Subarachnoid Hemorrhage: Early Evaluation and Optimization of Management

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Subarachnoid hemorrhage: Early evaluation and optimization of management

Germans, M.R.

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Subarachnoid hemorrhage: early evaluation and optimization of management Menno R. Germans 31452 Germans.qxp_cover 07-01-15 14:04 Pagina 1 Pagina 14:04 07-01-15 Germans.qxp_cover 31452

Subarachnoid hemorrhage Early evaluation and optimization of management

Funding: ABN-AMRO, Covidien, Promedics Medical Systems BV, Stichting ter Bevordering van Neurochirurgische Ontwikkeling, Zeiss

Cover design and layout: Ferdinand van Nispen tot Pannerden, Citroenvlinder DTP & Vormgeving, Bilthoven, The Netherlands Printing: GVO drukkers en vormgevers, Ede, The Netherlands Subarachnoid hemorrhage

Early evaluation and optimization of management

ACADEMISCH PROEFSCHRIFT

ter verkrijging van de graad van doctor aan de Universiteit van Amsterdam op gezag van de Rector Magnificus prof. dr. D.C. van den Boom ten overstaan van een door het College voor Promoties ingestelde commissie, in het openbaar te verdedigen in de Agnietenkapel op woensdag 4 maart 2015, te 14.00 uur door

Menno Robbert Germans

geboren te Geleen Promotiecommissie Promotor: prof. dr. W.P. Vandertop prof. dr. G.J.E. Rinkel

Co-promotor: dr. D. Verbaan dr. B.A. Coert

Overige leden: prof. dr. R.J. de Haan prof. dr. M.B. Vroom prof. dr. C.B.L.M. Majoie prof. dr. C.M.F. Dirven dr. A. van der Zwan

Faculteit der Geneeskunde Subarachnoid hemorrhage: early evaluation and optimization of management Contents

Chapter 1 General introduction and outline 9

Part 1 Early rebleed risk and reduction of rebleeds 23

Chapter 2 Time intervals from subarachnoid hemorrhage to 25 rebleed Journal of Neurology 2014;261(7): 1425-1431

Chapter 3 Time intervals from aneurysmal subarachnoid 41 hemorrhage to treatment and factors contributing to delay Journal of Neurology 2014;261(3): 473-479

Chapter 4 Antifibrinolytic therapy for aneurysmal subarachnoid 57 haemorrhage (review) (Adapted from) Cochrane Database of Systematic Reviews 2013;8: CD001245

Chapter 5 Ultra-early tranexamic acid after subarachnoid 109 hemorrhage (ULTRA): study protocol for a randomized controlled trial Trials 2013;14: 143 Part 2 Evaluation of the spinal axis in non-aneurysmal 121 subarachnoid hemorrhage

Chapter 6 Spinal vascular malformations in non-perimesencephalic 123 subarachnoid hemorrhage Journal of Neurology 2008;255(12): 1910-1915

Chapter 7 Spinal axis imaging in non-aneurysmal subarachnoid 137 hemorrhage: a prospective cohort study Journal of Neurology 2014;261(11): 2199-2203

Chapter 8 Yield of spinal imaging in non-aneurysmal, non- 149 perimesencephalic subarachnoid hemorrhage Neurology; accepted for publication

Chapter 9 General discussion and future considerations 157

Chapter 10 Summary 171

Chapter 11 Samenvatting 179

List of abbreviations 186

List of publications 187

Dankwoord 189

Curriculum vitae 191

Chapter 1

General introduction and outline Chapter 1

GENERAL INTRODUCTION

Introduction A subarachnoid hemorrhage (SAH) is a life-threatening disease that was first described in the 18th century, but it took until the early 20th century until the term “spontaneous subarachnoid hemorrhage” was introduced by the English neurologist Sir Charles P. Symonds1. Nowadays, the term spontaneous SAH describes the presence of blood in the subarachnoid space that is not the result of a trauma.

In approximately 85% of cases a SAH is caused by a rupture of an aneurysm on one of the intracranial arteries and this is called an aneurysmal SAH (aSAH)2. Because the intracranial arteries lie within the subarachnoid space, where also the cerebrospinal fluid (CSF) is located, the blood is able to spread over the complete brain and spinal cord. This blood can mostly be visualized on a plain computed tomography (CT-) scan of the brain or, when the amount of blood is too small or the blood has been washed out in time, it can be diagnosed by a lumbar puncture (LP) or magnetic resonance (MR-) scan2-6. A SAH is considered a medical emergency due to the severity of the hemorrhage and the high risk of early complications, which is reflected in the high mortality of approximately 40% and significant neurological and cognitive deficits in the majority of the survivors 7-9. A CT-scan of the brain is made as soon as possible to confirm the diagnosis and patients are admitted to specialized SAH treatment centers. The purpose is to treat the aneurysm as early as feasible, and at least within the first 72 hours, according to the most recent guidelines6, 10. The most severe complication that is prevented by early diagnosis and aneurysm treatment is a recurrent hemorrhage, which is associated with an even worse outcome than a single hemorrhage6, 10-13.

In 15% of all SAH patients no aneurysm is visualized on initial vascular imaging investigations, which classifies these patients into the group of non-aneurysmal SAH2. About two-thirds of these hemorrhages are a perimesencephalic hemorrhage (PMSAH), first described by van Gijn et al in 1985, and this reflects a separate type of hemorrhage with a more favorable course of the disease14. Its exact pathogenic mechanism is unknown but ruptures of small angiomas, capillary teleangiectasias or aneurysms of perforating arteries have been

10 General introduction and outline

discussed as possible explanations, and also atypical venous drainage patterns or intramural hematomas of the basilar artery have been seen in this type of hemorrhage15-17. Moreover, some case reports mention a spinal vascular 1 malformation causing a PMSAH18, 19. The remaining non-aneurysmal patients, those who do not have a PMSAH, have a non-perimesencephalic SAH (NPSAH)6. In some of these patients an aneurysm is found on repeat investigations and those are finally also classified as an aSAH. Almost half of the NPSAH patients develop similar complications as in aSAH20, 21. This indicates that this type of hemorrhage resembles an aSAH more than a PMSAH. A search for every possible cause in NPSAH patients seems warranted to prevent potential complications and to inform patients properly about the course of their disease. This might also include a search for a spinal origin, which can not only cause a recurrent hemorrhage, but also slowly progressive spinal cord deficits over months to years22.

Aneurysmal SAH

Aneurysm after second investigation NPSAH Non-‐aneurysmal S AH PMSAH

Overview of classification of patients with spontaneous subarachnoid hemorrhage after first vascular imaging investigaton (SAH = subarachnoid hemorrhage; NPSAH = non-perimesencephalic SAH with first negative digital subtraction angiography; PMSAH = perimesencephalic SAH). See text for explanation.

11 Chapter 1

Epidemiology Aneurysmal subarachnoid hemorrhage The incidence of aneurysmal rupture is approximately 9 per 100.000 persons per year, although in some countries, such as Finland and Japan, the incidence is higher23-25. It comprises only 5% of stroke in the complete population, but due to the high morbidity and mortality in the relatively young population (average age at onset is 50 years), the impact on the socioeconomic and health-care system is high2, 9, 23, 26. The prevalence of an intracranial aneurysm is between 3 and 5%27, 28, but the risk that it ruptures is only 1.1-1.4% per year29, 30, leading to a lifetime risk between 0.02% and 7.2%31. Some known risk factors for growth and rupture of aneurysms are female gender, age, hypertension, history of SAH, aneurysm size and location, smoking and excessive alcohol intake10, 29. In 3-7% of SAH patients no hemorrhage is seen on the CT-scan despite clinical suspicion of SAH. This is probably a consequence of a small amount of blood in the CSF or a long interval since the hemorrhage2, 32. These patients are diagnosed afterwards by LP and approximately 45% of them appear to have an intracranial aneurysm32, 33.

Non-aneurysmal subarachnoid hemorrhage Patients with PMSAH encompass 10% of all spontaneous SAH, with a reported incidence of 0.5 per 100.000 persons per year34. These patients are significantly younger and less likely to be women. Because of the much more favorable course of the disease, the impact on the socioeconomic and health-care system is much lower. When there is no evidence for intracranial vascular pathology in a SAH that has been proven by either an aneurysmal hemorrhage pattern on CT or a negative CT with positive LP, the patient is categorized into NPSAH. This type of hemorrhage comprises 5% of all SAH and the demographic characteristics are comparable with those of aSAH patients32, 35 .

Diagnosis Aneurysmal subarachnoid hemorrhage Approximately three quarters of aSAH patients have a classic presentation and complain of an acute onset headache (“worst of their life”), often accompanied by nausea and vomiting2, 36. A decreased, or even loss of, consciousness and

12 General introduction and outline

seizures after the hemorrhage are seen in 66% and 7%, respectively2. Three- dimensional digital subtraction angiography (DSA) remains the gold standard for detecting an aneurysm6, 37. On the other hand, CT-angiography (CTA) and 1 MR-angiography (MRA) are acceptable alternatives as these are less invasive, can be performed immediately following the radiological investigation that diagnosed the SAH, are less time-consuming and can also be used for follow- up38-40.

Non-aneurysmal subarachnoid hemorrhage Patients with a perimesencephalic hemorrhage pattern usually do not have a loss of consciousness after their hemorrhage, nor do they develop seizures. They present fully conscious, or slightly disoriented, with no focal neurological deficits14, 41. The pattern on the initial CT-scan includes blood strictly confined to the subarachnoid cisterns around the midbrain, and the center of the bleeding is immediately anterior to the midbrain. The extension of the hemorrhage is maximally to the medial one-third of the Sylvian fissures or the anterior part of the interhemispheric fissure, and some sedimentation of blood in the posterior horns of the lateral ventricles may occur42. The chance of finding an aneurysm in a patient who presents with a perimesencephalic hemorrhage pattern on the initial CT-scan is low (4%)43, but additional imaging of the intracranial arteries is recommended in order not to miss a treatable cause of the hemorrhage20, 44. A single CTA is enough to rule out an intracranial aneurysm and confirms the diagnosis PMSAH44. Nevertheless, if the CTA is considered to be insufficient for a reliable interpretation, a DSA can be useful to definitely rule out the presence of an aneurysm20, 44. Once the diagnosis PMSAH has been confirmed, no further diagnostic investigations searching for intracranial vascular pathology are necessary6. Especially the NPSAH patients with an aneurysmal hemorrhage pattern generally present in a more severe clinical state than PMSAH patients, whereas LP-proven NPSAH patients present in a good clinical state16, 32, 45. If no aneurysm is detected and the patient is classified as NPSAH, a second investigation is advised to rule out the presence of an occult vascular abnormality, which might have been missed initially. The yield for finding an intracranial aneurysm with repeated imaging in this group is between 5 and 35% for DSA20, 46-50 and 9% for CTA51. When the presence of intracranial vascular pathology in NPSAH patients is definitely ruled out, other rare causes can be investigated, such

13 Chapter 1

as posterior reversible encephalopathy syndrome (PRES), pituitary apoplexy, bleeding disorder, cocaine abuse or a lesion in the spinal axis2, 6, 52-54.

Complications Aneurysmal subarachnoid hemorrhage One of the most severe early complications is recurrent hemorrhage from the aneurysm (“rebleed”), which is associated with a 62-88% risk for poor outcome11-13, 55-58. Recent studies have reported an incidence of 7-21% in the first 24 hours, with the highest risk in the first few hours after the initial hemorrhage55-59. Another well-known complication following aSAH is hydrocephalus, which is associated with an increased risk of poor outcome, cognitive disturbance and memory difficulties6, 10. Its incidence is 15-87% and approximately 25% of all aSAH patients need a procedure for definitive CSF diversion as a consequence of chronic hydrocephalus35, 60-63. A third SAH- related complication is the development of delayed cerebral ischemia (DCI), which occurs in approximately 30%, with the highest risk between day 4 and 10 after the hemorrhage64-66. The diagnosis is determined after exclusion of other possible causes for delayed neurological deterioration and is sometimes difficult to confirm, especially when patients are sedated and neurological examination is therefore not reliable65, 66. Alongside these intracranial complications, SAH patients are also at risk for systemic problems, such as cardiopulmonary complications and electrolyte disturbances67. Additionally, patients who present in a poor neurological state are usually treated in the intensive care unit and/or are confined to bed for a long time, increasing the risk of the development of infections, deep venous thrombosis, pulmonary embolisms, compressive ulcers, muscle wasting and contractures68.

Non-aneurysmal subarachnoid hemorrhage Patients with a PMSAH have no risk for a rebleed and hydrocephalus occurs in a small number of patients and is most often transient21, 45. Clinically relevant DCI and electrolyte disturbances are rarely seen45, 54, 69. Because of the less severe impact of the hemorrhage, no cardiopulmonary complications occur and complications due to hospital admission are hardly seen. In NPSAH patients however, complications as in aneurysmal SAH are known to occur in almost half of the patients, indicating a less benign course of the disease than PMSAH20, 21.

14 General introduction and outline

Treatment Aneurysmal subarachnoid hemorrhage As soon as these patients enter the health-care system, treatment is aimed at 1 the optimization of cerebral perfusion pressure, cardiovascular stabilization, securing the aneurysm and support and prevention of SAH-related complications. These complications are thought to cause 23% of deaths70. The aim is to transport a patient to an emergency department as soon as possible. Patients are best treated in a specialized center that treats a high volume of SAH patients and where all necessary specialists, such as experienced (neuro) intensivists, neurovascular surgeons and neurointerventional radiologists, are readily available10, 68. By this means, patients are often transferred from the hospital where the diagnosis is made to a SAH treatment center to ensure optimal treatment. One major reason for early transfer to a SAH center is to prevent a rebleed by early treatment of the aneurysm, because this will eliminate the risk for a rebleed. The optimal timing for securing the aneurysm has not yet been elucidated, but recent guidelines advise treatment as early as feasible and at least within the first 72 hours6, 10. Several factors make early aneurysm treatment difficult71-74, with consequently a rebleed rate higher that than desired, so other options need to be explored. Antifibrinolytic therapy, i.e. administration of medication that prevents breakdown of the blood clot on the aneurysm, reduces the number of rebleeds. Unfortunately, a review summarizing the results showed that this treatment does not improve overall outcome, presumably due to a simultaneous increase in DCI75. In more recent years, studies with earlier and shorter administration of antifibrinolytics showed better results, which might indicate that the outcome could be improved with current treatment protocols and earlier start of medication administration58, 59. The SAH-related complications are best managed by active monitoring of patients and, if necessary, prevention and treatment of complications68. Moreover, the physicians should also be aware of complications that can occur during the follow-up period after discharge from hospital, such as a normal pressure hydrocephalus and cognitive deficits7.

