The diagnostic yield of inferior petrosal sinus sampling in Cushing syndrome in the era of ovine CRH shortage.

PURPOSE: The ovine corticotropin-releasing hormone (oCRH) stimulation test has been routinely used in the diagnostic work-up of ACTH-dependent Cushing syndrome (CS). With oCRH currently being out-of-stock in Europe, we aimed at evaluating the diagnostic performance of inferior petrosal sinus sampling (IPSS) without oCRH stimulation. METHODS: We compared the values of 40 patients with ACTH-dependent CS and negative MRI findings in whom ACTH was measured before and after oCRH stimulation. RESULTS: The ratio of central-to-peripheral ACTH measurement (IPS:P) before the combined 3, 5, and 10 min of oCRH stimulation yielded diminished sensitivity (85% vs. 97%), alongside markedly decreased specificity (57% vs. 71%), as well as reduced positive and negative predictive values (90% vs. 94% and 44% vs. 83%), respectively. CONCLUSIONS: With the current drug shortages in Europe, ACTH measurements without oCRH stimulation in IPSS cannot be recommended. Thus, we call for desmopressin or the commercially available human CRH as a potential alternative in the confirmation of ACTH excess by IPSS in equivocal MRI findings.

Bilateral inferior petrosal sinus sampling in the differential diagnosis of ACTH-dependent Cushing's syndrome: A reappraisal.

Cushing's syndrome (CS) is a rare disorder, once exogenous causes have been excluded. However, when diagnosed, the majority of cases are adrenocorticotropic hormone (ACTH)-dependent, of which a substantial minority are due to a source outside of the pituitary, ectopic ACTH syndrome (EAS). Differentiating among pituitary-dependent CS, Cushing's disease (CD) and an ectopic source can be problematic. Because non-invasive tests in the evaluation of CS patients often lack adequate sensitivity and specificity, bilateral inferior petrosal sinus sampling (BIPSS), a minimally invasive procedure performed during the investigation of ACTH-dependent CS, can be extremely helpful. BIPSS is considered to be the gold standard for differentiating CD from the EAS. Furthermore, although such differentiation may indeed be challenging, BIPSS is itself a complex investigation, especially in recent times due to the widespread withdrawal of corticotrophin-releasing hormone and its replacement by desmopressin. We review current published data on this investigation and, in the light of this and our own experience, discuss its appropriate use in diagnostic algorithms.

[Diagnostic value of bilateral inferior petrosal sinus sampling in various modifications and methods of radiation and radionuclide imaging in the diagnosis and differential diagnosis of ACTH-dependent endogenous hypercortisolism].

AIM: To analyze the diagnostic performance of bilateral inferior petrosal sinus sampling (BIPSS) with desmopressin as a stimulation agent and prolactin measurements to control catheter position with or without the ACTH/prolactin normalized ratio calculation in the differential diagnosis of ACTH-dependent endogenous hypercortisolism, and the diagnostics performance of ectopic ACTH-syndrome (EAS) visualization. MATERIALS AND METHODS: A single-center diagnostic study with a retrospective analysis of the data was carried out. The study included patients with ACTH-dependent endogenous hypercorticism with no visualization of pituitary adenoma on MRI or adenoma sizes less than 6 mm. All patients underwent BIPSS with and without calculation of the ACTH/prolactin normalized ratio. Visualization of an EAS included pituitary MRI (to exclude EAS), whole-body CT scan with contrast, and somatostatin receptor scintigraphy with 99mTc-Tectrotide and CT (99mTc-Tectrotide SPECT). The final verification was based on immunohistochemical confirmation of the tumor or stable remission of Cushing's disease (CD) after surgical treatment. Statistical data processing was carried out by using IBM SPSS Statistics 23. Confidence intervals were calculated using the JavaStat online calculator. RESULTS: 230 BIPSS were performed in 228 patients (166 women, 62 men), of which 178 patients were verified as CD and 50 cases were EAS of various localization. The effectiveness of catheterization of petrosal sinuses was 96.9%. The sensitivity of BIPSS without ACTH/prolactin ratio calculation (n=70) was 95.9% (95% CI 86.3-98.9), specificity was 92% (95% CI 75.0-97.8), for the BIPSS with additional determination of ACTH/prolactin-normalized ratio (n=51) - 97.3% (95% CI 86.2-99.5) and 93.8% (95% CI 71.7-98.9), respectively. The use of the MRI method for this sample of patients had a sensitivity of 60.2% (95% CI 52.6-67.5), specificity of 59.2% (95% CI 44.2-73.0), the total body CT with contrast has a sensitivity of 74% (95% CI 59.7-85.4), specificity of 100% (95% CI 97.95-100). The diagnostic accuracy for 99mTc-Tectrotide SPECT in NET visualization has a sensitivity of 73.3% (95% CI 44.9-92.2), specificity of 100% (95% CI 95.3-100). CONCLUSION: BIPSS with desmopressin stimulation and prolactin measurements to control catheter position, as well as the additional calculation of the ACTH/prolactin-normalized ratio, is an optimal method for the differential diagnosis of EAS. Patients who are identified an EAS on BIPSS may be further referred for 99mTc-Tectrotide SPECT and CT for tumor visualization.

