Accepted Manuscript Postoperative cerebral vasospasm following transsphenoidal pituitary adenoma surgery Chikezie I. Eseonu, MD, Karim ReFaey, MD, Romergryko G. Geocadin, MD, Alfredo Quinones-Hinojosa, MD PII: S1878-8750(16)30228-5 DOI: 10.1016/j.wneu.2016.04.099 Reference: WNEU 4028 To appear in: World Neurosurgery Received Date: 14 March 2016 Revised Date: 22 April 2016 Accepted Date: 25 April 2016 Please cite this article as: Eseonu CI, ReFaey K, Geocadin RG, Quinones-Hinojosa A, Postoperative cerebral vasospasm following transsphenoidal pituitary adenoma surgery, World Neurosurgery (2016), doi: 10.1016/j.wneu.2016.04.099. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ACCEPTED MANUSCRIPT Vasospasm and transsphenoidal surgery Eseonu et al. 1 RI PT Postoperative cerebral vasospasm following transsphenoidal pituitary adenoma surgery Chikezie I. Eseonu, MDb, Karim ReFaeyb, MD, Romergryko G. Geocadin, MDa, Alfredo Quinones-Hinojosa, MDb Department of Anesthesiology/Critical Care Medicine Division of Neuroscience Critical Care Department of Neurological Surgery and Oncology. Johns Hopkins University, Baltimore, Maryland Corresponding author: TE D Alfredo Quiñones-Hinojosa, M.D. M AN U b SC a Brain Tumor Stem Cell Laboratory Department of Neurosurgery and Oncology 1550 Orleans Street Baltimore, MD 21231 EP Cancer Research Building II Room 247 E-mail: aquinon2@jhmi.edu AC C Disclosure: No funding was received in the publication of this article. ACCEPTED MANUSCRIPT Vasospasm and transsphenoidal surgery Eseonu et al. 2 Abstract Purpose: Cerebral vasospasm following a transsphenoidal resection of a pituitary adenoma is a devastating occurrence that can lead to delayed cerebral ischemia and poor neurological outcome if not diagnosed and treated in RI PT a timely manner. The etiology of this condition is not well understood, but can lead to significant arterial vasospasm that causes severe ischemic insults. In this paper, we identify common presenting symptoms and essential management strategies to treat this harmful disease. Methods: A retrospective case report and literature review of presentation, treatment, and outcome of cerebral vasospasm following transsphenoidal surgery. SC Results: We present 1 case and review 12 known cases in the literature on vasospasm following transsphenoidal surgery. Mean age was 48 (± 13.8) years. There were 46.2% male patients. Factors associated with vasospasm, such as cerebral spinal fluid leaks following surgery were seen in 38.5% of cases, and postoperative subarachnoid M AN U hemorrhage (SAH) was seen in 84.6% of cases. Hemiparesis was the presenting symptom of delayed cerebral ischemia in 61.5% of cases. For management, maintaining at least a euvolemic volume status was used in 76.9%, induced hypertension was used in 61.5%, and nimodipine was administered in 46.2% of cases. Patients returned to their neurological baseline in 61.5% of cases, had new permanent deficits in 7.7% of cases, and died in 30.8% of cases. Conclusion: Cerebral vasospasm following transsphenoidal surgery is a dangerous disease that can lead to a high likelihood of mortality if not identified and treated. Early postoperative events, such as peritumoral SAH and TE D hemiparesis, may be factors associated with post-transsphenoidal surgery vasospasm. Effective treatment options used in patients that regained complete neurological recovery were by inducing hypertension, maintaining Keywords EP euvolemia, and administering nimodipine. Cerebral vasospasm, pituitary, macroadenoma, transsphenoidal, treatment AC C Running Title: Vasospasm and transsphenoidal surgery ACCEPTED MANUSCRIPT Vasospasm and transsphenoidal surgery Eseonu et al. 3 Introduction Cerebral vasospasm following transsphenoidal surgery (TSS) of a pituitary tumor is a rare occurrence that can result in long-term morbidity and death [1]. The pathophysiology of cerebral vasospasm following a TSS is not RI PT well understood and has mainly been described in the literature through case reports [2-7]. In accordance with the Neurocritical Care Society's (NCS) multidisciplinary consensus conference, the term vasospasm refers to radiographic evidence of arterial narrowing following SAH, while delayed cerebral ischemia (DCI) refers to neurological deteriorations that results from ischemia [8]. The mechanism of