Non-aneurysmal subarachnoid hemorrhage When patients are diagnosed with PMSAH without evidence for hydrocephalus, their treatment includes adequate pain management and they can be

15 Chapter 1

discharged early. On the other hand, NPSAH patients need observation for several days and treatment according to aSAH protocols, because they are at risk for SAH-related complications which need prompt and proper treatment in the hospital45.

Outcome Aneurysmal subarachnoid hemorrhage The outcome after an aSAH is mainly related to the severity of the primary hemorrhage, but age, location and size of the aneurysm, rebleed, DCI, type of treatment and experience of the treatment center are also factors that influence outcome6, 10, 76. Approximately 8-12% of patients die before reaching the hospital8, 9 and the mortality among the remaining patients, although improved significantly over the last decades, is still approximately 30%77. The outcome of patients who reach the hospital is favorable, defined as being independent and able to take care of oneself, in 55-67%9, 78. Even when patients have a favorable outcome, many still have cognitive deficits, which prevent them from returning to their jobs. When taking all admitted aSAH patients into account, only 6-17% return to their previous jobs7.

Non-aneurysmal subarachnoid hemorrhage PMSAH patients have a favorable functional outcome, with neither a reduced quality of life nor decreased capacity to work79, 80. Nevertheless, a consistent part of the patients complain of headaches, irritability, depression, weariness and reduced endurance at the long-term follow-up80. The functional outcome of NPSAH patients is better than the aSAH population, but worse than the PMSAH population15, 21, 45, 81.

AIM AND OUTLINE OF THIS THESIS

As outlined before, not only the initial hemorrhage, but also rebleeds and complications related to the hemorrhage affect the course of the disease and outcome. Therefore, multiple factors need to be addressed to improve the course of the disease and patients’ outcome. Early diagnosis and treatment of SAH patients with the goal to reduce rebleeds might contribute to this improvement.

16 General introduction and outline

As this thesis encompasses both aSAH and non-aneurysmal SAH patients, it is split into two parts for a separate evaluation of both patient groups. The first aim of this thesis is to gain better insight into the rebleed risk in the early 1 phase after aSAH and to examine options that can reduce the risk for a rebleed. The second aim is to assess whether routine MR-imaging of the spinal axis is useful in non-aneurysmal SAH patients to identify a treatable cause of the hemorrhage.

Part 1. Early rebleed risk and reduction of rebleeds The study in Chapter 2 was performed to examine the time interval between the initial hemorrhage and rebleeds in the first hours after aSAH, and the location of the patients during the rebleed in order to elucidate when and where we need to intervene for a maximal reduction of rebleeds. In Chapter 3 the time intervals between aSAH and aneurysm treatment are outlined to get more insight into the factors that lead to delay in aneurysm treatment. Improving these delaying factors can theoretically reduce the interval to aneurysm treatment, leading to a reduction of rebleeds. The only proven drugs that can reduce rebleeds are antifibrinolytic agents, and Chapter 4 gives an update on the randomized studies that have been performed with antifibrinolytic agents in order to determine whether this treatment improves outcome. Because of the weak evidence for improving functional outcome with ultra-early (start within 24 hours) and short-term antifibrinolytic therapy, a randomized, multicenter clinical trial in the Netherlands was developed and initiated. The protocol of this study is presented in Chapter 5.

Part 2. Evaluation of the spinal axis in non-aneurysmal subarachnoid hemorrhage As case reports have described spinal causes in NPSAH patients where its treatment can potentially prevent recurrent hemorrhage in the acute phase, we performed a retrospective study to assess the rate of spinal vascular malformations in NPSAH patients. The results of this study are outlined in Chapter 6. In addition to this study, a prospective, observational study was performed to establish the yield of MR-imaging of the spinal neuraxis for finding a spinal origin in the complete non-aneurysmal population (Chapter 7) and exclusively in NPSAH patients (Chapter 8). A general discussion and future considerations are presented in Chapter 9, followed by an English (Chapter 10) and Dutch summary (Chapter 11).

17 Chapter 1

REFERENCE LIST

(1) Longstreth WT, Jr., Koepsell TD, Yerby MS, van Belle G. Risk factors for subarachnoid hemorrhage. Stroke 1985 May;16(3):377-85. (2) van Gijn J, Kerr RS, Rinkel GJ. Subarachnoid haemorrhage. Lancet 2007 January 27;369(9558):306- 18. (3) Barkovich AJ, Atlas SW. Magnetic resonance imaging of intracranial hemorrhage. Radiol Clin North Am 1988 July;26(4):801-20. (4) Linn FH, Voorbij HA, Rinkel GJ, Algra A, van Gijn J. Visual inspection versus spectrophotometry in detecting bilirubin in cerebrospinal fluid. J Neurol Neurosurg Psychiatry 2005 October;76(10):1452-4. (5) Mitchell P, Wilkinson ID, Hoggard N, Paley MN, Jellinek DA, et al. Detection of subarachnoid haemorrhage with magnetic resonance imaging. J Neurol Neurosurg Psychiatry 2001 February;70(2):205-11. (6) Steiner T, Juvela S, Unterberg A, Jung C, Forsting M, Rinkel G. European Stroke Organization Guidelines for the Management of Intracranial Aneurysms and Subarachnoid Haemorrhage. Cerebrovasc Dis 2013 February 7;35(2):93-112. (7) Al-Khindi T, Macdonald RL, Schweizer TA. Cognitive and functional outcome after aneurysmal subarachnoid hemorrhage. Stroke 2010 August;41(8):e519-e536. (8) Huang J, van Gelder JM. The probability of sudden death from rupture of intracranial aneurysms: a meta-analysis. Neurosurgery 2002 November;51(5):1101-5. (9) Nieuwkamp DJ, Setz LE, Algra A, Linn FH, de Rooij NK, Rinkel GJ. Changes in case fatality of aneurysmal subarachnoid haemorrhage over time, according to age, sex, and region: a meta- analysis. Lancet Neurol 2009 July;8(7):635-42. (10) Connolly ES, Jr., Rabinstein AA, Carhuapoma JR, Derdeyn CP, Dion J, 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 June;43(6):1711- 37. (11) Broderick JP, Brott TG, Duldner JE, Tomsick T, Leach A. Initial and recurrent bleeding are the major causes of death following subarachnoid hemorrhage. Stroke 1994 July;25(7):1342-7. (12) Naidech AM, Janjua N, Kreiter KT, Ostapkovich ND, Fitzsimmons BF, et al. Predictors and impact of aneurysm rebleeding after subarachnoid hemorrhage. Arch Neurol 2005 March;62(3):410-6. (13) Roos YB, Beenen LF, Groen RJ, Albrecht KW, Vermeulen M. Timing of surgery in patients with aneurysmal subarachnoid haemorrhage: rebleeding is still the major cause of poor outcome in neurosurgical units that aim at early surgery. J Neurol Neurosurg Psychiatry 1997 October;63(4):490-3. (14) van Gijn J, van Dongen KJ, Vermeulen M, Hijdra A. Perimesencephalic hemorrhage: a nonaneurysmal and benign form of subarachnoid hemorrhage. Neurology 1985 April;35(4):493-7. (15) Beseoglu K, Pannes S, Steiger HJ, Hanggi D. Long-term outcome and quality of life after nonaneurysmal subarachnoid hemorrhage. Acta Neurochir (Wien ) 2010 March;152(3):409-16. (16) Khan AA, Smith JD, Kirkman MA, Robertson FJ, Wong K, et al. Angiogram negative subarachnoid haemorrhage: outcomes and the role of repeat angiography. Clin Neurol Neurosurg 2013 August;115(8):1470-5. (17) Schievink WI, Wijdicks EF. Pretruncal subarachnoid hemorrhage: an anatomically correct description of the perimesencephalic subarachnoid hemorrhage. Stroke 1997 December;28(12):2572. (18) Fassett DR, Rammos SK, Patel P, Parikh H, Couldwell WT. Intracranial subarachnoid hemorrhage resulting from cervical spine dural arteriovenous fistulas: literature review and case presentation. Neurosurg Focus 2009 January;26(1):E4. (19) Hashimoto H, Iida J, Shin Y, Hironaka Y, Sakaki T. Spinal dural arteriovenous fistula with perimesencephalic subarachnoid haemorrhage. J Clin Neurosci 2000 January;7(1):64-6. (20) Dalyai R, Chalouhi N, Theofanis T, Jabbour PM, Dumont AS, et al. Subarachnoid Hemorrhage With Negative Initial Catheter Angiography: A Review of 254 Cases Evaluating Patient Clinical Outcome and Efficacy of Short- and Long-term Repeat Angiography. Neurosurgery 2013 April;72(4):646-52.

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(21) Hui FK, Tumialan LM, Tanaka T, Cawley CM, Zhang YJ. Clinical differences between angiographically negative, diffuse subarachnoid hemorrhage and perimesencephalic subarachnoid hemorrhage. Neurocrit Care 2009;11(1):64-70. (22) Koch C. Spinal dural arteriovenous fistula. Curr Opin Neurol 2006 February;19(1):69-75. 1 (23) de Rooij NK, Linn FH, van der Plas JA, Algra A, Rinkel GJ. Incidence of subarachnoid haemorrhage: a systematic review with emphasis on region, age, gender and time trends. J Neurol Neurosurg Psychiatry 2007 December;78(12):1365-72. (24) Feigin VL, Lawes CM, Bennett DA, Barker-Collo SL, Parag V. Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. Lancet Neurol 2009 April;8(4):355-69. (25) Ingall T, Asplund K, Mahonen M, Bonita R. A multinational comparison of subarachnoid hemorrhage epidemiology in the WHO MONICA stroke study. Stroke 2000 May;31(5):1054-61. (26) Taylor TN, Davis PH, Torner JC, Holmes J, Meyer JW, Jacobson MF. Lifetime cost of stroke in the United States. Stroke 1996 September;27(9):1459-66. (27) Rinkel GJ, Djibuti M, Algra A, van Gijn J. Prevalence and risk of rupture of intracranial aneurysms: a systematic review. Stroke 1998 January;29(1):251-6. (28) Vlak MH, Algra A, Brandenburg R, Rinkel GJ. Prevalence of unruptured intracranial aneurysms, with emphasis on sex, age, comorbidity, country, and time period: a systematic review and meta- analysis. Lancet Neurol 2011 July;10(7):626-36. (29) Greving JP, Wermer MJ, Brown RD, Jr., Morita A, Juvela S, et al. Development of the PHASES score for prediction of risk of rupture of intracranial aneurysms: a pooled analysis of six prospective cohort studies. Lancet Neurol 2014 January;13(1):59-66. (30) Juvela S, Poussa K, Lehto H, Porras M. Natural history of unruptured intracranial aneurysms: a long- term follow-up study. Stroke 2013 September;44(9):2414-21. (31) Vlak MH, Rinkel GJ, Greebe P, Greving JP, Algra A. Lifetime risks for aneurysmal subarachnoid haemorrhage: multivariable risk stratification.J Neurol Neurosurg Psychiatry 2013 June;84(6):619- 23. (32) Bakker NA, Groen RJ, Foumani M, Uyttenboogaart M, Eshghi OS, et al. Appreciation of CT-negative, lumbar puncture-positive subarachnoid haemorrhage: risk factors for presence of aneurysms and diagnostic yield of imaging. J Neurol Neurosurg Psychiatry 2013 December 19. (33) Chalouhi N, Witte S, Penn DL, Soni P, Starke RM, et al. Diagnostic yield of cerebral angiography in patients with computed tomography-negative, lumbar puncture-positive subarachnoid hemorrhage. Neurosurgery 2013 August;73(2):282-8. (34) Flaherty ML, Haverbusch M, Kissela B, Kleindorfer D, Schneider A, et al. Perimesencephalic subarachnoid hemorrhage: incidence, risk factors, and outcome. J Stroke Cerebrovasc Dis 2005 November;14(6):267-71. (35) Little AS, Zabramski JM, Peterson M, Goslar PW, Wait SD, et al. Ventriculoperitoneal shunting after aneurysmal subarachnoid hemorrhage: analysis of the indications, complications, and outcome with a focus on patients with borderline ventriculomegaly. Neurosurgery 2008 March;62(3):618-27. (36) Linn FH, Rinkel GJ, Algra A, van Gijn J. Headache characteristics in subarachnoid haemorrhage and benign thunderclap headache. J Neurol Neurosurg Psychiatry 1998 November;65(5):791-3. (37) van Rooij WJ, Sprengers ME, de Gast AN, Peluso JP, Sluzewski M. 3D rotational angiography: the new gold standard in the detection of additional intracranial aneurysms. AJNR Am J Neuroradiol 2008 May;29(5):976-9. (38) Dammert S, Krings T, Moller-Hartmann W, Ueffing E, Hans FJ, et al. Detection of intracranial aneurysms with multislice CT: comparison with conventional angiography. Neuroradiology 2004 June;46(6):427-34. (39) Schaafsma JD, Velthuis BK, Majoie CB, van den Berg R, Brouwer PA, et al. Intracranial aneurysms treated with coil placement: test characteristics of follow-up MR angiography--multicenter study. Radiology 2010 July;256(1):209-18. (40) White PM, Teasdale EM, Wardlaw JM, Easton V. Intracranial aneurysms: CT angiography and MR angiography for detection prospective blinded comparison in a large patient cohort. Radiology 2001 June;219(3):739-49.

