AACE/ACE Disease State Clinical Review

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1 AACE/ACE Disease State Clinical Review Whitney W. Woodmansee, MD 1 ; John Carmichael, MD 2 ; Daniel Kelly, MD 3 ; Laurence Katznelson, MD 4 ; on behalf of the AACE Neuroendocrine and Pituitary Scientific Committee Abbreviations: ADH = antidiuretic hormone; CSF = cerebrospinal fluid; DDAVP = desmopressin; DI = diabetes insipidus; GH = growth hormone; MRI = magnetic resonance imaging; SIADH = syndrome of inappropriate ADH release; TSS = transsphenoidal surgery Submitted for publication September 30, 2014 Accepted for publication December 23, 2014 From the 1 Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts; 2 Departments of Medicine and Neurosurgery, Keck School of Medicine of University of Southern California, Los Angeles, California; 3 John Wayne Cancer Institute at Providence Saint John s Health Center, Santa Monica, California; 4 Departments of Medicine and Neurosurgery, Stanford University School of Medicine, Stanford, California. Address correspondence to Dr. Whitney Woodmansee; Brigham and Women s Hospital, Division of Endocrinology, Diabetes and Hypertension; 221 Longwood Avenue; Boston, MA wwoodmansee@partners.org DOI: /EP14541.DSCR To purchase reprints of this article, please visit: Copyright 2015 AACE. The opinions represented in the AACE/ACE Disease State Clinical Review: Postoperative Management Following Pituitary Surgery are the expressed opinions of the Neuroendocrine and Pituitary Scientific Committee of the American Association of Clinical Endocrinologists. AACE/ACE Disease State Clinical Reviews are systematically developed documents written to assist health care professionals in medical decision making for specific clinical conditions, but are in no way a substitute for a medical professional s independent judgment and should not be considered medical advice. Most of the content herein is based on literature reviews. In areas of uncertainty, professional judgment of the authors was applied. This review article is a working document that reflects the state of the field at the time of publication. Because rapid changes in this area are expected, periodic revisions are inevitable. We encourage medical professionals to use this information in conjunction with, and not a replacement for, their best clinical judgment. The presented recommendations may not be appropriate in all situations. Any decision by practitioners to apply these guidelines must be made in light of local resources and individual patient circumstances. Copyright 2015 AACE. ABSTRACT Pituitary lesions are common in the general population. Patients can present with a wide range of signs and symptoms that can be related to tumor mass effects or pituitary hormonal alterations. Evaluation involves assessing patients for the extent of tumor burden and pituitary hyperor hypofunction and includes clinical exams, hormonal testing, and brain imaging. Preoperative diagnosis and treatment planning generally require a multidisciplinary team approach with expertise from endocrinologists, neurosurgeons, neuro-ophthalmologists, and neuroradiologists. This review will outline considerations for the evaluation and management of patients with pituitary masses at each stage in their treatment including the pre-, peri- and postoperative phases. (Endocr Pract. 2015;21: ) INTRODUCTION Pituitary lesions are common in the general population with approximately 15 to 20% of individuals having evidence of an identifiable lesion on brain imaging (1,2). As recently documented in the Central Brain Tumor Registry of the United States, pituitary tumors are the second most common brain pathology observed (3). Pituitary lesions can present with mass effects (headaches, visual loss, cranial nerve dysfunction), pituitary hormonal hypersecretion, or hormonal deficiency. Although medical therapy is typically considered first line for prolactinomas, surgery is generally considered the treatment of choice for other endocrine-active pituitary adenomas (acromegaly, Cushing disease, and thyrotrope adenomas), as well as clinically nonfunctioning adenomas, pituitary apoplexy, Rathke cleft cysts, craniopharyngiomas, and other parasellar tumors such as meningiomas and clival chordomas. The decision to proceed with neurosurgical tumor resection can be quite complex and is best considered in a multidisciplinary clinical setting (4). Once the decision has been made to 832 ENDOCRINE PRACTICE Vol 21 No. 7 July 2015