cerebral vasospasm following a transsphenoidal surgery is likely multifactorial, and may result when an intraoperative tear of the arachnoid leads to SC subarachnoid hemorrhage (SAH) in the basal cistern and eventually arterial narrowing in the circle of Willis that can lead to devastating ischemic insults [2, 4, 5, 9]. The rarity of this condition makes it difficult to predict and manage which can lead to a worse outcome [2, 5, 7]. The appropriate management for this condition is also poorly M AN U understood [10]. The case of a patient with cerebral vasospasm with delayed cerebral ischemia following a transsphenoidal resection of a large pituitary macroadenoma is presented and we evaluate 12 other known cases of cerebral vasospasm following TSS in the literature. We present the largest comprehensive review and analysis in the literature of all the reported cases on this topic. The etiology, presentation, and management of postoperative TSS vasospasm are also discussed. Methods TE D Our case report is based on one patient with postoperative cerebral vasospasm following TSS that was treated in 2014 at the Johns Hopkins Hospital. We reviewed the medical records for the purpose of this study. For the literature review, we searched the database of PUBMED using search terms: vasospasm, pituitary, transsphenoidal, and adenoma in all combinations. All original articles reviewed were published between 1980 and 2013 and included 12 cases of transsphenoidal surgeries for pituitary lesions. We performed an analysis on all 13 EP patients regarding age, gender, preoperative symptom presentation, postoperative cerebral spinal fluid (CSF) leak, postoperative subarachnoid hemorrhage, delayed cerebral ischemia, duration of vasospasm, management, and Case AC C clinical outcome. A 43 year old otherwise healthy female, with no history of migraines, presented to her primary care physician with headache, fatigue, and blurred vision for several days. Physical examination revealed a bitemporal hemianopsia and a left optic nerve atrophy, with no other neurological deficits or symptoms of Cushing's disease. Endocrinology studies showed an elevated 8 AM cortisol and ACTH level. (Table 1). A subsequent preoperative MRI revealed a 2.9 x 3.1 x 3.9 cm (in the transverse, anteroposterior, and craniocaudal dimensions) enhancing pituitary mass with suprasellar extension and compression of the optic chiasm (Fig 1). The mass also extended laterally into the right cavernous sinus. No dedicated vascular imaging was done preoperatively, but a review of the MRI showed normal flow voids of the supraclinoidal internal carotid arteries ACCEPTED MANUSCRIPT Vasospasm and transsphenoidal surgery Eseonu et al. 4 (ICA) and proximal middle cerebral arteries (MCA) bilaterally. Given the large size of the pituitary tumor and the symptoms of the patient, a surgical resection was pursued. The patient underwent an endoscopic endonasal transsphenoidal approach for resection of a pituitary RI PT tumor. She was intubated under general anesthesia and sedated using fentanyl and propofol infusions. The suprasellar component of the tumor was fibrous and extended into the third ventricle, pushing up against the hypothalamus. An extensive resection was safely conducted with preservation of the normal pituitary gland. There was cerebral spinal fluid (CSF) leak seen intraoperatively after the resection, which required a comprehensive skull base reconstruction using a fat graft, polymer hemostatic agents (surgicel, Ethicon), absorbable gelatin sponges SC (Gelfoam, Pfizer), and fibrin glue (DuraSeal, Covidien). No complications were incurred during the procedure and the pathology specimen showed a pituitary adenoma, positive for ACTH immunoreactivity. The patient tolerated the procedure well, and postoperatively remained without any new neurological M AN U deficits. A postoperative MRI showed a small amount of residual tumor along the suprasellar surgical bed with some hemorrhage in the tumor bed (Fig 2). The patient spent six days in the neurocritical care unit for management of diabetes insipidus (DI), which required close monitoring of volume status and was treated with vasopressin and free water repletion. Upon transferring to the neurosurgical floor, she continued to experience a milder form of headache that would self