[A diagnostic maze: Cushing's disease]. / Diagnoselabyrinth: Morbus Cushing.

The case of a 78-year-old female presenting to the authors' department with heart failure with dyspnea at minimal exertion (NYHA III) as well as hypertensive blood pressure and hypokalaemia is reported. Laboratory workup showed hypercortisolism. Further workup, including imaging studies and selective catheterisation of the inferior petrosal sinus, resulted in the diagnosis of Cushing's disease caused by a pituitary microadenoma.

Detecting the interferences in adrenocorticotropic hormone measurement - three cases reinforcing the efficiency of the complementary clinical and laboratory audit.

Accurate measurement of adrenocorticotropic hormone (ACTH) is crucial in the evaluation of pituitary and adrenal disorders. Although great progress has been achieved in ACTH measurement with immunometric assays, interference may occur and adversely affect the clinical management. The report contributes to compiling the evidence on the clinical challenges with the management of the interferences in the ACTH measurement by presenting three cases: two with clinically overt hypercortisolism and discrepant ACTH concentrations within the reference interval; the third case describes the falsely elevated ACTH in a patient with secondary adrenal insufficiency. In all patients, the results obtained with the two immunometric platforms, chemiluminescence (CLIA) immunoassay (Siemens, Immulite) and electrochemiluminescence (ECLIA) immunoassay (Roche, Cobas), were discordant. Serial dilution of plasma samples revealed nonlinearity. After polyethylene glycol (PEG) precipitation recoveries were less than 22%, 26%, and 3%, respectively, supporting interference. Moreover, a decrease in ACTH concentration after incubation in a heterophile antibody-blocking tube was observed in the second case. In the first case, misinterpretation of ACTH led to inferior petrosal sinus sampling (IPSS), whereas timely detection of assay interference prevented further investigations in other cases. Increasing awareness regarding ACTH interference and comprehensive approach in evaluation could allow timely detection, helping to prevent unnecessary testing and perplexing clinical outcomes.

Cateterismo de senos petrosos en el diagnóstico etiológico de síndrome de Cushing: primera experiencia en Uruguay / Petrosal sinus sampling for etiological diagnosis of Cushing's syndrome: first experience in Uruguay / Cateterismo dos seios petrosos no diagnóstico etiológico da síndrome de Cushing: primeira experiência no Uruguai

Resumen: Identificar la causa de un síndrome de Cushing dependiente de adrenocorticotropina (ACTH) es esencial para realizar un tratamiento correcto. La hipersecreción de ACTH es debida en su mayoría a un tumor hipofisario (enfermedad de Cushing) o, en un 10%-20%, a tumores con producción ectópica de esta hormona. Los test no invasivos tienen baja sensibilidad y especificidad para diferenciar estas dos etiologías. El patrón oro lo constituye el cateterismo bilateral de los senos petrosos inferiores (CSP). Mediante el CSP se demuestra la hipersecreción de ACTH a nivel hipofisario al documentar un gradiente de ACTH central a periférico en el drenaje del tumor. Se recomienda realizarlo en todo síndrome de Cushing ACTH dependiente, aunque suele reservarse para pacientes con diagnóstico de hipercortisolismo y hallazgos negativos o equívocos en la resonancia nuclear magnética (RNM) de la región selar. Presentamos el primer caso en Uruguay en que se utilizó el CSP como método diagnóstico, una mujer de 55 años que presentó un hipercortisolismo ACTH-dependiente con una imagen adenohipofisaria <6 mm. El gradiente petroso-periférico confirmó el diagnóstico de enfermedad de Cushing y no hubo complicaciones durante el procedimiento. Posteriormente se realizó la resección del adenoma mediante cirugía transesfenoidal, con buena evolución y confirmación inmunohistoquímica del tumor.

Summary: Identifying the cause of adrenocorticotropin (ACTH)-dependent Cushing's syndrome is key to define the appropriate treatment. Hypersecretion of the adrenocorticotropic hormone (ACTH) is mainly caused by a pituitary tumor (Cushing's syndrome) or, in 10% to 20% of cases, by tumors with ectopic production of this hormone. Differentiation between these two etiologies may not be easy due to the low sensitivity and specificity of non- invasive tests. Bilateral sampling of the lower petrosal sinus is the gold standard to differentiate between a pituitary and an ectopic origin, showing the pituitary ACHT hypersecretion and recording the central-to-peripheral ACTH gradient in the tumor's drainage. Despite it being highly recommended for all cases of ACTH-dependent Cushing's syndrome, it is reserved for patients with a diagnosis of hypercortisolism and negative or misleading findings in the MRI of the sellar region. The study presents the first case of petrosal sinus sampling for diagnostic purposes in Uruguay, in a 55-year-old woman with ACHT-dependent hypercortisolism showing an adenohypophysis image < 6 mm. The petrosal-peripheral gradient confirmed the diagnosis of Cushing's syndrome and no complications arose during the procedure. Afterwards a transsphenoidal surgery was performed for resection of the adenoma. Evolution was good and immunochemistry confirmed the tumor's etiology.

