Background: Psychosis secondary to paediatric Cushing’s disease (CD) is extremely rare and presents a significant management challenge. Method: We report a 14.7-year-old CD patient with acute psychosis and self-inflicted injuries following failed transsphenoidal pituitary surgery. Her mental state rapidly deteriorated precluding medical therapy. Results: Emergency intravenous low-dose etomidate infusion (3–3.5 mg/h) with dose titration according to the serum cortisol combined with a hydrocortisone infusion, in an intensive care setting, was effective in controlling the hypercortisolaemia. Her mental state improved with normalisation of her cortisol levels enabling oral administration of ketoconazole and bilateral adrenalectomy to be performed. Conclusion: This case illustrates the safe and effective use of a low-dose etomidate infusion in an unusual case of paediatric CD.

Keywords:
Cushing’s disease, Psychosis, Childhood, Etomidate
1.
Magiakou MA, Mastorakos G, Oldfield EH, Gomez MT, Doppman JL, Cutler GB Jr, Nieman LK, Chrousos GP: Cushing’s syndrome in children and adolescents. Presentation, diagnosis, and therapy. N Engl J Med 1994;331:629–636.
2.
Storr HL, Chan LF, Grossman AB, Savage MO: Paediatric Cushing’s syndrome: epidemiology, investigation and therapeutic advances. Trends Endocrinol Metab 2007;18:167–174.
3.
Nieman LK, Biller BMK, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM: The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2008;93:1526–1540.
4.
Storr HL, Plowman PN, Carroll PV, Francois I, Krassas GE, Afshar F, Besser GM, Grossman AB, Savage MO: Clinical and endocrine responses to pituitary radiotherapy in pediatric Cushing’s disease: an effective second-line treatment. J Clin Endocrinol Metab 2003;88:34–37.
5.
Chan LF, Storr HL, Plowman PN, Perry LA, Besser GM, Grossman AB, Savage MO: Long-term anterior pituitary function in patients with paediatric Cushing’s disease treated with pituitary radiotherapy. Eur J Endocrinol 2007;156:477–482.
6.
Greening JE, Brain CE, Perry LA, Mushtaq I, Sales Marques J, Grossman AB, Savage MO: Efficient short-term control of hypercortisolaemia by low-dose etomidate in severe paediatric Cushing’s disease. Horm Res 2005;64:140–143.
7.
Rothermel LK: Newer pharmacologic agents for procedural sedation of children in the emergency department – etomidate and propofol. Curr Opin Pediatr 2003;15:200–203.
8.
Butovas S, Rudolph U, Jurd R, Schwarz C, Antkowiak B: Activity patterns in the prefrontal cortex and hippocampus during and after awakening from etomidate anesthesia. Anesthesiology 2010;113:48–57.
9.
Nieman LK: Medical therapy of Cushing’s disease. Pituitary 2002;5:77–82.
10.
Jeffcoate WJ, Silverstone JT, Edwards CR, Besser GM: Psychiatric manifestations of Cushing’s syndrome: response to lowering of plasma cortisol. Q J Med 1979;48:465–472.
11.
Sonino N, Fava GA: Psychiatric disorders associated with Cushing’s syndrome. Epidemiology, pathophysiology and treatment. CNS Drugs 2001;15:361–373.
12.
Sonino N, Bonnini S, Fallo F, Boscaro M, Fava GA: Personality characteristics and quality of life in patients treated for Cushing’s syndrome. Clin Endocrinol (Oxf) 2006;64:314–318.
13.
Hirsch D, Orr G, Kantarovich V, Hermesh H, Stern E, Blum I: Cushing’s syndrome presenting as a schizophrenia-like psychotic state. Isr J Psychiatry Relat Sci 2000;37:46–50.
14.
Tran M, Elias AN: Severe myopathy and psychosis in a patient with Cushing’s disease macroadenoma. Clin Neurol Neurosurg 2003;106:1–4.
15.
Marshall WA, Tanner JM: Variations in pattern of pubertal changes in girls. Arch Dis Child 1969;44:291–303.
16.
