Complications Associated With Transsphenoidal Pituitary Surgery: Review of the Literature.

Abstract

ADH: antidiuretic hormone CSF: cerebrospinal fluid CT: computed tomography DI: diabetes insipidus HPA: hypothalamic-pituitary-adrenal ICA: internal carotid artery SIADH: syndrome of antidiuretic hormone secretion TSS: transsphenoidal surgery Although the transsphenoidal approach is preferred for a majority of pituitary tumor resections, modern pituitary surgery is built on a long history of varied approaches to the sella turcica. Beginning with Caton and Paul's first attempted subtemporal approach in 1893, pioneering surgeons championed several ingenious approaches to the pituitary fossa, comprising both transcranial and transfacial routes and including the transsphenoidal approach utilized by Hermann Schloffer in 1907 and subsequently popularized by Hirsch and Cushing in the 1910-20s.1,2 Although transsphenoidal surgery (TSS) grew out of favor for a period of several decades, it has gained widespread use since Hardy introduced the operative microscope in the 1960s, and since then, a large number of studies have demonstrated excellent surgical outcomes with low rates of morbidity and mortality. Despite the long history of TSS, it remains a potential source of a number of significant associated complications, ranging from perioperative medical, to endocrine, to surgical issues. Complications encountered during TSS may in part be explained by a variety of opportunities for procedural error in a small anatomic space with unique physiology and structural variability. This review serves to highlight operative and perioperative complications associated with TSS, and specific characteristics of sellar anatomy and physiology that contribute to the risks inherent to TSS. NORMAL PITUITARY PHYSIOLOGY AND ANATOMY OF ITS SURROUNDING STRUCTURES Pituitary Gland The pituitary gland is a bilobed endocrine organ responsible for secreting eight distinct hormones, 2 from its posterior lobe and 6 from its anterior lobe. The posterior lobe, an extension of the central nervous system comprising specialized glial cells, lacks a blood–brain barrier and acts as a conduit for hypothalamus-derived vasopressin and oxytocin. In contrast, the anterior lobe, which is ectodermally derived, is made up of actively secreting pituitary cells and wraps around the caudal pituitary stalk. The pituitary stalk, a thin collection of magnocellular hypothalamic axons, connects the pituitary gland via its posterior lobe to the hypothalamus superiorly. Sellar Region and Cavernous Sinuses While the structure of the pituitary gland is itself complex, so is the bony anatomy in which it lies. Except for the opening of the thin, often rectangular diaphragma sellae overlying it, the pituitary gland is fully surrounded by sphenoid bone. Resting in the sella turcica, the gland is bounded anteriorly by the sellar floor and tuberculum sellae, posteriorly by the dorsum sellae and laterally by the cavernous sinus dura. The cavernous sinuses each contain the internal carotid artery and abducens nerve, as well as the oculomotor nerve, trochlear nerve, and ophthalmic and maxillary divisions of trigeminal nerve in its lateral walls.3 Suprasellar Region The optic chiasm may either sit directly above the diaphragma sellae, as is the case in a majority of the population, or it may be “prefixed” above the tuberculum sellae, or “postfixed” above the dorsum sellae.4 The optic chiasm is formed by the confluence of optic tracts posterolaterally and gives rise to the optic nerves anterolaterally. Other cranial nerves in this space include the oculomotor nerve, which parallels the optic nerve as it travels toward the superior orbital fissure, and olfactory tracts, which cross the optic nerves inferiorly and bifurcate superior to the anterior clinoid processes. Sphenoid Sinus Anterior and inferior to the sella is the sphenoid sinus, which is part of the body of the sphenoid bone. The sinus grows with age and has highly variable septal and cavitary architecture, factors that reduce the reliability of anatomic landmarks and reinforce the importance of thorough preoperative imaging.4-6 Also variable are the characteristics of the sphenoid ostia that drain the sphenoid sinus into the nasal cavity, specifically the spheno-ethmoidal recesses situated superiorly and posteriorly to the superior nasal turbinates. A thorough understanding of this variability, as well as the physical characteristics of the gland, itself, is critical to a safe sellar approach and tumor resection. Just as important as understanding an individual's sphenoid sinus anatomy is knowing their anatomy lateral to the sphenoid sinus walls. This area contains several important structures, including the optic canal, maxillary division of trigeminal nerve, and internal carotid artery. These structures closely abut the sinus’ outer surface, and in many cases, protrude or erode through where there is bony dehiscence of the sinus