approach and importance of vigilant monitoring

Introduction Dural AV fistulas (AVFs) are a type of heterogeneous vascular malformations accounting for 10‐15% of cerebral vascular malformations. They tend to bleed, grow and compress. The risk of neurological deficits is associated with their drainage. Cognard and Bogden grading uses such characteristics. Decision to treat is dependent on grading of AVF and symptomatology. The aetiology of the AV fistulas is likely secondary to thrombosis, trauma, inflammation or can be idiopathic. It occurs between 40‐60 years of age with no gender predisposition. Here we describe a patient who presented with multiple dural AVFs that required frequent monitoring and treatment. Patient course A 72 year old male patient with a past medical history of treated Renal Cancer, Myocardial infarction, Hepatic cysts, treated prostate cancer presents to the clinic with pulsatile tinnitus. Patient underwent MR angiogram that revealed left skull base dural AVF. A coil pack in the right ophthalmic artery was also found. He endorsed a history of protrusion and redness of the right eye which was treated at Barnes Jewish Hospital. Based on the records, concern was of a possible carotid‐cavernous fistula(CCF) on the right side. Patient opted for non‐invasive monitoring of the skull base AVF. 3 months later, patient presented with worsening tinnitus and proceeded with a diagnostic cerebral angiogram(DCA). DCA through the right internal carotid artery(ICA) revealed prominent meningohypophyseal arteries, pointing to remnants of the possible CCF. Right external carotid artery(ECA) revealed Cognard grade 1 grade AVF between the occipital and middle meningeal arteries with antegrade drainage into the transverse sinus. Left ICA was normal. Left ECA revealed a grade 1 AVF between the occipital artery and the inferior petrosal and cavernous sinuses with retrograde flow into the superior ophthalmic vein. Left vertebral artery was normal whereas the right vertebral artery revealed a subtle AVF from the posterior meningeal artery without any cortical vein involvement. 1 month later, symptoms worsened with throbbing, red and watery left eye with double vision. DCA was performed with plan to treat. Bilateral approach was planned due to concern for increasing the pressure on the right side. Patient underwent bilateral arterial embolization and was observed postoperatively overnight. Patient had some remnants of middle meningeal arteries feeding into the cavernous sinus, which were not treated. He endorsed no improvement in ophthalmological symptoms. In 6 weeks, he continued to have diplopia with injection. DCA was performed with the aim of endovenous embolization but was unsuccessful. Hence, endoarterial embolization of the cavernous branches of the MMA was performed, resulting in symptom resolution in 6 weeks. Conclusion Dural AV fistulas are vascular malformations that present themselves either incidentally or with occult and insidious progression of subtle symptoms which can also be fatal. Early acknowledgement of incidental findings, consideration for deeper investigation in case of incidental cases can help monitor the growth of the fistula and make planned decisions on their treatment whilst reducing the risk of sudden neurological injury that can lead to devastating disabilities and also death.

12530 Inferior Petrosal Sinus Sampling In Cushing’s Disease

Abstract Disclosure: A. Gondhi: None. S. Antharam: None. I. Moledina: None. Inferior Petrosal Sinus Sampling in Cushing’s Disease Introduction: Cushing's disease (CD) is the most common cause of endogenous Cushing syndrome( CS) caused by ACTH secreting pituitary tumor. MRI is typically used for imaging, but standard MRI may only detect 50% of microadenomas. In these cases, inferior petrosal sinus sampling (IPSS) is the gold standard in detecting pituitary source of ACTH. Case presentation:A 53-year-old man presented with signs and symptoms of CS: fatigue, weight gain, decreased libido, mood swings, new onset prediabetes. Physical examination revealed cushingoid appearance with facial flushing, easy bruising, abdominal purple striae. Initial work up revealed ACTH dependent CS: elevated late night Salivary cortisol 0.39 mcg/dL (<0.09 mcg/dL), 24hr urine free cortisol 192 mcg/24 hour (4 – 50 mcg/24 hour)Non suppressed cortisol 8.1 mcg/dL (<1.8 mcg/dL) after 1mg dexamethasone suppression test8 AM ACTH 56 pg/ml (7.2 – 63 pg/ml), DHEAS 491 mcg/dL (38-318 mcg/dL)Pituitary hormonal work up: normal Prolactin 7.8 ng/mL (2.6-13.1 ng/mL)Low TSH 0.29 ng/ml (0.45-5.3 ng/ml) with normal Free T4 0.76 ng/dl (0.58-1.6 ng/dl)Low Total Testosterone 150 ng/dl (175-781 ng/dl), Low FSH<0.7 mInt units/ml(1.27-19.26 mInt units/ml), Low LH 1 mInt units/ml (1.24- 8.62 mInt units/ml), Normal IGF 180 ng/mL (65-222 ng/mL), A1C 6% (Prediabetes – 5.7-6.4) MRI Brain showed normal pituitary gland. IPSS was performed with DDAVP: +2, +5, +10, +15: Right/ periphery ratio- 31.8, 10.75, 7.6, 5.3. left/periphery ratio- 26.6, 18.8, 8.3, 7.5. All the ratios >=3, which showed clear central to peripheral gradient. and no left or right difference consistent with Cushing's disease. Subsequently, a transsphenoidal pituitary gland resection was performed. Suspicious tissue was excised from both sides during the surgery, showing positive ACTH immunostaining, consistent with pituitary microadenoma. Post-operative labs showed significant improvement with normalization of Cortisol 3.2 mcg/dl, ACTH 45 pg/ml, TSH 3.14 ng/ml, FT4 0.61 ng/dl, FSH 1.7 mInt units/ml, LH 2.4 mInt units/ml, Prolactin 7.1 ng/ml, A1C 5.4 %He was discharged on physiological dose of Hydrocortisone and passed cortisol stimulation test (3.4 mcg/dl ---> 18.1 mcg/dl) Conclusion: Distinguishing between CD and ectopic ACTH secretion is crucial due to the differing treatment options. The most accurate method for differentiation is IPSS, which boasts high sensitivity and specificity compared to other analyses. Despite its invasiveness, IPSS is associated with rare adverse events, making it a valuable tool in clinical practice. Presentation: 6/3/2024