2 833 proceed with pituitary tumor removal, the team must consider postoperative management of the patient. Although a minority of patients with giant adenomas and/or invasive suprasellar adenomas may require a craniotomy, the vast majority (over 95%) of pituitary adenomas are best treated by transsphenoidal surgery (TSS) (5). Over the last 15 years, TSS is increasingly being performed using an endonasal endoscopic technique, often in a collaborative effort including a neurosurgeon and otolaryngologist (4,6). Neuronavigation is used frequently at many centers, while intraoperative magnetic resonance imaging (MRI) is used less commonly; at this time neither of these surgical adjuncts is considered standard of care. While there is some evidence that the more panoramic endoscopic view leads to higher rates of complete tumor removal than the traditional microscopic view (7,8), it remains to be proven whether the endoscopic approach results in higher remission rates for functional adenomas such as those causing acromegaly or Cushing disease (9,10). Postoperative management following tumor removal utilizing any approach or technique includes both immediate inpatient assessment and short-term assessment for pituitary hormone recovery or deficits, as well as development of a long-term surveillance plan for tumor/lesion recurrence and endocrine status. This review will focus on the peri- and postoperative considerations of patients undergoing neurosurgical resection of sellar/suprasellar lesions. PREOPERATIVE EVALUATION Before discussing postoperative management, it is important to outline the typical preoperative evaluation. Findings from preoperative evaluations of patients with pituitary tumors have a significant impact on perioperative management. All patients with sellar/suprasellar lesions require a complete medical history, physical exam including formal neuro-ophthalmologic assessment with formal visual field testing if the MRI shows evidence that the tumor is abutting or compressing the optic chiasm, and evaluation for potential medical comorbidities. All patients should have a thorough assessment for a functioning tumor (e.g., prolactinoma, acromegaly, Cushing disease, or the rarely encountered thyrotropin-secreting tumor) and for hypopituitarism prior to development of the treatment plan. Typical preoperative baseline endocrine testing includes measurement of serum prolactin (11), assessment of hypercortisolism if there is clinical suspicion of Cushing syndrome (12), and measurement of insulin-like growth factor-1 (IGF-I) with further assessment of growth hormone (GH) hypersecretion for acromegaly as indicated (13). Preoperative prolactin measurements are essential, as medical therapy with dopamine agonists is the preferred initial treatment modality for prolactinoma patients (11). Sample dilution may be required in patients with large tumors and minimally elevated prolactin levels to rule out the hook effect that can be seen in some laboratory assays, leading to artificially low prolactin levels (11). Assessment of pituitary hypofunction includes evaluation for hypothyroidism (thyroid-stimulating hormone and free thyroxine); hypogonadism (serum testosterone in males; follicle-stimulating hormone/luteinizing hormone, estradiol in a premenopausal woman with history of oligomenorrhea/amenorrhea or postmenopausal females), and adrenal insufficiency (there are a number of protocols used including measurement of morning serum cortisol and cosyntropin stimulation testing). It is imperative that adrenocortical and thyroid status be evaluated prior to surgery to initiate appropriate hormonal replacement pre- and perioperatively if a deficiency is identified. It is important to recognize adrenal insufficiency preoperatively to ensure glucocorticoid coverage during surgery. It is likely important to identify hypothyroidism, as replacement may prevent potential surgical complications (i.e., cardiac dysfunction, hyponatremia, postoperative ileus) (14,15). Although found far less common in pituitary adenoma patients at initial presentation, diabetes insipidus (DI) can occur, particularly in concert with suprasellar lesions such as craniopharyngiomas, and needs to be identified and managed preoperatively. A careful history, along with measurement of serum electrolytes and urine specific gravity, will often alert the clinician to this condition. Ideally, all patients will receive replacement hormonal therapy for adrenal insufficiency, hypothyroidism or DI if indicated prior to surgery; however, it may not be prudent to delay surgery to achieve normal replacement levels (i.e., hypothyroidism) in all cases. Initiation of sex steroid and GH replacement therapy is typically deferred until a later point in the postoperative management. In addition to preoperative endocrine evaluation, patients are generally evaluated for other potential comorbidities including diabetes mellitus and cardiopulmonary disease that should be addressed prior to surgery. Patients with acromegaly and Cushing disease are particularly prone to have associated cardiovascular and metabolic comorbidities such as diabetes mellitus, hypertension, and cardiac dysfunction and may benefit from preoperative medical management. There is debate regarding preoperative treatment of acromegaly or Cushing disease with hormone-lowering medications prior to surgical intervention, and it is beyond the scope of this review to address these concerns. Currently, there is no consensus on the preoperative treatment of these diseases to improve surgical cure rate, but there may be a role in improving comorbidities and reducing complications (16). PERIOPERATIVE MANAGEMENT All patients with adrenal insufficiency identified preoperatively should be treated with stress-dose glucocorticoid treatment both peri- and postoperatively, with