resolve, as well as DI that required a low dose of nightly desmopressin upon discharge on postoperative day 10. Two days after discharge, the patient experienced an acute onset of left sided paresthesia, left arm weakness, and expressive aphasia while at home. She returned to the hospital, and given the concern for stroke, TE D an MRA was obtained which showed narrowing of the bilateral supraclinoid internal carotid arteries and M1 segments of the middle cerebral arteries consistent with vasospasm (Fig 3). A small focus of restricted diffusion was also found in the right insular region. Transcranial dopplers (TCDs) showed elevated cerebral blood flow velocities of 312 cm/s on the right M1 MCA and 265 cm/s on the left M1 MCA with Lindegaard ratios of 8.9 and 7.6 respectively. The patient was admitted to the neurocritical care unit and hemodynamic management using induced EP hypertension and euvolemia was started with saline boluses as well as a phenylephrine infusion to help meet mean arterial pressure goals. Oral nimodipine was also administered, and no signs of hypotension were observed. Neurologically, her exam began to improve 48 hours after beginning the hemodynamic therapy, and there was AC C gradual resolution of her vessel narrowing on serial imaging and TCDs over the course of sixteen days, at which point she returned to her neurological baseline. She was discharged home and postoperative hormonal profile normalized (Table 2). Results Cases were searched for on Pubmed.org using keywords vasospasm, pituitary, transsphenoidal, and adenoma in all combinations. We identified all cases of cerebral vasospasm following transsphenoidal surgery, identified by digital subtraction angiography (DSA) or magnetic resonance angiography, between 1980 to 2013, which comprised of 12 cases that were reported as case reports. Table 3 summarizes the demographics, presenting symptoms, management, and outcome of all 13 patients, including our case report. ACCEPTED MANUSCRIPT Vasospasm and transsphenoidal surgery Eseonu et al. 5 The mean age at presentation was 48 ± 13.8 years (range 30-74), and 46.2% of the patients were male. Preoperative symptom presentation consisted of headaches (38.5%), vision changes (69.2%), galactorrhea (23.1%), amenorrhea (15.4%), decreased libido (7.7%), and fatigue (7.7%). Vision loss was the first presenting symptom in RI PT 53.8% of the patients (Table 4). Following the surgical procedure, CSF leak was seen in 38.5% of cases, and postoperative subarachnoid hemorrhage were seen in 84.6% of cases that had postoperative imaging. Vasospasm occurred at a mean of 8.62 ± 3.0 days after surgery. Symptoms of delayed cerebral ischemia presented as hemiparesis (61.5%), aphasia (30.8%), lethargy (30.8%), cranial nerve palsies (7.7%), cognitive decline (15.4%), seizures (7.7%), and paresthesias (7.7%). SC DCI symptoms lasted for a mean of 14.6 ± 11.7 days (Table 5). For management, euvolemia or hypervolemia were used in 76.9% of cases, hypertension (61.5%), hemodilution (53.8%), nimodipine (46.2%), intra-arterial papaverine (30.8%), balloon angioplasty (15.4%), intra- M AN U arterial verapamil (15.4%), and thromboxane A2 antagonist (7.7%) (Table 6). Eight of the patients (61.6%) returned to their neurological baseline. Of these, one patient was treated with balloon angioplasty alone, one patient with balloon angioplasty, hypertension, hypervolemia, and hemodilution, two patients with hypertension, hypervolemia, hemodilution, and nimodipine, one patient with hypertension, euvolemia, and nimodipine, one patient with intra-arterial verapamil, hypertension, hypervolemia, hemodilution, and nimodipine, one patient with intra-arterial papaverine, hypertension, hypervolemia, hemodilution, and nimodipine, and one patient with intra-arterial papaverine, hypertension, hypervolemia, hemodilution, and thromboxane A2 TE D antagonist. (30.8%) died. Discussion Etiology EP One patient (7.7%) had a new permanent neurological deficit following her vasospasm, and four patients Multiple proposals for why vasospasm occurs after TSS have been made. Blood collection in the basal AC C cisterns, direct arterial wall damage, and hypothalamic damage have been a few of the proposals [10-12]. Additional hypotheses suggest that cerebral vasospasm tends to occur with pituitary tumors that have