Abstract BACKGROUND Cerebral vasospasm leading to delayed cerebral infarction (DCI) is a central source of poor outcome in patients with aneurysmal subarachnoid hemorrhage (aSAH). Current treatments of cerebral vasospasm are insufficient. Cisternal blood clearance is a promising treatment option. However, a generally applicable, safe, and effective method to access the cisterns of the brain is lacking. OBJECTIVE To report on stereotactic catheter ventriculocisternostomy (STX-VCS) as a method to access the cisterns of the brain for clearance of subarachnoid hemorrhage in patients with aSAH and coiled aneurysms. METHODS In 9 aSAH patients at high risk for DCI (Hunt and Hess grade ≥3, modified Fisher grade ≥3), access to the basal cisterns of the brain was created by STX-VCS. Fibrinolytic and/or spasmolytic lavage therapy was administered. RESULTS STX-VCS was feasible and safe in all patients. Subarachnoid blood was rapidly cleared by irrigation with urokinase. Vasospasm occurred in 2 patients and was interrupted by irrigation with nimodipine. There was 1 fatality due to pneumogenic sepsis. Minor DCI occurred in 1 patient. Eight survived without DCI and are independent (modified Rankin score [mRS] ≤ 3) at 6 mo after aSAH. CONCLUSION STX-VCS allows for rapid clearance of subarachnoid hemorrhage in patients with coiled aneurysms. Subarachnoid hemorrhage, Cerebral vasospasm, Delayed cerebral infarction ABBREVIATIONS ABBREVIATIONS aSAH aneurysmal subarachnoid hemorrhage CT computed tomography CVS cerebral vasospasm DCI delayed cerebral infarction EVD external ventricular drain ICP intracranial pressure MRI magnetic resonance imaging mRS modified Rankin score STX-VCS stereotactic catheter ventriculocisternostomy Aneurysmal subarachnoid hemorrhage (aSAH) carries a fatality rate of 50%, and a large proportion of survivors do not reach functional independence.1 Cerebral vasospasm (CVS) is pivotal for patient outcome, as it frequently leads to delayed cerebral infarction (DCI).2 Current DCI prevention strategies—systemic nimodipine, hemodynamic management, and endovascular procedures—are insufficient.3 CVS is induced by blood breakdown products in the subarachnoid space. Therefore, various treatments aiming at subarachnoid blood clearance and/or local spasmolysis have been investigated for over 20 yr. After open surgical aneurysm repair, catheters may be placed into the basal cisterns for lavage therapy. Promising results have been achieved with this method. However, no safe access route to the subarachnoid space is currently available after aneurysm coiling.4 Stereotactic catheter ventriculocisternostomy (STX-VCS) has been safely performed in humans for the treatment of hydrocephalus since the 1970s.5-9 We applied this method to create a continuous treatment access to the subarachnoid space in 9 aSAH patients with coiled aneurysms at high risk for DCI. METHODS The Institutional Review Board of our University Medical Center was informed prior to the first implementation of this novel treatment. The legal representatives of all patients provided informed consent. The study is reported according to the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) guidelines for reporting of observational studies.10 The experimental therapy was introduced in our department in September 2015. It was offered to patients considered at high risk for DCI according to an individualized risk evaluation. Only patients with an admission Hunt and Hess grade ≥3 and modified Fisher grade ≥3 were considered potential candidates. Successful endovascular aneurysm repair (irrespective of treatment complications) and an external ventricular drain (EVD) in place were inclusion criteria. We did not offer the experimental therapy to patients with a per se dismal prognosis (eg, postictal cardiopulmonary resuscitation or signs of brain stem herniation for more than 60 min, massive intracerebral hemorrhage). Intensive care management was conducted according to current guidelines.11 Outcome was assessed according to modified Rankin score (mRS)12 at hospital discharge and 3 and 6 mo after aSAH. Presence or absence of DCI was assessed by computed tomography (CT) or magnetic resonance imaging (MRI) ≥ 21 d after