46 Endocrine Complications After Endoscopic Skull Base Surgery

Zachary M. Bush, Mary Lee Vance, and John A. Jane Jr.

Tips and Pearls

• Optimal perioperative management of patients undergoing endoscopic transsphenoidal surgery requires an experienced multidisciplinary team including specialists from neurosurgery and endocrinology.

• Postoperative hormone deficiencies are the most common complication of modern transsphenoidal surgery, and can cause significant morbidity and mortality if unrecognized and untreated.

• Preoperative evaluation of pituitary function in patients undergoing transsphenoidal surgery is critical in surgical and postoperative care planning.

• Preoperative high-resolution magnetic resonance imaging (MRI) of the sella to localize normal pituitary is important in surgical planning.

• Postoperative management is individualized according to the type of pituitary or sellar lesion, especially in secretory pituitary adenomas.

• Non-Cushing’s patients with any preoperative pituitary dysfunction are often given empiric stress dose steroids for 24 hours after surgery as a safety measure.

• Hormone deficiencies noted in preoperative evaluation are not expected to resolve rapidly, and empiric treatment for central hypothyroidism, adrenal insufficiency, and diabetes insipidus should be continued until the first follow-up visit 8 to 10 weeks after surgery.

• Posterior pituitary dysfunction is common following pituitary surgery, with diabetes insipidus often occurring in the first 72 hours, and a delayed risk of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and symptomatic hyponatremia occurring 5 to 14 days postoperative.

• Patients who are not on steroid replacement therapy, must be evaluated for iatrogenic adrenal insufficiency with an early-morning plasma cortisol level before the patient leaves the hospital. Physiologic glucocorticoid replacement should be instituted upon discharge if the morning cortisol is low (<10 μg/dL).

• Detailed discharge instructions should include a description of the symptoms of adrenal insufficiency (AI), diabetes insipidus, and hyponatremia (SIADH). Patients should be asked to report to the nearest emergency room if symptoms of AI or hyponatremia occur, with instructions to have a cortisol and sodium level measured.

• Reevaluation of all anterior pituitary hormones should be performed at the first postoperative visit.

Introduction

The endonasal surgical approach to the sella was first described by Hirsch and subsequently modified by Halstead¹ in 1910. By 1912 Cushing² adopted a sublabial variation of Halstead’s procedure to perform over 200 pituitary operations with a perioperative mortality rate of 5.2%. The poorly illuminated and limited surgical field, along with high rates of meningitis delayed the widespread use of the surgical technique; not until the advent of the antibiotic era and the development of the operating microscope during the 1950s and 1960s was the renaissance of transsphenoidal surgery possible.³ Over the last four decades transsphenoidal surgery has become the principal technique for approaching sellar and parasellar lesions, and advances in medical and surgical practice have improved the safety of the procedure, with most authors reporting mortality rates of 0 to 1%.^4–7 The pure endoscopic transsphenoidal surgery was popularized by Jho and Carrau⁴ in the 1990s, and has now either replaced surgical microscopes or is serving as an important adjuvant technique at many medical centers around the world.⁸

As rates of iatrogenic complications such as infection, cerebrospinal fluid (CSF) leaks, hemorrhage, and neuronal injury, have declined, endocrine complications have become the most common cause of postoperative morbidity following skull base surgery.⁹ Published complication rates are generally reported only by experienced surgeons, thus underestimating the actual rate of complications in the community. A large survey published in 1997 by Ciric et al⁹ offers a more realistic look at complication rates through self-reported data from 958 American neurosurgeons with a wide range of skull base surgery experience; the cohort as a whole reported anterior pituitary insufficiency in 19.4% and diabetes insipidus in 17.8% (7.6–19%) of transsphenoidal cases.

Expertise of the Surgeon Predicts Endocrine Complication Rates

Not surprisingly, the experience of the surgeon is a critical determinant in predicting perioperative complications from transsphenoidal skull base surgery. Ciric et al’s 9 published survey shows at lease a threefold increase in complication rates in the least experienced tertile (87.3% of respondents with <200 operations) compared with the most experienced tertile (3% of respondents with >500 operations). Rates of anterior pituitary insufficiency in the two groups were 20.6% versus 7.2%, rates of diabetes insipidus were 19% versus 7.6%, and mortality rates were 1.2% versus 0.2%, respectively.