suprasellar extension, given the proximity of the tumor with the circle of Willis, or with TSS that is complicated with SAH or meningitis [1, 9]. The arterial spasm may be aggravated by hemoglobin degradation products (oxyhemoglobin and methemoglobin), synthetic hemostatic material, and peritumoral humoral factors [1]. These factors activate proinflammatory cytokines that lead to oxidative stress and reduce endothelium nitric oxide which can narrow the diameter of the cerebral vasculature [13, 14]. A concomitant cerebral aneurysm near the pituitary tumor that ruptures during surgery can also be a cause of postoperative aneurysmal subarachnoid hemorrhage induced vasospasm, however, in our case, postoperative cerebral angiograms taken two months after surgery showed no signs of any aneurysms. ACCEPTED MANUSCRIPT Vasospasm and transsphenoidal surgery Eseonu et al. 6 In the literature, we reviewed the handful of case reports and case series that have reported cerebral vasospasm following transsphenoidal surgical resections of pituitary adenomas [2-7, 10-12, 15, 16]. The first description of cerebral vasospasm following TSS was described in 1980 by Camp et al. The authors suggested that RI PT SAH with direct extension into the basal cisterns or the fat/synthetic material influence on the basal cisterns could be a cause [2]. Puri et al. hypothesized that patients with large macroadenomas with significant suprasellar extension who underwent a subtotal resection with postoperative blood product within the tumor capsule and subarachnoid space were more susceptible to vasospasm [1]. In our case, the postsurgical blood in the resection cavity may have extended to the basal cistern and caused this spastic response in the cerebral vessels. We found that in the reported SC cases, postoperative SAH was seen in 84.6% of the cases and hemiparesis was seen in 61.5% of cases. The large percentage of cases with these findings suggest that they may prove to be key warning signs postoperatively that M AN U indicate increased risk for cerebral vasospasm. Management Strategy The radiographic findings of vasospasm, and onset of delayed cerebral ischemia after TSS has been reported to range from 3 days to 2 weeks after surgery [7, 11, 17]. We found in our review that symptom onset began around 8-9 days. With mortality occurring in over 30% of the 13 reported cases, appropriate treatment strategies must be implemented once these symptoms present and vasospasm has been confirmed with angiographic imaging. TE D Multiple treatment modalities have been proposed for postoperative TSS vasospasm including hemodynamic augmentation therapy using hypertension and euvolemia, thromboxane A2 antagonists, calcium channel blockers, endovascular angioplasty or intra-arterial vasodilators, and intrathecal thombolytics [6, 7]. For decades, triple-H therapy (hypertension, hypervolemia, and hemodilution) was the standard treatment for DCI, however studies evaluating the contribution of triple-h therapy for improving cerebral blood flow (CBF) and brain EP tissue oxygenation (PbtO2), key aspects when treating DCI, have found only certain components of the therapy effective [8]. Hypervolemia was a commonly used treatment modality for DCI in the reviewed studies, however, for intravascular volume expansion, hypervolemia has been shown to not offer any additional benefit over euvolemia AC C when treating DCI, and has had complications of fluid overload, congestive heart failure, pulmonary edema, and cardiac arrhythmias [8, 18, 19]. Regardless of the patient's volume status, induced hypertension, however, has been shown to raise cerebral blood flow (CBF) and improve neurological status in the majority of treated patients [19-23]. Hypervolemia alone was used in two of the cases where a patient died, and likely proved to be a less effective therapy without adequate maintenance of a hypertensed state.