Journal of Clinical Neuroscience 34 (2016) 33–38 Contents lists available at ScienceDirect Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn Review Cerebral vasospasm and delayed ischaemic deficit following elective aneurysm clipping Anastasia Tsyben a,1, Iddo Paldor b,1, John Laidlaw b,c,⇑ a School of Clinical Medicine, University of Cambridge, Cambridge, UK Department of Neurosurgery, Royal Melbourne Hospital, Parkville, VIC 3050, Australia c Department of Surgery, University of Melbourne, Parkville, VIC, Australia b a r t i c l e i n f o Article history: Received 25 May 2016 Accepted 23 June 2016 Keywords: Clipping Delayed ischaemic deficit Intracranial aneurysm Unruptured aneurysm Vasospasm a b s t r a c t Although common after subarachnoid haemorrhage, cerebral vasospasm (CVS) and delayed ischaemic neurological deficit (DIND) rarely occur following elective clipping of unruptured aneurysms. The onset of this complication is variable and its pathophysiology is poorly understood. We report two patients with CVS associated with DIND following unruptured aneurysmal clipping. The literature is reviewed and the potential mechanisms in the context of patient presentations are discussed. A woman aged 53 and a man aged 70 were treated with elective clipping of unruptured middle cerebral artery aneurysms, the older patient also having an anterior communicating artery aneurysm clipped. The operations were uncomplicated with no intra-operative bleeding, no retraction, no contusion, no middle cerebral artery (MCA) temporary clipping, and no intra-operative rupture. Routine post-operative CT scan and CT angiogram showed that in both patients the aneurysms were excluded from the circulation and there was no perioperative subarachnoid blood. Both patients had no neurological deficit post-operatively, but on day 2 developed DIND and vasospasm of the MCA. Both patients had angiographic improvement with intraarterial verapamil treatment. In one patient, this was done promptly and the patient made a complete recovery, but in the other, the diagnosis was delayed for more than 24 hours and the patient had residual hemiparesis and dysphasia due to MCA territory infarction. CVS and DIND following treatment of unruptured aneurysms is a very rare event. However, clinicians should be vigilant as prompt diagnosis and management is required to minimise the risk of cerebral infarction and poor outcome. Ó 2016 Elsevier Ltd. All rights reserved. 1. Introduction Cerebral vasospasm (CVS) is commonly seen following subarachnoid haemorrhage (SAH), occurring in 2/3 of patients, beginning around day 3–5 following haemorrhage and resolving around day 14 [1]. It is characterised by arterial narrowing seen on radiological imaging that is not due to atherosclerosis or catheterinduced spasm [2,3]. The incidence of CVS following SAH closely correlates with the amount of blood within the subarachnoid space [4,5]. Approximately one third of CVS patients after SAH develop delayed ischaemic neurological deficits (DIND) [2,6,7]. Previous studies have indicated that CVS following SAH is associated with the breakdown of clot in the subarachnoid space, [8–10] implicating a role for the vasospastic mediators released from lysed red blood cells [11–13]. The onset of DIND also occurs ⇑ Corresponding author. Tel.: +61 3 93471533; fax +61 3 93472633. 1 E-mail address: john.laidlaw@mh.org.au (J. Laidlaw). These authors have contributed equally to the manuscript. http://dx.doi.org/10.1016/j.jocn.2016.06.006 0967-5868/Ó 2016 Elsevier Ltd. All rights reserved. at approximately the time of maximal haemolysis [14]. Based on the widely-held assumption that CVS was the primary cause of DIND, the somewhat misleading term of ‘‘clinical vasospasm” was previously used interchangeably with DIND [15,3]. However, because the role of CVS as the sole or primary cause of DIND is currently debated [16,17] we will confine the use of the term CVS to demonstrable arterial narrowing, and DIND to a clinical deficit. Only 20–40% of SAH vasospasm patients develop DIND [2,6,7]. The severity of CVS also does not always correlate