wall. Logically, protrusion of these structures as well as any bony dehiscence into the sinus can complicate the transsphenoidal approach with hemorrhage, visual loss, or cranial nerve palsy.7 TSS COMPLICATION RATES IN THE LITERATURE Multiple studies analyzing outcomes of microscopic TSS approaches to the sella have shown excellent outcomes with low rates of morbidity and mortality.8-10 In a comprehensive 1997 survey study, Ciric et al9 polled practicing neurosurgeons with a spectrum of surgical experience in a variety of practice settings and determined the most common TSS complications to be anterior pituitary insufficiency (19.4%), diabetes insipidus (17.8%), sinusitis (8.5%), septal perforation (6.7%), cerebrospinal fluid (CSF) leak (3.9%), epistaxis (3.4%), hemorrhage (2.9%), anesthetic complications (2.8%), loss of vision (1.8%), meningitis (1.5%), ophthalmoplegia (1.4%), central nervous system injury (1.3%), carotid artery injury (1.1%), and death (0.9%).9 Other studies involving microscopic endonasal TSS have demonstrated a similar array of complications, with rates of major morbidity of 1% to 2%, CSF leak in 2% to 9% and death in less than 1%.8-17 More recent studies have additionally shown better outcomes in high-volume surgical centers and with high-caseload surgeons, including lower rates of mortality and overall complications, shorter hospital length of stay, and superior discharge disposition.9,18 This supports the intuitive notion that patient safety, in addition to procedural efficacy, is enhanced by greater familiarity with a procedure and the associated anatomy and its variability. As it specifically relates to TSS for pituitary adenomas, this mastery, conferred by experience, seems to decrease the risk of complications across the spectrum. A closer look at the most common of these complications will highlight the specific anatomic and physiologic factors that must be considered in every case. Cerebrospinal Fluid Leak Pituitary adenomas are extra-arachnoidal tumors and, by definition, grow outside the confines of the CSF. Even with massive invasive disease, tumors do not often violate the arachnoid membrane and extend into the subarachnoid space. This means that the mechanism is frequently iatrogenic in nature whenever the arachnoid membrane is breached and a CSF fistula forms. This can occur at several stages of a particular operation, in several different locations. The diaphragma sellae is the most common location where CSF fistulae may arise. This is especially true in resections of larger pituitary adenomas, where a tumor's large mass can create redundancy in the arachnoid that, once the tumor is removed, may descend or herniate into the expanded sellar cavity. CSF fistula may also form as a consequence of operating too far superiorly, where cribriform plate injury in the ethmoidal region is possible, and may be associated with outfracturing of the middle turbinates.9 Not only could this lead to a CSF leak, but direct damage to the olfactory epithelium of the superior nasal cavity has the potential to lead to either transient or permanent anosmia. No matter the cause of a CSF leak, the consequences of one can be severe. If not repaired primarily or if treatment is inadequate, fluid loss may be significant enough to cause a decrease in CSF pressure below atmospheric, facilitating progression to pneumocephalus, tension pneumocephalus, or possible meningitis.19,20,13 Epistaxis There are several important sources of delayed postoperative epistaxis, including the sphenopalatine artery and the intracavernous internal carotid artery (ICA). When opening the sphenoid sinus anteriorly and inferiorly, there is a risk of injury to the sphenopalatine artery.13,21 It is critical to preserve the sphenopalatine artery and associated vascular pedicle to the nasal septum, in the event that a pedicled nasal-septal flap is required for repair of a high-grade CSF leak. Visual Loss Visual loss can result from physical insult to the optic nerves or chiasm, either from direct trauma or extreme traction. This can occur at multiple stages of the operation, both by advancing too far into the sphenoid body and by deviating the approach to its superior lateral wall.22 As discussed earlier, the bony structures separating sinus from adjacent structures in this location, such as optic canal, are often thin or missing, making any deviation in approach potentially perilous. Regardless of the cause, physical deformation of the optic canal and subsequent optic nerve compression may lead to ischemic injury. The nerve is especially susceptible at the proximal opening of the optic canal, where the overlying dura forms the falciform process.23 More commonly, vision loss associated with TSS develops as a result of overpacking of the sella when reconstructing the skull base. If acted on quickly, edema and monocular blindness may be reversed with prompt decompression and administration of high-dose steroids.24,25 Vision loss can