8169 Bilateral Inferior Petrosal Sinus Sampling Using Metyrapone as a Reliable Alternative to Differentiate Between Cushing Disease and Ectopic ACTH Syndrome- A Single Center Experience

Abstract Disclosure: M. Azmath: None. S. Faisal: None. C. Caetano: None. T. Vedere: None. H. Aftab: None. B. Tendler: None. C. Malchoff: None. Introduction: Bilateral IPSS is a crucial test in accurately diagnosing Cushing disease (CD) and differentiating it from ectopic ACTH syndrome (EAS). [1] CRH stimulated IPSS is the gold standard technique but cannot be performed due to current shortage of CRH. Metyrapone is a safe and reliable alternative to CRH that can stimulate corticotrophs to secrete ACTH and hence used for IPSS. [2] We would like to share a single center experience using a novel low dose metyrapone protocol for IPSS that successfully helped differentiate CD and EAS. Methods: This was a retrospective analysis of patients presenting with Cushing syndrome. Initial diagnosis was confirmed based on standard testing including 24-hour urinary free cortisol (UFC), late night saliva concentrations (LNSC) and MRI. Metyrapone 500 mg every 4 hours for 3 doses was administered orally starting midnight prior to IPSS performed in the morning. ACTH levels drawn during initial evaluation for Cushing syndrome was compared to ACTH values post metyrapone from the peripheral vein sample to calculate a gradient. Ultimately, pituitary CD or EAS was confirmed based on cure following surgery and /or positive ACTH of tumor staining on pathology and/or concordant results with CRH stimulated IPSS. Results: There were 9 patients, out of which 5 had pituitary CD, and 4 had EAS. Pre ACTH levels for patients ranged between 14.5 and1164 pg/ml (normal reference range 6-50). Following metyrapone, ACTH level rose to 40-4705 pg/ml (normal reference range 6-50). The increase in ACTH levels ranged from 81-547% pre and post metyrapone. An average of 5-6 ACTH samples were drawn during IPSS. Catheterization was successful in all patients and was confirmed by IR. The mean central to peripheral (C/P) ACTH ratio for patients with confirmed CD was 20.53 in comparison with a ratio of 1.34 in patients with EAS. IPSS was confirmed to be diagnostic for pituitary CD if the peak ratio after metyrapone administration was more than 3. No adverse effects were observed during or after the procedure and no hospitalization was required pre-procedure. Discussion: We present single center experience with a novel low dose metyrapone protocol for IPSS. Our protocol was successful in increasing ACTH/cortisol secretion by tumorous cells as evidenced by increase in ACTH levels post metyrapone. It is an easy oral protocol which proved to be safe without the risk for adrenal insufficiency that can occur with higher doses. It also mitigates the small thromboembolic risk that can occur with DDAVP administration. A clear distinction in C/P ACTH ratios was observed in patients with CD versus EAS as early as the 3rd sample. In conclusion, our low dose metyrapone protocol was safe and reliable in accurately differentiating between CD and EAS in small sample of patients at our institution. Presentation: 6/1/2024