aSAH. Patients were prospectively followed until death or November 30, 2016, and neurological outcome was evaluated by mRS13 (mRS 0: no symptoms, mRS 1: no significant disability, mRS 2: slight disability, mRS 3: moderate disability, mRS 4: moderately severe disability, mRS 5: severe disability, mRS 6: dead) rating at discharge and at 3 and 6 mo after aSAH. Stereotactic procedures were performed using a Leksell G-Frame (Elekta, Stockholm, Sweden). For planning, we used stereotactic CT-Angiography or MR-Angiography and Elekta Surgiplan© planning software (Elekta, Stockholm, Sweden). A right or left frontal twist drill burr hole (3.5 mm) was performed under stereotactic guidance. Standard catheters otherwise used as EVD (typical diameter: 2.8 mm) were stereotactically implanted via the lateral ventricle, the foramen of Monroe, the third ventricle, perforating the floor, creating a third ventriculocisternostomy (Figures 1 and 2). Implantation of a parenchymatous intracranial pressure (ICP) monitoring device (Neurovent P, Raumedic AG, Helmbrechts, Germany) under stereotactic guidance was included as a standard procedure after the first 2 patients. All patients underwent CT after the intervention to verify accurate catheter placement and assess for surgical complications. Two patients in the present series received anticoagulant therapy with heparin for 72 h after aneurysm coiling, which was temporarily paused for the stereotactic procedure following a careful evaluation of potential risks and benefits. FIGURE 1. View largeDownload slide Stereotactic catheter access to the basal cisterns. Postoperative CT (A, coronar; B, axial; C, sagittal) of the first patient after catheter implantation. Intraoperatively injected contrast agent distributes within the basal cisterns and the third and fourth ventricle, confirming the desired distribution of fluids applied via the catheter. FIGURE 1. View largeDownload slide Stereotactic catheter access to the basal cisterns. Postoperative CT (A, coronar; B, axial; C, sagittal) of the first patient after catheter implantation. Intraoperatively injected contrast agent distributes within the basal cisterns and the third and fourth ventricle, confirming the desired distribution of fluids applied via the catheter. FIGURE 2. View largeDownload slide Three-dimensional volume rendering of EVD and STX-VCS catheters. Fusion imaging of a postoperative CT (containing both EVD and STX-VCS catheters) and a follow-up MRI (providing precise delineation of the ventricular system) of patient 9. The STX-VCS catheter (pink) passes through the left frontal lobe, enters the third ventricle via foramen of Monroe, and perforates its floor to create a third ventriculocisternostomy. The catheter tip comes to lie within the basal cistern between the clivus and the brain stem. Holes for lavage therapy are present both above and below lamina terminalis to administer lavage therapy both intraventricularly and cisternally. The EVD (green) serves as the outflow tract. FIGURE 2. View largeDownload slide Three-dimensional volume rendering of EVD and STX-VCS catheters. Fusion imaging of a postoperative CT (containing both EVD and STX-VCS catheters) and a follow-up MRI (providing precise delineation of the ventricular system) of patient 9. The STX-VCS catheter (pink) passes through the left frontal lobe, enters the third ventricle via foramen of Monroe, and perforates its floor to create a third ventriculocisternostomy. The catheter tip comes to lie within the basal cistern between the clivus and the brain stem. Holes for lavage therapy are present both above and below lamina terminalis to administer lavage therapy both intraventricularly and cisternally. The EVD (green) serves as the outflow tract. Both intrathecal application of electrolyte solution (Jonosteril, Fresenius-Kabi GmbH, Bad Homburg, Germany) and urokinase (Medac GmbH, Wedel, Germany) represent experimental therapies, as neither has been approved in this indication by regulatory authorities. Nimodipine (Bayer Vital GmbH, Leverkusen, Germany) is approved for intrathecal application. Fibrinolytic lavage using electrolyte solution containing 100 IU/mL urokinase was administered at a rate of 50 to 100 mL/h, typically