The Multidisciplinary Team

Coordinated preoperative evaluation by neurosurgeons and endocrinologists ensures optimal perioperative hormone management. At least 50% of the hormone deficits present in the preoperative state will persist following surgery, and appropriate preoperative hormone replacement to address adrenal insufficiency, diabetes insipidus, or central hypothyroidism is necessary and can reduce anesthesia and surgical complications and speed recovery in the immediate postoperative period.¹⁰ It is imperative to identify patients who have adrenal insufficiency prior to initiating thyroid replacement to avoid an adrenal crisis.¹¹ Accurate analysis of thyroid and gonadal function is best done in the preoperative outpatient setting because the stress of surgery and administration of corticosteroids can transiently suppress these hormone axes. Furthermore, accurate characterization of functional pituitary lesions can prevent the need for surgery (prolactinomas), or identify patients at high risk for respiratory failure after anesthesia (acromegaly) or perioperative thromboembolism (Cushing’s disease).¹²^,¹³

The Role of Preoperative Imaging

High-resolution magnetic resonance imaging (MRI) of the sella is a critical component of preoperative planning. The size and the type of sellar lesion are important predictors of postoperative hormone deficiencies.¹⁰ As a result of differential uptake of gadolinium contrast, MRI can also help to differentiate mass lesions from regions of normal pituitary tissue, thus minimizing intraoperative exploration or unnecessary resection of the normal pituitary gland. Preservation of 30 to 40% of the normal anterior pituitary is usually adequate to preserve postoperative hormone function; however, pituitary glands that have been compressed by very large macroadenomas are often less resilient to surgical resection, and rates of postoperative hormone deficiency are more common.

Surgical Techniques to Minimize Endocrine Dysfunction

Careful anatomical analysis with preoperative MRI studies is essential in maintaining the midline approach.⁸ The preservation of midline structures and careful hemostasis allow the surgeon to maintain anatomical orientation until the sella is opened, and once in the sella, careful hemostasis is necessary to allow the surgeon to identify the subtle tissue characteristics that differentiate the anterior and posterior pituitary as well as the tumor capsule and parenchyma. To further guide the surgical approach, lateral-view x-ray control or frameless stereotactic image guidance can be used. Diabetes insipidus can best be prevented by avoiding traction on the pituitary stalk and manipulation of the posterior pituitary. If an individual case necessitates exposure of the posterior pituitary or perturbation of the pituitary stalk, the postoperative care team should be made aware of the increased likelihood of iatrogenic diabetes insipidus. Preservation of the normal pituitary gland depends on the ability of the surgeon to recognize remnants of the normal pituitary, which can be fibrous in character when tumor compression has occurred.⁶

Immediate Postoperative Management

In the first 24 hours after surgery, clinical attention should focus on the potential for acute adrenal insufficiency or diabetes insipidus. Aside from surgical remission of Cushing’s disease, acute adrenal insufficiency is an uncommon complication of endoscopic skull base surgery, but failure to recognize the condition can lead to untoward morbidity and mortality. For this reason, many centers empirically treat non-Cushing’s patients with stress-dose glucocorticoids for 24 hours, with the first dose given before the patient leaves the operating room. Intravenous hydrocortisone 50 mg every 6 hours or 100 mg every 8 hours for 24 hours are common regimens.¹⁰^,¹⁴ The short half-life of hydrocortisone (t_½ = 90–120 minutes) leads to rapid clearance so that the exogenous glucocorticoid does not interfere with the necessary evaluation of the patient’s endogenous cortisol production before discharge from the hospital. Another reasonable practice is to give stress-dose glucocorticoids only to patients who are found to have adrenal insufficiency preoperatively. In these patients it is reasonable to begin stress-dose steroids and then taper them to a standing oral glucocorticoid regimen after discharge from the hospital. All other patients can be monitored clinically and biochemically for signs of adrenal insufficiency.

Symptoms of acute adrenal insufficiency usually develop within 24 to 72 hours of surgery (e.g., lethargy, headache, nausea/abdominal pain, and orthostatic hypotension). A morning serum cortisol of less than 10 μg/dL in a symptomatic postoperative patient establishes the diagnosis, and should be treated with moderate stress-dose steroids until stable for discharge (intravenous [IV] hydrocortisone 50 mg every 6 hours in the first 48 hours after surgery, or hydrocortisone PO 40 mg in the a.m./20 mg in the p.m. in the stable patient approaching discharge) before transitioning to physiologic doses. Asymptomatic patients should be evaluated for relative adrenal insufficiency with a plasma cortisol between 6 a.m. and 8 a.m. on the day of discharge. A value of less than 10 μg/dL is suggestive of relative adrenal insufficiency, and patients should be treated with physiologic glucocorticoid replacement upon discharge (prednisone 5 mg daily, or hydrocortisone 20 mg daily in divided doses).