7277 Diabetic Ketoacidosis As The First Manifestation Of Ectopic Cushing’s Syndrome

Abstract Disclosure: R.S. Medeiros: None. Introduction: Ectopic Cushing’s Syndrome (ECS) represents 10-20% of all ACTH-dependent CS, and the majority of cases arise from lung carcinoids. These indolent lesions usually evolve clinically over 6-24 months, whereas carcinomas are associated with faster onset of ECS. Diabetic Ketoacidosis (DKA) as a presenting manifestation of Cushing’s Syndrome (CS) is very rare, with the few cases published to date related to Cushing’s disease. Clinical Case: A 42-year-old woman was admitted in the emergency room with DKA and COVID-19. During stabilization, florid CS was clinically suspected. She reported a 6-month history of secondary amenorrhea, lack of concentration and memory, easy bruising, proximal myopathy with frequent falls evolving to daily life dependency from relatives. She also reported a 2-month diagnosis of dyslipidemia, Diabetes and hypertension, and a diagnosis of atypical pneumonia 6 months ago. Physical exam showed typical cushingoid appearance, especially for marked limb sarcopenia and proximal myopathy. An overnight dexamethasone suppression test (morning cortisol: 25.7 ug/dL), 24h urinary free cortisol (UFC; 1072.5 ug/dL; reference: <176) and serum cortisol at 23h00 (25.5 ug/dL) confirmed CS. ACTH-dependent CS was diagnosed. She had non-suppressible serum cortisol in high dose dexamethasone suppression test, and CRH stimulation test was suggestive of Cushing’s disease only by a 20% rise of cortisol at 30 minutes. Pituitary MRI was normal. Inferior Petrosal Sinus sampling was postponed for several months due to healthcare strikes. The patient started 750 mg of metyrapone in three divided doses but rapidly decreased the dose and stopped it due to clinical resolution of CS, a dramatic improvement of all glucocorticoid-related comorbidities leading to discontinuation of statin, insulin, main oral anti-hyperglycemic and antihypertensive medications, and normal midnight salivary cortisol and 24h UFC. She remained in this eucortisolemic state for 12 months. Thoracic CT scan revealed thymic hyperplasia and a 25x15 mm well-defined nodule in the lingula. A 68Ga-DOTANOC PET/CT showed a single uptake in the same lung region. The patient underwent lingulectomy plus excisional biopsy of interlobar lymph nodes, and pathology revealed a low-grade neuroendocrine tumor (Ki67<2%, <2 mitosis) without involved lymph nodes. The patient is weaning off from physiologic doses of hydrocortisone. Conclusion: DKA can rarely be the presenting manifestation of severe CS, including ECS. Clinicians should suspect on this etiology of DKA based on clinical signs and cumulative morbidity not typical of a young patient. This hint would lead to the expedite implementation of targeted therapies for initial stabilization of the CS patient, and the timely institution of a proper diagnostic approach and definitive treatment of this challenging patients. Presentation: 6/2/2024

Cushing’s Disease Complicated with Multiple Thrombotic Phenomena Following Inferior Petrosal Sinus Sampling

Cushing’s syndrome is an endocrinologic disorder that occurs due to an excessive secretion of adrenal cortex-stimulating hormones or an overproduction of cortisol in the adrenal glands. Patients present with a variety of clinical symptoms such as obesity, hypertension, impaired glucose tolerance, and cardiovascular complications have been known for major contributors to the mortality. The inferior petrosal sinus sampling (IPSS) test is a useful diagnostic tool for identifying the source of Cushing’s disease. This procedure involves process of collecting samples through venous access and is generally considered safe. Here, we present 44-year-old patient diagnosed with Cushing’s disease presenting pulmonary thromboembolism and multiple embolic infarctions following IPSS.

Maximizing the Sensitivity of Bilateral Inferior Petrosal Sinus Sampling.

Maximizing the Sensitivity of Bilateral Inferior Petrosal Sinus Sampling.

Bilateral Inferior Petrosal Sinus Sampling Without Lateralization Is Less Accurate for the Diagnosis of Cushing Disease.

During bilateral inferior petrosal sinus sampling (BIPSS), the side-to-side adrenocorticotropic hormone (ACTH) ratio, referred to as sampling lateralization, was used to predict pituitary adenoma localization. To investigate the potential different diagnostic accuracy of BIPSS for differentiating Cushing disease (CD) and ectopic ACTH secretory syndrome (EAS) patients with low lateralization (inferior petrosal sinus [IPS]:IPS ≤ 1.4) and high lateralization (IPS:IPS > 1.4). This single-center retrospective study (2011-2021) included (all patients had BIPSS results and confirmed pathologic diagnoses) 220 consecutive CD patients (validation set), 30 EAS patients, and 40 of the CD patients who had digital subtraction angiography (DSA) videos (discovery set). In the discovery set, the low-lateralization CD group (n = 11) had a higher median plasma ACTH concentration (62.2, IQR 44.7-181.0 ng/L) than the high-lateralization CD group (n = 29) (33.0, IQR 18.5-59.5, P = .013). Lower IPS to peripheral ratios were observed in the low-lateralization group during BIPSS, both before and after stimulation (P = .013 and P = .028). The sensitivity of BIPSS before stimulation in differentiating CD from EAS was lower in the low-lateralization group than the high-lateralization group (54.6% vs 93.1%, P = .003), as validated in the validation set. DSA videos revealed higher vascular area difference visible in the 2 sides of the pituitary in low lateralization (median 1.2 × 105 pixels, IQR 0.5-1.8) than the high-lateralization group (0.4 × 105 pixels, IQR 0.1-0.7, P = .008). The vascular area ratio of the 2 sides was also significantly higher in low (1.55, IQR 1.31-2.20) than high lateralization (1.19, IQR 1.07-1.35, P = .010). Our study suggested that low lateralization in CD patients may reduce the diagnostic sensitivity of BIPSS, which might be potentially associated with peripituitary vascular anatomy.