19 Chapter 1

(41) Rinkel GJ, Wijdicks EF, Vermeulen M, Hasan D, Brouwers PJ, van Gijn J. The clinical course of perimesencephalic nonaneurysmal subarachnoid hemorrhage. Ann Neurol 1991 May;29(5):463-8. (42) Rinkel GJ, Wijdicks EF, Vermeulen M, Ramos LM, Tanghe HL, et al. Nonaneurysmal perimesencephalic subarachnoid hemorrhage: CT and MR patterns that differ from aneurysmal rupture. AJNR Am J Neuroradiol 1991 September;12(5):829-34. (43) Velthuis BK, Rinkel GJ, Ramos LM, Witkamp TD, van Leeuwen MS. Perimesencephalic hemorrhage. Exclusion of vertebrobasilar aneurysms with CT angiography. Stroke 1999 May;30(5):1103-9. (44) Ruigrok YM, Rinkel GJ, Buskens E, Velthuis BK, van Gijn J. Perimesencephalic hemorrhage and CT angiography: A decision analysis. Stroke 2000 December;31(12):2976-83. (45) Boswell S, Thorell W, Gogela S, Lyden E, Surdell D. Angiogram-negative subarachnoid hemorrhage: outcomes data and review of the literature. J Stroke Cerebrovasc Dis 2013 August;22(6):750-7. (46) Bakker NA, Groen RJ, Foumani M, Uyttenboogaart M, Eshghi OS, et al. Repeat digital subtraction angiography after a negative baseline assessment in nonperimesencephalic subarachnoid hemorrhage: a pooled data meta-analysis. J Neurosurg 2014 January;120(1):99-103. (47) Inamasu J, Nakamura Y, Saito R, Horiguchi T, Kuroshima Y, et al. “Occult” ruptured cerebral aneurysms revealed by repeat angiography: result from a large retrospective study. Clin Neurol Neurosurg 2003 December;106(1):33-7. (48) Jung JY, Kim YB, Lee JW, Huh SK, Lee KC. Spontaneous subarachnoid haemorrhage with negative initial angiography: a review of 143 cases. J Clin Neurosci 2006 December;13(10):1011-7. (49) Kaim A, Proske M, Kirsch E, von WA, Radu EW, Steinbrich W. Value of repeat-angiography in cases of unexplained subarachnoid hemorrhage (SAH). Acta Neurol Scand 1996 May;93(5):366-73. (50) Topcuoglu MA, Ogilvy CS, Carter BS, Buonanno FS, Koroshetz WJ, Singhal AB. Subarachnoid hemorrhage without evident cause on initial angiography studies: diagnostic yield of subsequent angiography and other neuroimaging tests. J Neurosurg 2003 June;98(6):1235-40. (51) Delgado Almandoz JE, Crandall BM, Fease JL, Scholz JM, Anderson RE, et al. Diagnostic Yield of Catheter Angiography in Patients with Subarachnoid Hemorrhage and Negative Initial Noninvasive Neurovascular Examinations. AJNR Am J Neuroradiol 2012 September 27. (52) Khurram A, Kleinig T, Leyden J. Clinical associations and causes of convexity subarachnoid hemorrhage. Stroke 2014 April;45(4):1151-3. (53) Rinkel GJ, van Gijn J, Wijdicks EF. Subarachnoid hemorrhage without detectable aneurysm. A review of the causes. Stroke 1993 September;24(9):1403-9. (54) van Gijn J, Rinkel GJ. Subarachnoid haemorrhage: diagnosis, causes and management. Brain 2001 February;124(Pt 2):249-78. (55) Cha KC, Kim JH, Kang HI, Moon BG, Lee SJ, Kim JS. Aneurysmal rebleeding : factors associated with clinical outcome in the rebleeding patients. J Korean Neurosurg Soc 2010 February;47(2):119-23. (56) Fujii Y, Takeuchi S, Sasaki O, Minakawa T, Koike T, Tanaka R. Ultra-early rebleeding in spontaneous subarachnoid hemorrhage. J Neurosurg 1996 January;84(1):35-42. (57) Guo LM, Zhou HY, Xu JW, Wang Y, Qiu YM, Jiang JY. Risk factors related to aneurysmal rebleeding. World Neurosurg 2011 September;76(3-4):292-8. (58) Hillman J, Fridriksson S, Nilsson O, Yu Z, Saveland H, Jakobsson KE. Immediate administration of tranexamic acid and reduced incidence of early rebleeding after aneurysmal subarachnoid hemorrhage: a prospective randomized study. J Neurosurg 2002 October;97(4):771-8. (59) Starke RM, Connolly ES, Jr. Rebleeding after aneurysmal subarachnoid hemorrhage. Neurocrit Care 2011 September;15(2):241-6. (60) de Oliveira JG, Beck J, Setzer M, Gerlach R, Vatter H, Seifert V, Raabe A. Risk of shunt-dependent hydrocephalus after occlusion of ruptured intracranial aneurysms by surgical clipping or endovascular coiling: a single-institution series and meta-analysis. Neurosurgery 2007 November;61(5):924-33. (61) Komotar RJ, Hahn DK, Kim GH, Starke RM, Garrett MC, et al. Efficacy of lamina terminalis fenestration in reducing shunt-dependent hydrocephalus following aneurysmal subarachnoid hemorrhage: a systematic review. Clinical article. J Neurosurg 2009 July;111(1):147-54. (62) Rincon F, Gordon E, Starke RM, Buitrago MM, Fernandez A, et al. Predictors of long-term shunt- dependent hydrocephalus after aneurysmal subarachnoid hemorrhage. Clinical article. J Neurosurg 2010 October;113(4):774-80.

20 General introduction and outline

(63) Woernle CM, Winkler KM, Burkhardt JK, Haile SR, Bellut D, et al. Hydrocephalus in 389 patients with aneurysm-associated subarachnoid hemorrhage. J Clin Neurosci 2013 June;20(6):824-6. (64) Dorhout Mees SM, Kerr RS, Rinkel GJ, Algra A, Molyneux AJ. Occurrence and impact of delayed cerebral ischemia after coiling and after clipping in the International Subarachnoid Aneurysm Trial (ISAT). J Neurol 2012 April;259(4):679-83. 1 (65) Macdonald RL. Delayed neurological deterioration after subarachnoid haemorrhage. Nat Rev Neurol 2014 January;10(1):44-58. (66) Vergouwen MD, Vermeulen M, van Gijn J, Rinkel GJ, Wijdicks EF, et al. Definition of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage as an outcome event in clinical trials and observational studies: proposal of a multidisciplinary research group. Stroke 2010 October;41(10):2391-5. (67) Mayer SA, Fink ME, Homma S, Sherman D, LiMandri G, et al. Cardiac injury associated with neurogenic pulmonary edema following subarachnoid hemorrhage. Neurology 1994 May;44(5):815-20. (68) Diringer MN, Bleck TP, Claude HJ, III, Menon D, Shutter L, et al. Critical care management of patients following aneurysmal subarachnoid hemorrhage: recommendations from the Neurocritical Care Society’s Multidisciplinary Consensus Conference. Neurocrit Care 2011 September;15(2):211-40. (69) Sheehan JP, Polin RS, Sheehan JM, Baskaya MK, Kassell NF. Factors associated with hydrocephalus after aneurysmal subarachnoid hemorrhage. Neurosurgery 1999 November;45(5):1120-7. (70) Solenski NJ, Haley EC Jr., Kassell NF, Kongable G, Germanson T, et al. Medical complications of aneurysmal subarachnoid hemorrhage: a report of the multicenter, cooperative aneurysm study. Participants of the Multicenter Cooperative Aneurysm Study. Crit Care Med 1995 June;23(6):1007- 17. (71) Lamb JN, Crocker M, Tait MJ, Anthony BB, Papadopoulos MC. Delays in treating patients with good grade subarachnoid haemorrhage in London. Br J Neurosurg 2011 April;25(2):243-8. (72) Larsen CC, Eskesen V, Hauerberg J, Olesen C, Romner B, Astrup J. Considerable delay in diagnosis and acute management of subarachnoid haemorrhage. Dan Med Bull 2010 April;57(4):A4139. (73) Nuno M, Patil CG, Lyden P, Drazin D. The effect of transfer and hospital volume in subarachnoid hemorrhage patients. Neurocrit Care 2012 December;17(3):312-23. (74) O’Kelly CJ, Spears J, Urbach D, Wallace MC. Proximity to the treating centre and outcomes following subarachnoid hemorrhage. Can J Neurol Sci 2011 January;38(1):36-40. (75) Roos YB, Rinkel GJ, Vermeulen M, Algra A, van Gijn J. Antifibrinolytic therapy for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev 2003;(2):CD001245. (76) Li H, Pan R, Wang H, Rong X, Yin Z, et al. Clipping versus coiling for ruptured intracranial aneurysms: a systematic review and meta-analysis. Stroke 2013 January;44(1):29-37. (77) Lovelock CE, Rinkel GJ, Rothwell PM. Time trends in outcome of subarachnoid hemorrhage: Population-based study and systematic review. Neurology 2010 May 11;74(19):1494-501. (78) Rinkel GJ, Algra A. Long-term outcomes of patients with aneurysmal subarachnoid haemorrhage. Lancet Neurol 2011 April;10(4):349-56. (79) Brilstra EH, Hop JW, Rinkel GJ. Quality of life after perimesencephalic haemorrhage. J Neurol Neurosurg Psychiatry 1997 September;63(3):382-4. (80) Marquardt G, Niebauer T, Schick U, Lorenz R. Long term follow up after perimesencephalic subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry 2000 July;69(1):127-30. (81) Canovas D, Gil A, Jato M, de MM, Rubio F. Clinical outcome of spontaneous non-aneurysmal subarachnoid hemorrhage in 108 patients. Eur J Neurol 2012 March;19(3):457-61.

Part 1

Early rebleed risk and reduction of rebleeds

Chapter 2

Time intervals from subarachnoid hemorrhage to rebleed

M.R. Germans, MD B.A. Coert, MD, PhD W.P. Vandertop, MD, PhD D. Verbaan, PhD

Journal of Neurology (2014) 261(7): 1425-1431 Chapter 2

ABSTRACT

Introduction: The most threatening early complication and predictor of poor outcome after an aneurysmal subarachnoid hemorrhage is a rebleed. To evaluate what proportion of rebleeds might be prevented by early treatment we assessed the time interval from the initial hemorrhage to rebleed, and the location of the patient at the time of rebleed.

Methods: Patient characteristics, World Federation of Neurological Surgeons grade on admission and modified Rankin Scale outcome scores, referring hospitals and time intervals from initial hemorrhage to treatment of 293 patients treated between 2008 and 2011 were evaluated. Time intervals to rebleeds and location of the patients at the time of rebleed were retrieved.

Results: Rebleeds were confirmed by CT in 12% of patients, and an additional 4% of patients were diagnosed as having a possible rebleed. Sixty percent of rebleeds occurred after admission to the treatment center. Almost all rebleeds occurred within 24 hours, with a median time interval between initial hemorrhage and rebleed of 180 minutes. A significantly shorter time to treatment and a higher mortality were seen in the group of patients with a rebleed.

Conclusions: Approximately one in six patients with an aneurysmal subarachnoid hemorrhage had a rebleed, of which a majority might have been preventable because they occurred after admission to the treatment center. A reduction in the rebleed rate seems feasible by securing the aneurysm as soon as possible by improving in-hospital logistics for early aneurysm treatment. Alternative options, such as immediate administration of antifibrinolytics, are being explored in a multicenter trial.

26 Time intervals to rebleed

INTRODUCTION

Recurrent bleeding after aneurysmal subarachnoid hemorrhage (aSAH) is an early and devastating complication and a major cause of poor outcome1, 2. The reported incidence of rebleeds is 4-22% and its risk is highest within the first hours after the initial hemorrhage3-8. 2 The only proven treatments to reduce the risk for rebleeds are obliteration of the aneurysm9, 10 and administration of antifibrinolytics11.Since antifibrinolytic treatment does not improve outcome due to a concurrent increase in delayed cerebral ischemia (DCI) 11,the focus lies on decreasing the time interval between the initial SAH and aneurysm treatment. Therefore, recent international guidelines advise aneurysm treatment as early as feasible to prevent rebleeds; if possible, it should be aimed to intervene at least within 72 hours after onset of first symptoms12, 13. Although changes in treatment policies altogether have resulted in improved functional outcome over the years8-10, 14, the percentage of patients with a poor outcome is still higher than desirable. An important contributing factor is an ultra-early rebleed4-6, occurring within the first hours after the initial hemorrhage, which apparently cannot be prevented by the current policy of aneurysm treatment8-10. To evaluate which proportion of rebleeds could be prevented by reducing the time interval to aneurysm treatment towards only several hours after the initial hemorrhage, more insight in the time intervals between initial hemorrhage and rebleed is necessary. Literature about time intervals between initial hemorrhage and rebleed is sparse, and does not specifically elucidate the location of the patient at the time of rebleed3, 4, 7, 8, 10. The aim of this study was to assess as accurately as possible the time interval between initial hemorrhage and rebleed and the location of the patient at the time of rebleed.

METHODS

Patient population The patients for this study were selected from our SAH database, and include 300 patients admitted between November 2008 and July 2011 with an aSAH to the neurosurgical department of the Academic Medical Center, Amsterdam

27 Chapter 2

(AMC), a tertiary referral center for SAH patients in a region of approximately 1.3 million people. Our policy is to transfer all patients whose SAH is diagnosed in one of the referring centers to our center, independent of their clinical condition. Five patients were excluded because of atypical presentation, leading to a patient delay of more than one week. One patient was excluded because the clinical features were so unclear that it took more than a week to diagnose the SAH. A seventh patient was excluded as extensive neurological and radiological evaluation had led to a diagnosis of posterior reversible encephalopathy syndrome. In 278 patients the SAH was confirmed by a computed tomography (CT) scan and in 15 patients by lumbar puncture (LP) and the presence of an aneurysm was diagnosed by CT angiography and/or digital subtraction angiography.