Resumo: Identificar a causa da síndrome de Cushing dependente de adrenocorticotropina (ACTH) é essencial para o tratamento adequado. A hipersecreção de ACTH se deve principalmente a um tumor hipofisário (doença de Cushing) ou, em 10%-20%, a tumores com produção ectópica desse hormônio. Os testes não invasivos apresentam baixa sensibilidade e especificidade para diferenciar essas duas etiologias. O padrão ouro é o cateterismo bilateral dos seios petrosos inferiores (CEP). O CSP demonstra hipersecreção de ACTH no nível da hipófise, documentando um gradiente de ACTH central a periférico na drenagem do tumor. É recomendado nos casos de síndrome de Cushing dependente de ACTH, embora seja geralmente reservado para pacientes com diagnóstico de hipercortisolismo e achados negativos ou duvidosos na ressonância magnética (RNM) da região selar. Apresentamos o primeiro caso no Uruguai em que o CSP foi usado como método diagnóstico, uma mulher de 55 anos que apresentava hipercortisolismo ACTH dependente com imagem da hipófise anterior <6 mm. O gradiente petroso-periférico confirmou o diagnóstico de doença de Cushing e não houve complicações durante o procedimento. A seguir, o adenoma foi ressecado por cirurgia transesfenoidal, com boa evolução e confirmação imunohistoquímica do tumor.

Sampling of the petrosal sinuses. Indications, results and usefulness / Muestreo de senos petrosos. Indicaciones, resultados y utilidad

Abstract Objectives: to analyze, evaluate and describe the usefulness of petrosal sinus sampling for diagnosing central Cushing's syndrome. Materials and methods: the technical aspects and results of bilateral venous sampling of the petrosal sinuses at the Hospital Universitario San Vicente de Paul in Medellín, Colombia, from January 1, 2012 to December 31, 2018, were analyzed. Results: the average age was 43.3 years, with a range from 19 to 69 years. Laterality could be shown in 68.2% of cases, with a tendency to be located on the left in 53.3%. The central source of ACTH production could be shown in 95.4% of cases, with a basal average central/peripheral ratio of 21.7, and 70.8 after stimulation. All samples at 3, 5 and 10 minutes were confirmatory following stimulation. Conclusion: in our retrospective study, petrosal sinus catheterization provided laboratory confirmation of the central source of ACTH production in a high percentage of patients, with no immediate complications.

Resumen Objetivos: analizar, evaluar y describir la utilidad del muestreo de senos petrosos para diagnóstico del síndrome de Cushing de origen central. Material y métodos: se analizaron los aspectos técnicos y resultados del muestreo bilateral venoso de senos petrosos, desde el 1° de enero de 2012 a 31 de diciembre de 2018 en el Hospital Universitario San Vicente de Paúl en Medellín, Colombia. Resultados: el promedio de edad fue 43.3 años con un rango de edad desde los 19 hasta los 69 años. La lateralidad pudo ser demostrada en 68.2% de los casos con una tendencia a la localización en el lado izquierdo en 53.3%. El origen central de producción de ACTH logró ser demostrado en 95.4% de los casos, con una relación central/periferia basal promedio de 21.7 y postestimulación de 70.8. Todas las muestras a los 3, 5 y 10 minutos fueron confirmatorias tras la estimulación. Conclusión: en nuestro estudio retrospectivo el cateterismo de senos petrosos confirmó la fuente central de producción de ACTH por laboratorio en un alto porcentaje de pacientes sin ninguna complicación inmediata.

The 4Ds of ectopic ACTH syndrome: diagnostic dilemmas of a difficult disease

SUMMARY Cushing's syndrome (CS) is an uncommon condition that leads to high morbidity and mortality. The majority of endogenous CS is caused by excessive ACTH secretion, mainly due to a pituitary tumor - the so-called Cushing's disease (CD) - followed by ectopic ACTH syndrome (EAS), an extra-pituitary tumor that produces ACTH; adrenal causes of CS are even rarer. Several methods are used to differentiate the two main etiologies: specific laboratory tests and imaging procedures, and bilateral inferior petrosal sinus sampling (BIPSS) for ACTH determination; however, identification of the source of ACTH overproduction is often a challenge. We report the case of a 28-year-old woman with clinical and laboratory findings consistent with ACTH-dependent CS. All tests were mostly definite, but several confounding factors provoked an extended delay in identifying the origin of ACTH secretion, prompting a worsening of her clinical condition, with difficulty controlling hyperglycemia, hypokalemia, and hypertension. During this period, clinical treatment was decisive, and measurement of morning salivary cortisol was a differential for monitoring cortisol levels. This report shows that clinical reasoning, experience and use of recent methods of nuclear medicine were decisive for the elucidation of the case.