Utility of Simple and Non-Invasive Strategies Alternative to Inferior Petrosal Sinus Sampling and Peripheral CRH Stimulation in Differential Diagnosis of ACTH-Dependent Cushing Syndrome.

We aimed to evaluate the utility of simple, cost-effective, and non-invasive strategies alternative to BIPSS and peripheral CRH stimulation in differential diagnosis of ACTH-dependent CS. First, we performed ROC analysis to evaluate the performance of various tests for differential diagnosis of ACTH-dependent CS in our cohort (CD, n=76 and EAS, n=23) and derived their optimal cut-offs. Subsequently, combining various demographic (gender), clinical (hypokalemia), biochemical (plasma ACTH, HDDST, peripheral CRH stimulation) and imaging (MRI pituitary) parameters, we derived non-invasive models with 100% PPV for CD. Patients with pituitary macroadenoma (n=14) were excluded from the analysis involving non-invasive models. Relative percent ACTH (AUC: 0.933) and cortisol (AUC: 0.975) increase on peripheral CRH stimulation demonstrated excellent accuracy in discriminating CD from EAS. Best cut-offs for CD were plasma ACTH<97.3 pg/ml, HDDST≥57% cortisol suppression, CRH stimulation≥77% ACTH increase and≥11% cortisol increase. We derived six models that provided 100% PPV for CD and precluded the need for BIPPS in 35/85 (41.2%) patients with ACTH-dependent CS and no macroadenoma (in whom BIPSS would have otherwise been recommended). The first three models included basic parameters and avoided both peripheral CRH stimulation and BIPSS in 19 (22.4%) patients, while the next three models included peripheral CRH stimulation and avoided BIPSS in another 16 (18.8%) patients. Using simple and non-invasive alternative strategies, BIPSS can be avoided in 41% and peripheral CRH stimulation in 22% of patients with ACTH-dependent CS and no macroadenoma; such patients can be directly referred for a pituitary surgery.

Angiographic cross-filling between inferior petrosal sinuses and alteration of adrenocorticotropic hormone sampling results for tumor localization in Cushing disease.

Inferior petrosal sinus (IPS) sampling (IPSS) is a diagnostic procedure used to guide diagnostic localization of imaging-negative adrenocorticotropic hormone (ACTH)-secreting pituitary microadenomas. However, the efficacy of IPSS has been suboptimal at accurately lateralizing the adenoma, reducing surgical cure rates and leading to unintended pituitary dysfunction due to the added exploration. One rationale for the occasional imprecision is the existence of additional petrosal sinus collateral channels that connect the IPS bilaterally, which may lead to false localization results during sampling. The aim of this study was to explore a potential connection between normal anatomical variation in the angioarchitecture of the IPSs and the ACTH results obtained in subsequent IPSS tests. A retrospective review was performed on all cases between 1998 and 2013 involving patients at a single institution who underwent IPSS for radiographically equivocal pituitary microadenomas. Cases were reviewed for tumor laterality noted on either operative or pathology reports, as well as the presence of angiographic evidence of cross-filling between the sinuses. In addition, ACTH levels from the right and left IPSs were documented at baseline and at 2, 5, and 10 minutes after corticotropin-releasing hormone (CRH) administration. A ratio of the change in ACTH levels measured at the time of maximal response (10 minutes) versus the levels measured at the initial response (2 minutes) was computed for each patient and compared between patients by their angiographic cross-filling status. There were 41 patients with a histopathologically confirmed right- or left-sided ACTH-secreting pituitary microadenoma who underwent preoperative IPSS. Among these patients, 28 (68%) showed angiographic evidence of cross-filling between the IPSs, and 13 showed no cross-filling. On average, ACTH levels increased by a factor of 3.91 ± 0.77 in the contralateral IPS in patients with angiographic cross-filling, compared with a factor increase of only 1.80 ± 0.27 in patients without cross-filling (p = 0.014). In comparison, ACTH levels increased by a factor of 2.01 ± 0.57 in the ipsilateral IPS in patients with cross-filling, and by 8.78 ± 7.30 in those without cross-filling (p = 0.373). The presence of angiographic cross-filling, suggestive of a greater degree of vascular channel networking between the right and left IPS, is a significant factor influencing the measured rates of change of ACTH in IPSS and may impact the specificity of this test to accurately determine microadenoma laterality in the preoperative setting.

