Introduction: Cushing disease(CD) comprises a spectrum of clinical manifestations secondary to hypercortisolism due to ACTH-secreting pituitary adenoma. Transsphenoidal adenomectomy remains the standard treatment with recent surge in endoscopic approaches.

Methods: Data of all patients undergoing surgery for CD from 2009-16 was analyzed retrospectively. Post-operative cortisol level of <2µg/dL was taken as remission and value 2 to 5 µg/dL as possible remission. Remission during follow-up was defined as morning cortisol< 5.0 µg/dl or suppression of serum cortisol (<2µg/dl) after overnight dexamethasone test.

Results: 123 patients of CD were included for analysis and were divided into two groups; Group A comprising 98 patients who underwent primary pituitary surgery and Group B of 25 patients who underwent pituitary surgery for non-remission. In group A, 47 patients underwent microscopic surgery, 49 endoscopic surgery, two were operated transcranially; in group B, the numbers are 15,8 and 2 respectively. Remission was achieved in 75% patients in group A and in 55% patients in group B. In statistical analysis, factors significantly associated with remission were (1) type of surgery (p=0.01) (2) postoperative day-1 morning cortisol (p=0.004) and (3) postoperative day-1 morning ACTH (p=0.015). ROC curve showed a cut-off value of 10.5 µgm/dl (p<0.001 with 87% sensitivity and 80% specificity. The chance of remission was significantly more with endoscopic Transsphenoidal-Surgery-TSS approach than microscopic or transcranial surgery. The chance of intraoperative CSF leak increased with macroadenoma (p=0.07) and in redo surgery (p=0.03).

Conclusions: Postoperative plasma cortisol level is a strong independent predictor of remission and value less than 10.5µgm/dl can be taken as cut off for predicting remission though it does not positively predict long-term recurrence. So all patients with CD cured by surgery require long-term follow-up. Endoscopic TSS has gained limelight than microscopic approach in recent past. Remission provided by endoscopy appears to be significantly better than microscopic approach.

Patient Care: Our study is based on a detailed neuro-endocrine work-up and management of ACTH-secreting pituitary adenoma manifesting as Cushings disease. The study highlights the factors responsible for remission in these patients especially the type of surgery i.e. endoscopic wrt Microscopic TSS and post-operative serum cortisol.

Learning Objectives: Cushing disease(CD) - ACTH-secreting pituitary adenoma- number = 123. Factors significantly associated with remission were (1) type of surgery - endoscopic TSS wrt Microscopic TSS (p=0.01) (2) postoperative day-1 morning cortisol (p=0.004) and (3) postoperative day-1 morning ACTH (p=0.015). Postoperative plasma cortisol level value less than 10.5µgm/dl can be taken as cut off for predicting remission though it does not positively predict long-term recurrence.