with the development of neurological symptoms [15,3]. Although the pathophysiology behind this discrepancy is not well understood, endothelial dysfunction, loss of autoregulation and microvascular thrombosis have been proposed to play a major role [18]. In addition to CVS, other factors may play a causative role in the development of DIND including early brain injury and cortical spreading depolarisation [19,20]. Although common after SAH, CVS and DIND are extremely rare following elective treatment of unruptured aneurysms. We report two cases, one of a 53-year-old woman and another of a 34 A. Tsyben et al. / Journal of Clinical Neuroscience 34 (2016) 33–38 70-year-old man developing CVS with DIND on the second postoperative day following elective clipping of unruptured aneurysms. To our knowledge this is the first reported case of angiographically proven CVS and DIND in a male patient following successful clipping of an unruptured aneurysm, and both patients demonstrated onset of CVS and DIND earlier than has been previously reported. A B C 2. Clinical presentation 2.1. Patient 1 A 53-year-old, right handed woman, presented for elective clipping of a 5 mm distal left M1 segment middle cerebral artery (MCA) aneurysm. The aneurysm had been discovered coincidentally on CT scan and MRI for unrelated neck and shoulder pain. There was no history or radiographic evidence to suggest prior bleeding from the aneurysm. The aneurysm was confirmed preoperatively with digital subtraction angiography (DSA) (Fig. 1A). The patient underwent a left pterional craniotomy and uneventful exposure of the aneurysm, which arose from the origin of a significant frontal branch of the M1, about 8 mm proximal to the main MCA bifurcation. Miniclip application across the aneurysm neck caused initial compromise of flow to this frontal branch, and the clip was repositioned three times until satisfactory flow could be determined. There was no evidence of any prior SAH and no intraoperative rupture of the aneurysm. No temporary clipping or retractors were used during the operation and no veins or arterial branches were injured or sacrificed. The patient awoke and was extubated immediately post-operative and had no speech, motor or any other neurological deficit, and was walking the day of surgery. Routine post-operative CT scan on the day of surgery showed no blood in the Sylvian fissure or basal cisterns. The patient remained perfectly well until 30 hours after the operation, when she rapidly developed dysphasia and fluctuant right hemiparesis predominantly affecting the upper limb. The diagnosis of vasospasm was not initially considered, and a presumptive diagnosis at that time was thrombosis of the frontal branch, or possibility subclinical seizure. CT scan showed no intradural haemorrhage and CTA demonstrated that the aneurysm had been excluded from the circulation. EEG was negative for epileptiform activity. MRI was then performed which did not show evidence of acute infarction. The patient was treated with moderate induced hypertension and hypervolaemia in an attempt to optimise collateral circulation, but with no clinical improvement. A cerebral DSA performed on the third post-operative day (more than 24 hours after the onset of symptoms) demonstrated significant left MCA vasospasm (Fig. 1B). Intra-arterial verapamil was given, with good angiographic response (Fig. 1C). However, the patient continued to have significant dysphasia and hemiparesis, and repeat MRI on the 6th post-operative day showed evidence of a left MCA infarct (Fig. 2). The patient was discharged to a rehabilitation facility, and at a 3 month follow-up was independent with minimal dysphasia but persisting right upper limb weakness. 