Bilateral simultaneous sampling of the cavernous and inferior petrosal sinuses in the differential diagnosis of Cushing’s disease

Background. Currently, the “gold standard” of differential diagnosis of Cushing’s disease is inferior petrosal sinus sampling and measurement of the adenocorticotropic hormone (ACTH) level. The studied literature data indicate a wide variability in the sensitivity and specificity of inferior petrosal sinus sampling in the range of 85–100 and 67–100 %, respectively, which can lead to an erroneous diagnosis of the source of ACTH hyperproduction and, as a consequence, to incorrect and untimely treatment.Aim.To improve the results of differential diagnosis of Cushing»s disease by using bilateral simultaneous sampling of the cavernous and inferior petrosal sinuses.Materials and methods. Cohort single-center retro/prospective study of 70 patients with confirmed ACTH-dependent Cushing’s syndrome. For the purpose of differential diagnosis, a number of indicators were calculated: central-peripheral ratio, prolactin-normalized ACTH ratio, successful catheterization. Sampling results were evaluated in comparison with contrast-enhanced pituitary magnetic resonance imaging data and intraoperative data.Results. The study of the central-peripheral ratio showed the need to assess it simultaneously at the level of the cavernous and inferior petrosal sinuses. This approach makes it possible to significantly increase the sensitivity and specificity of the applied gradient to 93.1 and 85.7 %, respectively. Prolactin-normalized ACTH ratio is a second line predictor in the differential diagnosis of Cushing’s disease with sensitivity and specificity reaching 94.7 and 28.6 %, respectively. The gradient of successful catheterization is a reflection of possible hemodynamic features of a particular sinus, does not serve as an indicator of the correct positioning of microcatheters in the vascular bed.Conclusion. Bilateral simultaneous sampling of the cavernous and inferior petrosal sinuses is an effective method of differential diagnosis of Cushing’s disease and ectopic ACTH-dependent syndrome.

P-61 From Cushing to Nelson Syndrome: Diagnostic challenges and Surgical Dilemma

Abstract Introduction Diagnosis of the origin of ACTH-dependent Cushing's syndrome (CS) can be difficult in some cases, especially when MRI of the pituitary gland does not reveal an adenoma. Inferior petrosal (IPSS) or cavernous sinus sampling (CSS) with CRH stimulation helps confirm the central origin in most cases. CSS also helps lateralize the tumor within the pituitary gland with a sensitivity of 80%. Because transsphenoidal pituitary surgery is successful in the majority of MRI-negative cases, bilateral adrenalectomy is performed less frequently. Even with advanced radiologic studies, the origin may not be detected. Adrenalectomy may be an option in these cases. However, loss of feedback inhibition of the hypothalamic-pituitary-adrenal axis; can lead to aggressive transformation of an existing ACTH-secreting pituitary adenoma into Nelson's syndrome within 1-5 years. Clinical Case A 46-year-old female patient complaining of hot flashes and unable to lose weight was evaluated for CS and referred to the Department of Neurosurgery for a pituitary adenoma (Table 1). Since the adenoma was &amp;lt;6mm CSS with CRH stimulation was performed. The results did not support central origin (Table 2). Ectopic ACTH secretion was considered, but without finding the origin of the tumor on radiological examination, and treatment with ketoconazole and metyrapone was started for CS. However the patient then discontinued outpatient follow-up. The patient presented to our clinic 6 years later with a new pituitary MRI showing tumor growth (Fig.1b). She complained of fatigue and obesity. She was depressed and anxious. The skin on her face, hands and hump was dark and patchy (Fig.1c). During these years, she consulted several endocrinologists. MRI was performed annually. Brain MRI had showed a fronto-basal extraaxial mass lesion. The patient underwent microsurgical resection and pathology revealed a microcystic meningioma (WHO grade I). 3 months later bilateral nodular hyperplasia of adrenal gland was detected; she underwent bilateral laparoscopic adrenalectomy (no neoplasia). ACTH gradually increased up to 418pg/ml; the diagnosis of Nelson's syndrome was established. The patient underwent endoscopic transsphenoidal adenomectomy. The ACTH level was found to be 12pg/ml on the 2nd postoperative day. Pathological examination revealed a ACTH secreting pituitary adenoma (Ki-67:7%). CS patients suffer from emotional lability due to the effects of elevated cortisol and to the physical changes of their body. Proximal muscle weakness and obesity causes fatigue symptoms. The diagnosis is often delayed until complications occur. Differential diagnosis could be difficult and challenging. Patient's emotional lability could adversely affect treatment/follow-up compliance. The presented case had meningioma resection which could be delayed until remission from CD and bilateral adrenalectomy which could be avoided by endoscopic pituitary surgery. This case is a good example of the need for pituitary centers of excellence.Figure.Fig.1.a. MRI scan of the pituitary gland at first admission shows (a) a lesion extending posteriorly inferior to the right half of the pituitary gland, hyperintense at T2-weighted, iso-hypointense at T1-w, with heterogeneous contrast enhancement consistent with pituitary microadenoma (4mm*2mm) Fig.1.b. Progression in size of the adenoma (6mm*4mm) Fig.1.c. Darkening of the skin due to hypersecretion of ACTH. Table 1.Cavernous sinus sampling with corticotropin-releasing hormone stimulation Table 2.Laboratory tests in different times