Data collection The medical records, radiological investigations, ambulance data and referral letters of the patients with a rebleed were reviewed retrospectively after approval of the Medical Ethics Committee of the AMC. Lacking data of referring hospitals were retrieved. We recorded patient demographics, referring hospital, World Federation of Neurological Surgeons (WFNS) grade15 on admission, date and time-points (time of the initial hemorrhage, primary presentation, diagnosis, treatment and rebleed on a 24-hour scale) and location of the patient during the rebleed. When no time-point could be retrieved, it was recorded as ‘irretrievable’ and not used for the analysis of the time interval. Clinical outcome was assessed by two independent reviewers after reviewing the medical records, the outpatient clinic records at follow-up, and the letter from the rehabilitation center, if present. All patients were scored according to the modified Rankin Scale score (mRS)16. Any inconsistencies between outcome assessments were cleared after discussion with the first author. In case of insufficient information for a reliable mRS assessment, the patient was excluded from outcome analysis. We decided to use only dichotomized mRS scores to make the retrospective outcome assessment as reliable as possible. A rebleed was defined as a sudden spontaneous neurological deterioration with the presence of more subarachnoid blood, intraventricular or intracerebral hemorrhage on a plain CT-scan compared to a previous investigation (i.e. confirmed rebleed), or a sudden spontaneous neurological deterioration with loss of consciousness, hypertension and bradycardia, stated as being

28 Time intervals to rebleed

suggestive of a rebleed (i.e. possible rebleed). The instances of possible rebleeds were selected by the first author (MRG) and reviewed by a second author (BAC); both experienced in treating SAH patients. In a consensus meeting, taking into account the reports of the clinical team in charge at the time of the suspected rebleed, and also the follow-up of patients, both authors decided whether the deterioration was based on a possible rebleed or more likely on other causes, 2 such as electrolyte disturbances, a seizure or hydrocephalus. Rebleeds during endovascular or surgical treatment (n=6) were not selected for analysis because they were not considered as a spontaneous rebleed.

Clinical management All patients were treated according to our standardized protocol which closely follows international guidelines12, 13 with an adequate blood pressure to optimize cerebral perfusion but avoidance of severe hypertension (i.e. mean arterial blood pressure above 135 mmHg) to reduce the risk of rebleed. Patients with a suspected rebleed were taken to the CT-scan as soon as they were clinically stable for transport. All ruptured aneurysms were treated as early as feasible (preferably within 24 hours), and a rebleed was an indication for emergency treatment as it illustrates instability of the bloodclot4, 17. The choice of treatment modality (clipping, coiling or none) was made in consensus between neurologist, neurosurgeon and interventional neuroradiologist.

Statistical analysis Time intervals were computed by calculating the difference between the retrieved time-points of the variables. When one of the time-points was missing, the patient was excluded from calculation of that specific time interval. The WFNS grades and mRS scores were dichotomized into groups with a good (WFNS-grade 1-3) or poor grade (WFNS-grade 4-5), and a favorable (mRS 0-3) or poor outcome (mRS 4-6), respectively. Normally distributed variables were expressed as means with standard deviations (SD) and tested with the Student’s T test (two group comparison); unequally distributed variables as medians with interquartile ranges (IQR 25%-75%) and tested with the Mann-Whitney U test (two group comparison) or Kruskal-Wallis (multiple group comparison). The Chi-square test was used to assess differences in proportions. A p value <0.05 was considered significant. All analyses were performed using PASW version 20.0.

29 Chapter 2

RESULTS

Patient characteristics CT-confirmed rebleeds were seen in 36 patients, resulting in a CT-confirmed rebleed rate of 12% (95% CI 9-16%). A possible rebleed was diagnosed in 12 additional patients, resulting in an overall rebleed rate of 16% (95% CI 12- 21%) (table 1). Four patients suffered more than one rebleed and all rebleeds occurred before aneurysm treatment.

Table 1: Patient characteristics Patient characteristics With rebleed Without rebleed Total patients p value (n=48) (n=245) n=(293) Age, years; mean ± SD 55 ± 11 56 ± 13 56 ± 13 0.53a

Female 28 (58) 159 (65) 179 (61) 0.41b

CT confirmation of rebleed yes 36 (75) n/a 36 (12) - no 12 (25) 12 (4)

WFNS at first presentation 1-3 28 (58) 158 (64) 185 (63) 4-5 20 (42) 87 (36) 108 (37) 0.42b

Site of first presentation referring hospital 36 (75) 199 (81) 235 (80) treatment center 12 (25) 46 (19) 58 (20) 0.32b

Type of treatment clip 1 (2) 32 (13) 33 (11) coil 39 (81) 187 (76) 226 (77) none 8 (10) 26 (11) 34 (12) 0.06b

Outcomec favorable (mRS 0-3) 25 (53) 163 (67) 188 (65) 0.06b death (mRS 6) 17 (36) 49 (20) 66 (23) 0.02b

Data are shown as n (%) or mean ± standard deviation (SD) n/a not applicable; CT computed tomography; WFNS World Federation of Neurological Surgeons; mRS modified Rankin Scale score a Student’s T-test b Chi-square test c n=290 patients (see text)

Comparison of patients with and without rebleeds There were no significant differences in age (p=0.53), WFNS grade (p=0.42) or hospital of primary presentation (referring hospital or treatment center;

30 Time intervals to rebleed

p=0.32) between patients with or without rebleeds (table 1). These differences were neither significant when the analyses were solely done on patients with confirmed rebleeds. Each time interval was calculated using a different number of patients, due to the inability to retrieve some time-points, which resulted in different proportions of patients used for each time interval. The proportions of patients used varied between 85% and 95%. All calculated time intervals 2 were significantly shorter in patients with a rebleed, compared to patients without a rebleed (p≤0.01 for all time intervals; table 2).

Table 2: Time intervals between patients with and without rebleeds Type of interval With rebleed Without rebleed p valuea Initial hemorrhage to presentation 60 (50-145) 143 (71-753) <0.01 Presentation to diagnosis 20 (7-33) 29 (12-64) 0.01 Initial hemorrhage to diagnosis 106 (66-145) 192 (102-728) <0.01 Diagnosis to start of treatment 481 (140-995) 1136 (714-1527) <0.01 Initial hemorrhage to treatment 626 (242-1115) 1202 (636-1781) <0.01 Data are shown as median (interquartile range) in minutes a Mann-Whitney U test

Three patients were lost at follow-up, therefore clinical outcome was evaluated at a median time interval (IQR) of 4 (0-7) months in 47 patients with a rebleed, and in 243 patients without a rebleed, respectively. The mortality percentage was significantly higher in patients with a rebleed compared to patients without a rebleed (36% vs. 20%, p=0.02). Poor outcome was also more frequent in patients with a rebleed (47% vs. 33% , p=0.06), but this difference was not significant.

Patients with a rebleed: location and time intervals to the rebleed Thirteen percent of all rebleeds occurred before primary presentation at a hospital and 27% during the stay at the referring hospital or transportation to the treatment center. The remaining 60% of rebleeds occurred after admission to the treatment center (table 3).

31 Chapter 2

Table 3 Location of patients during rebleed Location Number (n=48) At site of initial bleeding 3 (6) Transport to primary hospital 3 (6) At referring hospital 9 (19) Transport between referring hospital and treatment center 4 (8) In treatment center 29 (60) Data are shown as n (%) Sum of percentages is not 100, due to rounding off

In 29 patients (60% of patients with a rebleed) we were able to retrieve the time-points of initial hemorrhage and rebleed. The median (IQR) time interval between initial hemorrhage and rebleed was 180 minutes (95-531); 83% of the rebleeds occurred within the first 12 hours after the initial hemorrhage, and 97% of the rebleeds occurred within the first 24 hours (figure 1). The time intervals in relation to location of the patient during the rebleed are outlined in figure 2 and shows a significant longer interval to rebleed in patients admitted to the treatment center (p<0.05). No significant association was found between time interval to rebleed and WFNS grade (p=0.77), outcome (p=0.21) or type of hospital of primary presentation (p=0.23).

Fig. 1 Rebleeds in the first 24 hours after initial hemorrhage in 29 patients Reference line at 720 minutes (12 hours)

32 Time intervals to rebleed

P=0,03*

Fig. 2 Time intervals from initial hemorrhage to rebleed per location in 29 patients Boxes represent IQR Thick lines represent median time * Kruskal-Wallis test comparing “in treatment center” and other locations

DISCUSSION

This study illustrates the time interval between initial hemorrhage and rebleed in patients with aSAH, and the location of the patient at the time of the rebleed in order to examine what proportion of rebleeds could possibly be prevented by reducing the time interval to treatment towards only several hours after the initial hemorrhage. The rebleed rate in our cohort was 16% with a median time interval to rebleed of 180 minutes. Sixty percent of patients suffer their rebleed after admission to the treatment center. According to these data, the current approach of aneurysm treatment as early as feasible, if possible within 72 hours after initial hemorrhage, might not be fast enough to reduce a large number of rebleeds13. Even with our protocol, which strives for treatment within the first 24 hours resulting in a median time interval to treatment of approximately 18 hours, a large number of rebleeds was still not prevented. Our overall rebleed rate is high (16%), even if we only include our CT- confirmed rebleeds (12%). In older studies the rebleed rate was reported to be

33 Chapter 2

approximately 4%7, but our rate is more comparable to recent studies, which report an incidence of close to 12%7,with some studies even reporting rates up to 22%3-8.Our high rate of rebleeds is probably a result of early presentation of patients after their initial aSAH because our region is densely populated with short distances to hospitals and ambulances which are present within 15 minutes. Therefore, patients with early rebleeds who might have died without receiving medical assistance in case of a more delayed presentation, may have been included. Additionally, we transferred all patients whose SAH was diagnosed in one of the referring centers to our center, independent of their clinical condition. In this way we also included the poor grade patients who potentially could have suffered from a rebleed. Our rate of rebleeds may be underestimated because patients with fatal early rebleeds may not have been diagnosed with SAH, because they arrived dead at the hospital or were first treated for cardiac instability and died afterwards without a brain CT-scan13, 18. A remarkably high proportion of rebleeds (60%) occurred in patients who were already admitted to the treatment center. Their time interval to rebleed is significantly longer, owing to the waiting time in the treatment center before the aneurysm is secured. This implies that an important reduction in the rebleed rate might be achieved by a more expeditious securement of the aneurysm. The significantly shorter intervals to treatment in patients with a rebleed confirms that it is possible to secure the aneurysm within the first hours after hemorrhage, probably as a result of emergency management4, 17. If this sense of urgency is applied to all aSAH patients, i.e. also in the patients who do clinically well and have not yet suffered a rebleed, at least some rebleeds might possibly be prevented. This urgent treatment, which has proven its benefit in the treatment of ischemic stroke by applying the ‘time-is-brain’ concept19-21, would necessitate an optimization of in-hospital logistics, and could thus improve outcome8-10, 14. Nevertheless, 40% of patients still have their rebleed before admission to the treatment center. Although patient transfers could be optimized by further education of general practitioners and ambulance employees in order to increase the awareness for SAH22, or by the presence of a mobile CT-unit in the ambulance, which has shown to significantly shorten the time to diagnosis and treatment in ischemic stroke23, these measures have appeared difficult to achieve. Therefore, other options must be examined to prevent out-of- hospital rebleeds within the first hours after the initial hemorrhage. One option

34 Time intervals to rebleed

could be the administration of an antifibrinolytic agent. Although this has been shown to reduce the rebleed rate, standard administration after aSAH is not recommended because it also increases DCI11. Recently, our group therefore has started a multicenter randomized controlled trial to evaluate the clinical outcome after ultra-early and very short-term administration of antifibrinolytics24. 2 Both a worse outcome and higher mortality have been reported in patients with a rebleed1, 2, 5, 25, whereas in our population only mortality was significantly higher. Our results may have been influenced by the retrospective analysis of outcome assessment or smaller proportion of patients with poor outcome compared to other studies with rebleed rates of 4-22% and therefore have to be interpreted with care3-8. This lack of a significantly worse outcome is possibly a result from our early aneurysm treatment management and aggressive treatment of poor grade aSAH patients26. This study has some limitations. First, a quarter of rebleeds was not confirmed with consecutive CT-scans, which could have overestimated the overall rebleed rate and may have influenced the time interval calculations. However, by assessing all the data at time of the rebleed as well as the clinical follow-up by two neurosurgeons with experience in treating SAH patients, we think that the selected patients very likely had a rebleed. In addition, no differences in baseline characteristics were seen between analyses including all rebleeds and including solely the confirmed rebleeds. To our opinion, the inclusion of possible rebleeds reflects the daily clinical practice where treatment decisions are made on the presence of possible rebleeds as well, Second, the time-points were retrieved retrospectively, and this could have led to a less reliable estimation of the exact (re)hemorrhage time and time intervals. Third, the amount of patients with a rebleed is relatively small and important differences in time intervals and outcome assessment could therefore have not been discovered. Finally, the mRS scores have to be interpreted with care, because they were based on outpatient clinical records and rehabilitation letters at different time intervals after the hemorrhage owing to the retrospective study design. However, the median mRS evaluation time of four months after hemorrhage is comparable with the outcome assessment at three months, which is often used in aSAH studies. In summary, we found a rebleed rate of 16% at a median time interval of 180 minutes and almost all rebleeds occurred within 24 hours. A rebleed was

35 Chapter 2

associated with increased mortality, with a tendency towards poor outcome. In 60% the rebleed occurred after admission to the treatment center, so in- hospital logistics for early aneurysm treatment need to be improved. Faster transportation to the treatment center with immediate aneurysm treatment or alternative treatment options such as ultra-early and short-time antifibrinolytic therapy could prevent a consistent part of the rebleeds, and this is being further investigated.

ACKNOWLEDGEMENTS

We thank Jantien Hoogmoed and Stéphanie van Straaten for their help in the collection of data.