[2, 6] Hemodilution was also often reported for treating DCI, however this strategy has been shown to reduce arterial oxygen content, in the setting of hypervolemic increases of CBF, which causes a reduction in the overall amount of oxygen being delivered to the brain [24]. From triple-H therapy, induced hypertension appears to be an effective component for treatment of DCI, while euvolemia provides adequate intravascular expansion while limiting the complications that result from fluid overload. ACCEPTED MANUSCRIPT Vasospasm and transsphenoidal surgery Eseonu et al. 7 Unlike cerebral vasospasm management following aneurysmal SAH, after transsphenoidal surgery, additional challenges with volume management given the frequent development of diabetes insipidus make maintaining euvolemic therapy for DCI difficult. Some studies have reported an association between hyponatremia RI PT and vasospasm following aneurysmal SAH, but none following TSS [25-28]. However, hyponatremia cannot be considered as solely a standard hormonal dysequilibrium in the first postoperative week of a TSS and may serve as an early sign of DCI [9]. From our review, we found that induced hypertension was used in 87.5%, maintaining at least a euvolemic volume state was used in 87.5%, and nimodipine was administered in 75% of the TSS vasospasm cases that resulted SC in complete neurological recovery. Similar to vasospasm following aneurysmal SAH, induced hypertension (often with a vasopressor), euvolemia, and nimodipine cause intra-arterial hypertension that attempts to expand the circulating blood volume in a patient to counteract the arterial vasospasm and has been shown to be beneficial [29]. M AN U In addition, preoperative imaging for TSS routinely consists of a contrast enhanced MRI scan, with no dedicated vascular imaging. If postoperative cerebral vasospasm occurs then there is no comparative prior imaging to help guide intensity or duration of the treatment strategy. From our review, it may prove helpful to obtain a quick computed tomography or magnetic resonance angiography (MRA) following TSS in cases that have postoperative peritumoral SAH, or add an MRA sequence to the preoperative imaging for a baseline scan. For our reported case, the postoperative MRA provided us with adequate imaging with serial, less invasive MRA scans to follow the resolving vasospasm. The patient responded well to medical management and did not need any endovascular TE D intervention, so a DSA was not used in this case. From the four reported deaths in the case reports that were reviewed, various management strategies were used from hypervolemia to intra-arterial papaverine [1, 2, 5, 6]. Interventions were made immediately following image confirmation of vasospasm, however, in each of these cases, the patients never showed any clinical or imaging improvements in their condition. In two of the cases, hypervolemic therapy alone was used unsuccessfully EP without proper maintenance of a hypertensed state, suggesting that the combination of a hypertensed state while maintaining at least euvolemia may be more effective treatment for vasospasm. Prevention AC C Given the unknown etiology of vasospasm following TSS, little is known about prevention of this occurrence. Applying effective cauterization and ample irrigation during the surgical operation may minimize the amount of subarachnoid blood that develops in the basal cistern which may reduce the occurrence of vasospasm. In addition, three of the four deaths reported in this paper also presented with CSF leaks intraoperatively that were repaired during the case. Although no signs of sepsis or meningitis were reported, two of the patients did have poikilothermia prior to death. While the cause of the poikilothermia is unknown, thorough CSF leak repair, appropriate postoperative antimicrobials, along with aggressive vasospasm may treat infectious agents that could exacerbate vasospasm. More importantly, preventing vasospasm-associated delayed cerebral ischemia is clinically a more relevant issue. Following aneurysmal subarachnoid hemorrhage, vasospasm is found to occur in 60-70% of patients, but not ACCEPTED MANUSCRIPT Vasospasm and transsphenoidal surgery Eseonu et al. 8 all of these patients experience DCI or any clinical symptoms. Methods that can be used to prevent DCI include calcium channel blockers, such as nimodipine, and most recently, nitric oxide delivery drugs, like molsidomine, which have been shown to reduce the risk of DCI [30]. Nimodipine in our review proved an effective therapy in the RI PT treatment of TSS vasospasm as well. It could be postulated that utilizing nimodipine once SAH is observed, postTSS, may reduce the incidence of neurological deficits, but first, more