False-Negative Inferior Petrosal Sinus Sampling in Young-Onset Cushing Disease: What Happens Next

Introduction: False-negative results during inferior petrosal sinus sampling (IPSS) may complicate the diagnostic evaluation of patients with ACTH-dependent Cushing syndrome (CS). The management of these patients can be confusing for clinicians and lead to delayed management. Methods: We studied patients with young-onset (Results: We recorded a rare incidence of false-negative IPSS results in 5 out of the 142 IPSS procedures (3.5%), performed in 4 unique patients. Patients with negative IPSS did not differ in demographic (age and sex) or biochemical (diurnal ACTH/cortisol or 24-hour urinary free cortisol) data from the remaining. Additional workup was performed in three of the four patients including evaluation for ectopic sources of CS and repeat IPSS. Two of these patients also received medical treatment for suppression of cortisol production. One patient decided to proceed with pituitary exploration without additional evaluation. All patients finally underwent surgery and achieved remission. Discussion/Conclusion: In patients with CD, IPSS may rarely lead to false-negative results. Management of these patients usually includes screening for ectopic sources of ACTH/CRH secretion, repeating IPSS if ectopic workup is negative, and considering medical management until final diagnosis of the source of hypercortisolism is made.

Inferior Petrosal Sinus Sampling Tumor Lateralization and the Surgical Treatment of Cushing Disease: A Meta-Analysis and Systematic Review

To determine whether accurate inferior petrosal sinus sampling (IPSS) tumor lateralization is associated with improved clinical outcomes following the surgical treatment of Cushing disease. The presented study was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Data regarding patient demographics, IPSS tumor lateralization, and postoperative endocrinologic outcomes were abstracted and pooled with random effects meta-analysis models. Additional meta-regression models were used to examine the association between the accuracy of IPSS tumor lateralization and postoperative outcomes (recurrence/persistence or remission/cure). Statistical analyses were performed using the Comprehensive Meta-Analysis software (significance of P < 0.05). Seventeen eligible articles were identified, yielding data on 461 patients. Within average follow-up duration (∼59months), the rate of correct IPSS tumor lateralization was 69% [95% confidence interval: 61%, 76%], and the rate of postoperative remission/cure was 78% [67%, 86%]. Preoperative IPSS tumor lateralization was concordant with magnetic resonance imaging lateralization for 53% of patients [40%, 66%]. There was no significant association between the rate of correct IPSS tumor lateralization and postoperative remission/cure among study-level data (P= 0.735). Additionally, there was no association among subgroup analyses for studies using stimulatory agents during IPSS (corticotropin-releasing hormone or desmopressin, P= 0.635), nor among subgroup analyses for adult (P= 0.363) and pediatric (P= 0.931) patients. Limited data suggest that the rate of correct IPSS tumor lateralization may not be positively associated with postoperative remission or cure in patients with Cushing disease. These findings bring into question the utility of IPSS tumor lateralization in the context of preoperative planning and surgical approach rather than confirming a pituitary source.

Letter: Toward Optimized and Cost-Efficient Protocols for Inferior Petrosal Sinus Sampling in the Diagnosis of Cushing Disease.

Letter: Toward Optimized and Cost-Efficient Protocols for Inferior Petrosal Sinus Sampling in the Diagnosis of Cushing Disease.