36 Time intervals to rebleed

REFERENCE LIST

(1) Broderick JP, Brott TG, Duldner JE, Tomsick T, Leach A. Initial and recurrent bleeding are the major causes of death following subarachnoid hemorrhage. Stroke 1994 July;25(7):1342-7. (2) Roos YB, Beenen LF, Groen RJ, Albrecht KW, Vermeulen M. Timing of surgery in patients with aneurysmal subarachnoid haemorrhage: rebleeding is still the major cause of poor outcome in neurosurgical units that aim at early surgery. J Neurol Neurosurg Psychiatry 1997 October;63(4):490-3. (3) Cha KC, Kim JH, Kang HI, Moon BG, Lee SJ, Kim JS. Aneurysmal rebleeding : factors associated with clinical outcome in the rebleeding patients. J Korean Neurosurg Soc 2010 February;47(2):119-23. 2 (4) Fujii Y, Takeuchi S, Sasaki O, Minakawa T, Koike T, Tanaka R. Ultra-early rebleeding in spontaneous subarachnoid hemorrhage. J Neurosurg 1996 January;84(1):35-42. (5) Guo LM, Zhou HY, Xu JW, Wang Y, Qiu YM, Jiang JY. Risk factors related to aneurysmal rebleeding. World Neurosurg 2011 September;76(3-4):292-8. (6) Hillman J, Fridriksson S, Nilsson O, Yu Z, Saveland H, Jakobsson KE. Immediate administration of tranexamic acid and reduced incidence of early rebleeding after aneurysmal subarachnoid hemorrhage: a prospective randomized study. J Neurosurg 2002 October;97(4):771-8. (7) Starke RM, Connolly ES, Jr. Rebleeding after aneurysmal subarachnoid hemorrhage. Neurocrit Care 2011 September;15(2):241-6. (8) Wong GK, Boet R, Ng SC, Chan M, Gin T, et al. Ultra-early (within 24 hours) aneurysm treatment after subarachnoid hemorrhage. World Neurosurg 2012 February;77(2):311-5. (9) Laidlaw JD, Siu KH. Ultra-early surgery for aneurysmal subarachnoid hemorrhage: outcomes for a consecutive series of 391 patients not selected by grade or age. J Neurosurg 2002 August;97(2):250-8. (10) Phillips TJ, Dowling RJ, Yan B, Laidlaw JD, Mitchell PJ. Does treatment of ruptured intracranial aneurysms within 24 hours improve clinical outcome? Stroke 2011 July;42(7):1936-45. (11) Baharoglu MI, Germans MR, Rinkel GJ, Algra A, Vermeulen M, et al. Antifibrinolytic therapy for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev 2013;8:CD001245. (12) Connolly ES, Jr., Rabinstein AA, Carhuapoma JR, Derdeyn CP, Dion J, 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 June;43(6):1711- 37. (13) Steiner T, Juvela S, Unterberg A, Jung C, Forsting M, Rinkel G. European Stroke Organization Guidelines for the Management of Intracranial Aneurysms and Subarachnoid Haemorrhage. Cerebrovasc Dis 2013 February 7;35(2):93-112. (14) Weil AG, Zhao JZ. Treatment of ruptured aneurysms: earlier is better. World Neurosurg 2012 February;77(2):263-5. (15) Teasdale GM, Drake CG, Hunt W, Kassell N, Sano K, et al. A universal subarachnoid hemorrhage scale: report of a committee of the World Federation of Neurosurgical Societies. J Neurol Neurosurg Psychiatry 1988 November;51(11):1457. (16) Rankin J. Cerebral vascular accidents in patients over the age of 60. II. Prognosis. Scott Med J 1957 May;2(5):200-15. (17) Larsen CC, Sorensen B, Nielsen JD, Astrup J. Reduced clot-stability during the first 6 hours after aneurysmal subarachnoid haemorrhage--a prospective case-control study. Thromb Res 2012 May;129(5):e229-e232. (18) Skrifvars MB, Parr MJ. Incidence, predisposing factors, management and survival following cardiac arrest due to subarachnoid haemorrhage: a review of the literature. Scand J Trauma Resusc Emerg Med 2012;20:75. (19) Kwan J, Hand P, Sandercock P. Improving the efficiency of delivery of thrombolysis for acute stroke: a systematic review. QJM 2004 May;97(5):273-9. (20) Lindsberg PJ, Happola O, Kallela M, Valanne L, Kuisma M, Kaste M. Door to thrombolysis: ER reorganization and reduced delays to acute stroke treatment. Neurology 2006 July 25;67(2):334-6. (21) Mikulik R, Kadlecova P, Czlonkowska A, Kobayashi A, Brozman M, et al. Factors influencing in- hospital delay in treatment with intravenous thrombolysis. Stroke 2012 June;43(6):1578-83.

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(22) Bouckaert M, Lemmens R, Thijs V. Reducing prehospital delay in acute stroke. Nat Rev Neurol 2009 September;5(9):477-83. (23) Walter S, Kostopoulos P, Haass A, Keller I, Lesmeister M, et al. Diagnosis and treatment of patients with stroke in a mobile stroke unit versus in hospital: a randomised controlled trial. Lancet Neurol 2012 May;11(5):397-404. (24) Germans MR, Post R, Coert BA, Rinkel GJ, Vandertop WP, Verbaan D. Ultra-early tranexamic acid after subarachnoid hemorrhage (ULTRA): study protocol for a randomized controlled trial. Trials 2013 May 16;14(1):143. (25) Naidech AM, Janjua N, Kreiter KT, Ostapkovich ND, Fitzsimmons BF, et al. Predictors and impact of aneurysm rebleeding after subarachnoid hemorrhage. Arch Neurol 2005 March;62(3):410-6. (26) van den Berg R, Foumani M, Schroder RD, Peerdeman SM, Horn J, et al. Predictors of outcome in World Federation of Neurologic Surgeons grade V aneurysmal subarachnoid hemorrhage patients. Crit Care Med 2011 December;39(12):2722-7.

Chapter 3

Time intervals from aneurysmal subarachnoid hemorrhage to treatment and factors contributing to delay

M.R. Germans, MD J. Hoogmoed, MD H.A.S. van Straaten, MD B.A. Coert, MD, PhD W.P. Vandertop, MD, PhD D. Verbaan, PhD

Journal of Neurology (2014) 261(3): 473-479 Chapter 3

ABSTRACT

Introduction: In the management of aneurysmal subarachnoid hemorrhage (aSAH), aneurysm treatment as early as feasible is mandatory to minimize the risk of a rebleed and may thus improve outcome. We assessed the different time intervals from the first symptoms of aSAH to start of aneurysm treatment in an effort to identify which factors contribute mostly to a delay in time to treatment.

Methods: In 278 aSAH patients, time intervals between the different steps from initial hemorrhage to aneurysm treatment were retrospectively reviewed, and delaying factors were determined.

Results: Half of the patients presented to a hospital within 115 minutes (IQR 60- 431). The median (IQR) interval from hemorrhage to diagnosis was 169 minutes (96-513), and from diagnosis to treatment 1057 minutes (416-1428), or 17.6 hours. Aneurysm treatment started within 24 hours in 76% of treated patients. Independent factors predicting delay to treatment were primary presentation at a referring hospital and admission to the treatment center later in the day. Delay in treatment was not independently related to poor outcome.

Conclusions: The interval to aneurysm treatment might be improved upon by immediate and direct transport to the treatment center combined with optimization of in-hospital logistics, following the ‘time-is-brain’ concept so successfully adopted in the treatment of ischemic stroke.

42 Time intervals to treatment

INTRODUCTION

An aneurysmal subarachnoid hemorrhage (aSAH) is a medical emergency with an in-hospital case fatality rate of 35%1. The outcome of patients who have experienced an aSAH is very likely affected by the timing of diagnosis and treatment. The optimal timing of treatment has been a point for discussion for several years2-7. Nowadays, there is consensus on the value of securing the aneurysm as early as feasible8, 9 as the most threatening complication in the initial phase after an aSAH is a rebleed2, 10, which is an independent predictor for poor outcome3, 4, 8. Recently, it was reported that patients are more likely 3 to die when treated in lowest volume hospitals11, but transfer of the patient after diagnosis, and longer duration of the transfer, might be associated with an increase in unfavorable outcome11-13. Many factors hinder the expedition of care, as shown by a recent study in Greater London where treatment was significantly delayed in 75% of good grade SAH patients14, and also by a delay in treatment in patients with a longer time to first presentation and diagnosis15. As delaying factors thwart efforts to effectively secure aneurysms ultra-early, i.e. within 24 hours after initial hemorrhage and even earlier if feasible, more insight is necessary in the specific time intervals and the factors related to delay in these intervals, in order to optimize ultra-early treatment. The aim of this study was to assess as accurately as possible the different time intervals from the first symptoms of aSAH to start of aneurysm treatment, and to determine which factors delayed treatment. Additionally, we investigated whether the time intervals or the delaying factors were related to outcome.

METHODS

Patient population From November 2008 to July 2011, 300 patients with an aSAH were admitted to our hospital, a referral center for the treatment of SAH patients in a region of approximately 1.3 million people. Twenty-two patients were excluded: five because they presented more than one week after the hemorrhage, one because it took more than one week to diagnose the SAH and another because of posterior reversible encephalopathy syndrome. Fifteen patients, diagnosed

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by lumbar puncture (LP) at least 12 hours after the onset of headache, were excluded because the inherent delay in diagnosis interfered with our policy of ultra-early treatment. The diagnosis of the included patients was established by computed tomography (CT), and the aneurysm that was held responsible for the hemorrhage was demonstrated by CT-angiography (CTA) and/or digital subtraction angiography (DSA). All DSA investigations and the majority of CTAs were performed at our center.

Data collection All medical records, radiological investigations, ambulance data and referral letters were reviewed retrospectively with approval of the Medical Ethics Committee of the Academic Medical Center, Amsterdam. Lacking data from referring hospitals were retrieved. We recorded patient demographics, referring hospital, World Federation of Neurological Surgeons (WFNS) grade16 at primary presentation to a medical facility, dates and times (of hemorrhage, primary presentation, diagnosis and treatment) and treatment modalities (clipping, coiling or none). If a patient was not admitted primarily to our center but was referred from another hospital, the date and time of presentation at our center was recorded as well. Clinical outcome was scored using the modified Rankin Scale (mRS)17 by reviewing the medical records of the outpatient clinic at follow-up or the letter from the rehabilitation center. If no exact initial hemorrhage time, i.e. time of onset of SAH, was known, it was approximated based on information about the patient’s activity during which the SAH occurred, such as “going to work” or “during dinner”, if mentioned in the medical records. To approximate the hemorrhage time as reliable as possible, we developed a checklist containing standard activities throughout the day linked to a specific time point. Three authors (MG, HvS and DV) approximated the hemorrhage time independently based on the information in the medical records and the checklist, with the assumption that the hemorrhage occurred at least one hour before admission. In case of inconsistencies, consensus was achieved after discussion. In case of finding a patient unconscious, the time point in between last seen healthy and time of discovery was reported as the hemorrhage time. If no time could be retrieved it was recorded as ‘irretrievable’.

44 Time intervals to treatment

Clinical management All patients were treated according to our standardized protocol which closely follows international guidelines8, 9. In short, on admission to the intensive care unit or medium care facility, an adequate blood pressure to optimize cerebral perfusion is maintained but severe hypertension is avoided. An adequate oxygenation, pH value and diuresis are maintained at a standard intake of at least 2L fluids/day. Standard medications are nimodipin, low molecular weight heparin prophylaxis, acetaminophen analgesia, supported with additional analgesics when necessary, and laxatives. When patients are admitted with a WFNS grade 4 or 5 and enlarged ventricles on the CT they receive 3 cerebrospinal fluid (CSF) diverting treatment, which usually contains external ventricular catheter placement. Patients with a WFNS grade 1-3 only receive CSF-diverting treatment on indication. All aneurysms are secured as early as feasible, preferably within 24 hours after the last hemorrhage, and within daytime hours (8 a.m.-10 p.m.), unless dictated otherwise by the patient’s clinical condition. The choice of treatment modality (clipping, coiling or none) is made in consensus between neurologist, neurosurgeon and interventional neuroradiologist.

Statistical analysis Time points during the day were outlined on a 24-hour scale, starting at 12 o’clock midnight (00:00). Consequently, a time point later in the day relates to a longer interval from midnight. Time intervals were computed by calculating the difference between the retrieved time points. The WFNS grades and mRS scores were dichotomized into groups with a good (WFNS grade 1-3) or poor grade (WFNS grade 4-5), and into groups with a favorable (mRS 0-3) or poor outcome (mRS 4-6), respectively. Normally distributed variables were expressed as means with standard deviations (SD) and tested with the Student’s T test (two group comparison); unequally distributed variables were expressed as medians with interquartile ranges (IQR 25%-75%) and tested with the Mann-Whitney U test (two group comparison) or Kruskal-Wallis test (multiple group comparison). The Chi- square test was used to assess differences in proportions. Spearman’s rho was used to assess the relation between two continuous variables (with at least one unequally distributed variable).

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Univariate analyses were performed to assess the predictive value of potential predictors on both delays in the different time intervals and poor outcome. The potential predictors were based on previous literature and included age (in years), WFNS grade, type of treatment, time of initial hemorrhage, diagnosis and admission to treatment center (all on 24 hours-scale), and presentation at referring hospital or treatment center12, 13, 18, 19. With respect to outcome, the different time intervals were also included in the univariate analysis as potential predictors. To identify parameters that are independently related to delay between diagnosis and treatment, a multivariate backward linear regression analysis was performed including the parameters that were significantly related to delay in the univariate analysis. The time interval between diagnosis and treatment was log transformed to obtain a normal distribution. Values of the standardized betas were transformed back to normal values. To identify parameters that are independently related to poor outcome, a multivariate backward logistic regression analysis was performed including the parameters that were significantly related to poor outcome in the univariate analysis. A P value <0.05 was considered significant. All analyses were performed using SPSS Statistics.