for 14 d. The EVD served as the outflow tract. Irrigation without urokinase was continued until removal of the catheter, usually after 21 d. In case of sonographic CVS (mean flow velocity of either cerebral artery ≥160 cm/s), spasmolytic lavage therapy containing nimodipine (0.005 mg/mL, Bayer Vital GmbH, Leverkusen, Germany) was administered. Median values and averages were calculated using GraphPad Prism version 5 (GraphPad Software, San Diego, California). Volume-rendering 3-D visualization of the stereotactic catheter (Figure 2) was performed using Brainlab Elements software (Brainlab AG, Feldkirchen, Germany). RESULTS Baseline, treatment, and outcome characteristics of patients are summarized in Table. Nine high-risk aSAH patients underwent stereotactic catheter placement as described above (Figures 1 and 2). Seven patients survived without DCI as visualized by CT ≥ 21 d after aSAH. Patient 9 developed a small (1.5 cm) symptomatic precentral cortical infarction 19 d after aSAH in the absence of sonographic CVS. Patient 8 developed a severe ventilator-associated pneumonia and died due to septic multiorgan failure 16 d after aSAH. TABLE. aSAH Patients Treated by Stereotactic Cisternal Lavage Therapy Pat. no. Age, sex Aneurysm Hunt and Hess grade Modified Fisher grade aSAH onset to catheter implantation (h) DCI Riska DCI Risk for in-hospital mortality (HAIR score) mRS (discharge) mRS (3 mo) mRS (6 mo) 1 49, m Right VA 3 3 34 41% No 4.5% 3 2 1 2 64, f AcoA 5 3 75 56% No 83.3% 5 3 1 3 63, f AcoA 4 4 24 60% No 34.5% 5 4 0 4 64, m ACA 4 4 47 49% No 34.5% 5 3 3 5 63, f AcoA 4 3 39 44% No 34.5% 4 2 1 6 82, f Right and left P-comm 4 4 34 54% No 52.9% 4 3 2 7 68, f AcoA 4 4 60 49% No 52.9% 5 2 2 8 54, f Right PICA 5 4 47 55% N/A 83.3% 6 – – 9 63, f AcoA 3 4 34 41% Yes 9.1% 4 2 0 Pat. no. Age, sex Aneurysm Hunt and Hess grade Modified Fisher grade aSAH onset to catheter implantation (h) DCI Riska DCI Risk for in-hospital mortality (HAIR score) mRS (discharge) mRS (3 mo) mRS (6 mo) 1 49, m Right VA 3 3 34 41% No 4.5% 3 2 1 2 64, f AcoA 5 3 75 56% No 83.3% 5 3 1 3 63, f AcoA 4 4 24 60% No 34.5% 5 4 0 4 64, m ACA 4 4 47 49% No 34.5% 5 3 3 5 63, f AcoA 4 3 39 44% No 34.5% 4 2 1 6 82, f Right and left P-comm 4 4 34 54% No 52.9% 4 3 2 7 68, f AcoA 4 4 60 49% No 52.9% 5 2 2 8 54, f Right PICA 5 4 47 55% N/A 83.3% 6 – – 9 63, f AcoA 3 4 34 41% Yes 9.1% 4 2 0 Abbreviations: N/A: not available; mRS: modified Rankin Scale; VA: vertebral artery; PICA: posterior inferior cerebellar artery; AcoA: anterior communicating artery; ACA: anterior cerebral artery; P-comm: posterior communicating artery. aRisk according to average of 3 current scores for early prediction of DCI after aSAH: average of Vasograde,8 de Rooij10 and BEHAVIOR9 scores. View Large Median time between aSAH onset and catheter implantation was 39 h (range: 24-75 h). Lavage therapy was initiated immediately after catheter implantation. No surgical complications were observed and exact catheter placement was confirmed by CT in all cases. Clearance of subarachnoid blood was obtained within 24 h upon fibrinolytic lavage (Figure 3). No adverse effects or increase of ICP due to lavage therapy were observed. FIGURE 3. View largeDownload slide Fibrinolytic cisternal lavage therapy. CT scan before (A) and 24 h after (B) cisternal lavage with urokinase in patient 1 showing near-complete resolution of subarachnoid blood. The catheter tip is visible as a white spot between the basilar artery and the clivus (B). FIGURE 3. View largeDownload slide Fibrinolytic cisternal lavage therapy. CT scan before (A) and 24 h after (B) cisternal lavage with urokinase in patient 1 showing near-complete resolution of subarachnoid blood. The catheter tip is visible as a white spot between the basilar artery and the clivus (B). Continuous cisternal lavage was feasible in 7 patients. Continuous lavage >24 h was not performed due to loss of the EVD (irrigation outflow tract) in patient 1 and increased intracranial pressure due to posterior inferior cerebellar artery infarction (complication of aneurysm coiling) in patient 9. Several episodes of sonographic CVS occurred in patients 1 and 9. Each of these episodes subsided within minutes after cisternal