Aspectos técnicos e funcionais da cateterização dos seios petrosos inferiores na síndrome de Cushing ACTH dependente / Technical and functional aspects of catheterization of inferior petrosal sinuses in ACTH dependent Cushing’s syndrome

Objetivo Descrever e analisar a técnica empregada para a cateterização bilateral dos seios petrosos inferiores (SPI) em nosso serviço, discutindo as dificuldades e as taxas de sucesso encontradas. Sujeitos e métodos Entre 2009 e 2012, foram submetidos ao cateterismo bilateral dos SPI 14 pacientes com suspeita de síndrome de Cushing, sendo descrita a técnica empregada para o cateterismo e para a análise hormonal. Resultados O procedimento foi bem tolerado por todos os pacientes, sendo alcançada a cateterização adequada dos SPI em 92,85% dos casos. O diagnóstico de doença de Cushing foi firmado em 10 casos, sendo o resultado do cateterismo dos SPI após estímulo com CRH coerente em todos, não havendo falso-negativos. Conclusão O cateterismo dos SPI, apesar de ser uma técnica invasiva, é um procedimento seguro. A sua realização pode ser feita de forma adequada na maioria dos casos e, quando bem indicada, permanece como padrão-ouro na distinção da forma hipofisária da ectópica na síndrome de Cushing. .

Objective To describe and analyze technique for bilateral catheterization of inferior petrosal sinus in our service, discussing the difficulties and success rates found. Subjects and methods Fourteen patients with suspected Cushing’s syndrome underwent bilateral inferior petrosal sinuses (IPS) catheterization between 2009 and 2012. The technique for catheterization and for hormone analysis were described. Results The procedure was well tolerated by all patients, and adequate catheterization was achieved in 92.85% of cases. The diagnosis of Cushing’s disease was confirmed in 10 cases. The result of IPS catheterization after CRH infusion was coherent in all cases, without false negatives. Conclusion The catheterization of IPS, despite being an invasive technique, is a safe procedure. The objectives can be done properly in most cases. When well indicated, this procedure remains the gold standard in distinguishing the ectopic form to pituitary source in Cushing’s syndrome. .

Muestreo de senos petrosos inferiores en el diagnóstico de pacientes con síndrome de Cushing dependiente de hormona adrenocorticotrópica / Inferior petrosal sinus sampling in the diagnosis of patients with adrenocorticotropic hormone-dependent Cushing’s syndrome

Resumen: El síndrome de Cushing endógeno es una de las enfermedades más difíciles de estudiar, dado que sus diferentes etiologías requieren una cuidadosa valoración diagnóstica desde el punto de vista clínico, bioquímico y radiológico. Con frecuencia, las características clínicas se solapan con las de enfermedades comunes y algunos pacientes tienen una presentación atípica. Una vez se establece la sospecha clínica, las pruebas bioquímicas de tamizaje permiten definir si existe un estado de hipercor-tisolismo endógeno; en caso afirmativo, el estudio prosigue con pruebas de laboratorio que ayudan a localizar la causa de la hipercortisolemia. En este punto es fundamental determinar si se trata de un síndrome de Cushing dependiente o no dependiente de hormona adrenocorticotrópica (ACTH) y en caso que sea dependiente, diferenciar entre origen hipofisario y un origen ectópico de la enfermedad. Dicha situación se puede resolver mediante el cateterismo y muestreo de los senos petrosos inferiores, el cual es un procedimiento invasivo y sensible para el diagnóstico diferencial entre el tumor hipofisario y el tumor ectópico secretor de ACTH...

Abstract: Endogenous Cushing’s syndrome is one of the most difficult diseases to study. It has different etiologies and requires a careful clinical, biochemical, and radiological diagnosis. Often, its signs and symptoms overlap those of common diseases and some patients have atypical presentations. Once the clinical suspicion is established, screening biochemical tests allow identifying of endogenous hypercortisolism.After identification, it is necessary to use the appropriate diagnostic approach that helps to recognize the source of hypercortisolism. It then becomes imperative to differentiate between an adrenocorticotropic hormone (ACTH)-dependent or ACTH-independent Cushing’s syndrome. In the case of an ACTH-dependent Cushing’s syndrome, one must further distinguish between pituitary and ectopic etiology. This diagnostic challenge can be solved with inferior petrosal sinus sampling, an invasive but sensitive procedure used to discriminate between ACTH-producing pituitary or ectopic ACTH-producing tumors...