RESULTS

Patient characteristics The mean (SD) age of the 278 patients was 56.2 years (12.5) and 64% was female (table 1). About one-fifth of all patients presented primarily at our center. Twenty hospitals referred their patients to our center, ranging from 1 to 46 patients per hospital with twelve hospitals referring at least five patients. The median (IQR) distance between the referring hospitals and our center was 18.6 miles (11.6-33.9). Patients presenting at a referring hospital significantly more often had a good WFNS grade and endovascular treatment when compared to patients presenting at the treatment center (table 1).

46 Time intervals to treatment

Table 1. Baseline characteristics of 278 patients with aneurysmal subarachnoid hemorrhage Hospital of primary presentation

Patient characteristics Total Treatment center Referring hospital p value (n= 278) (n= 59) (n=219) Age, years 56.2 ± 12.5 55.3 ± 11.6 56.4 ± 12.7 0.55a Female 179 (64) 37 (63) 142 (65) 0.76b

WFNS at presentation 1-3 172 (62) 26 (44) 146 (67) 4-5 106 (38) 33 (56) 73 (33) <0.01b

Treatment modality clip 30 (11) 11 (19) 19 (9) coil 215 (77) 39 (66) 176 (80) 3 none 33 (12) 9 (15) 24 (11) 0.04b

Data are shown as n (%) or mean ± standard deviation (SD) WFNS World Federation of Neurological Surgeons a Student’s T-test b Chi-square test

Time data Not all time points could be retrieved and therefore not all patients were used to calculate the time intervals (table 2). The exact time of initial hemorrhage could be retrieved in 127 patients (46%), was approximated in 133 patients (48%), and was irretrievable in 18 patients. There were no significant differences between the three groups in distribution of dichotomized WFNS grade (P=0.91).

Time intervals The median (IQR) interval from initial hemorrhage to diagnosis was 169 minutes (96-513) (table 2). When patients presented at a referring hospital, the median time interval (IQR) between diagnosis at the referring hospital and admission to the treatment center was 114 minutes (89-155). Half of the patients was treated within 1057 minutes (IQR 416-1428) (17.6 hours) after diagnosis. Aneurysm treatment started within 24 hours after diagnosis in 179 patients (76% of treated patients with established time interval). Percentages of patients treated at different time intervals show peaks in frequency of treatment at approximately 240 and 1140 minutes (4 and 19 hours, respectively) after diagnosis (figure 1).

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Table 2. Different time intervals in 278 patients with aneurysmal subarachnoid hemorrhage Type of time interval Number of patients Time intervals (n=278) (minutes) Initial hemorrhage to presentation 244 (88) 115 (60-431) Before diagnosis Presentation to diagnosis 248 (89) 26 (11-58) Initial hemorrhage to diagnosis 252 (91) 169 (96-513)

Diagnosis to admission treatment center 120 (55 a) 114 (89-155) After diagnosis Diagnosis to start of treatment 235 (96 b) 1057 (416-1428)

Data are shown as n (%) or medians (interquartile range) a of referred patients b of treated patients

Fig. 1 Frequency distribution (in %) of 247 patients treated at different time intervals from diagnosis to start of treatment

Factors predicting delay A delay in all separate time intervals was significantly related to a good WFNS grade and primary presentation at a referring hospital (table 3). A longer time interval between initial hemorrhage and both presentation and diagnosis was significantly related to older age and later admission to the treatment center. Furthermore, a longer time interval between diagnosis and treatment was significantly related to later admission to the treatment center. There were no other significant relations between longer time intervals and potential predictors in the univariate analysis.

48 Time intervals to treatment

Table 3. Univariate analysis of the relation between different time intervals and significant predictors for delay Type of time interval Potential predictors Initial Presentation Initial Diagnosis to Diagnosis hemorrhage to to diagnosis hemorrhage admission to start of presentation to diagnosis treatment treatment center Agea 0.04 n.s. 0.03 n.s. n.s. WFNS at first <0.01 <0.01 <0.01 0.02 <0.01 presentation (1-3 vs 4-5)b Time point of <0.01 n.s. <0.01 n.s. <0.01 admission in a 3 treatment center Primary 0.02 <0.01 <0.01 n/a <0.01 presentation at treatment center vs. referring hospitalb Before diagnosis After diagnosis n.s. not significant; WFNS World Federation of Neurological Surgeons; n/a not applicable a Spearman’s rho b Mann-Whitney U test

The multivariate analysis showed that presentation at a referring hospital (standardized Beta (95% CI): 1.4 (1.2-1.6)) and admission to the treatment center later in the day (standardized Beta (95% CI): 1.3 (1.1-1.5)) were independently related to a longer time interval between diagnosis and treatment (adjusted R2: 14%, ANOVA total multivariate model P<0.01). The delaying influence of primary presentation at a referring hospital on the different time intervals is illustrated in table 4. Significantly more patients were treated within 24 hours when the primary presentation was at the treatment center, compared to primary presentation at a referring hospital (89% and 73%, respectively; P=0.02).

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Table 4. Time intervals in patient groups according to hospital of primary presentation Hospital of primary presention Type of interval Treatment Referring p valuea center hospital Initial hemorrhage to presentation 92 (56-213) 130 (64-522) 0.02 Before diagnosis Presentation to diagnosis 14 (4-40) 30 (14-63) <0.01 Initial hemorrhage to diagnosis 114 (62-261) 175 (105-599) <0.01

Diagnosis to admission treatment - 114 (89-155) n/a After center diagnosis Diagnosis to start of treatment 388 (116-1093) 1123 (709-1488) <0.01 Data are shown as medians (interquartile range) n/a not applicable a Mann-Whitney U test

Outcome Outcome assessment was performed in 264 patients at a median (IQR) interval of four months (2-7) after the hemorrhage. Of those patients, 35% had a poor outcome and 24% died. Higher age, poor WFNS grade, a shorter time interval between presentation and diagnosis, and no aneurysm treatment were significantly related to poor outcome. The multivariate analysis (OR (95% CI)) showed that higher age: 1.1 (1.0-1.1), poor WFNS grade at presentation: 4.1 (2.1- 7.9), and no treatment (no treatment vs. coiling: 47.2 (6.0-368.2), no treatment vs. clipping: 47.9 (5.2-445.5)) were independently related to poor outcome (Nagelkerke R square: 40%, Hosmer & Lemeshow-test, p=0.366, Omnibus test total multivariate model P<0.01).

DISCUSSION

We assessed different time intervals from initial aSAH to start of aneurysm treatment and found relatively short intervals from initial hemorrhage to diagnosis and from diagnosis to treatment. However, our data also show that delays in aneurysm treatment seem to be caused by presentation to a referring hospital and by admission later in the day. The median interval between diagnosis and start of treatment in our study was 18 hours, and in 76% of treated patients, treatment started within 24 hours. This is considerably faster than reported elsewhere14, 15. An explanation for delay in

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aneurysm treatment is usually the impossibility to treat aneurysms 24/7 due to low admission numbers and a lack of routine provision of clipping at weekends and next day coiling services15. The policy in the referring hospitals is to transfer every SAH patient to our hospital, so 2-3 aSAH patients are admitted to our center each week. With four neurovascular surgeons and four interventional neuroradiologists we have the ability to treat the aneurysms 24/7 and strive to initiate aneurysm treatment as early as feasible, preferably during working hours. By performing the majority of CTA investigations and all DSA investigations in our center we have all necessary radiological investigation immediately available. 3 Multivariate regression analysis showed that primary presentation at a referring hospital, and admission to the treatment center later in the day were independent predictors for delay to treatment. The additional transfer to the treatment center after diagnosis at the referring hospital would be a reasonable explanation for the delay in these patients. However, the median time from diagnosis to admission in the treatment center was only 114 minutes whereas the total delay in treatment was much longer (12 hours). Other reasons for this delay could be the addition of logistical steps, such as radiological investigations in the treatment center20, 21, or a lower sense of emergency treatment in these patients as their WFNS grade at the treatment center may have improved after first admission owing to clinical stabilization of the patient at the referring hospital. Unfortunately, since we only evaluated the WFNS grade at the primary presentation, we cannot confirm this with our data. Admission to the treatment center later in the day most likely introduces a delay due to the higher probability of postponement of treatment to the next day, especially because we do not perform aneurysm treatment between 10 p.m. and 8 a.m. unless there is a life-threatening situation or history of a rebleed. This could be reflected in our data which show peaks in the percentage of treated patients at 4 (same-day) and 19 hours (next-day) after diagnosis. The overall outcome in our patient population is worse in comparison to large aSAH studies18, 22, but can be explained by our ultra-early treatment strategy which also includes all WFNS grade V patients7, 23, 24. Poor WFNS grade at admission, higher age, and absence of treatment were independently related to poor outcome. However, we found no significant relation between poor outcome and time interval between diagnosis and treatment. There are several explanations for the lack of finding this association. First, there are patients,

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both in the groups of good and poor WFNS grades, in whom improvement or deterioration in outcome is not possible, irrespective of their time to treatment. Second, since clinical practice is already aimed at aneurysm treatment as early as feasible, there is a substantial group of patients with a good outcome without a delay in treatment, which also may have distorted the association between time to treatment and outcome. Finally, clinical characteristics, such as delayed ischemic deficits, and surgical and medical complications are not taken into account in this study and may therefore make the outcome model incomplete. Therefore, although no significant association between ultra- early aneurysm treatment and good outcome was found in this study, we are convinced that this relation does exist12, 13 and evaluation of this relation needs to be performed either in large (multicenter) studies or in studies evaluating specific subgroups. Our policy of ultra-early aneurysm treatment, i.e. all aneurysms are secured as early as feasible, shows similarities with thrombolysis in acute ischemic stroke. The ‘time-is-brain’ concept should perhaps be extrapolated to patients with an aSAH. The proposed adjustments could include: 1) immediate and direct transportation to the treatment center if there is suspicion of an aSAH and 2) preparation of a treatment plan as soon as a patient is transported from another hospital. Direct transportation to the treatment center of aSAH patients can be optimized by education of general practitioners and ambulance employees in order to increase the awareness for SAH25, or by the presence of a CT-unit in the ambulance, which shortens the time to diagnosis and treatment in ischemic stroke26. Additional education has shown to improve the delay to presentation in patients with acute ischemic stroke25, 27, and easy assessment instruments have proven their efficiency in ischemic stroke care28-30. A reduction in our delay to treatment after diagnosis could be realized by improving the in-hospital logistics for ultra-early treatment as effectuated in the treatment of ischemic stroke27, 31, 32. This means that especially more attention is given to emergency aneurysm treatment in transferred patients and prevention of postponement of aneurysm obliteration when patients are admitted at a later time point in the day, i.e. aneurysm treatment in evening hours and at night as well. This study has some limitations. First, our data are based on a single center with the Dutch emergency care system and extrapolation of these data may be difficult, as time intervals to treatment appear to be related to the type of center and country33. Second, the time of initial hemorrhage was approximated in

52 Time intervals to treatment

almost half of the patients. To reduce the bias herein, approximation occurred in a standardized way by three authors independently and only in those cases where the moment of hemorrhage was linked to a specific event during the day. If there was any uncertainty about the time point, it was stated as irretrievable and excluded from analysis. Although we weren’t able to perform a sensitivity analysis on these data, we estimate to have an inaccuracy of just several hours. Finally, the mRS scores have to be interpreted with care, because they were based on outpatient clinical records and rehabilitation letters at different time intervals after the hemorrhage with a wide range, owing to the retrospective study design. However, the median mRS evaluation time of four months after 3 hemorrhage is comparable with the outcome assessment at three months, which is often used in aSAH studies. In conclusion, a delay in aneurysm treatment is caused by presentation at a referring hospital instead of primarily at a treatment center but is not solely related to the delay of the transport itself. Admission to the treatment center later in the day also contributes to delay, putting patients further at risk for a rebleed. Although the intervals between initial hemorrhage, diagnosis and start of treatment of patients suffering aSAH were short, there is still room for improvement to optimize ultra-early aneurysm treatment. Immediate and direct transport to a treatment center, and optimization of the in-hospital logistics for ultra-early aneurysm treatment, following the ‘time-is-brain’ concept so successfully adopted in the treatment of ischemic stroke, especially for patients who are transferred from a referring hospital or are admitted later in the day, might lead to an improved ultra-early treatment. It still needs to be established whether such ultra-early treatment improves functional outcome.