also occur by traumatic injury to the orbit itself. Although not often used in the modern era of endoscopic endonasal approaches, the bivalve speculum historically favored for the transsphenoidal approach could fracture not only the sphenoid body, but the orbital wall as well. This potentially precipitated hemorrhage, either intrasellar or suprasellar, and could lead to orbital compartment syndrome and subsequent ischemia.26 Prompt hematoma evacuation for such events is critical. Other notable, albeit infrequent causes of postoperative visual loss include cerebral vasospasm and traction injury, especially in revision surgeries for previous craniotomies.27 The superior hypophyseal artery is an important vessel to identify and preserve during extended endonasal approaches for craniopharyngiomas and entities of the suprasellar region. Finally, empty sella syndrome with chiasm prolapse has also been documented as a cause of gradual postoperative visual deterioration.22,28 Ophthalmoplegia Of all the cranial nerves of the cavernous sinus, the abducens nerve is the most frequently injured, traveling medial to the ICA and lateral to V1.9 Oculomotor nerve palsy has also been documented after surgical manipulation in the cavernous sinus or excessive packing of the sella, often presenting with down-and-out gaze, ptosis, and mydriasis.24 Internal Carotid Artery Injury Although cadaveric studies have shown the intracavernous ICA to be typically 1–3 mm and as far as 7 mm away from the pituitary gland, it may sometimes protrude through the cavernous sinus wall and abut the gland itself.5,3 The close apposition of gland to ICA, combined with potentially deficient bony protection, reinforces the importance of maintaining a midline approach, even with adenomas extending laterally into the cavernous sinuses. Along with a thorough understanding of sellar region anatomy, additional strategies for reducing the risk of iatrogenic ICA injury associated with TSS include routine use of a micro-Doppler flow probe, neuronavigation, and avoidance of sharp instruments in the cavernous sinus region. Proximity to vital structures and thin or missing bone pose similar risks within the sphenoid sinus, as well. Multiple cadaveric and computed tomography (CT)-based studies have demonstrated ICA protrusion in 26% to 41% and dehiscence in 4% to 8% of cases, factors that increase the risk of iatrogenic injury.4,29-31 The most feared complication of such injuries is potential hemorrhage, which can be severe. Packing is the first-line treatment in these cases, and should be followed by postoperative angiography. Overpacking may lead to occlusion or stenosis and cerebral infarcts. Embolization is indicated when packing is ineffective or there is progression to pseudo-aneurysms or carotid cavernous fistulae.32,33 Diabetes Insipidus It is generally accepted that overly aggressive pituitary stalk manipulation accounts for the spectrum of water and electrolyte disturbances observed after TSS. Diabetes insipidus (DI) is one of the most common of these disturbances, occurring transiently in approximately 4% to 18% of resections.21,34 Traction to the stalk or direct posterior lobe injury can damage the magnocellular hypothalamic axons within and lead to subsequent deficits in antidiuretic hormone (ADH) production and secretion.35 The persistence and degree of DI is often associated with the level of injury to the infundibulum and posterior pituitary gland, with higher level stalk injuries posing a greater risk for permanent DI. In the setting of pituitary surgery, DI may present in multiple clinical patterns, including a transient phenotype, a permanent phenotype, and a classical triphasic phenotype in cases of extreme pituitary damage. In this triphasic phenotype, initial reductions in ADH cause a transient DI. Several days later, necrotic posterior lobe releases stored ADH, creating a clinical presentation of hyponatremia or normonatremia. Finally, around postoperative day 7 to 10, any SIADH-like presentation is replaced by a permanent DI.34,36,37 While there is limited research quantifying decreases in ADH secretion following pituitary damage, it is understood that reduced traction and careful handling of the gland decreases the risk for endocrine complications. A recent study mathematically modeled the hormonal changes associated with incremental pituitary damage, predicting possible transient DI after 20% posterior pituitary damage and permanent DI after 20% to 40%.37 Tumor characteristics and size are also important, as macroadenomas can provide the stalk a fibrous layer that helps prevent traction injury. Syndrome of Inappropriate Antidiuretic Hormone Secretion The same mechanisms that underlie the development of DI are thought to explain postoperative syndrome of antidiuretic hormone secretion (SIADH), including manipulation of the posterior lobe, stalk, and hypothalamus. Hyponatremia is typically delayed, presenting at around postoperative day 7. Depending