Cateterização dos seios petrosos inferiores: aspectos técnicos / Inferior petrosal sinus catheterization: technical aspects

OBJETIVO: O cateterismo dos seios petrosos inferiores (SPI) ajuda a diferenciar as formas hipofisária e ectópica na síndrome de Cushing (SC). O objetivo desse trabalho é descrever a técnica empregada em nosso serviço, discutir a solução de dificuldades e verificar o índice de sucesso atingido. CASUÍSTICA E MÉTODO: Foram submetidos a cateterismo bilateral dos SPI 42 pacientes com SC, entre setembro de 2000 e setembro de 2005. As dificuldades para o posicionamento do cateter foram correlacionadas com as soluções empregadas. RESULTADOS: As variações anatômicas, a semelhança entre o SPI e a veia emissária do plexo basilar e a dificuldade de contrastar as estruturas a contrafluxo para localizá-las foram os principais problemas. Foram utilizados cateter pré-moldado, fio-guia semicurvo e dirigível, road-maping e venografia por injeção contralateral, além de critérios para diferenciar o SPI da veia emissária. Dos 84 SPI abordados, um apresentava trombose, e dos 83 possíveis, 80 (96,4 por cento) foram cateterizados. Não se observaram complicações. CONCLUSÃO: A cateterização dos SPI pode ser feita na maioria dos pacientes. A identificação da veia emissária do plexo basilar e o uso de flebografia por injeção contralateral melhoraram o desempenho do método.

PURPOSE: Inferior petrosal sinus catheterization and sampling for corticotropin dosage helps to differentiate hypophisary and ectopic forms of Cushing syndrome. The aim of this paper is to describe the technique used in inferior petrosal sinus catheterization in our service, emphasizing the solution found for frequent difficulties, and verify the success rate achieved. PATIENTS AND METHODS: Between September/2000 and September/2005, forty-two (eighty-four sinuses) patients were submitted to inferior petrosal sinus sampling. The difficulties for correct catheter positioning were identified and correlated with their solutions. RESULTS: Anatomical variations, similarity between IPS and emissary vein of the basilar plexus and unfavorable flow to the contrastation of the structures (retrograde catheterization) were the main problems. Using pre-shaped catheters, curved, steerable guide-wires, road-maping and venography by contalateral injection, besides criteria to differentiate IPS from the emissary vein. Of the 84 sinuses approached, one was thrombosed, and 80 (96.4 percent) of 83 possible were selectively catheterized. No clinical complication occurred. CONCLUSION: IPSC can be safe and successfully performed in most cases. The identification of the emissary vein of the basilar plexus and use of venography by contralateral injection, improved the method performance.

Resposta do ACTH plasmático ao estímulo com CRH ou CRH + desmopressina em pacientes com síndrome de Cushing ACTH- dependente submetidos a cateterismo bilateral simultâneo dos seios petrosos inferiores / Response of plasmatic ACTH to CRH or combined CRH/desmopressin stimulation in patients with ACTHdependent Cushing's syndrome submitted to simultaneous bilateral petrosal sinuses sampling

OBJETIVO: Comparar a resposta do ACTH plasmático após estímulo com CRH ou CRH + desmopressina em pacientes com síndrome de Cushing ACTH-dependente que realizaram cateterismo bilateral simultâneo dos seios petrosos inferiores. MATERIAIS E MÉTODOS: O procedimento foi realizado em 21 pacientes - 14 mulheres e 7 homens - com síndrome de Cushing ACTH-dependente no período de janeiro de 1998 a dezembro de 2003. Após a cateterização de ambos os seios petrosos, amostras de sangue para ACTH foram colhidas, simultaneamente, nos seios petrosos e veia periférica, tanto no estado basal como após três e cinco minutos da administração de CRH humano (100 mg) (6 pacientes) ou CRH + desmopressina (100 mg + 10 mg) (15 pacientes). RESULTADOS: Aos três minutos, houve aumento percentual do ACTH tanto no grupo CRH (257,77 ± 240,36 no seio petroso direito e 718,78 ± 1.358,82 no seio petroso esquerdo [média ± desvio-padrão]) como no grupo CRH + desmopressina (1.263,35 ± 1.842,91 no seio petroso direito [p = 0,06] e 583,93 ± 1.020,03 no seio petroso esquerdo [p = 0,83]). Aos cinco minutos houve declínio percentual do ACTH no grupo do CRH (181,07 ± 217,39 no seio petroso direito e 188,25 ± 270,15 no seio petroso esquerdo) e aumento progressivo no grupo do CRH + desmopressina (1.365,29 ± 1.832,31 no seio petroso direito [p = 0,03] e 866,43 ± 1.431,72 no seio petroso esquerdo [p = 0,11]). Nos três pacientes com secreção ectópica não houve gradiente. CONCLUSÃO: A estimulação combinada CRH + desmopressina induziu maior produção de ACTH em adenomas corticotróficos em comparação ao CRH, o que pode melhorar a sensibilidade diagnóstica deste procedimento.