2.2. Patient 2 A 70-year-old right-handed man was admitted for an elective clipping of an anterior communicating artery (ACoA) aneurysm and also two small left MCA aneurysms. These aneurysms had been discovered coincidentally on a previous CT scan following minor trauma. There was no clinical or radiographic evidence of previous SAH. His past medical history was significant for type 2 diabetes mellitus, smoking and essential hypertension. In preoperative discussion conservative management options were emphasised, but the patient requested treatment of the aneurysms. A Fig. 1. Digital subtraction angiography of patient 1. (A) Preoperative left internal carotid artery (ICA) injection, anteroposterior projection. (B) Postoperative day 3 left ICA injection, AP projection, showing cerebral vasospasm. (C) Postoperative day 3 left ICA injection, AP projection after intra-arterial 10 mg verapamil infusion with resolution of vasospasm. Fig. 2. MRI patient 1, diffusion-weighted imaging protocol on day 6 demonstrating established infarct in the left MCA territory. (A) Restricted diffusion and (B) low apparent diffusion coefficient (ADC) attenuation in the left MCA territory. Old xanthochromic staining of the arachnoid immediately adjacent to one of the MCA aneurysm was noted intra-operatively, but there was no evidence of any recent SAH. The operative procedure was uncomplicated with no intraoperative aneurysm rupture. The MCA aneurysms were exposed and clipped with no temporary clipping, no retraction, no contusion and no venous or arterial injury. The ACoA aneurysm was also exposed with no retraction, but about 1 cm of gyrus rectus was resected to clearly identify both A2 vessels prior to clipping. Temporary clipping of both A1 segments was used for 4 minutes for final dissection and clipping of the ACoA aneurysm. Intraoperative DSA demonstrated exclusion of all aneurysms from the circulation (Fig. 3A, B) and normal vessel calibre. The patient awoke and was extubated immediately after the operation, and was neurologically intact and walking within a few hours of surgery. Routine post-operative CT scan on the day of surgery showed no blood in the Sylvian fissure or basal cisterns. On post-operative day 2, the patient deteriorated such that he opened his eyes to pain only, was severely dysphasic, and had a right hemiparesis. Urgent CT scan revealed no intracranial bleed and DSA demonstrated severe arterial vasospasm involving the left M2 and M3 branches (Fig. 3C). During the angiogram, 20 mg of Verapamil was injected into the left M1 in divided doses, with good angiographic response (Fig. 3D) and good clinical response. The patient was then treated with a 21 day course of nimodipine and also moderate induced hypertension and hypervolaemia for 3 days. A day 6 post-operative MRI did not demonstrate an acute infarct and MRA at that time demonstrated normal calibre of left M1 and M2 branches. The patient was discharged to home on day 11 with no residual neurological deficit. A. Tsyben et al. / Journal of Clinical Neuroscience 34 (2016) 33–38 35 Fig. 3. Digital subtraction angiography (DSA) of patient 2. (A) Preoperative DSA, left internal carotid artery (ICA) injection, left transorbital oblique projection. (B) Intraoperative post-clipping DSA, left ICA injection, left transorbital oblique protection. (C) DSA post-operative day 2, after clinical deterioration, left ICA injection, anteroposterior projection (AP), showing vasospasm. (D) DSA post-operative day 2, after intra-arterial 20 mg verapamil infusion, left ICA injection, AP projection, showing improvement in vasospasm. 3. Review of the literature Our review of the peer-reviewed literature has identified eight reported patients with angiographically proven vasospasm associated with delayed neurological deficit following clipping of unruptured and previously asymptomatic aneurysms [21–26]. The clinical characteristics, artery of origin and post-operative course are described in Table 1. Reports pre-dating the regular use of MRI and CT scan were omitted due to their questionable ability to exclude post-operative SAH. All patients reported thus far with CVS following elective clipping of aneurysms were women, with a mean age of 51 (range 21–63). To our knowledge, we observed the first symptomatic CVS following elective clipping of unruptured aneurysms in a male patient. All listed patients had CVS involving the anterior circulation, with half involving the ICA and half affecting the MCA. The patient