References: 1. Acebes JJ, Martino J, Masuet C, Montanya E, Soler J. Early post-operative ACTH and cortisol as predictors of remission in Cushing's disease. Acta Neurochir (Wien) 149(5):471-7; discussion 477-9, 2007 2. Alfieri A, Jho HD. Endoscopic endonasal approaches to the cavernous sinus:surgical approaches. Neurosurgery 49(2):354-360; discussion 360-362, 2001 3. Ammini AC, Bhattacharya S, Sahoo JP, Philip J, Tandon N, Goswami R, et al. Cushing's disease: results of treatment and factors affecting outcome. Hormones (Athens) 10(3):222-9, Jul-Sep 2011 4. Arnott RD, Pestell RG, McKelvie PA, Henderson JK, McNeill PM, Alford FP: A critical evaluation of transsphenoidal pituitary surgery in the treatment of CD: prediction of outcome. Acta Endocrinol 123:423–430,1990 5. Berker M, Isikay I, Berker D, Bayraktar M, Gürlek A. Early promising results for the endoscopic surgical treatment of Cushing's disease. Neurosurg Rev 37:105–114, 2014 6. Black PM, Zervas NT, Candia GL. Incidence and management of complications of transsphenoidal operation for pituitary adenomas. Neurosurgery 20:920–924, 1987 7. Bochicchio D, Losa M, Buchfelder M: Factors influencing the immediate and late outcome of CD treated by transsphenoidal surgery: a retrospective study by the European Cushing’s CD Survey Group. J Clin Endocrinol Metab 80: 3114–3120, 1995 8. Brand IR, Dalton GA, Fletcher RF: Long-term follow up of transsphenoidal hypophysectomy for CD. J R Soc Med 78:291–293, 1985 9. Buchfelder M, Nistor R, Fahlbusch R, Huk WJ: The accuracy of CT and MR evaluation of the sella turcica for detection of adrenocorticotrophic hormone-secreting adenomas in Cushing disease. AJNR 14:1183–1190, 1993 10. Cappabianca P, Cavallo LM, Colao A, Del Basso De Caro M, Esposito F, Cirillo S, et al. Endoscopic endonasal transsphenoidal approach: outcome analysis of 100 consecutive procedures. Minim Invasive Neurosurg 45(4):193-200, Dec 2002. 11. Chen JC, Amar AP, Choi S, Singer P, Couldwell WT, Weiss MH: Transsphenoidal microsurgical treatment of Cushing disease:postoperative assessment of surgical efficacy by application of an overnight low-dose dexamethasone suppression test. J Neurosurg 98:967–973, 2003 12. Ciric I, Ragin A, Baumgartner C, Pierce D. Complications of transsphenoidal surgery: results of a national survey, review of the literature, and personal experience. Neurosurgery 40:225–236. 1997 13. D'Haens J, Van Rompaey K, Stadnik T, Haentjens P, Poppe K, Velkeniers B. Fully endoscopic transsphenoidal surgery for functioning pituitary adenomas: a retrospective comparison with traditional transsphenoidal microsurgery in the same institution. Surg Neurol 72(4):336-40, Oct 2009 14. Dehdashti AR, Ganna A, Karabatsou K, Gentili F. Pure endoscopic endonasal approach for pituitary adenomas: early surgical results in 200 patients and comparison with previous microsurgical series. Neurosurgery 62(5):1006-15; discussion 1015-7, May 2008 15. Doppman JL, Frank JA, Dwyer AJ, Oldfield EH, Miller DL, Nieman LK, et al: Gadolinium-DTPA enhanced imaging of ACTHsecreting microadenomas of the pituitary gland: Correlation of MR appearance with surgical findings. J Comput Assist Tomogr 12:728–735, 1988. 16. Dusick JR, Esposito F, Mattozo CA, Chaloner C, McArthur DL,Kelly DF. Endonasal transsphenoidal surgery: the patient’s perspectivesurveyresults from 259 patients. Surg Neurol 65:332–41[discussion 341–332], 2006 17. Esposito F, Dusick JR, Cohan P, Moftakhar P, McArthur D, Wang C, et al: Clinical review: early morning cortisol levels as a predictor of remission after transsphenoidal surgery for CD.J Clin Endocrinol Metab 91:7–13, 2006 18. Fahlbusch R, Buchfelder M, Muller OA: Transsphenoidal surgery for CD. J R Soc Med 79:262–269, 1986 19. Frank G, Pasquini E, Farneti G, Mazzatenta D, Sciarretta V, Grasso V, et al: The endoscopic versus the traditional approach in pituitary surgery. Neuroendocrinology 83(3–4):240– 248, 2006 20. Goel A, Nadkarni T. Surgical management of giant pituitary tumours-a review of 30 cases. Acta Neurochir (Wien) 138(9):1042–9,1996 21. Gold EM: The cushing syndrome : changing views of diagnosis and treatment, Ann intern med 90:829-844, 1979 22. Goudakos, J.K., Markou, K.D. & Georgalas. Endoscopic versus microscopic trans-sphenoidal pituitary surgery: a systematic review and meta-analysis. Clin Otolaryngol 36(3):212-20, Jun 2011 23. Hammer GD, Tyrrell JB, Lamborn KR, Applebury CB, Hannegan ET, Bell S, et al: Transsphenoidal microsurgery for CD: initial outcome and long-term results. J Clin Endocrinol Metab 89:6348–6357, 2004 24. Han ZL, He DS, Mao ZG, Wang HJ. Cerebrospinal fluid rhinorrhea following trans-sphenoidal pituitary macroadenoma surgery: experience from 592 patients. Clin Neurol Neurosurg 110(6):570-9, Jun 2008 25. Hardy J: The transsphenoidal surgical approach to the pituitary. Hosp Pract 14:81–89, 1979 26. Hassan-Smith ZK, Sherlock M, Reulen RC, Arlt W, Ayuk J, Toogood AA, et al. Outcome of Cushing's disease following transsphenoidal surgery in a single center over 20 years. J Clin Endocrinol Metab 97(4):1194-201, Apr 2012 27. Jho H.D. & Alfieri A. Endoscopic endonasal pituitary urgery: evolution of surgical technique and equipment in 150 operations. Minim. Invasive Neurosurg. 