3 834 Fig. 1. American Association of Clinical Endocrinologists perioperative management of pituitary tumors. GH = growth hormone; MRI = magnetic resonance imaging; SIADH = syndrome of inappropriate antidiuretic hormone secretion. postoperative testing for endogenous production only if there is likelihood for a return to normal hypothalamicpituitary-adrenal axis function. For patients with normal preoperative adrenal function, glucocorticoids may be administered perioperatively to cover for potential iatrogenic adrenal insufficiency. However, protocols in many centers involve steroid sparing management both peri- and postoperatively to avoid unnecessary exposure to glucocorticoids if possible (an approach to perioperative corticosteroid replacement strategies will be further discussed below). POSTOPERATIVE MANAGEMENT The general framework for postoperative management of patients undergoing pituitary tumor surgery can be considered to occur in 2 main phases: the early postoperative period and the longer term outpatient follow-up period, which includes the initial outpatient management as well as long-term observation. Early Postoperative Management The postoperative inpatient stay typically lasts from 1 to 3 nights (17). Serious complications following pituitary adenoma surgery are relatively uncommon, particularly with an experienced surgical team. Not surprisingly, the number and degree of complications have been shown to correlate negatively with the experience of the neurosurgeon (18-21). Regardless, given the potential for significant complications, TSS patients warrant careful monitoring for at least the first postoperative night and then typically in a monitored bed. Increasingly at many pituitary centers, Foley catheters are removed right after surgery, and arterial lines are not routinely used for patients undergoing most pituitary adenoma surgeries. More invasive monitoring may be used selectively for patients with significant medical comorbidities or those with large or complex parasellar lesions (e.g., giant or highly invasive pituitary adenomas, craniopharyngiomas, and meningiomas) who require an extended transsphenoidal approach. Major complications in the immediate postoperative period after TSS can be categorized into surgical and endocrine. The most serious early surgical complications (typically seen within hours of surgery) include sellar hematoma, often with associated visual loss, diplopia, and/or headache and cerebrospinal fluid (CSF) leak. Hydrocephalus, meningitis, sinusitis, and epistaxis (typically from a sphenopalatine artery) may develop within the first 1 to 3 weeks after surgery. Patients should be monitored closely for potential neurologic or ophthalmologic

4 835 deterioration using serial visual field assessments and neurologic exams, particularly in the first 24 hours following surgery. An early postoperative CT or sellar MRI should be performed in any patient with a new or worsened neurological deficit such as visual deterioration or diplopia, and in anyone with significant rhinorrhea and a suspected CSF leak. Although not performed routinely at all centers, sellar imaging within 24 hours of surgery can also be useful to assess skull base reconstruction integrity; degree of pneumocephalus; and for the presence of a sellar or suprasellar hematoma, particularly after removal of a large macroadenoma, craniopharyngioma, or suprasellar meningioma. The most important potential endocrine complications in the immediate postoperative period include fluid and electrolyte abnormalities and acute adrenal insufficiency. Alterations in sodium and fluid balance are relatively common in the early postoperative phase. These include alterations in arginine vasopressin/antidiuretic hormone (ADH), either insufficiency causing central DI or excess leading to the syndrome of inappropriate ADH release (SIADH). DI, which may occur in up to 25% of patients after pituitary adenoma surgery, is most frequently observed in within the first 48 hours of surgery (22). It is thought to occur from manipulation, traction, or disruption of the pituitary stalk during tumor removal leading to interruption of ADH release. Patients typically complain of excessive thirst and demonstrate polydipsia with polyuria and dilute urine (urine specific gravity typically 1.005), indicating an inability to concentrate the urine due to ADH deficiency. Although usually transient, DI may be permanent if there is stalk transection (22). Fluid intake, urinary output, volume status, as well as serial serum sodium and urine specific gravity or urine osmolality should be assessed to allow prompt recognition of the condition. One study showed a lower incidence of postoperative DI in patients who were not routinely treated with glucocorticoids (23). DI can be managed with desmopressin (DDAVP), which is available as a subcutaneous or intravenous (0.5-2 mcg every 24 hours as needed), intranasal (10 mcg metered dose), or oral formulation (often starting with mg oral as a single dose with doses up to 0.3 mg oral 3 times daily sometimes necessary). Intranasal DDAVP is not generally used until after the nose has healed and nasal congestion has improved. Many patients do not require any therapy as long as they are able to drink to thirst and their serum sodium remains within the normal range. For others, only 1 or 2 