reported by Hashimoto et al. with vasospasm involving the MCA and ACA also reported bilateral involvement of posterior cerebral arteries [26]. The size of the electively treated aneurysms ranged from 4–7 mm, with only one reported to be ‘very large’ [24]. The onset of CVS was reported to occur between 5 and 28 days following elective surgery with the mean time to onset of 15 days. Of interest, both of our patients developed DIND on post-operative day 2, which is significantly early than any of the previously reported patients, and also somewhat earlier than the typical onset of CVS following SAH. This variable temporal profile suggests that several mechanisms may underlie vasospasm, some of which are discussed later. With respect to treatment and outcome, four patients used triple H therapy (hypertension, hypervolemia and haemodilution, HHH), and three used hypervolemic therapy alone. Two patients received additional intraarterial papaverine and another two received intraarterial nicardipine. In addition, one patient was given dexamethasone. Four of the patients achieved full recovery, while the remaining half sustained residual hemiparesis or aphasia. 4. Discussion The mechanisms underlying CVS and DIND have been predominantly studied in the context of SAH. Following SAH, the major instigators appear to be erythrocytes and their breakdown products such as oxyhaemoglobin [27,28]. These may act as spasmogens by generating reactive oxygen species (ROS) and activating the Rho kinase and protein kinase C pathways, which are both known to cause smooth muscle contraction [29,28]. Also, both ROS and free haemoglobin may inhibit nitric oxide synthase thereby decreasing the levels of nitric oxide (NO), which has been demonstrated to have a direct effect on arterial smooth muscle contraction and an important role in the regulation of regional cerebral blood flow [30]. These mechanisms are consistent with – 6 10 5 28 6 5 Light headed, extremity numbness, faintness Vertigo Headache 47 F 62 F 41 F 61 F Yang et al., 2015 [25] – Incidental 21 F L ICA bifurcation L MCA bifurcation 5 Large 4 5 L paraclinoid ICA L paraclinoid ICA R MCA bifurcation L ICA (PCoA) Incidental 63 F ACA = anterior cerebral artery, GCS = Glasgow Coma Scale score, HHH = hypertension, hypervolemia and hemodilution, IA = intra-arterial, ICA = internal carotid artery, L = left, MCA = middle cerebral artery, PCA = posterior cerebral artery, PCoA = posterior communicating artery, R = right. Minimal aphasia Minimal aphasia Acalculia, Paraphasia Hypervolemia, antiplatelet agents Hypervolemia, antiplatelet agents, IA nicardipine Hypervolemia, antiplatelet agents, IA nicardipine Bilateral A1, bilateral PCA, L M1, R M3-M4 L A1, M1 – 11 Good recovery HHH, antiplatelet agents R M1 segment 12 hr 28 Good recovery HHH, IA papaverine L M2 14 12 5 10 – Intraarterial (IA) papaverine M1, M2, A1, A2 HHH, hyperbaric oxygenation M1, M2, A1, A2 – – R hemiparesis, aphasia and coma Aphasia, R hemiparesis Aphasia, Gerstmann syndrome L lower facial droop, L hemiparesis Aphasia, R hemiplegia Aphasia, R facial numbness Aphasia 5 Chronic headache 55 F L ICA Incidental 54 F Bloomenfield & Sonntag 1985 [21] Gutierrez et al., 2001 [22] Kitazawa et al., 2004 [23] Kitazawa et al., 2004 [23] Paolini et al., 2005 [24] Hashimoto et al., 2015 [26] Yang et al., 2015 [25] R MCA near bifurcation 7 L hemiparesis 9 7 R ICA-supra-clinoid segment, R ACA, R MCA HHH & steroid Outcome Treatment Location of VS Duration days Onset days Postoperative symptoms Neurological symptoms Size mm Aneurysm Location Presentation Age Sex Case Report Table 1 Summary of documented cases of symptomatic, angiographically demonstrated, vasospasm following uneventful clipping of unruptured aneurysms Slight residual R hemiparesis, GCS 15/15 Good recovery A. Tsyben et al. / Journal of Clinical Neuroscience 34 (2016) 33–38 Good recovery 36 the observation that the degree of CVS is often proportional to the volume of blood initially found in the subarachnoid space [31]. However, the CVS and DIND observed in our patients occurred in the absence of subarachnoid