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REFERENCE LIST

(1) Lovelock CE, Rinkel GJ, Rothwell PM. Time trends in outcome of subarachnoid hemorrhage: Population-based study and systematic review. Neurology 2010 May 11;74(19):1494-501. (2) Laidlaw JD, Siu KH. Ultra-early surgery for aneurysmal subarachnoid hemorrhage: outcomes for a consecutive series of 391 patients not selected by grade or age. J Neurosurg 2002 August;97(2):250-8. (3) Naidech AM, Janjua N, Kreiter KT, Ostapkovich ND, Fitzsimmons BF, et al. Predictors and impact of aneurysm rebleeding after subarachnoid hemorrhage. Arch Neurol 2005 March;62(3):410-6. (4) Roos YB, Beenen LF, Groen RJ, Albrecht KW, Vermeulen M. Timing of surgery in patients with aneurysmal subarachnoid haemorrhage: rebleeding is still the major cause of poor outcome in neurosurgical units that aim at early surgery. J Neurol Neurosurg Psychiatry 1997 October;63(4):490-3. (5) Siddiq F, Chaudhry SA, Tummala RP, Suri MF, Qureshi AI. Factors and Outcomes Associated with Early and Delayed Aneurysm Treatment in Subarachnoid Hemorrhage Patients in United States. Neurosurgery 2012 May 30. (6) Whitfield PC, Kirkpatrick PJ. Timing of surgery for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev 2001;(2):CD001697. (7) Wong GK, Boet R, Ng SC, Chan M, Gin T, et al. Ultra-early (within 24 hours) aneurysm treatment after subarachnoid hemorrhage. World Neurosurg 2012 February;77(2):311-5. (8) Connolly ES, Jr., Rabinstein AA, Carhuapoma JR, Derdeyn CP, Dion J, 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 June;43(6):1711- 37. (9) Steiner T, Juvela S, Unterberg A, Jung C, Forsting M, Rinkel G. European Stroke Organization Guidelines for the Management of Intracranial Aneurysms and Subarachnoid Haemorrhage. Cerebrovasc Dis 2013 February 7;35(2):93-112. (10) Guo LM, Zhou HY, Xu JW, Wang Y, Qiu YM, Jiang JY. Risk factors related to aneurysmal rebleeding. World Neurosurg 2011 September;76(3-4):292-8. (11) Nuno M, Patil CG, Lyden P, Drazin D. The effect of transfer and hospital volume in subarachnoid hemorrhage patients. Neurocrit Care 2012 December;17(3):312-23. (12) Naval NS, Chang T, Caserta F, Kowalski RG, Carhuapoma JR, Tamargo RJ. Impact of pattern of admission on outcomes after aneurysmal subarachnoid hemorrhage. J Crit Care 2012 October;27(5):532-7. (13) O’Kelly CJ, Spears J, Urbach D, Wallace MC. Proximity to the treating centre and outcomes following subarachnoid hemorrhage. Can J Neurol Sci 2011 January;38(1):36-40. (14) Lamb JN, Crocker M, Tait MJ, Anthony BB, Papadopoulos MC. Delays in treating patients with good grade subarachnoid haemorrhage in London. Br J Neurosurg 2011 April;25(2):243-8. (15) Larsen CC, Eskesen V, Hauerberg J, Olesen C, Romner B, Astrup J. Considerable delay in diagnosis and acute management of subarachnoid haemorrhage. Dan Med Bull 2010 April;57(4):A4139. (16) Teasdale GM, Drake CG, Hunt W, Kassell N, Sano K, et al. A universal subarachnoid hemorrhage scale: report of a committee of the World Federation of Neurosurgical Societies. J Neurol Neurosurg Psychiatry 1988 November;51(11):1457. (17) Rankin J. Cerebral vascular accidents in patients over the age of 60. II. Prognosis. Scott Med J 1957 May;2(5):200-15. (18) Molyneux A, Kerr R, Stratton I, Sandercock P, Clarke M, et al. International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomized trial. J Stroke Cerebrovasc Dis 2002 November;11(6):304-14. (19) Nieuwkamp DJ, Vaartjes I, Algra A, Bots ML, Rinkel GJ. Age- and gender-specific time trend in risk of death of patients admitted with aneurysmal subarachnoid hemorrhage in the Netherlands. Int J Stroke 2013 March 12. (20) Kassell NF, Kongable GL, Torner JC, Adams HP, Jr., Mazuz H. Delay in referral of patients with ruptured aneurysms to neurosurgical attention. Stroke 1985 July;16(4):587-90. (21) Sved PD, Morgan MK, Weber NC. Delayed referral of patients with aneurysmal subarachnoid haemorrhage. Med J Aust 1995 March 20;162(6):310-1.

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(22) Qureshi AI, Janardhan V, Hanel RA, Lanzino G. Comparison of endovascular and surgical treatments for intracranial aneurysms: an evidence-based review. Lancet Neurol 2007 September;6(9):816-25. (23) Hillman J, Fridriksson S, Nilsson O, Yu Z, Saveland H, Jakobsson KE. Immediate administration of tranexamic acid and reduced incidence of early rebleeding after aneurysmal subarachnoid hemorrhage: a prospective randomized study. J Neurosurg 2002 October;97(4):771-8. (24) Starke RM, Connolly ES, Jr. Rebleeding after aneurysmal subarachnoid hemorrhage. Neurocrit Care 2011 September;15(2):241-6. (25) Bouckaert M, Lemmens R, Thijs V. Reducing prehospital delay in acute stroke. Nat Rev Neurol 2009 September;5(9):477-83. (26) Walter S, Kostopoulos P, Haass A, Keller I, Lesmeister M, et al. Diagnosis and treatment of patients with stroke in a mobile stroke unit versus in hospital: a randomised controlled trial. Lancet Neurol 2012 May;11(5):397-404. (27) Kwan J, Hand P, Sandercock P. Improving the efficiency of delivery of thrombolysis for acute stroke: a systematic review. QJM 2004 May;97(5):273-9. 3 (28) Harbison J, Hossain O, Jenkinson D, Davis J, Louw SJ, Ford GA. Diagnostic accuracy of stroke referrals from primary care, emergency room physicians, and ambulance staff using the face arm speech test. Stroke 2003 January;34(1):71-6. (29) Kidwell CS, Starkman S, Eckstein M, Weems K, Saver JL. Identifying stroke in the field. Prospective validation of the Los Angeles prehospital stroke screen (LAPSS). Stroke 2000 January;31(1):71-6. (30) Kothari RU, Pancioli A, Liu T, Brott T, Broderick J. Cincinnati Prehospital Stroke Scale: reproducibility and validity. Ann Emerg Med 1999 April;33(4):373-8. (31) Lindsberg PJ, Happola O, Kallela M, Valanne L, Kuisma M, Kaste M. Door to thrombolysis: ER reorganization and reduced delays to acute stroke treatment. Neurology 2006 July 25;67(2):334-6. (32) Meretoja A, Strbian D, Mustanoja S, Tatlisumak T, Lindsberg PJ, Kaste M. Reducing in-hospital delay to 20 minutes in stroke thrombolysis. Neurology 2012 July 24;79(4):306-13. (33) Mikulik R, Kadlecova P, Czlonkowska A, Kobayashi A, Brozman M, et al. Factors influencing in- hospital delay in treatment with intravenous thrombolysis. Stroke 2012 June;43(6):1578-83.

Chapter 4

Antifibrinolytic therapy for aneurysmal subarachnoid haemorrhage (review)

M.I. Baharoglu, MD M.R. Germans, MD G.J.E. Rinkel, MD, PhD A. Algra, PhD M. Vermeulen, MD, PhD J. van Gijn, MD, PhD Y.B.W.E.M. Roos, MD, PhD

(Adapted from) Cochrane Database of Systematic Reviews (2013) 8: CD001245 Chapter 4

ABSTRACT

Background: Rebleeding is an important cause of death and disability in people with aneurysmal subarachnoid haemorrhage. Rebleeding is probably related to dissolution of the blood clot at the site of aneurysm rupture by natural fibrinolytic activity. This review is an update of a previously published Cochrane review.

Objectives: To assess the effects of antifibrinolytic treatment in people with aneurysmal subarachnoid haemorrhage.

Search methods: We searched the Cochrane Stroke Group Trials Register (February 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 1), MEDLINE (1948 to December 2012), and EMBASE (1947 to December 2012). In an effort to identify further published, unpublished, and ongoing studies we searched reference lists and trial registers, performed forward tracking of relevant references and contacted drug companies.

Selection criteria: Randomised trials comparing oral or intravenous antifibrinolytic drugs (tranexamic acid, epsilon amino-caproic acid, or an equivalent) with control in people with subarachnoid haemorrhage of suspected or proven aneurysmal cause.

Data collection and analysis: Two review authors independently selected trials for inclusion and extracted the data. Three review authors assessed trial quality. For the primary outcome we converted the outcome scales between good and poor outcome for the analysis. We scored death from any cause and rates of rebleeding, cerebral ischaemia, and hydrocephalus per treatment group. We expressed effects as risk ratios (RR) with 95% confidence intervals (CI). We used random-effects models for all analyses.

Main results: We included 10 trials involving 1904 participants. The risk of bias was low in six studies. Four studies were open label and were rated as high risk of performance bias. One of these studies was also rated as high risk for

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attrition bias. Four trials reported on poor outcome (death, vegetative state, or severe disability) with a pooled risk ratio (RR) of 1.02 (95% confidence interval (CI) 0.91 to 1.15). All trials reported on death from all causes with a pooled RR of 1.00 (95% CI 0.85 to 1.18). In a trial that combined short-term antifibrinolytic treatment (< 72 hours) with preventative measures for cerebral ischaemia the RR for poor outcome was 0.85 (95% CI 0.64 to 1.14). Antifibrinolytic treatment reduced the risk of re-bleeding reported at the end of follow-up (RR 0.65, 95% CI 0.44 to 0.97; 78 per 1000 participants), but there was heterogeneity (I² = 62%) between the trials. The pooled RR for reported cerebral ischaemia was 1.41 (95% CI 1.04 to 1.91, 83 per 1000 participants), again with heterogeneity between the trials (I² = 52%). Antifibrinolytic treatment showed no effect on the reported rate of hydrocephalus in five trials (RR 1.11, 95% CI 0.90 to 1.36). 4 Authors’ conclusions: The current evidence does not support the use of antifibrinolytic drugs in the treatment of people with aneurysmal subarachnoid haemorrhage, even in those who have concomitant treatment strategies to prevent cerebral ischaemia. Results on short-term treatment are promising, but not conclusive. Further randomised trials evaluating short-term antifibrinolytic treatment are needed to evaluate its effectiveness.

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PLAIN LANGUAGE SUMMARY

Drugs for preventing blood clot dissolution (antifibrinolytic therapy) to reduce the occurrence of rebleeding in aneurysmal subarachnoid haemorrhage

A subarachnoid haemorrhage (SAH) is a bleed into the small space between the brain and skull that contains blood vessels that supply the brain (the subarachnoid space). The cause of a bleeding here is usually a rupture of a weak spot in one of these vessels. A SAH is a relatively uncommon type of stroke, but it often occurs at a young age (half the patients are younger than 50 years). The outcome of SAH is often poor: one-third of people die after the haemorrhage and of those who survive, one-fifth will require help for everyday activities. An important cause of poor recovery after SAH is a second bleed from the weakened vessel (rebleeding). This is thought to be caused by the dissolving of the blood clot at the original bleeding site that results from natural blood clot dissolving (fibrinolytic) activity. Antifibrinolytic therapy that reduces this activity was introduced as a treatment for reducing rebleeding and therefore for improving recovery after SAH. This review included 10 trials, totaling 1904 participants that investigated the effect of these drugs in people with SAH. Antifibrinolytic treatment does indeed reduce the risk of rebleeding, but does not improve survival or the chance of being independent in everyday activities. This may be due to an increase in one of the other common complications of SAH. We conclude that antifibrinolytic treatment should not routinely be given to people with SAH, but new randomised trials are needed to establish if short- term treatment might be beneficial.

BACKGROUND

Description of the condition In people with aneurysmal subarachnoid haemorrhage (SAH) rebleeding is an important cause of death and disability. Without aneurysm treatment approximately 30% of such people experienced a rebleed within one month of the initial haemorrhage (Locksley 1966). The rebleeding rate has now been reduced to about 15% because in most people the aneurysm is occluded early

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after admission (Roos 2000b). The risk of rebleeding is highest in the first 24 hours after SAH, with a peak in the first six hours (Guo 2011). The prognosis after rebleeding is poor: approximately 60% of people who rebleed die and another 30% remain dependent for activities of daily living (Naidech 2005).

Description of the intervention Antifibrinolytic drugs were introduced to reduce the occurrence of rebleeding. These drugs are administered orally or intravenously and block endogenous fibrinolytic activity and could help prevent bleeding.

How the intervention might work Dissolution of the blood clot at the site of the ruptured aneurysm is thought to be an important factor in the development of rebleeding. This dissolution 4 probably results from endogenous fibrinolytic activity after SAH. Since antifibrinolytic agents reduce fibrinolytic activity, antifibrinolytic therapy may reduce the occurrence of rebleeding and thereby improve clinical outcome after SAH. However, reducing rebleeding might not automatically improve clinical outcome in all instances. Concerns have been raised that antifibrinolytic therapy might increase the occurrence of cerebral ischaemia. Cerebral ischaemia is a complication of SAH that occurs in about 30% to 40% of people between four and 14 days after SAH. In older trials the beneficial effect of antifibrinolytic treatment (reducing rebleeding) was offset by an increase in cerebral ischaemia, resulting in a neutral effect on outcome (Roos 2003).

Why it is important to do this review In 1967 Gibbs and O’Gorman published the first report on antifibrinolytic treatment in people with SAH (Gibbs 1967). Since then, over 50 studies on antifibrinolytic therapy in aneurysmal SAH have been published. Unfortunately most of these studies are uncontrolled and only a minority of the controlled studies are randomised. Moreover, the results of some of the individual randomised studies contradict each other. Furthermore, as mentioned above, concerns have been raised that antifibrinolytic therapy might increase the occurrence of cerebral ischaemia. In a previous version of this review we found that even in people treated with measures to prevent and reverse cerebral ischaemia (such as administration of nimodipine), clinical outcome was not improved by antifibrinolytic treatment despite a reduction in rebleeding

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rate. The hypothesis has been posed that, when people with aneurysmal SAH are treated with antifibrinolytic agents, recovery from cerebral ischaemia is impeded by antifibrinolytic treatment. More recently it has been proposed that if antifibrinolytic treatment is discontinued before the period in which cerebral ischaemia typically occurs, the negative effect of antifibrinolytic therapy may be avoided. In this update of a previously published Cochrane review (Roos 2003), we sought to evaluate the effectiveness of short-term antifibrinolytic treatment in people concomitantly treated with measures to prevent or reverse cerebral ischaemia.

METHODS

Criteria for considering studies for this review Types of studies All truly randomised unconfounded trials were eligible in which, after concealed allocation, antifibrinolytic drugs were compared with control treatment (open studies) or placebo (blind studies) in an intention-to-treat analysis. We excluded all trials in which allocation to treatment or control group was not concealed (e.g. trials in which people were allocated by means of an open random number list, alternation, or based on date of birth, days of the week, or hospital-number), since foreknowledge of treatment allocation might lead to biased treatment allocation (i.e. selective enrolment). We also excluded trials in which an intention-to-treat analysis was not performed and could not be reconstructed on the basis of published data without a loss of 20% or more of all randomised participants.