Lymphatic vessels accompanying dorsal and basal dural sinuses in the human brain

Recent investigations showed the presence of meningeal lymphatic vessels (mLVs) along the superior sagittal and transverse dural sinuses which drain both fluid and immune cells from the cerebrospinal fluid (CSF) to the deep cervical lymph nodes. This study uses immunohistochemistry (IHC) and the Western Blot technique to show the presence of mLV accompanying the dorsal (superior sagittal, inferior sagittal, transverse, sigmoid, and straight) and basal (cavernous, sphenoparietal, superior, and inferior petrosal) dural sinuses in the human brain. Samples for IHC were obtained from dorsal and basal meningeal dural sinuses of 3 human cadavers and 3 autopsies. Routine histological techniques were carried out for the specimens. Podoplanin (PDPN, lymphatic vessel endothelial cell marker) and CD31 (vascular endothelial cell marker) IHC staining were applied to the 5 µm thick paraffin sections. Furthermore, PDPN and CD31 protein expressions were evaluated using Western Blot to the tissue samples from the same regions of 4 autopsies. Two consecutive sections from each sinus were PDPN, and CD31 was stained to differentiate blood vessels (BV) from mLV. The IHC staining showed the presence of mLVs accompanying both dorsal and basal dural sinuses. The mLVs accompanying the dorsal dural sinuses had a larger dimensions range compared to the basal dural sinuses. However, the number of mLVs along the basal dural sinuses was more than the mLVs along the dorsal ones. Further, fluid channels were closely localized to the mLV, with varying diameters and densities. Western Blotting technique showed the presence of PDPN expression in both dorsal and basal dural sinus samples. The knowledge of the presence of mLV along both dorsal and basal dural sinuses in humans can increase the understanding of how mLV contributes to the brain lymphatic circulation and may help understand the neuropathophysiological processes of various neurological diseases.

SAT598 7mg-dexamethasone Suppression Test For The Differential Diagnosis Of Cushing’s Syndrome

Abstract Disclosure: D. Cuevas Ramos: None. G. Garza García: None. W. Hernández Núñez: None. F.J. Gómez Pérez: None. Introduction: Establishing the cause of Cushing’s syndrome remains challenging. Bilateral Inferior Petrosal Sinus Sampling (BIPSS) is the gold standard for distinguishing between Cushing's disease (ACHT-secreting pituitary adenoma) and an ectopic source of ACTH. However, BIPSS is an invasive test and is not widely available. Therefore, we sought to explore the diagnostic efficacy of the 7 mg dexamethasone suppression test (7mg-dexa) for establishing the diagnosis of Cushing's disease (CD). Methods: We reviewed 1375 cases with pituitary adenomas. From them, 191 cases had confirmed diagnosis of CD from 1999 to 2022. Of these, 25 patients underwent 7 mg dexamethasone suppression test together with BIPSS during their diagnosis workup. A diagnosis of CD was established in 21 patients, confirmed after neurosurgery, with a pathology report of ACTH+ secreting pituitary adenoma, and a biochemical resolution of CS. The additional 4 cases showed an adrenal source of CS. Suppression of 50% or more in the afternoon (of day 1 after 7 mg-dexa IV infusion by 7h starting at 7:00 hrs at 1 mg/hr) was considered consistent with CD. A central-to-peripheral plasma ACTH gradient of ≥2 before and after desmopressin stimulation was also considered consistent with CD during the BIPSS. We calculated kappa index to evaluate concordance between diagnostic test. Also, sensitivity (S), specificity (E), positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (LR+) and negative likelihood ratio (LR-) were calculated. Results: The mean age was 43±12.1 years, with a BMI of 30±5.6 kg/m2, 86% females. For the basal ACTH values during BIPSS, the S=76%, E=75%, PPV=94%, NPV=37%, LR+=3, LR-=0.3. For the post-stimulation BIPSS, the S=95%, E=75%, PPV=95%, NPV=75%, LR+=3, LR-=0.06. Using the 7mg-dexa, a S=91%, E=75%, PPV=95%, NPV=60%, LR+=3.6, LR-=0.12. Kappa between test was 0.6 before stimulation, and 0.7 after desmopressin stimulation showing acceptable concordance. Conclusion: The 7 mg-dexa showed similar and acceptable diagnostic performance in comparison with basal or stimulated BIPSS. Since 7mg-dexa inhibition test is less invasive and less expensive, further clinical research to evaluate its utility in CD diagnostic approach is in order. Presentation: Saturday, June 17, 2023

THU037 Diagnostic Accuracy Of Bilateral Inferior Petrosal Sinus Sampling In Adrenocorticotropin-dependent Cushing’s Syndrome, And The Utility Of Maximum-stimulated Petrosal Sinus ACTH To Baseline Petrosal Sinus ACTH Ratio