blood, implicating other factors in its pathogenesis. It has also been previously postulated that the aforementioned vasoactive agents may diffuse from the inside of the aneurysm following clipping [32]. However, the extremely rare occurrence of vasospasm after elective aneurysm clipping (particularly large or giant aneurysms) would seem to make this mechanism unlikely, as is the finding that almost all of the rarely reported patients with CVS following elective clipping had small aneurysms. Although no intraoperative haemorrhage was noted in our patients and the routine early post-operative CT scans showed no radiological evidence of SAH, the cerebral arteries would almost certainly be exposed to a small amount of blood in any elective aneurysm surgery. However, intraoperative extravasated blood alone would not be expected to be responsible for the vasospasm, as it would otherwise be expected to precipitate many more patients with CVS following most craniotomies for various pathologies and most severe traumatic head injuries. The rarely reported episodes of CVS and DIND following clipping of unruptured aneurysms in the absence of prior SAH have an unknown pathophysiological aetiology, but we assume that it is multifactorial including the effects of vascular and primary brain injury, production of spasmogens and failure of the arterial wall to respond accordingly. In all reported patients with vasospasm following elective aneurysm clipping, the vasospasm occurred near the site of the original aneurysm. It is known that aggressive manipulation of the vessel wall during surgery may damage the endothelium, as will the local clip pressure on the treated aneurysm neck. As well as the effects on NO production, endothelial damage releases vasoactive agents such as endothelin-1, lipid peroxidase agents and vasoactive cytokines [33–35]. Other factors may include endothelial remodelling in the vicinity of the aneurysm [36]. The complex turbulent flow within the aneurysm leads to shear stresses on the surrounding vascular wall, which can cause endothelial damage and lead to imbalance in the production of NO [37]. It has also been postulated that the areas of turbulence may contain relatively hypoxic blood that increases the generation of ROS, thus making the vessel more prone to vasospasm [38,39]. However, turbulence is expected to be more pronounced prior to aneurysm clipping, and the vessel manipulation in our reported patients, was relatively minimal compared to most aneurysm surgery. The trigeminal innervation of cerebral vasculature has also been suggested as having a role in the pathophysiology of CVS. Intracranial vessels and meninges, particularly the dura, have been demonstrated to have trigeminal innervation, predominantly through the ophthalmic division [40,41]. The pseudounipolar fibres originating in the trigeminal ganglion project onto second order neurons in the trigeminal nucleus caudalis [42]. In response to arterial vasoconstriction, these fibres release stored calcitonin-gene related peptide (CGRP), which acts as a potent vasodilator to return the vessel to its original calibre [41,43,44]. In SAH patients, the levels of CGRP in the external jugular venous blood and cerebrospinal fluid have been demonstrated to directly correlate with the amount of vasospasm measured by Doppler ultrasound [45,46]. In addition, samples taken during maximal CVS following SAH show a 50% depletion of CGPR when compared with controls [47]. Differences in the rate of synthesis, release and consequent depletion of CGPR, as well as differences in the concentration of spasmogens such as haemoglobin and prostaglandins in the vicinity of the vessel, have been suggested as mechanisms causing this ‘‘trigemino-cerebrovascular reflex” to fail to correct CVS is many but not all SAH patients [48,49]. However, this remains A. Tsyben et al. / Journal of Clinical Neuroscience 34 (2016) 33–38 speculative, and the relative role of this potential mechanism in CVS following SAH is currently unknown. It is currently not possible to speculate about whether failure of this reflex might have