comprehensive prospective multi-center studies are needed to determine this and more standardized management approaches to TSS vasospasm.. Limitations of the Study This study is a retrospective analysis of case reports gathered over the past thirty-five years. Although this SC represents the cases that have been reported in the literature, it is a small sample size of what we suspect is a more common issue in neuro-critical care. Future randomized controlled, prospective studies are needed to evaluate the significance of potential predictors and effective treatment modalities reported in this study. In addition, evaluating M AN U tumor volumetrics and extent of resection in relation to occurrence of post TSS vasospasm may also give insight to vasospasm predictors. Conclusion Vasospasm and delayed cerebral ischemia following TSS are devastating occurrences that can have damaging postoperative ischemic events, neurological morbidity, and high mortality in a patient. Potential factors associated with TSS vasospasm may include postoperative peritumoral SAH and hemiparesis. We found that common treatment options that resulted in complete neurological recovery from DCI included treating with induced TE D hypertension, maintaining euvolemia, and administering nimodipine. Conflict of Interest: The authors declare that they have no conflict of interest. EP References AC C 1. Puri AS, Zada G, Zarzour H et al (2012) Cerebral vasospasm after transsphenoidal resection of pituitary macroadenomas: report of 3 cases and review of the literature. Neurosurgery 71(1 Suppl Operative):173-80; discussion 180-1. 10.1227/NEU.0b013e31824aae21 [doi] 2. Camp PE, Paxton HD, Buchan GC et al (1980) Vasospasm after trans-sphenoidal hypophysectomy. Neurosurgery 7(4):382-386 3. Barrow DL, Tindall GT (1990) Loss of vision after transsphenoidal surgery. Neurosurgery 27(1):60-68 4. Friedman JA, Meyer FB, Wetjen NM et al (2001) Balloon angioplasty to treat vasospasm after transsphenoidal surgery. Case illustration. J Neurosurg 95(2):353. 10.3171/jns.2001.95.2.0353 [doi] 5. Hyde-Rowan MD, Roessmann U, Brodkey JS (1983) Vasospasm following transsphenoidal tumor removal associated with the arterial changes of oral contraception. Surg Neurol 20(2):120-124 6. Kasliwal MK, Srivastava R, Sinha S et al (2008) Vasospasm after transsphenoidal pituitary surgery: a case report and review of the literature. Neurol India 56(1):81-83 ACCEPTED MANUSCRIPT Vasospasm and transsphenoidal surgery Eseonu et al. 9 7. Nishioka H, Ito H, Haraoka J (2001) Cerebral vasospasm following transsphenoidal removal of a pituitary adenoma. Br J Neurosurg 15(1):44-47 RI PT 8. Diringer MN, Bleck TP, Claude Hemphill J,3rd et al (2011) Critical care management of patients following aneurysmal subarachnoid hemorrhage: recommendations from the Neurocritical Care Society's Multidisciplinary Consensus Conference. Neurocrit Care 15(2):211-240. 10.1007/s12028-011-9605-9 [doi] 9. Kim EH, Oh MC, Kim SH (2013) Angiographically documented cerebral vasospasm following transsphenoidal surgery for pituitary tumors. Pituitary 16(2):260-269. 10.1007/s11102-012-0415-7 [doi] SC 10. Bejjani GK, Sekhar LN, Yost AM et al (1999) Vasospasm after cranial base tumor resection: pathogenesis, diagnosis, and therapy. Surg Neurol 52(6):577-83; discussion 583-4. S0090301999001081 [pii] 11. Aoki N, Origitano TC, al-Mefty O (1995) Vasospasm after resection of skull base tumors. Acta Neurochir (Wien) 132(1-3):53-58 M AN U 12. Mawk JR, Ausman JI, Erickson DL et al (1979) Vasospasm following transcranial removal of large pituitary adenomas. Report of three cases. J Neurosurg 50(2):229-232. 10.3171/jns.1979.50.2.0229 [doi] 13. Asano T (1999) Oxyhemoglobin as the principal cause of cerebral vasospasm: a holistic view of its actions. Crit Rev Neurosurg 9(5):303-318. 90090303.329 [pii] 14. Provencio JJ, Vora N (2005) Subarachnoid hemorrhage and inflammation: bench to bedside and back. Semin Neurol 25(4):435-444. 10.1055/s-2005-923537 [doi] TE D 15. el Hendawy M, Wronski J, Juniewicz H et al (2000) Cerebral vasospasm detection by TCD after supratentorial brain tumours surgery. Neurol Neurochir Pol 34(6 Suppl):114-123 16. LeRoux PD, Haglund MM, Mayberg MR et al (1991) Symptomatic cerebral vasospasm following tumor resection: report of two cases. Surg Neurol 36(1):25-31 EP 17. Gupta R, Sharma A, Vaishya R et al (2013) Ischemic complications after pituitary surgery: a report of two cases. J Neurol Surg A Cent Eur Neurosurg 74 Suppl 1:e119-23. 