OBJECTIVE: To compare the responses of plasmatic ACTH to CRH or combined CRH/desmopressin stimulation in patients with ACTH-dependent Cushing's syndrome submitted to simultaneous, bilateral inferior petrosal sinuses sampling. MATERIALS AND METHODS: The procedure was performed in 21 patients - 14 women and 7 men - diagnosed with ACTH-dependent Cushing's syndrome in the period between January 1998 and December 2003. Upon catheterization of both inferior petrosal sinuses, blood samples for ACTH test were simultaneously collected from the petrosal sinuses and peripheral vein, both in the basal state and three to five minutes after injection of human CRH (100 mg) (six patients), or combined CRH/desmopressin (100 mg + 10 mg) (15 patients). RESULTS: After three minutes, both groups presented increased ACTH levels: CRH (257.77 ± 240.36 in the right petrosal sinus, and 718.78 ± 1358.82 in the left petrosal sinus [mean ± standard error]); combined CRH/desmopressin (1263.35 ± 1842.91 in the right petrosal sinus [p = 0.06], and 583.93 ± 1020.03 in the left petrosal sinus [p = 0.83]). After five minutes, the ACTH levels decreased in the group with CRH (181.07 ± 217.39 in the right petrosal sinus, and 188.25 ± 270.15 in the left petrosal sinus), and presented a progressive increase in the group with combined CRH/desmopressin (1365.29 ± 1832.31 in the right petrosal sinus [p = 0.03], and 866.43 ± 1431.72 in the left petrosal sinus [p = 0.11]). Gradient was absent in the three patients with ectopic secretion. CONCLUSION: Combined CRH/desmopressin stimulation induced a higher production of ACTH in cases of corticotroph adenomas as compared with CRH stimulation, which can improve the diagnostic sensibility of this procedure.

Differential diagnosis of Cushing's syndrome: [review]

The differential diagnosis of Cushing's syndrome requires careful multidisciplinary interaction with a number of specialities, co-ordinated through endocrine centres with good experience of this condition. It is essential that the diagnosis of Cushing's syndrome be fully established before differential diagnosis is attempted. The endocrinologist needs to be aware of the pitfalls and advantages of the tests in use. We discuss the approach to the differential diagnosis of this challenging condition.

O diagnóstico diferencial da síndrome de Cushing requer uma interação multidisciplinar cuidadosa entre várias especialidades, coordenadas através de centros de endocrinologia com boa experiência nessa condição. É essencial que o diagnóstico da síndrome de Cushing seja estabelecido antes da tentativa de diagnóstico diferencial. O endocrinologista precisa estar atento às possíveis falhas e vantagens dos testes empregados. Nós discutiremos a abordagem do diagnóstico diferencial nessa condição desafiadora.

Pitfalls in the diagnosis of Cushing's syndrome: [review]

Among endocrine disorders, Cushing's syndrome (CS) is certainly one of the most challenging to endocrinologists due to the difficulties that often appear during investigation. The diagnosis of CS involves two steps: confirmation of hypercortisolism and determination of its etiology. Biochemical confirmation of the hypercortisolaemic state must be established before any attempt at differential diagnosis. Failure to do so will result in misdiagnosis, inappropriate treatment, and poor management. It should also be kept in mind that hypercortisolism may occur in some patients with depression, alcoholism, anorexia nervosa, generalized resistance to glucocorticoids, and in late pregnancy. Moreover, exogenous or iatrogenic hypercortisolism should always be excluded. The three most useful tests to confirm hypercortisolism are the measurement of 24-h urinary free cortisol levels, low-dose dexamethasone-suppression tests, and determination of midnight serum cortisol or late-night salivary cortisol. However, none of these tests is perfect, each one has different sensitivities and specificities, and several are usually needed to provide a better diagnostic accuracy. The greatest challenge in the investigation of CS involves the differentiation between Cushing's disease and ectopic ACTH syndrome. This task requires the measurement of plasma ACTH levels, non-invasive dynamic tests (high-dose dexamethasone suppression test and stimulation tests with CRH or desmopressin), and imaging studies. None of these tests had 100 percent specificity and their use in combination is usually necessary. Bilateral inferior petrosal sinus sampling is mainly indicated when non-invasive tests do not allow a diagnostic definition. In the present paper, the most important pitfalls in the investigation of CS are reviewed.