contributed to the development of vasospasm in our patients. We have also considered that a possible factor in the development of vasospasm observed in our patients may have been drying of the exposed middle cerebral artery during surgical exposure and clipping. Both aneurysms were operated by the senior author (JDL), who is an experienced cerebrovascular surgeon. He has not previously encountered this complication, and the occurrence of two incidents in a relatively short time space has prompted review of surgical techniques. Over the last 5 years this surgeon has not routinely used fixed retractors during surgery, and routinely uses a very small craniotomy with the minimal required opening of the Sylvian fissure for aneurysm clipping. The small Sylvian exposure often precludes the routine use of wet cottonoids inside the fissure, and the exposure requires almost constant application of a controlled-pressure fine suction tip on the vessel and the aneurysm during dissection and clipping. The combination of continuous suction and the heat of the microscope light have been noted at times to dry the exposed vessels, and requires vigilant attention to intermittent irrigation. We question whether in our patients excessive or prolonged drying of the exposed middle cerebral artery might have affected the integrity and physiology of endothelium, decreasing its ability to respond to vasodilatory mediators and promoting subsequent delayed vasospasm and DIND. CVS and DIND following SAH affects women somewhat more commonly than men [50]. Prior to our patient, all patients affected by CVS following unruptured aneurysm clipping have also been women. This gender discrepancy may be partly explained by the finding that unruptured intracranial aneurysms are on average 1.6 times more common in women when compared to men [51]. While women may be at an increased risk, this finding is inconclusive due to the small number of patient reports. 5. Conclusion Although commonly encountered following aneurysmal SAH, delayed CVS and DIND are rarely encountered after uncomplicated elective surgery for unruptured aneurysms. Although the aetiology of CVS and DIND is multifactorial and not completely understood, both are potentially treatable, [52–54], and adverse outcome is associated with delayed diagnosis and treatment. Therefore, clinicians are advised to consider the rare condition of CVS in any patient experiencing neurological deterioration following treatment of unruptured aneurysms. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. References [1] Weir B, Grace M, Hansen J, et al. Time course of vasospasm in man. J Neurosurg 1978;48:173–8. [2] Kassell NF, Torner JC, Haley Jr EC, et al. The International Cooperative Study on the timing of aneurysm surgery. Part 1: Overall management results. J Neurosurg 1990;73:18–36. [3] Frontera JA, Fernandez A, Schmidt JM, et al. Defining vasospasm after subarachnoid hemorrhage: what is the most clinically relevant definition? Stroke 2009;40:1963–8. [4] Fisher CM, Kistler JP, Davis JM. Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by computerized tomographic scanning. Neurosurgery 1980;6:1–9. [5] Kistler JP, Crowell RM, Davis KR, et al. The relation of cerebral vasospasm to the extent and location of subarachnoid blood visualized by CT scan: a prospective study. Neurology 1983;33:424–36. 37 [6] Crowley RW, Medel R, Dumont AS, et al. Angiographic vasospasm is strongly correlated with cerebral infarction after subarachnoid hemorrhage. Stroke 2011;42:919–23. [7] Connolly Jr ES, Rabinstein AA, Carhuapoma JR, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/american Stroke Association. Stroke 2012;43:1711–37. [8] Trojanowski T. Early effects of experimental arterial subarachnoid haemorrhage on the cerebral circulation. Part I: experimental subarachnoid haemorrhage in cat and its pathophysiological effects. Methods of regional cerebral blood flow measurement and evaluation of microcirculation. Acta Neurochir (Wien) 1984;72:79–94. [9] Trojanowski T. Early effects of experimental arterial subarachnoid haemorrhage on the cerebral circulation. Part