on the severity of ADH deviation, hyponatremia may be asymptomatic or present clinically with lethargy, headache, nausea, or vomiting when serum sodium falls below 130 mEq/L. As discussed previously, preceding transient DI is a significant risk factor for the release of stored ADH and subsequent hyponatremia and euvolemia, and any indication for more thorough gland exploration will increase the risk of postoperative water and electrolyte disturbances.36,38 New or Worsened Hypopituitarism Preoperative hypopituitarism arising from a growing adenoma is thought to involve the hypothalamic-pituitary axes in a predictable sequence, with the somatotropic axis (growth hormone) most vulnerable, followed by the gonadal (follicle stimulating hormone and luteinizing hormone), thyroid (thyroid stimulating hormone), and adrenal (adrenocorticotrophic hormone) axes. Interruption of these axes can arise secondarily to several mechanisms, ranging from stalk and gland displacement to compression and obliteration. Depending on the size and growth pattern of the adenoma, subsequent impairment in hormonal transport can thus be either reversible or permanent in nature. Under ideal conditions, selective adenomectomy and gland or stalk decompression would therefore not only preserve existing pituitary function, but often improve it.39 Despite the potential for endocrine normalization, TSS also carries with it the risk of worsening preoperative hypopituitarism or development of new hypopituitarism. Although few studies differentiate among the axes involved in new or worsened hypopituitarism, a recent retrospective study suggested the hypothalamic-pituitary-adrenal (HPA) axis may be the most susceptible, with affected patients lacking postoperative ACTH and cortisol stress responses.40,41 For these surgeries complicated by HPA or other axis deficits, damage to normal residual gland may occur whenever the anterior pituitary gland is manipulated, with the risk especially high in large tumors that distort, diminish, and lift the gland superiorly towards the diaphragma sellae. This characteristic displacement of residual gland may partly explain the higher incidence of new hypopituitarism after transcranial surgeries, which inherently involve a superior sellar approach. Logically, the risk of dissecting attenuated, albeit normal gland is mitigated by a transsphenoidal approach that accesses the tumor from below, as does careful identification of any residual gland while working in the sella.42 Normal gland can be distinguished by its orange color and structural integrity that resists curettage and suction. Visualized anatomy should be compared with the glandular anatomy studied on preoperative T1-weighted imaging.9 Summary of Important Techniques to Minimize Operative Complications The potential for physical and endocrine morbidity following TSS is significant, and a thorough understanding of a patient's individual pituitary and sellar characteristics cannot be understated. Preoperative head CT scans and pituitary MRI with thin slices are paramount to mapping the patient's unique anatomy and serve as roadmaps to ensure the approach remains both midline and vertical in orientation. Deviation from this course can lead to significant morbidity and mortality, as an extreme superior angle may cause cribriform plate injury and subsequent CSF leak as well as ansomia, and an off-center approach may risk injury to lateral structures such as the intracavernous carotid arteries and cranial nerves. Just as crucial to familiarity with preoperative bony anatomy is the careful study of a patient's tumor growth patterns and gland displacement on preoperative T1-weighted imaging. This will help guide the surgical approach and enable gland preservation. When it comes to handling the pituitary gland, care should be taken to identify both lobes intraoperatively and differentiate tumor from both normal gland and stalk. This can prove to be very difficult, especially in large adenomas where the anterior pituitary gland, if not obliterated completely, may remain as a distorted, displaced remnant draping the tumor superiorly.43,44 While proper handling can be difficult when attempting to separate tumor from a normal but grossly distorted gland, it is critical for prevention of postoperative hypopituitarism. CONCLUSION The transsphenoidal approach remains the mainstay of treatment for a majority of PAs, with low rates of mortality or major disability when performed by experienced surgeons. It is nevertheless important to acknowledge the spectrum of adverse medical, endocrine, and surgical outcomes that can complicate PA resection, either in approaching the gland or treating its pathology. This necessitates a comprehensive knowledge of pituitary physiology and normal variation in sellar anatomy, factors that will not only improve procedural efficacy, but promote innovation to improve patient safety. Disclosure The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.