Krakoff J, Koch CA, Calis KA, Alexander RH, Nieman LK: Use of a parenteral propylene glycol-containing etomidate preparation for the long-term management of ectopic Cushing’s syndrome. J Clin Endocrinol Metab 2001;86:4104–4108.
17.
Frank R, Doerr HG: Mania in a girl with Cushing’s disease. J Am Acad Child Adolesc Psychiatry 1989;28:610–611.
18.
Starkman MN, Giordani B, Berent S, Schork MA, Schteingart DE: Elevated cortisol levels in Cushing’s disease are associated with cognitive decrements. Psychosom Med 2001;63:985–993.
19.
Sapolsky RM: The possibility of neurotoxicity in the hippocampus in major depression: a primer on neuron death. Biol Psychiatry 2000;48:755–765.
20.
Wolkowitz OM, Burke H, Epel ES, Reus VI: Glucocorticoids. Ann NY Acad Sci 2009;1179:19–40.
21.
Lindsay JR, Nansel T, Baid S, Gumowski J, Nieman LK: Long-term impaired quality of life in Cushing’s syndrome despite initial improvement after surgical remission. J Clin Endocrinol Metab 2006;91:447–453.
22.
Arnaldi G, Angeli A, Atkinson AB, Bertagna X, Cavagnini F, Chrousos GP, Fava GA, Findling JW, Gaillard RC, Grossman AB, Kola B, Lacroix A, Mancini T, Mantero F, Newell-Price J, Nieman LK, Sonino N, Vance ML, Giustina A, Boscaro M: Diagnosis and complications of Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab 2003;88:5593–5602.
23.
Dorn LD, Burgess ES, Friedman TC, Dubbert B, Gold PW, Chrousos GP: The longitudinal course of psychopathology in Cushing’s syndrome after correction of hypercortisolism. J Clin Endocrinol Metab 1997;82:912–919.
24.
Bourdeau I, Bard C, Noel B, Leclerc I, Cordeau MP, Belair M, Lesage J, Lafontaine L, Lacroix A: Loss of brain volume in endogenous Cushing’s syndrome and its reversibility after correction of hypercortisolism. J Clin Endocrinol Metab 2002;87:1949–1954.
25.
Forget H, Lacroix A, Cohen H: Persistent cognitive impairment following surgical treatment of Cushing’s syndrome. Psychoneuroendocrinology 2002;27:367–383.
26.
Merke DP, Giedd JN, Keil MF, Mehlinger SL, Wiggs EA, Holzer S, Rawson E, Vaituzis AC, Stratakis CA, Chrousos GP: Children experience cognitive decline despite reversal of brain atrophy one year after resolution of Cushing syndrome. J Clin Endocrinol Metab 2005;90:2531–2536.
27.
Tiemensma J, Kokshoorn NE, Biermasz NR, Keijser BJ, Wassenaar MJ, Middelkoop HA, Pereira AM, Romijn JA: Subtle cognitive impairments in patients with long-term cure of Cushing’s disease. J Clin Endocrinol Metab 2010;95:2699–2714.
28.
Tiemensma J, Biermasz NR, Middelkoop HA, van der Mast RC, Romijn JA, Pereira AM: Increased prevalence of psychopathology and maladaptive personality traits after long-term cure of Cushing’s disease. J Clin Endocrinol Metab 2010;95:E129–E141.
29.
Keil MF, Merke DP, Gandhi R, Wiggs EA, Obunse K, Stratakis CA: Quality of life in children and adolescents one year after cure of Cushing syndrome: a prospective study. Clin Endocrinol (Oxf) 2009;71:326–333.
30.
Ledingham IM, Watt I: Influence of sedation on mortality in critically ill multiple trauma patients. Lancet 1983;1:1270.
31.
Watt I, Ledingham IM: Mortality amongst multiple trauma patients admitted to an intensive therapy unit. Anaesthesia 1984;39:973–981.
32.
Klausen NO, Moelgaard J, Ferguson AH, Jensen JK, Larsen C, Paaby P: Negative Synacthen test during etomidate infusion. Lancet 1983;2:848.
33.
Lambert A, Mitchell R, Frost J, Ratcliffe JG, Robertson WR: Direct in vitro inhibition of adrenal steroidogenesis by etomidate. Lancet 1983;2:1085–1086.