44, 1–12,2001 28. Kaptain GJ, Vincent DA, Sheehan JP, Laws Jr ER. Transsphenoidal approaches for the extracapsular resection of midline suprasellar and anterior cranial base lesions. Neurosurgery 49:94–100 [discussion 100–101], 2001 29. Kaye AH, Laws ER Jr: Brain Tumors: An Encyclopedic Approach. New York: Churchill Livingstone, 1995 30. Knosp E, Steiner E, Kitz K, Matula C. Pituitary adenomas with invasion of the cavernous sinus space: a magnetic resonance imaging classification compared with surgical findings. Neurosurgery 33(4): 610–7; discussion 617–8, Oct 1993. 31. Kuo CH, Yen YS, Wu JC, Chen YC, Huang WC, Cheng H. Primary Endoscopic Transnasal Transsphenoidal Surgery for Magnetic Resonance Image-Positive Cushing Disease: Outcomes of a Series over 14 Years. World Neurosurg 84(3):772-9, Sep 2015 32. Lamberts SW, van der Lely AJ, de Herder WW: Transsphenoidal selective adenomectomy is the treatment of choice in patients with CD. Considerations concerning preoperative medical treatment and the long-term follow-up. J Clin Endocrinol Metab 80:3111–3113, 1995 33. Laws ER Jr, Fode NC, Redmond MJ: Transsphenoidal surgery following unsuccessful prior therapy. An assessment of benefits and risks in 158 patients. J Neurosurg 63:823–829, 1985 34. Lindholm J, Juul S, Jorgensen JOL, Astrup J, Bjerre P, Feldt-Rasmussen U, et al: Incidence and late prognosis of Cushing’s syndrome: a population-based study. J Clin Endocrinol Metab 86:117–123, 2001 35. Locatelli M, Vance ML, Laws ER: Clinical review: the strategy of immediate reoperation for transsphenoidal surgery for CD. J Clin Endocrinol Metab 90:5478–5482, 2005 36. McCance DR, Besser M, Atkinson AB. Assessment of cure after transsphenoidal surgery for CD. Clin Endocrinol 44: 1-6. 1996 37. Mindermann T, Wilson CB: Pediatric pituitary adenomas. Neurosurgery 36:259–269, 1995 38. Netea-Maier RT, van Lindert EJ, den Heijer M, van der Eerden A,Pieters GF, Sweep CG, et al: Transsphenoidal pituitary surgery via the endoscopic technique: results in 35 consecutive patients with CD. Eur J Endocrinol 154:675–684, 2006 39. Newell-Price J: Transsphenoidal surgery for CD:defining cure and following outcome. Clin Endocrinol (Oxf) 56:19–21, 2002 40. Nishioka H, Haraoka J, Ikeda Y. Risk factors of cerebrospinal fluid rhinorrhea following transsphenoidal surgery. Acta Neurochirurgica 147:1163–6 [discussion 1166], 2005 41. Pikkarainen L, Sane T, Reunanen A: The survival and well-being of patients treated for Cushing’s syndrome. J Intern Med 245: 463–468, 1999 42. Rees DA, Hanna FW, Davies JS, Mills RG, Vafidis J, Scanlon MF: Long-term follow-up results of transsphenoidal surgery for CD in a single centre using strict criteria for remission.Clin Endocrinol (Oxf) 56:541–551, 2002 43. Seiler RW, Mariani L. Sellar reconstruction with resorbable Vicryl patches, gelatin foam, and fibrin glue in transsphenoidal surgery: a 10-year experience with 376 patients.J Neurosurg 93:762–765. 2000 44. Semple PL, Laws ER Jr : Complications in a contemporary series of patients who underwent trans-sphenoidal surgery for CD. J Neurosurg 91(2): 175–179, 1999 45. Shiley SG, Limonadi F, Delashaw JB, Barnwell SL, Andersen PE, Hwang PH, et al. Incidence, etiology, and management of cerebrospinal fluid leaks following trans-sphenoidal surgery. Laryngoscope 113(8):1283-8, Aug 2003 46. Shimon I, Ram Z, Cohen ZR, Hadani M: Transsphenoidal surgery for CD: endocrinological follow-up monitoring of 82 patients. Neurosurgery 51:57–62, 2002 47. Starke RM, Reames DL, Chen CJ, Laws ER, Jane JA Jr. Endoscopic transsphenoidal surgery for cushing disease: techniques, outcomes, and predictors of remission. Neurosurgery 72(2):240-7; discussion 247, Feb 2013 48. Storr HL, Drake WM, Evanson J, Matson M, Berney DM, Grossman AB, et al Endonasal endoscopic transsphenoidal pituitary surgery: early experience and outcome in paediatric Cushing's disease. Clin Endocrinol (Oxf) 80(2):270-6, Feb 2014 49. Thomas JP, Richards SH: Long term results of radical hypophysectomy for CD. Clin Endocrinol (Oxf) 19: 629–636, 1983 50. Tindall GT, Herring CJ, Clark RV, Adams DA, Watts NB: Cushing’s disease: results of transsphenoidal microsurgery with emphasis on surgical failures. J Neurosurg 72:363–369, 1990 51. Trainer PJ, Lawrie HS, Verheist J, Howlett TA, Lowe DG, Grossman AB, et al: Transsphenoidal resection in CD: undetectable serum cortisol as the definition of successful treatment. Clin Endocrinol 38:73–78,1993 52. Vance ML: Perioperative management of patients undergoing pituitary surgery. Endocrinol Metab Clin North Am 32: 355–365, 2003 53. Wagenmakers MA, Boogaarts HD, Roerink SH, Timmers HJ, Stikkelbroeck NM, Smit JW, et al: a good and safe primary treatment option for Cushing's disease, even in case of macroadenomas or invasive adenomas. Eur J Endocrinol. 169(3):329-37, Aug 2013 54. Zada G, Kelly DF, Cohan P, Wang C, Swerdloff R. Endonasal transsphenoidal approach for pituitary adenomas and other sellar lesions: an assessment of efficacy, safety, and patient impressions. J Neurosurg 98(2):350-8, Feb 2003 55. Zervas NT. Surgical results in pituitary adenomas: results of an international survey. In: Black PM, Zervas NT, Ridgway EC, Martin JB, eds. Secretory Tumors of the Pituitary Gland. New York: Raven,:377–385, 1984