Abstract Disclosure: A.N. Maldar: None. P.H. Chauhan: None. A. Kulkarni: None. N.F. Shah: None. B.K. Misra: None. M. Chadha: None. Methods: The diagnosis of Cushing’s Syndrome (CS) was made as per the prevalent endocrine society guidelines. CS patients with serum ACTH&amp;gt;15 pg/mL were considered as ACTH-dependent CS. Baseline ACTH (both inferior petrosal sinuses and peripheral) values were obtained, and since 2014, stimulated ACTH values (5 and 10 minutes post one unit iv vasopressin) were obtained as standard protocol. Prolactin corrected ACTH ratios were additionally being calculated since 2016. The highest central to peripheral ACTH gradient &amp;gt;2 in baseline samples (bC:P), &amp;gt;3 in samples after vasopressin stimulation (sC:P), and &amp;gt;0.8 in PRL-corrected ratios (pC:P) was used as reference value indicative of Cushing’s Disease (CD). An inter-petrosal gradient &amp;gt;1.4 was considered to be suggestive of an adenoma located on the side of the petrosal sinus with the higher ACTH concentration. Results: Of the 51 patients with ACTH-dependent CS who underwent BIPSS, four patients with incomplete data, one patient with unilateral petrosal sinus catheterization, one patient with Cortisol Resistance Syndrome were excluded from the analysis. Mean age of our cohort was 37.5 years, with 77.8% females. 39 patients had CD (positive histopathology-immunohistochemistry in 34, and remission post-surgery in additional five with hyperplasia), while six had ectopic CS (one each of bronchial carcinoid, lung NET, thymic NET, pancreatic NET, and two with undiagnosed ectopic source). bC:P&amp;gt;2 (N=45) demonstrated 92.3% sensitivity, 83.3% specificity, 97.3% PPV and 62.5% NPV, while sC:P&amp;gt;3 (N=31) demonstrated 96.3% sensitivity, 100% specificity, 100% PPV and 80% NPV to diagnose CD. pC:P&amp;gt;0.8 (N=20) improved the sensitivity and NPV to 100%, with a 75% specificity and 94.1% PPV. On ROC analysis, cut-point ratio of 2.55 for bC:P value gave a sensitivity of 89.7% and specificity of 100% (AUC=0.964); sC:P ratio of 2.95 had 96.3% sensitivity and 100% specificity (AUC=0.991); 0.93 for pC:P ratio provided a sensitivity of 93.8% and specificity of 100% for diagnosis of CD (AUC=0.984). Maximum-stimulated petrosal sinus ACTH to baseline petrosal sinus ACTH ratio of &amp;lt;1.11 provided a 100% sensitivity, while a ratio &amp;gt;1.75 provided 100% specificity towards diagnosis of CD. 71.4% (10/14) patients with left sided adenoma, and 85% (17/20) patients with right sided adenoma were correctly lateralised on BIPSS. In patients whom adenoma was detected on pituitary MRI, 66.7% (6/9) were correctly lateralised to the left side, and 94.1% (16/17) to the right side. Conclusion: BIPSS provides high sensitivity and specificity to diagnose CD. Vasopressin stimulation improves the sensitivity and specificity, while prolactin correction improves the sensitivity of BIPSS, as compared to baseline ratios. Maximum-stimulated petrosal sinus ACTH to baseline petrosal sinus ACTH ratio can be additionally used, especially in CD patients suspected of false negative localization. Presentation: Thursday, June 15, 2023

Toward Optimized and Cost-Efficient Protocols for Inferior Petrosal Sinus Sampling in the Diagnosis of Cushing Disease.

Conventional protocols for inferior petrosal sinus sampling (IPSS) during the workup of hypercortisolemia require adrenocorticotrophic hormone (ACTH) measurement at multiple time points with corticotropic-releasing hormone (CRH) used as a stimulator. Modernized evidence-based protocols must also reflect the increased utilization of desmopressin (DDAVP) for ACTH stimulation as the manufacturing shortage of traditionally used CRH continues. We model the diagnostic accuracy and potential economic savings of DDAVP utilization and reduced time point sampling. A single-institution, retrospective review of patients undergoing IPSS between 2007 and 2021 was performed. A computational search for the minimal set of time points which preserves conventional diagnostic accuracy was performed by testing all 1 through 5-point combinations generated using a binomial expansion. Economic savings were modeled using a publicly available hospital chargemaster. A total of 50 patients qualified for inclusion, 47 of whom were diagnosed with Cushing disease and 3 with ectopic Cushing syndrome. Single-point diagnostic accuracy for DDAVP-stimulated tests was 71.4%-92.9%, and seven 2-point combinations (5-25 procedural minutes) were found, which preserved conventional diagnostic accuracy. Single-point accuracy for CRH-stimulated tests was 67.9%-89.3%, and two 2-point combinations ( t = -15, t = +2 and t = -15, t = +10) preserved accuracy. For every time point removed, the cost of ACTH laboratory tests was reduced by $507 from $3042 for 6-point IPSS). The shortest and most economical stimulator and time point combination that preserved conventional accuracy was DDAVP sampling at t = 0 and t = +5 or t = +2 and t = +5 minutes, which cost $2028 total compared with the most expensive 6-point IPSS option with CRH ($6392). DDAVP is a cost-efficient and effective alternative to CRH during IPSS. Our results encourage prospective evaluation of potentially fewer sampling time points in the interest of time and cost efficiency balanced with preserved accuracy.