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Submitted on December 13, 2004
Accepted on June 6, 2005
Dipartimento di Neuroscienze Ospedale Maggiore Policlinico IRCCS Milano; Department of Neurological Surgery, Department of Internal Medicine-Endocrinology, University of Virginia Health Sciences Center, Charlottesville, Virginia
* To whom correspondence should be addressed. E-mail: el5g{at}virginia.edu.
Context: Transsphenoidal surgery is currently the primary therapeutic option for Cushing's disease. Despite considerable initial success, 10-30% of patients fail to achieve lasting remission.
Evidence Acquisition: We evaluated a strategy of immediate reoperation in surgical failures judged by plasma cortisol levels that did not fall to 
2 µg/dl within 72 h of surgery. Of 215 patients with presumed ACTH microadenomas, treated between 1993 and 2004, 12 met inclusion criteria and had prompt (within 15 days) reoperation for residual or missed ACTH microadenoma. These 12 patients represent 28% of those who did not have evidence of postoperative adrenal insufficiency.
Evidence Synthesis: Based on an outcome measure of sustained subnormal or normal plasma cortisol levels, 8/12 patients (67%) achieved remission from the two operations. Adjunctive therapies (radiotherapy, Gamma Knife radiosurgery and adrenalectomy) led to remission in another 3 patients. It is recognized that this outcome required either total hypophysectomy (1 patient) or postoperative hypopituitarism (all patients in remission).
Conclusion: Magnetic resonance imaging was not usually helpful in determining therapeutic strategies, however, inferior petrosal sinus sampling was critical in providing confidence that the disease was of pituitary origin. A treatment algorithm is recommended, based on this study.
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