Entre as doenças endócrinas, a síndrome de Cushing (SC) é certamente uma das mais desafiadoras para o endocrinologista, devido às dificuldades que comumente surgem durante a investigação. O diagnóstico de SC envolve dois passos: a confirmação do hipercortisolismo e a determinação de sua etiologia. A confirmação bioquímica do excesso de cortisol precisa ser estabelecida antes de qualquer tentativa de diagnóstico diferencial; caso contrário, poderá resultar em diagnóstico incorreto, tratamento impróprio e manejo insuficiente. Deve também ser lembrado que hipercortisolismo pode ocorrer em certos pacientes com depressão, alcoolismo, anorexia nervosa, resistência generalizada aos glicocorticóides e no final da gravidez. Além disso, hipercortisolismo exógeno ou iatrogênico deverá ser sempre excluído. Os três testes mais úteis para a confirmação do hipercortisolismo são: a medida do cortisol livre em urina de 24 h, os testes de supressão com dexametasona (TSD) em doses baixas e a determinação do cortisol sérico à meia-noite ou do cortisol salivar no final da noite. Contudo, nenhum deles é perfeito, cada um com sua sensibilidade e especificidade, sendo vários deles usualmente necessários para fornecer uma melhor acurácia diagnóstica. O maior desafio na investigação da SC envolve a diferenciação entre a doença de Cushing e a síndrome do ACTH ectópico. Esta tarefa requer a medida dos níveis plasmáticos de ACTH, testes dinâmicos não-invasivos (TSD com doses altas e testes de estímulo com CRH ou desmopressina) e estudos de imagem. Nenhum desses testes tem 100 por cento de especificidade e muitas vezes é necessário seu uso combinado. Amostragem venosa do seio petroso inferior está indicada principalmente quando os testes não-invasivos não permitem uma definição diagnóstica. Neste artigo, revisaremos as mais importantes armadilhas na investigação da SC.

Ectopic ACTH syndrome

Ectopic adrenocorticotropic secretion (EAS) is responsible for 12-17 percent of cases of Cushing's syndrome (CS) and covers a range of tumours, from undetectable benign lesions to widespread metastases. The syndrome is often associated with severe hypercortisolaemia, which aggravates the underlying condition. EAS requires a complete workup that includes the establishment of endogenous CS, diagnosis of adrenocorticotropic hormone (ACTH) dependency, localization of the source of ACTH secretion and rapid biochemical control of hypercortisolaemia. Dynamic endocrine tests should include inferior petrosal sinus sampling with CRH stimulation. Localization studies depend on the availability of reliable high-resolution cross-sectional imaging. This systematic review of the largest published series of patients with EAS (over 380 patients) reveals the common trends in the prevalence and management of this syndrome. The concept of 'occult' EAS has been revisited and the terms 'overt' and 'covert' EAS introduced. In addition to small cell lung carcinoma, the most common causes of ectopic EAS are bronchial carcinoids, thymic tumours, islet cell tumour of the pancreas, medullary thyroid carcinomas, and phaeochromocytomas. Their prevalence and the best localization modalities are presented. Medical and surgical management is discussed on the basis of the extensive experience of major referral centres.

A secreção ectópica de ACTH (SEA) é responsável por 12-17 por cento dos casos de síndrome de Cushing (SC), cobrindo uma variedade de tumores, desde lesões benignas indetectáveis a metástases disseminadas. A SEA está freqüentemente associada com hipercortisolemia grave, que agrava a condição de base e requer uma avaliação completa, que inclui a confirmação da SC endógena, o diagnóstico da dependência ao ACTH, a localização da fonte da secreção de ACTH e o controle bioquímico rápido da hipercortisolemia. Testes endócrinos dinâmicos devem incluir a coleta de amostras do seio petroso inferior com estímulo pelo CRH. O estudo da localização da fonte depende da disponibilidade de procedimentos de imagem de alta-resolução confiáveis. A revisão sistemática das maiores séries publicadas de pacientes com SEA (mais de 380 pacientes) revela tendências comuns na prevalência e manejo dessa síndrome. O conceito de SEA "oculta" está sendo revisado e os termos SEA "manifesta" e "latente" são introduzidos. Além do carcinoma pulmonar de pequenas células, as causas mais comuns de SEA são os carcinóides brônquicos, tumores tímicos, tumor de ilhotas pancreáticas, carcinoma medular de tiróide e feocromocitoma; sua prevalência e as melhores modalidades para localização são apresentadas. O manejo clínico e cirúrgico é discutido com base na vasta experiência dos principais centros de referência.

The role of bilateral inferior petrosal sinus sampling in the diagnosis of Cushing's syndrome

Adrenocorticotropin hormone (ACTH)-dependent Cushing's syndrome is most often due to a pituitary corticotroph adenoma, with ectopic ACTH-secreting tumors representing approximately 15 percent of cases. Biochemical and radiological techniques have been established to help distinguish between these two entities, and thus aid in the localization of the neoplastic lesion for surgical resection. The test that offers the highest sensitivity and specificity is bilateral inferior petrosal sinus sampling (BIPSS). BIPSS is an interventional radiology procedure in which ACTH levels obtained from venous drainage very near the pituitary gland are compared to peripheral blood levels before and after corticotropin hormone (CRH) stimulation. A gradient between these two locations indicates pituitary Cushing's, whereas the absence of a gradient suggests ectopic Cushing's. Accurate BIPSS results require hypercortisolemia to suppress normal corticotroph ACTH production and hypercortisolemia at the time of the BIPSS to assure excessive ACTH secretion. In some cases, intrapituitary gradients from side-to-side can be helpful to localize small corticotroph adenomas within the sella. BIPSS has rare complications and is considered safe when performed at centers with experience in this specialized technique.