II: regional cerebral blood flow and cerebral microcirculation after experimental subarachnoid haemorrhage. Acta Neurochir (Wien) 1984;72:241–55. [10] Claassen J, Bernardini GL, Kreiter K, et al. Effect of cisternal and ventricular blood on risk of delayed cerebral ischemia after subarachnoid hemorrhage: the Fisher scale revisited. Stroke 2001;32:2012–20. [11] Pluta RM, Thompson BG, Dawson TM, et al. Loss of nitric oxide synthase immunoreactivity in cerebral vasospasm. J Neurosurg 1996;84:648–54. [12] Pluta RM. Delayed cerebral vasospasm and nitric oxide: review, new hypothesis, and proposed treatment. Pharmacol Ther 2005;105:23–56. [13] Pluta RM. Dysfunction of nitric oxide synthases as a cause and therapeutic target in delayed cerebral vasospasm after SAH. Neurol Res 2006;28:730–7. [14] Pluta RM, Afshar JK, Boock RJ, et al. Temporal changes in perivascular concentrations of oxyhemoglobin, deoxyhemoglobin, and methemoglobin after subarachnoid hemorrhage. J Neurosurg 1998;88:557–61. [15] Suarez JI, Qureshi AI, Yahia AB, et al. Symptomatic vasospasm diagnosis after subarachnoid hemorrhage: evaluation of transcranial Doppler ultrasound and cerebral angiography as related to compromised vascular distribution. Crit Care Med 2002;30:1348–55. [16] Macdonald RL, Kassell NF, Mayer S, et al. Clazosentan to overcome neurological ischemia and infarction occurring after subarachnoid hemorrhage (CONSCIOUS-1): randomized, double-blind, placebo-controlled phase 2 dose-finding trial. Stroke 2008;39:3015–21. [17] Macdonald RL, Higashida RT, Keller E, et al. Clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid haemorrhage undergoing surgical clipping: a randomised, double-blind, placebo-controlled phase 3 trial (CONSCIOUS-2). Lancet Neurol 2011;10:618–25. [18] Pluta RM, Hansen-Schwartz J, Dreier J, et al. Cerebral vasospasm following subarachnoid hemorrhage: time for a new world of thought. Neurol Res 2009;31:151–8. [19] Dreier JP, Woitzik J, Fabricius M, et al. Delayed ischaemic neurological deficits after subarachnoid haemorrhage are associated with clusters of spreading depolarizations. Brain 2006;129:3224–37. [20] Caner B, Hou J, Altay O, et al. Transition of research focus from vasospasm to early brain injury after subarachnoid hemorrhage. J Neurochem 2012;123:12–21. [21] Bloomfield SM, Sonntag VK. Delayed cerebral vasospasm after uncomplicated operation on an unruptured aneurysm: case report. Neurosurgery 1985;17:792–6. [22] Gutierrez O, Caldas JG, Rabello JP. Unruptured aneurysm: vasospasm after surgery and endovascular treatment. A case report. Interv Neuroradiol 2001;7:37–9. [23] Kitazawa K, Hongo K, Tanaka Y, et al. Postoperative vasospasm of unruptured paraclinoid carotid aneurysms: analysis of 30 cases. J Clin Neurosci 2005;12:150–5. [24] Paolini S, Kanaan Y, Wagenbach A, et al. Cerebral vasospasm in patients with unruptured intracranial aneurysms. Acta Neurochir (Wien) 2005;147:1181–8. [25] Yang K, Ahn JS, Park JC, et al. Clinical and angiographical delayed cerebral vasospasms after uncomplicated surgical clipping of unruptured intracranial aneurysms: illustrated review and two case reports. Turk Neurosurg 2015;25:662–5. [26] Hashimoto H, Kameda M, Yasuhara T, et al. A case of unexpected symptomatic vasospasm after clipping surgery for an unruptured intracranial aneurysm. J Stroke Cerebrovasc Dis 2016;25:e25–7. [27] Kasuya H, Weir BK, White DM, et al. Mechanism of oxyhemoglobin-induced release of endothelin-1 from cultured vascular endothelial cells and smoothmuscle cells. J Neurosurg 1993;79:892–8. [28] Kokkoris S, Andrews P, Webb DJ. Role of calcitonin gene-related peptide in cerebral vasospasm, and as a therapeutic approach to subarachnoid hemorrhage. Front Endocrinol (Lausanne) 2012;3:135. [29] Wickman G, Lan C, Vollrath B. Functional roles of the rho/rho kinase pathway and protein kinase C in the regulation of cerebrovascular constriction mediated by hemoglobin: relevance to subarachnoid hemorrhage and vasospasm. Circ Res 2003;92:809–16. [30] Garry PS, Ezra M, Rowland MJ, et al. The role of the nitric oxide pathway in brain injury and its treatment–from bench to bedside. Exp Neurol 2015;263:235–43. [31] Mayberg MR, Okada T, Bark DH. The role of hemoglobin in arterial narrowing after subarachnoid hemorrhage. J Neurosurg 1990;72:634–40. [32] DeLong WB. Severe vasospasm with an unruptured aneurysm: case report. Neurosurgery 1980;6:92–5. [33] Hubschmann OR, Kornhauser D. Cerebral arterial spasm. J Neurosurg 1980;53:732–3. 