irrigation with nimodipine. In patients with continuous lavage >24 h, no sonographic vasospasm was detected. At 6 mo after aSAH, all survivors are independent (mRS ≤ 3). DISCUSSION Despite improved patient survival over the last few decades,14 functional outcome remains poor in many aSAH survivors.1 Due to the young age of patients affected and the severity of deficits acquired, disease burden to both individuals and society is substantial.15 The severity of the initial bleeding event is an important determinant of neurological outcome. However, it is not amenable to medical treatments. DCI is equally important for neurological outcome after aSAH and, in contrast, may be influenced by therapeutic interventions.11 Yet, currently available treatments are plainly insufficient to prevent DCI.16-18 Because DCI results from CVS that is induced by subarachnoid blood, elimination of blood from the subarachnoid space by irrigation and fibrinolytic drugs is a promising treatment approach.4 Several smaller, nonrandomized studies and a few randomized clinical trials have been performed to assess the effect of cisternal fibrinolysis and vasodilation. Various compounds and application methods have been investigated.4 Surgical aneurysm clipping may be extended by placement of a catheter into the basal cisterns to access the subarachnoid space.4 Currently, however, the majority of aneurysms are secured by endovascular techniques that do not provide surgical access to the brain19. To overcome this obstacle and provide access to the subarachnoid space, 2 studies advanced catheters intracranially (into cisterna magna) via the lumbar spinal canal and subsequently applied fibrinolytic treatment. Hamada et al demonstrated both a reduction in symptomatic CVS from 28.1% to 9.4% and an increase in favorable outcome (Glasgow Outcome Scale20 1 or 2) from 75.4% (43/57) to 90.6% (48/53) of patients.21 However, in a subsequent study, the use of lumbar catheters was accompanied by injury to the spinal cord resulting in paraplegia in 2 patients.22 Thus, a safe, effective, and continuous access to the subarachnoid space after aneurysm coiling represents an unsolved medical problem. To the best of our knowledge, this is the first description of a STX-VCS performed to create a continuous treatment access to the basal cisterns of the human brain. We offered this experimental therapy to 9 patients with severe aSAH after endovascular aneurysm repair. We were able to show that a continuous access to the subarachnoid space can be safely obtained by stereotactic neurosurgery. We assume that a stereotactic approach offers specific advantages over an endoscopic third ventriculocisternostomy in the setting of aSAH. Endoscopic vision and anatomic orientation might be impaired when ventricular hemorrhage is present. Endoscopy could further be complicated by disruption of normal anatomy (eg, due to intracerebral hemorrhage) or slim configuration of the ventricular system, which is frequent after aSAH. Compared to an endoscopic access, the stereotactic procedure is less invasive, as it is performed using a twist-drill burr hole and the transparenchymal approach does not exceed the diameter of the catheter (typically 2.8 mm). Rapid clearance of subarachnoid blood was achieved. CVS was sonographically detected in 2 patients in whom a continuous lavage >24 h was not feasible. In these patients, CVS was promptly interrupted by cisternal application of nimodipine. According to our current experience, continuous cisternal irrigation beyond the point of blood clearance as visualized by CT is required for vasospasm prevention. The presumable rationale is that blood breakdown products are the trigger for vasospasm. Hence, their clearance from the subarachnoid space for an extended period is required. We have therefore decided to administer cisternal lavage for at least 14 d. According to current risk assessment scores, the expected average in-hospital mortality in the present patient series was 43% (HAIR score).23 We observed 1 fatality due to sepsis (11%). The expected average incidence of DCI was 50% (average VASOGRADE16: 35%, average de Rooij18: 49%, average BEHAVIOR17: 66%). In our series, 1 of 8 survivors developed minor