A síndrome de Cushing (SC) ACTH-dependente é mais freqüentemente devida a um adenoma corticotrófico da hipófise, com os tumores ectópicos secretores de ACTH representando aproximadamente 15 por cento dos casos. Técnicas bioquímicas e radiológicas foram estabelecidas para permitir a distinção entre essas duas entidades e, assim, auxiliar na localização da lesão neoplásica para ressecção cirúrgica. O teste que oferece a mais alta sensibilidade e especificidade é a coleta bilateral de amostras de sangue do seio petroso inferior (BIPSS). BIPSS é um procedimento de intervenção radiológica no qual os níveis de ACTH obtidos da drenagem venosa bem próxima da hipófise são comparados com os níveis sanguíneos periféricos antes e após estímulo com corticorrelina (CRH). Um gradiente entre essas duas localizações indica SC hipofisário, enquanto a ausência de gradiente sugere SC ectópica. Resultados acurados na BIPSS requerem a presença de hipercortisolemia e que ela suprima normalmente a produção de ACTH pelo corticotrofos por ocasião da BIPSS para garantir a secreção excessiva de ACTH. Em alguns casos, os gradientes intra-hipofisários de um lado para outro podem ser úteis na localização de pequenos adenomas corticotróficos no interior da sela. A BIPSS raramente apresenta complicações, sendo considerada segura quando realizada em centros com experiência nessa técnica especializada.

El cateterismo bilateral y simult neo de los senos petrosos inferiores en el diagnóstico diferencial del síndrome de Cushing / Bilateral inferior petrosal sinus sampling in the differential diagnosis of ACTH-dependent Cushing's syndrome

Background: The features of pituitary ACTH-dependent Cushing syndrome are often indistinguishable from those of occult ectopic ACTH-dependent Cushing syndrome (CS). Aim: To assess the diagnostic accuracy of bilateral inferior petrosal sinus sampling (BIPSS) in the differential diagnosis of ACTH-dependent Cushing's syndrome as compared with ACTH levels and the overnight high dose dexamethasone suppression test (HDDST). Material and methods: Retrospective review of medical records of 23 patients (aged 19 to 63 years, 16 women) with surgically proven CS, 20 pituitarymicroadenomas (CD) and 3 with occult ectopic ACTH secretion (EAS). Results: No tumor was identifiable by imaging techniques. Mean plasma ACTH values were higher in patients with EAS than in CD (103± 110.2 and 73.1±41.98 pg/mL respectively, p=NS). Three patients with EAS and 3 patients with CD did not suppress cortisol with the HDDST. The sensitivity of the test was 86 percent and the specificity 100 percent. To improve the diagnostic outcome of BIPSS, an stimulation with Desmopressin (9 fig i.v) was performed in 9 patients. The threshold for a pituitary source, was defined as an inferior petrosal sinus to peripheral ACTH basal and post Desmopression ratio >2. BIPSS was successfully carried out in 22 patients and no complications occurred. In 6 patients BIPSS failed to meet the threshold criteria. In 3 patients, bronchial carcinoid tumors which proved to synthesize ACTH, were removed. The diagnostic sensitivity of BIPSS greatly improved from 86 percent to 100 percent after Desmopressin stimulation. BIPSS accurately predicted the ¡ateralization of the microadenoma in 8 of 12 patients (66 percent). Conclusions: The combination of Desmopressin stimulation with BIPSS was useful for the differential diagnosis of ACTH-dependent Cushing's Syndrome. However, the preoperative location of pituitary microadenomas was poorly predicted by BIPSS.

Localización funcional de un microadenoma de hipófisis mediante la toma de muestras de acth en los senos petrosos inferiores. Presentación de un caso y revisión de la técnica / Functional localization of a pituitary microadenoma by acth venous sampling of the inferior pertosal sinuses. Case report and technical review

Presentación de un caso de microadenoma hipofisiario productor de ACTH visualizado en estudios convencionales, el cual fue localizado bioquímicamente mediante la toma de muestras simultáneas en los senos petrosos inferiores. Este método permitió su resección quirúrgica. Descripción del protocolo para la toma muestras de ACTH en los senos petrosos inferiores.

Anatomía microquirúrgica venosa: El agujero yugular / Venous microsurgical anatomy: The jugular foramen

A pesar de los avances en microcirugía, cirugía microvascular y cirugía de la base del cráneo, son muy pocas las intervenciones realizadas en los elementos venosos del sistema nervioso central, sin embargo, el conocimiento detallado de su anatomía microquirúrgica es importante por los abordajes que involucran el área. Los abordajes en los que debemos de manejar el agujero yugular y las áreas adyacentes son entre otros, el retrosigmoideo, el preauricular subtemporal-infratemporal, el transcondíleo lateral ampliado, el posauricular transtemporal y el que hemos descrito como dorsolateral suboccipital ampliado.