34.
Allolio B, Dorr H, Stuttmann R, Knorr D, Engelhardt D, Winkelmann W: Effect of a single bolus of etomidate upon eight major corticosteroid hormones and plasma ACTH. Clin Endocrinol (Oxf) 1985;22:281–286.
35.
Dorr HG, Kuhnle U, Holthausen H, Bidlingmaier F, Knorr D: Etomidate: a selective adrenocortical 11β-hydroxylase inhibitor. Klin Wochenschr 1984;62:1011–1013.
36.
Johnson TN, Canada TW: Etomidate use for Cushing’s syndrome caused by an ectopic adrenocorticotropic hormone-producing tumor. Ann Pharmacother 2007;41:350–353.
37.
Drake WM, Perry LA, Hinds CJ, Lowe DG, Reznek RH, Besser GM: Emergency and prolonged use of intravenous etomidate to control hypercortisolemia in a patient with Cushing’s syndrome and peritonitis. J Clin Endocrinol Metab 1998;83:3542–3544.
38.
Bilgin YM, van der Wiel HE, Fischer HR, De Herder WW: Treatment of severe psychosis due to ectopic Cushing’s syndrome. J Endocrinol Invest 2007;30:776–779.
39.
Allolio B, Schulte HM, Kaulen D, Reincke M, Jaursch-Hancke C, Winkelmann W: Nonhypnotic low-dose etomidate for rapid correction of hypercortisolaemia in Cushing’s syndrome. Klin Wochenschr 1988;66:361–364.
40.
Dabbagh A, Sa’adat N, Heidari Z: Etomidate infusion in the critical care setting for suppressing the acute phase of Cushing’s syndrome. Anesth Analg 2009;108:238–239.
41.
Lamberts SW, Bons EG, Bruining HA, de Jong FH: Differential effects of the imidazole derivatives etomidate, ketoconazole and miconazole and of metyrapone on the secretion of cortisol and its precursors by human adrenocortical cells. J Pharmacol Exp Ther 1987;240:259–264.
42.
Fassnacht M, Hahner S, Beuschlein F, Klink A, Reincke M, Allolio B: New mechanisms of adrenostatic compounds in a human adrenocortical cancer cell line. Eur J Clin Invest 2000;30(suppl 3):76–82.
43.
Lambert A, Frost J, Mitchell R, Robertson WR: On the assessment of the in vitro biopotency and site(s) of action of drugs affecting adrenal steroidogenesis. Ann Clin Biochem 1986;23:225–229.
44.
Vanden Bossche H, Willemsens G, Cools W, Bellens D: Effects of etomidate on steroid biosynthesis in subcellular fractions of bovine adrenals. Biochem Pharmacol 1984;33:3861–3868.
45.
Wagner RL, White PF, Kan PB, Rosenthal MH, Feldman D: Inhibition of adrenal steroidogenesis by the anesthetic etomidate. N Engl J Med 1984;310:1415–1421.
46.
Varga I, Racz K, Kiss R, Futo L, Toth M, Sergev O, Glaz E: Direct inhibitory effect of etomidate on corticosteroid secretion in human pathologic adrenocortical cells. Steroids 1993;58:64–68.
47.
Weber MM, Lang J, Abedinpour F, Zeilberger K, Adelmann B, Engelhardt D: Different inhibitory effect of etomidate and ketoconazole on the human adrenal steroid biosynthesis. Clin Investig 1993;71:933–938.
48.
Allolio B, Stuttmann R, Fischer H, Leonhard W, Winkelmann W: Long-term etomidate and adrenocortical suppression. Lancet 1983;322:626.
49.
Schulte HM, Benker G, Reincke M, Sippell WG, Allolio B: Infusion of low-dose etomidate: correction of hypercortisolemia in patients with Cushing’s syndrome and dose-response relationship in normal subjects. J Clin Endocrinol Metab 1990;70:1426–1430.
50.
Gartner R, Albrecht M, Muller OA: Effect of etomidate on hypercortisolism due to ectopic ACTH production. Lancet 1986;1:275.
© 2011 S. Karger AG, Basel
2011
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.