DCI. We note that our experience with this new therapeutic approach is limited to 9 cases. Highly precise planning and execution of the stereotactic procedure is essential for safe catheter placement. The anatomic challenges observed in the first patients represented a challenge even for a stereotactic frame-based approach. Minimum distances observed between cerebral blood vessels and the catheter trajectories were typically in the range of 1.5 to 3 mm. CONCLUSION In patients with aSAH and aneurysm coiling, a treatment access to the basal cisterns of the brain can be obtained by stereotactic neurosurgery. The suspected trigger of CVS—subarachnoid hemorrhage—can be removed by continuous lavage therapy. Further studies are needed to investigate the safety and effectivity of this novel therapeutic approach. Disclosure The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. REFERENCES 1. Rinkel GJ, Algra A. Long-term outcomes of patients with aneurysmal subarachnoid haemorrhage. Lancet Neurol . 2011; 10( 4): 349- 356. Google Scholar CrossRef Search ADS PubMed 2. van Gijn J, Kerr RS, Rinkel GJ. Subarachnoid haemorrhage. Lancet . 2007; 369( 9558): 306- 318. Google Scholar CrossRef Search ADS PubMed 3. Macdonald RL, Schweizer TA. Spontaneous subarachnoid haemorrhage. Lancet . 2017; 389( 10069): 655- 666. Google Scholar CrossRef Search ADS PubMed 4. Zhang YP, Shields LBE, Yao TL, Dashti SR, Shields CB. Intrathecal treatment of cerebral vasospasm. J Stroke Cerebrovasc Dis . 2013; 22( 8): 1201- 1211. Google Scholar CrossRef Search ADS PubMed 5. Poblete M, Zamboni R. Stereotaxic third ventriculocisternostomy. Confin Neurol . 1975; 37( 1-3): 150- 155. Google Scholar CrossRef Search ADS PubMed 6. Kelly PJ, Goerss S, Kall BA, Kispert DB. Computed tomography-based stereotactic third ventriculostomy: technical note. Neurosurgery . 1986; 18( 6): 791- 794. Google Scholar CrossRef Search ADS PubMed 7. Musolino A, Soria V, Munari C et al. Stereotaxic ventriculocisternostomy in the treatment of triventricular obstructive hydrocephalus. Apropos of 23 cases. Neurochirurgie . 1988; 34( 6): 361- 373. Google Scholar PubMed 8. Dalrymple SJ, Kelly PJ. Computer-assisted stereotactic third ventriculostomy in the management of noncommunicating hydrocephalus. Stereotact Funct Neurosurg . 1992; 59( 1-4): 105- 110. Google Scholar CrossRef Search ADS PubMed 9. Kelly PJ. Stereotactic third ventriculostomy in patients with nontumoral adolescent/adult onset aqueductal stenosis and symptomatic hydrocephalus. J Neurosurg . 1991; 75( 6): 865- 873. Google Scholar CrossRef Search ADS PubMed 10. von Elm E, Altman DG, Egger M et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol . 2008; 61( 4): 344- 349. Google Scholar CrossRef Search ADS PubMed 11. Steiner T, Juvela S, Unterberg A et al. European Stroke Organization guidelines for the management of intracranial aneurysms and subarachnoid haemorrhage. Cerebrovasc Dis . 2013; 35( 2): 93- 112. Google Scholar CrossRef Search ADS PubMed 12. Farrell B, Godwin J, Richards S, Warlow C. The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: final results. J Neurol Neurosurg Psychiatry . 1991; 54( 12): 1044- 1054. Google Scholar CrossRef Search ADS PubMed 13. Rankin J. Cerebral vascular accidents in patients over the age of 60. II. Prognosis. Scott Med J . 1957; 2( 5): 200- 215. Google Scholar CrossRef Search ADS PubMed 14. Nieuwkamp DJ, Setz LE, Algra A, Linn FHH, de Rooij NK, Rinkel GJE. Changes in case fatality of aneurysmal subarachnoid haemorrhage over time, according to age, sex, and region: a meta-analysis. Lancet Neurol . 2009; 8( 7): 635- 642. Google Scholar CrossRef Search ADS PubMed 15. Rivero-Arias O, Gray A, Wolstenholme J. Burden of disease and costs of aneurysmal subarachnoid haemorrhage (aSAH) in the United Kingdom. Cost Eff Resour Alloc . 2010; 8( 1): 6. Google Scholar CrossRef Search ADS PubMed 16. de Oliveira Manoel AL, Jaja BN, Germans MR et al. The VASOGRADE: a simple grading scale for prediction of delayed cerebral ischemia after subarachnoid hemorrhage. Stroke . 2015; 46( 7): 1826- 1831. Google Scholar CrossRef Search ADS PubMed 17. Jabbarli R, Reinhard M, Roelz R et al. Early identification of individuals at high risk for cerebral infarction after aneurysmal subarachnoid hemorrhage: the BEHAVIOR score. J Cereb Blood Flow Metab . 