DDAVP doses may be needed as an inpatient before the condition resolves. DI can be transient, permanent, or remit and then recur later postoperatively in a classic triphasic response (22). In the latter scenario, patients can initially develop DI in the first 24 to 48 hours followed by transient SIADH developing 4 to 10 days postoperatively, followed by the return of DI in a matter of weeks. When DI returns as the third phase, this disturbance can be permanent. Management depends on the phase, and it is important not to overtreat the first phase of DI, which can result in severe hyponatremia during the potential subsequent SIADH phase. Fortunately, permanent DI occurs in only approximately 2% of patients following TSS (24). Between 5 and 9% of patients may also develop isolated SIADH leading to symptomatic and delayed hyponatremia (25,26). Therefore, a sodium level is often checked 5 to 8 days postoperatively, typically after the patient has been discharged from the hospital. Mild hyponatremia (i.e., mmol/l) may be managed by fluid restriction as an outpatient, but severe or symptomatic hyponatremia (typically <125 mmol/l) requires hospitalization for more aggressive management including use of fluid restriction, hypertonic saline or administration of vaptans, competitive antagonists of vasopressin receptors. In a recent study by Jahangiri et al (27), postoperative hyponatremia was noted in 19% of subjects. In this study, use of vaptans resulted in more rapid plasma sodium correction versus hypertonic saline but did lead to overcorrection in 1 subject. Therefore, selective use of vaptans in the setting of severe hyponatremia may be useful and potentially lead to shorter hospital stays. Finally, the clinician should be aware of the critical need to monitor adrenal function and replace glucocorticoids as needed following pituitary surgery. There are several approaches toward glucocorticoid management in the peri- and postoperative timeframes, ranging from glucocorticoid treatment at surgery with gradual tapering, to steroid sparing protocols with careful observation. Some clinicians choose to empirically treat all patients perioperatively with glucocorticoids at stress doses (for example, mg intravenous hydrocortisone) immediately prior to or during the operation followed by a gradual tapering schedule with reassessment of adrenal function during the early postoperative follow-up as necessary once on lower replacement doses. In this scenario, the need for formal assessment of glucocorticoid deficiency in the postoperative setting is often dependent upon clinical judgment, presence of preoperative pituitary deficiencies, and intraoperative findings. A patient who has had an uncomplicated surgery with no clinical indication of pituitary deficiencies would have a low likelihood of postoperative adrenal insufficiency and may not require formal adrenal function testing (28). Another approach is to administer pre- or intraoperative stress dose glucocorticoids only if the preoperative assessment suggests or confirms adrenal insufficiency. In a steroid-sparing protocol, perioperative steroids would be withheld entirely in a patient with normal preoperative adrenal function. In the days following surgery, early morning cortisol levels are measured and glucocorticoids initiated if the value is consistent with insufficiency. While measurement of a basal morning cortisol level is only suggestive of and not diagnostic of adrenal insufficiency, various cut points have been proposed,

5 836 below which glucocorticoid replacement should be considered. Proposed cut points for guidance in management are based on studies that suggest a high likelihood of adrenal insufficiency with a morning cortisol less than 4 to 5 mcg/ dl and low likelihood if the level is above 10 to 15 mcg/ dl (28-32). There is no one best approach, and many factors need to be considered for an individual patient, but minimizing unnecessary glucocorticoid exposure may be desired. If glucocorticoids are initiated in the perioperative period based on morning cortisol levels dropping below a specified cut point, then physiologic replacement therapy should be maintained until further provocative testing (approximately 6 weeks postoperatively) can be performed to assess long-term replacement needs. Assessing for Early Remission in Patients with Functional Adenomas For patients with acromegaly, Cushing disease, and prolactinomas, morning measurement of growth hormone, cortisol and prolactin levels, respectively, on postoperative day one and two have been shown to be moderately predictive of early and long-term remission. For acromegaly, a fasting serum GH level below 2 ng/ml on postoperative day 1 may suggest biochemical remission in patients not preoperatively treated with somatostatin analogues (33). For prolactinoma patients, a serum prolactin level <10 ng/ml measured on postoperative day 1 has been shown to predict early and subsequent biochemical remission (34). For patients with Cushing disease, there are a number of protocols used to assess adrenal function in the postoperative period, as it is critical to determine need for repeat surgery if not in remission or begin treatment of adrenal insufficiency (35-42). It