10.1055/s-0032-1328955 [doi] AC C 18. Egge A, Waterloo K, Sjoholm H et al (2001) Prophylactic hyperdynamic postoperative fluid therapy after aneurysmal subarachnoid hemorrhage: a clinical, prospective, randomized, controlled study. Neurosurgery 49(3):593-605; discussion 605-6 19. Raabe A, Beck J, Keller M et al (2005) Relative importance of hypertension compared with hypervolemia for increasing cerebral oxygenation in patients with cerebral vasospasm after subarachnoid hemorrhage. J Neurosurg 103(6):974-981. 10.3171/jns.2005.103.6.0974 [doi] 20. Muench E, Horn P, Bauhuf C et al (2007) Effects of hypervolemia and hypertension on regional cerebral blood flow, intracranial pressure, and brain tissue oxygenation after subarachnoid hemorrhage. Crit Care Med 35(8):184451; quiz 1852. 10.1097/01.CCM.0000275392.08410.DD [doi] 21. Brown FD, Hanlon K, Mullan S (1978) Treatment of aneurysmal hemiplegia with dopamine and mannitol. J Neurosurg 49(4):525-529. 10.3171/jns.1978.49.4.0525 [doi] ACCEPTED MANUSCRIPT Vasospasm and transsphenoidal surgery Eseonu et al. 10 22. Otsubo H, Takemae T, Inoue T et al (1990) Normovolaemic induced hypertension therapy for cerebral vasospasm after subarachnoid haemorrhage. Acta Neurochir (Wien) 103(1-2):18-26 RI PT 23. Kosnik EJ, Hunt WE (1976) Postoperative hypertension in the management of patients with intracranial arterial aneurysms. J Neurosurg 45(2):148-154. 10.3171/jns.1976.45.2.0148 [doi] 24. Ekelund A, Reinstrup P, Ryding E et al (2002) Effects of iso- and hypervolemic hemodilution on regional cerebral blood flow and oxygen delivery for patients with vasospasm after aneurysmal subarachnoid hemorrhage. Acta Neurochir (Wien) 144(7):703-12; discussion 712-3. 10.1007/s00701-002-0959-9 [doi] SC 25. Qureshi AI, Suri MF, Sung GY et al (2002) Prognostic significance of hypernatremia and hyponatremia among patients with aneurysmal subarachnoid hemorrhage. Neurosurgery 50(4):749-55; discussion 755-6 26. Chandy D, Sy R, Aronow WS et al (2006) Hyponatremia and cerebrovascular spasm in aneurysmal subarachnoid hemorrhage. Neurol India 54(3):273-275 M AN U 27. McGirt MJ, Blessing R, Nimjee SM et al (2004) Correlation of serum brain natriuretic peptide with hyponatremia and delayed ischemic neurological deficits after subarachnoid hemorrhage. Neurosurgery 54(6):136973; discussion 1373-4 28. Wu CT, Wong CS, Yeh CC et al (2004) Treatment of cerebral vasospasm after subarachnoid hemorrhage--a review. Acta Anaesthesiol Taiwan 42(4):215-222 29. Awad IA, Carter LP, Spetzler RF et al (1987) Clinical vasospasm after subarachnoid hemorrhage: response to hypervolemic hemodilution and arterial hypertension. Stroke 18(2):365-372 EP Figures: TE D 30. Ehlert A, Schmidt C, Wolfer J et al (2016) Molsidomine for the prevention of vasospasm-related delayed ischemic neurological deficits and delayed brain infarction and the improvement of clinical outcome after subarachnoid hemorrhage: a single-center clinical observational study. J Neurosurg 124(1):51-58. 10.3171/2014.12.JNS13846 [doi] Figure 1 Contrast enhanced T1 MRI showing a pituitary macroadenoma in the A) sagittal, B) coronal, C) axial, and D) T2 weighted coronal views AC C Figure 2. Postoperative contrast enhancing T1 MRI showing extensive resection of a pituitary macroadenoma with small residual tumor (*) and postoperative blood in the resection cavity (↑) in the A) sagittal and B) coronal views Figure 3. MR angiography showing vasospasm of the bilateral supraclinoidal ICA (>) and M1 segments of the MCA (↑) in the A) coronal, B) left sagittal views ACCEPTED MANUSCRIPT Table 1: Preoperative hormonal profile taken at 8 AM Hormone (normal) Serum Level Free T4 (0.82-1.77) 0.83 ng/dl TSH (0.45-4.5) 1.430 mIU/L Cortisol (2.3-19.4) 22.4 mcg/dl Prolactin (4.8-23.3) 10.3 ng/ml Serum Level 1.7 mIU/ml 5.3 mIU/ml 63 pg/ml 162 ng/ml AC C EP TE D M AN U SC Hormone LH (1.7-11.2) FSH (1.5-12.4) ACTH (6-50) IGF-I (62-204) RI PT TABLES: ACCEPTED MANUSCRIPT Serum Level 33 pg/ml 128 ng/ml AC C EP TE D M AN U SC Hormone ACTH (6-50) IGF-I (62-204) RI PT Table 2: Postoperative hormonal profile taken at 8 AM Hormone (normal) Serum Level Free T4 (0.82-1.77) 1.1 ng/dl TSH (0.45-4.5) 