Diabetes insipidus (DI) occurs in 5 to 20% of patients and is often the earliest endocrinopathy to develop after surgical manipulation of the pituitary gland, usually within the first 12 to 24 hours of surgery. It is important to note that an avid postoperative diuresis is not adequate to establish the diagnosis. Patients with acromegaly who achieve surgical remission are expected to have a 3- to 10-L diuresis as the sodium and water retention effects of excess growth hormone resolves. Furthermore, polydipsia is common in patients undergoing transsphenoidal surgery because nasal packing and sinonasal congestion necessitate mouth-breathing. The accurate diagnosis of postoperative DI is established by routine serial measurements of urine specific gravity every 6 hours, daily or twice daily measurements of plasma sodium, and strict recording of daily fluid intake and output. Once again, multidisciplinary postoperative management is important in reducing complications.

Endocrine Complications After Discharge from the Hospital

After leaving the hospital, the most common endocrinopathy is transient posterior pituitary dysfunction resulting in a syndrome of inappropriate antidiuretic hormone secretion (SIADH). This occurs in 9% or more of patients undergoing transsphenoidal pituitary surgery, and may occur more often in patients who have transient diabetes insipidus during postoperative hospitalization.15 Nearly all postoperative SIADH spontaneously resolves within 72 hours of onset, and is often mild and clinically unrecognized. The occurrence of symptomatic hyponatremia can be minimized by instructing patients to regulate fluid intake only in response to symptomatic thirst during the first 7 to 10 days at home. The symptoms of hyponatremia are very similar to adrenal insufficiency: lethargy, confusion, headache, nausea, and generalized weakness (very severe hyponatremia can result in seizures). Patients should be educated about these symptoms before discharge and their onset should prompt an urgent visit to the nearest hospital center for measurement of serum sodium (sodium levels of 116–126 mmol/L are common in symptomatic patients). Prompt treatment should be implemented with inpatient observation and strict fluid restriction (500 mL/day).¹⁰ Because the clinical presentation can mimic adrenal insufficiency, serum cortisol should also be measured at the time of presentation if the patient is not receiving glucocorticoid replacement; a random cortisol <10 μg/dL in a symptomatic patient should prompt stress-dose glucocorticoid treatment for at least 24 hours followed by physiologic replacement until outpatient endocrinology follow-up occurs.

Outpatient Postoperative Follow-Up

A postoperative follow-up visit with a multidisciplinary team should be scheduled 8 to 10 weeks after surgery to allow time for potential recovery of preexisting or iatrogenic hormone deficiencies. Those patients requiring glucocorticoid replacement should stop treatment 24 hours before the first follow-up visit to allow measurement of the endogenous hypothalamic-pituitary-adrenal axis with a serum cortisol, and adrenocorticotropic hormone (ACTH). Similarly, patients receiving desmopressin treatment for DI should hold at least one dose before follow-up to evaluate for recurrence of polydipsia and polyuria.

A full clinical assessment and physical examination in all patients at the follow-up visit should be augmented by measurement of serum cortisol, free thyroxine (T₄), insulin-like growth factor 1 (IGF-1), and prolactin.¹⁰ Measurement of gonadotropins and estradiol in female patients with reproductive capacity may be unnecessary if return of normal menstrual function occurs (this is the most sensitive and accurate sign of normal gonadotropin function). In women with amenorrhea, gonadotropins and estradiol should be measured. A total testosterone, or a free testosterone, level should be measured in men.

If morning cortisol remains below 10 μg/dL, long-term physiologic steroid replacement is indicated and patients should wear a medical alert bracelet or necklace indicating adrenal insufficiency. Repeat testing should be performed at 6 and 12 months after surgery. Free T₄, not a thyroid-stimulating hormone (TSH) level, should be used to guide thyroid hormone replacement. Replacement of estrogen and progesterone in hypogonadotropic premenopausal women is appropriate. Testosterone replacement in hypogonadotropic hypogonadal men should be initiated only after age-appropriate screening for prostrate cancer (digital rectal exam, measurement of prostate-specific antigen). Growth hormone (GH) replacement may require an insulin tolerance test to confirm GH deficiency. If diabetes insipidus is persistent, the lowest therapeutic dose of desmopressin should be determined; once-daily dosing at bedtime can often ameliorate symptoms and reduce the risk of treatment related hyponatremia.

Recurrence of skull base tumors is common, and long-term clinical follow-up requires serial MRIs and biochemical evaluation. Successful long-term management of these patients demands involvement of specialists from neurosurgery (including radiosurgery), pathology, radiology, and endocrinology.