is generally recommended that morning serum cortisol levels be measured within the first postoperative week. Protocols for assessment vary and include either withholding glucocorticoid coverage postoperatively and measuring serial plasma cortisol values to assess for a drop in cortisol levels while the patient remains hospitalized versus administering perioperative glucocorticoids (low-dose dexamethasone) and measuring a morning plasma cortisol or urinary free cortisol excretion within the first week (42). Following discharge, patients are monitored closely for the next 1 to 2 weeks for reassessment of neurologic status (general neurologic exam, visual acuity and visual fields, cranial nerves) and screened for potential surgical complications such as meningitis or CSF leak. As shortterm follow up progresses over time, the main issues to address are typically related to assessment and management of pituitary function. Longer Term Postoperative Management It is generally recommended that all patients undergo a repeat full evaluation of pituitary function at least 6 weeks after surgery. As in the preoperative evaluation, all anterior pituitary hormonal axes are generally re-evaluated to determine pituitary function integrity. Specifically, thyroid, adrenal, gonadal, and GH axes may be assessed at this visit. Sometimes pituitary hormonal deficiencies will recover postoperatively and will be detected as part of this evaluation (43). If a patient was treated with glucocorticoids perioperatively, the long-term need for replacement therapy should be determined at this time. There are a number of methods for assessing adrenal function, including measurement of a morning cortisol as a screen. As discussed above, morning cortisol levels less than 5 mcg/dl are concerning for adrenal insufficiency, and levels greater than 10 to 15 mcg/dl make this diagnosis less likely (28-32). Provocative testing of adrenocorticotropic hormonecortisol reserve with either a cosyntropin stimulation test or an insulin tolerance test may be performed. The cosyntropin stimulation test is most commonly used due to its ease of administration, but it is recognized that falsely normal results may be observed in patients with hypopituitarism, particularly in the first couple of weeks after an acute event such as pituitary surgery or apoplexy (44-48). The insulin tolerance test is not routinely performed in many centers due to the fact it is labor intensive and requires close monitoring by a physician for the intended effects of hypoglycemia and is contraindicated in elderly patients or those at increased risk for seizures or myocardial ischemia. Replacement therapy is instituted for thyroid and adrenal insufficiency and is considered for gonadal insufficiency at this time. Although most new hormonal deficiencies will be detected relatively early and by the 6-week timeframe, repeat hormonal assessment may be necessary at the 12-week postoperative visit to confirm stability of endocrine function. Assessment of GH reserve and consideration for replacement therapy is performed at variable times after surgery. A postoperative MRI is typically performed at the 12-week visit and serves as the patient s new baseline imaging exam. Surgical changes interfering with optimal interpretation of the MRI scan usually have resolved by this time (49-51). Periodic clinical assessment in the first year following surgery is dictated by the clinical status of the patient and need for titration of hormonal replacement therapy or treatment of any persistent pituitary hormonal hyperfunction. Generally patients are followed at least on an annual basis for evaluation of pituitary function. Imaging for nonfunctioning pituitary adenomas/sellar masses is repeated annually for 3 to 5 years and thereafter per clinical judgment. Pituitary imaging for patients with hormonally hyperfunctioning tumors depends on tumor type, biochemical parameters, and overall disease activity. Patients with hyperfunctioning tumors such as acromegaly and Cushing disease also require long-term monitoring of clinical status including biochemical parameters and imaging. Many require an individualized multimodality treatment program for management and maintenance of biochemical remission.

6 837 CONCLUSION Following pituitary surgery, there are a number of surgical, metabolic, and endocrine disorders that need to be monitored and treated with a multidisciplinary team approach. Treatment of pituitary hormonal hyper- and hypofunction is necessary to optimize overall quality of life and reduce comorbidities and mortality. These patients require life-long observation to ensure optimal hormonal management and monitor for tumor recurrence. ACKNOWLEDGMENT AACE Neuroendocrine and Pituitary Scientific Committee: Laurence Katznelson, MD, Chair; Whitney W. Woodmansee, MD; John Carmichael, MD; Ved Vyas Gossain, MD, FRCP, MACP, FACE; Shereen Z. Ezzat, MD, FRCP(C), FACP; Maria Fleseriu, MD, FACE; Richard Allen Haas, MD, FACE; Amir H. Hamrahian, MD, FACE; Andrew R. Hoffman, MD; Daniel F. Kelly, MD; Susan Leanne Samson, MD, PhD, FACE, FRCPC; Nicholas A. Tritos, MD, DS, FACP, FACE; and Kevin Choong Ji Yuen, MD, FRCP (UK). 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