1.430 mIU/L Cortisol (2.3-19.4) 8.2 mcg/dl ACCEPTED MANUSCRIPT # of cases 1 Age 33 Gender F Presenting symptoms amenorrhea, galactorrhea CSF leak yes SAH no POD of vasospasm 6 symptoms during vasospasm left hemiparesis, left 6th & 7th nerve paresis Friedman et al.4, 2001 1 41 M acromegaly no no 10 aphasia, right arm weakness HydeRowan et al.5, 1983 Nishioka et al.7, 2001 1 30 F galactorrhea, headache, blurred vision no yes 2 1 41 M decreased libido, vision changes no yes 12 disorientation, left hemiparesis Kasliwal et al.6, 2008 1 34 F amenorrhea, galactorrhea, headache, vision changes yes yes 13 right weakness, right body convulsions Puri et al.1, 2012 3 59 M n/a no 36 F vision loss 66 M headache 51 M vision loss TE D SC M AN U lethargy 4 left cavernous and bifurcation ICA bilateral supraclinoid ICA, ACA, right MCA n/a Management volume expansion Outcome death 8 hours balloon angioplasty No deficits reported 19 n/a death 19 days intra-arterial papaverine, hypervolemia, hypertension, hemodilution therapy, thromboxane A2 antagonist hypervolemic therapy recovery to baseline intra-arterial verapamil, hypervolemia, hypertension, hemodilution therapy, nimodipine hypervolemia, hypertension, hemodilution therapy, nimodipine, endovascular intervention intra-arterial verapamil hypervolemia, discharge rehab, No deficits reported aphasia yes 9 aphasia diffuse vasospasm 30 days yes yes 9 somnolence n/a no yes 9 mental status bilateral ACA, left PCA right ACA AC C Kim et al.9, Duration of symptoms 30 days 5 no yes Vasospasm Location Right supraclinoid ICA, pcomm artery left supraclinoid ICA bilateral supraclinoid ICA Right MCA, ACA, distal ICA RI PT Author, Year Camp et al.2, 1980 EP Table 3:Previous case reports for Vasospasm following transsphenoidal surgery 24 days n/a death discharge home, No deficits reported death No deficits ACCEPTED MANUSCRIPT no yes 9 65 F vision loss no yes 7 51 F vision loss yes yes 43 F Headache, fatigue, vision loss No Yes RI PT vision loss, headache left weakness left ACA 2 days somnolence, subjective left weakness left ACA 3 days left weakness, somnolence Right MCA, ACA, distal ICA 3 days Aphasia, left weakness, paresthesia Bilateral supraclinoid ICA 16 days M AN U M 9 TE D 1 74 EP Eseonu et al., 2016 deterioration SC 2013 12 hypertension, hemodilution therapy, nimotop infusion papaverine, hypervolemia, hypertension, hemodilution therapy, nimotop infusion intra-arterial papaverine, hypervolemia, hypertension, hemodilution therapy intra-arterial papaverine, hypervolemia, hypertension, hemodilution therapy, nimotop Hypertension, euvolemia, phenylephrine, nimodipine reported No deficits reported Discharged with slight weakness No deficits reported No deficits reported AC C SAH: subarachnoid hemorrhage, POD: postoperative day, ICA: internal carotid, MCA: middle cerebral artery, ACA: anterior cerebral artery, PCA: posterior cerebral artery, pcomm: posterior communicating artery ACCEPTED MANUSCRIPT RI PT Table 4: Preoperative characteristics of the 13 patients n (%) 48 ± 13.8 years male headache 6 (46.2) 5 (38.5) vision 9 (69.2) galactorrhea amenorrhea 3 (23.1) 2 (15.4) acromegaly 1 (7.7) decreased libido fatigue 1 (7.7) 1 (7.7) AC C EP TE D M AN U SC age (mean ± SD) ACCEPTED MANUSCRIPT RI PT Table 5: Postoperative characteristics and vasospasm symptoms of the 13 patients aphasia 4 (30.8) lethargy cognitive decline 4 (30.8) 2 (15.4) CN palsy 1 (7.7) seizures paresthesia 1 (7.7) 1 (7.7) M AN U 8 (61.5) 5 (38.5) TE D Hemiparesis CSF leak EP 11 (84.6) AC C SAH SC n (%) ACCEPTED MANUSCRIPT RI PT Table 6: Postoperative management of the 13 patients Hypertension Hemodilution 8 (61.5) 7 (53.8) nimodipine 6 (46.2) intra-arterial papaverine balloon angioplasty 4 (30.8) 2 (15.4) intra-arterial verapamil 2 (15.4) thromboxan A2 antagonist 1 (7.7) M AN U 10 (76.9) AC C EP TE D Euvolemia, hypervolemia SC n (%) AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT Conflicts of Interest: None ACCEPTED MANUSCRIPT Highlights AC C EP TE D M AN U SC RI PT Etiology and physiology of vasospasm following a transsphenoidal pituitary surgery is hypothesized Thirteen known cases of vasospasm following transsphenoidal pituitary surgery are evaluated Common presenting symptoms and an effective systematic management strategy for posttranssphenoidal surgery vasospasm is presented