38 A. Tsyben et al. / Journal of Clinical Neuroscience 34 (2016) 33–38 [34] Ohta T, Kajikawa H, Funatsu N, et al. Cerebral vasospasm and its relaxation responses to vasodilators: pathological study of severe prolonged vasospasm. In: RW, editor. Cerebral Arterial Spasm. Baltimore: Williams & Wilkins; 1980. p. 132–9. [35] Sercombe R, Dinh YR, Gomis P. Cerebrovascular inflammation following subarachnoid hemorrhage. Jpn J Pharmacol 2002;88:227–49. [36] Valen-Sendstad K, Mardal KA, Mortensen M, et al. Direct numerical simulation of transitional flow in a patient-specific intracranial aneurysm. J Biomech 2011;44:2826–32. [37] Noris M, Morigi M, Donadelli R, et al. Nitric oxide synthesis by cultured endothelial cells is modulated by flow conditions. Circ Res 1995;76:536–43. [38] Hamer JD, Malone PC, Silver IA. The PO2 in venous valve pockets: its possible bearing on thrombogenesis. Br J Surg 1981;68:166–70. [39] Harrison DG, Widder J, Grumbach I, et al. Endothelial mechanotransduction, nitric oxide and vascular inflammation. J Intern Med 2006;259:351–63. [40] Edvinsson L. Functional role of perivascular peptides in the control of cerebral circulation. Trends Neurosci 1985;8:126–31. [41] Uddman R, Edvinsson L, Ekman R, et al. Innervation of the feline cerebral vasculature by nerve fibers containing calcitonin gene-related peptide: trigeminal origin and co-existence with substance P. Neurosci Lett 1985;62:131–6. [42] Goadsby PJ. Recent advances in understanding migraine mechanisms, molecules and therapeutics. Trends Mol Med 2007;13:39–44. [43] McCulloch J, Uddman R, Kingman TA, et al. Calcitonin gene-related peptide: functional role in cerebrovascular regulation. Proc Natl Acad Sci U S A 1986;83:5731–5. [44] Fischer JA, Born W, Muff R. Calcitonin gene-related peptide (Cgrp), adrenomedullin (Am), amylin, and calcitonin (Ct) receptors and overlapping biological actions. Sci World J 2001;1:4. [45] Juul R, Edvinsson L, Gisvold SE, et al. Calcitonin gene-related peptide-LI in subarachnoid haemorrhage in man. Signs of activation of the trigeminocerebrovascular system? Br J Neurosurg 1990;4:171–9. [46] Juul R, Hara H, Gisvold SE, et al. Alterations in perivascular dilatory neuropeptides (CGRP, SP, VIP) in the external jugular vein and in the cerebrospinal fluid following subarachnoid haemorrhage in man. Acta Neurochir (Wien) 1995;132:32–41. [47] Edvinsson L, Delgado-Zygmunt T, Ekman R, et al. Involvement of perivascular sensory fibers in the pathophysiology of cerebral vasospasm following subarachnoid hemorrhage. J Cereb Blood Flow Metab 1990;10:602–7. [48] Arienta C, Balbi S, Caroli M, et al. Depletion of calcitonin gene-related peptide in perivascular nerves during acute phase of posthemorrhagic vasospasm in the rabbit. Brain Res Bull 1991;27:605–9. [49] Edvinsson L, Ekman R, Jansen I, et al. Reduced levels of calcitonin gene-related peptide-like immunoreactivity in human brain vessels after subarachnoid haemorrhage. Neurosci Lett 1991;121:151–4. [50] Kongable GL, Lanzino G, Germanson TP, et al. Gender-related differences in aneurysmal subarachnoid hemorrhage. J Neurosurg 1996;84:43–8. [51] Haley Jr EC, Kassell NF, Torner JC. The International Cooperative Study on the timing of aneurysm surgery. The North American experience. Stroke 1992;23:205–14. [52] Archavlis E, Carvi Y, Nievas M. Cerebral vasospasm: a review of current developments in drug therapy and research. J Pharm Technol Drug Res 2013;2:18. [53] Bauer AM, Rasmussen PA. Treatment of intracranial vasospasm following subarachnoid hemorrhage. Front Neurol 2014;5:72. [54] Serrone JC, Maekawa H, Tjahjadi M, et al. Aneurysmal subarachnoid hemorrhage: pathobiology, current treatment and future directions. Expert Rev Neurother 2015;15:367–80.