2015; 35( 10): 1587- 1592. Google Scholar CrossRef Search ADS PubMed 18. de Rooij NK, Greving JP, Rinkel GJE, Frijns CJM. Early prediction of delayed cerebral ischemia after subarachnoid hemorrhage: development and validation of a practical risk chart. Stroke . 2013; 44( 5): 1288- 1294. Google Scholar CrossRef Search ADS PubMed 19. Smith GA, Dagostino P, Maltenfort MG, Dumont AS, Ratliff JK. Geographic variation and regional trends in adoption of endovascular techniques for cerebral aneurysms. J Neurosurg . 2011; 114( 6): 1768- 1777. Google Scholar CrossRef Search ADS PubMed 20. Jennett B, Bond M. Assessment of outcome after severe brain damage. Lancet . 1975; 1( 7905): 480- 484. Google Scholar CrossRef Search ADS PubMed 21. Hamada J, Kai Y, Morioka M et al. Effect on cerebral vasospasm of coil embolization followed by microcatheter intrathecal urokinase infusion into the cisterna magna: a prospective randomized study. Stroke . 2003; 34( 11): 2549- 2554. Google Scholar CrossRef Search ADS PubMed 22. Hänggi D, Eicker S, Beseoglu K, Behr J, Turowski B, Steiger H-J. A multimodal concept in patients after severe aneurysmal subarachnoid hemorrhage: results of a controlled single centre prospective randomized multimodal phase I/II trial on cerebral vasospasm. Cent Eur Neurosurg . 2009; 70( 2): 61- 67. Google Scholar CrossRef Search ADS PubMed 23. Lee VH, Ouyang B, John S et al. Risk stratification for the in-hospital mortality in subarachnoid hemorrhage: the HAIR score. Neurocrit Care . 2014; 21( 1): 14- 19. Google Scholar CrossRef Search ADS PubMed Acknowledgments We are grateful to Prof. Dr Heike L. Pahl, University Medical Center Freiburg, for extensive revision of the manuscript. We thank the team of our intensive care unit for excellent support in implementing the novel treatment concept. COMMENTS This is an interesting preliminary report of a novel, frame-based stereotactic technique to clear subarachnoid blood from the basal cisterns in order to reduce the incidence and severity of delayed cerebral infarction due to vasospasm. The technique is well-described and the rationale is self-evident. The initial results with the first 9 patients are quite promising. There are many questions regarding the selection of the thrombolytic agent, the dosage, the rate of infusion, and the duration of treatment. We are surprised that, while the IRB was notified of this intervention, formal IRB review and approval were not required for this experimental intervention. The alternative of the frameless stereotactic, endoscopic third ventriculostomy and placement of the catheter within the lateral ventricle should also be explored and compared (particularly for patients without intraventricular blood and with dilated ventricles). Is it important to continue the infusion for 14 days, or is simple clearance of blood (which occurs within 24 hours) sufficient? The longer periods of infusion increase the risk of infection. Is it important to check the position of the basilar artery prior to catheter placement? The catheter lies between 1.5 and 3 mm from the basilar artery. What are the limits of timing of initiation of this therapy? This is an intriguing preliminary report that raises more questions than it answers. We will be interested in seeing follow-up reports from this and other centers. Eric L. Zager Philadelphia, Pennsylvania The authors report a technique for cisternal blood clearance creating a stereotactic third ventriculocisternostomy, which they have used in 9 patients. A ventricular catheter was passed through a frontal burr hole using the Leksell G-Frame, and the floor of the third ventricle was perforated. Intrathecal lavage with Urokinase was performed for 14 days, and irrigation was continued for an additional 7 days. No complications directly related this procedure were noted. This technique may be useful particularly in patients with coiled aneurysms after SAH. Rafael J. Tamargo Baltimore, Maryland Copyright © 2017 by the Congress of Neurological Surgeons
Operative Neurosurgery – Oxford University Press
Published: Mar 1, 2018
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