Types of participants Trials in which participants were included with clinical symptoms and signs of SAH from a ruptured aneurysm with confirmation of the diagnosis by the presence of subarachnoid blood on computed tomography (CT) scan or on cerebrospinal fluid (CSF) examination were eligible for this review.

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Types of interventions Antifibrinolytic drugs (e.g. tranexamic acid, epsilon amino-caproic acid, or equivalent drugs), oral or intravenous, versus control treatment (open studies) or placebo treatment (blind studies). Since the risk of rebleeding is highest during the first two weeks after the initial bleeding, treatment had to start within two weeks after onset of the SAH. Distinction was made between early and short-term (< 72 hours of onset of symptoms, i.e. before usual timing of onset of cerebral ischaemia) versus long-term (> 72 hours) treatment duration.

Types of outcome measures Primary outcomes The primary outcome measure was ‘poor outcome’ (death, vegetative state, or severe disability, as assessed either with the Glasgow Outcome Scale or the 4 Modified Rankin Scale) at the end of follow-up at least three months after SAH. ‘Death from all causes’ at a minimum of at least three-weeks follow-up was our second primary outcome, since most studies only reported on case fatality. Secondary outcomes Secondary outcome measures were the effect of antifibrinolytic treatment on both the rates of reported and CT scan or autopsy confirmed (sensitivity analyses) episodes of rebleeding, cerebral ischaemia, and hydrocephalus. In this systematic review, we did not evaluate cerebral vasospasm without clinical signs of cerebral ischaemia.

Search methods for identification of studies See the ‘Specialized register’ section in the Cochrane Stroke Group module. We searched for trials in all languages and arranged translations of relevant reports published in languages other than English.

Electronic searches We searched the Cochrane Stroke Group Trials Register (last searched February 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 1), MEDLINE (1948 to December 2012) (Appendix 1) and EMBASE (1947 to December 2012) (Appendix 2). We developed comprehensive search strategies with the help of the Cochrane Stroke Group Trials Search Co-ordinator and adapted the MEDLINE strategy for CENTRAL.

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We also searched the following major ongoing trial registers (December 2012): ClinicalTrials.gov (http://www.clinicaltrials.gov/), EU Clinical Trials Register (https://www.clinicaltrialsregister.eu), Stroke Trials Registry (www.strokecenter. org/trials/), Current Controlled Trials (www.controlled-trials.com), and the WHO International Clinical Trials Registry Platform (http://apps.who.int/trialsearch/).

Searching other resources In an effort to identify further published, unpublished, and ongoing studies: we searched the list of references quoted in all included studies and reviews on antifibrinolytic therapy (Adams 1982; Adams 1987; Biller 1988; Carley 2005; Chawjol 2008; Connolly 2012; Fodstad 1982; Gaberel 2012; Lindsay 1987; Maira 2006; Mayberg 1994; Ramirez 1981; Rinkel 2008; Van Gijn 2001; Van Gijn 2007; Vermeulen 1980; Vermeulen 1996; Weaver 1994; Weir 1987); we used Science Citation Index Cited Reference Search for forward tracking of important articles; and for the first version of this review (1998) we contacted the pharmaceutical company Pharmacia and Upjohn, formerly Kabi, manufacturer and license holder of the antifibrinolytic drug tranexamic acid. We identified no additional (unpublished) studies.

Data collection and analysis Selection of studies Two authors (MIB, MRG) independently screened the titles and abstracts of the records obtained from the electronic searches and excluded obviously irrelevant studies. We obtained the full-text articles for the remaining studies and the same two authors independently selected the trials that met the predefined criteria for inclusion in the review. The authors resolved disagreements by discussion and when necessary in consultation with a third review author (YBWEMR).

Data extraction and management Two authors (MIB, MRG) independently reviewed all eligible studies and extracted details on the number of participants in the treated and the placebo or control group, the randomisation method, blinding method, the definitions for diagnosis and complications, and also ascertained whether an intention- to-treat analyses was done or could be reconstructed from the published data. Whenever consensus could not be reached, the review authors consulted a third review author (YBWEMR).

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Assessment of risk of bias in included studies Three authors (MIB, MRG, YBWEMR) independently assessed the risk of bias of each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We resolved any disagreements by discussion. We assessed the risk of bias according to the following domains. 1. Random sequence generation. 2. Allocation concealment. 3. Blinding of participants and personnel. 4. Blinding of outcome assessment. 5. Incomplete outcome data. 6. Selective outcome reporting. 7. Other bias. We graded each potential source of bias as high, low, or unclear and provided 4 information from each study in the ‘Risk of bias’ tables.

Measures of treatment effect We processed data in accordance with the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). For the primary outcome we converted the outcome scales between good and poor outcome for the analysis. We scored death from any cause and rates of rebleeding, cerebral ischaemia, and hydrocephalus per treatment group. We expressed effects as risk ratios (RR) with 95% confidence intervals (CI).

Unit of analysis issues The unit of analysis were individual participants, since we only included individually conducted randomised trials with a parallel design.

Dealing with missing data In trials without intention-to-treat analysis, we tried to reconstruct such an analysis based only on the published data. For two trials (Hillman 2002; Tsementzis 1990) we tried to contact the principal investigator to retrieve data on the number of participants in whom rebleeding or cerebral ischaemia were proven on CT scan or at autopsy. We received a reply from one of the authors. We made no effort to obtain additional information for studies published 15 or more years ago.

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Assessment of heterogeneity For each outcome we assessed heterogeneity using the Chi² test and I² index (Higgins 2011). Because we suspected substantial heterogeneity, we used random-effects models for all analyses.

Assessment of reporting biases To investigate possible publication bias in this review, we planned to perform funnel plots when possible.

Data synthesis We used the Review Manager software, RevMan 5.2, for statistical analysis (RevMan 2012), and used Mantel-Haenszel random-effects models for pooled analyses.

Subgroup analysis and investigation of heterogeneity To assess whether masked studies showed different results compared with unmasked studies we divided all analyses into two groups: trials with control treatment (open studies) and trials with placebo treatment (blind studies). We pre-planned an additional subgroup analysis to evaluate the effectiveness of antifibrinolytic therapy in trials with and without additional measures to prevent or reverse cerebral ischaemia and to evaluate the effectiveness of antifibrinolytic therapy according to treatment duration. We divided the included trials into one of three groups: (1) trials without ischaemia prevention and treatment duration > 72 hours, (2) trials with ischaemia prevention and treatment duration > 72 hours, and (3) trials with ischaemia prevention and treatment duration < 72 hours. We did not include a fourth group (trials without ischaemia prevention and treatment duration < 72 hours) as there were no trials that met these criteria. Additionally we checked whether data were available on aneurysm treatment (i.e. clipping or coiling) according to antifibrinolytic treatment, to evaluate whether a subgroup analysis on clipping versus coiling was possible.

Sensitivity analysis Because our secondary outcome measures were more prone to bias, we carried out sensitivity analyses on confirmed (rather than reported) rebleeding, cerebral ischaemia, and hydrocephalus rates.

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RESULTS

Description of studies Results of the search The updated search of the bibliographic databases yielded a total of 1521 records, from which we removed 476 duplicates, leaving a total of 1045 records. After screening titles and abstracts we excluded 931 records, leaving 114 records for which we obtained the full-text articles. Further assessment resulted in 32 potentially relevant trials. Ten trials met the inclusion criteria for the review and we excluded 21 trials. We identified one ongoing trial from the searches of the trial registers. For an overview of the search results see Figure 1.

Included studies 4 We included 10 studies (Chandra 1978; Fodstad 1981; Girvin 1973; Hillman 2002; Kaste 1979; Maurice 1978; Roos 2000a; Tsementzis 1990; Van Rossum 1977; Vermeulen 1984), which are described in detail in the Characteristics of included studies table. These 10 studies included 1904 participants of whom 959 were randomised to receive antifibrinolytic drugs, 597 received placebo treatment and 348 received control treatment. The Girvin 1973 study used epsilon-amino-caproic acid (39 participants), in all other studies tranexamic acid was used. In two studies participants were concomitantly treated with measures to prevent or reverse cerebral ischaemia (Hillman 2002; Roos 2000a). The duration of antifibrinolytic treatment differed considerably between studies and ranged from less than 72 hours up to six weeks. Short-term treatment was used in only one study (Hillman 2002). In this study, participants were treated up to 72 hours after SAH. All other studies treated participants for at least 10 days (or until occlusion of the aneurysm) after SAH. Clinical outcome was reported in four studies (Hillman 2002; Roos 2000a; Tsementzis 1990; Vermeulen 1984) and the number of participants with poor outcomes could be reconstructed. Death from all causes and rebleeding rates were reported in all 10 studies. In six studies, episodes of rebleeding were defined primarily by clinical symptoms.

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Fig. 1 Study flow diagram

Two trials (Fodstad 1981; Hillman 2002) reported CT scan or autopsy confirmed episodes of rebleeding. The Dutch-British trial (Vermeulen 1984) and the STAR study (Roos 2000a) defined and reported rebleeding in two ways: as ‘probable’ if the diagnosis was suspected solely on clinical grounds and as ‘definite’ when proven by CT (after comparison with an earlier CT) or at autopsy. Cerebral ischaemia was reported in six studies but defined in only three: in two studies (Roos 2000a; Vermeulen 1984) cerebral ischaemia was defined

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and reported in the same manner as episodes of rebleeding; as ‘probable’ and as ‘definite’ (CT-scan or autopsy confirmed) cerebral ischaemia. Again, as for rebleeding, Fodstad 1981 reported on CT-scan or autopsy confirmed cerebral ischaemia. Hillman 2002 reported percentage of transient and permanent delayed ischaemic neurological deficit. No clear definition was given and CT scans were not routinely used for confirmation of cerebral ischaemia. Because other studies did not make a distinction between permanent or transient cerebral ischaemia, we decided to combine these outcomes. In Hillman 2002, visible infarction on CT scan was reported; however, after contact with the author, we decided not to use this as a measure for cerebral ischaemia since this was not correlated to clinical signs of cerebral ischeamia.The other two studies (Girvin 1973; Tsementzis 1990) made no distinction between participants with episodes clinically suggestive of cerebral ischaemia or participants with 4 confirmed cerebral ischaemia, and reported only an all-inclusive number of participants. One study reported on ‘delayed cerebral ischaemia’ and ‘post operative ischaemia’ (Roos 2000a). Since all other studies did not make this distinction and reported an overall number of participants with cerebral ischaemia, we grouped these subgroups of ischaemia together for the analysis on cerebral ischaemia. Five trials reported on hydrocephalus. Hydrocephalus was defined in only one study by means other than clinical grounds and could therefore be included in the sensitivity analysis concerning ‘confirmed hydrocephalus’ (Roos 2000a). No trials reported on aneurysm treatment modality (i.e. coiling versus clipping) according to antifibrinolytic or control treatment and thus a subgroup analysis based on modality was not possible.

Excluded studies We excluded 21 studies for various reasons (see Characteristics of excluded studies): some were comparative trials between two or more antifibrinolytic agents, others used unconcealed randomisation methods, and some were not randomised but used historical controls. We excluded Fodstad 1978 as 23% of the participants in the trial were later excluded and an intention-to-treat analysis could not be reconstructed on the basis of the published data.

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Risk of bias in included studies For a summary of the risk of bias please see Figure 2 and Figure 3. Five of the 10 included trials used an intention-to-treat analysis; in one of the remaining trials (Maurice 1978) this analysis could be completely reconstructed using the available follow-up data. In the other trials (Fodstad 1981; Hillman 2002; Tsementzis 1990; Van Rossum 1977) there was no follow-up information available for participants who were excluded after randomisation. In three studies only very few participants (Fodstad 1981: n = 1; Tsementzis 1990: n = 4; Van Rossum 1977: n = 3) were excluded from the final analysis and therefore these studies could still be included in our review. In one study (Hillman 2002) 91 (15%) of the 596 participants were excluded after randomisation. Because this was less than the prespecified proportion of 20% we included this study in our analysis. We rated this study as high risk of bias for incomplete outcome data.

Six studies used a double-blind method (placebo controlled) and four used a control group with standard treatment without placebo.The control group studies were open label and we rated them as high risk of performance bias (all four studies) and attrition bias (one study). Girvin 1973 used ‘flip-of-a-coin’ randomisation as the method of allocation, which is more susceptible to bias compared with, for instance, the sealed envelope method. Nevertheless, we decided to include this study since this is an accepted form of randomisation with allocation concealment according to the Cochrane guidelines. All other studies used a method of concealed allocation that was considered appropriate at time of conducting the trial, although it was not always mentioned whether or not the sealed envelopes that were used were opaque.

Effects of interventions The pooled RR for our primary outcome measure, ‘poor outcome’, was 1.02 (95% CI 0.91 to 1.15) (Analysis 1.1). The pooled RR for our second primary outcome measure, ‘death from all causes’, was 1.00 (95% CI 0.85 to 1.18) (Analysis 1.2). In the analysis on rebleeding rates (Analysis 1.3), antifibrinolytic therapy significantly reduced the risk of rebleeding (RR 0.65, 95% CI 0.44 to 0.97; 78 per 1000 people). Considerable heterogeneity was detected for this comparison (I² = 62%). Similar results were found in the subgroup analysis of the six double-blind and placebo controlled studies (RR 0.64, 95% CI 0.43 to 0.97), the

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Fig. 2 Risk of bias summary: review authors’ judgements about each risk of bias item for each included study

Fig. 3 Risk of bias graph: review authors’ judgements about each risk of bias item presented as percentages across all included studies

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sensitivity analysis including four studies with CT scan or autopsy confirmed rebleeding (RR 0.44, 95% CI 0.26 to 0.75) (Analysis 1.4), as well as in the subgroup analysis of studies with and without ischaemia prevention according to duration of treatment (< 72 hours > 72 hours) (RR 0.65, 95% CI 0.44 to 0.97) (Analysis 1.5). In the six trials that reported cerebral ischaemia rates, antifibrinolytic treatment significantly increased the risk of cerebral ischaemia (RR 1.41, 95% CI 1.04 to 1.91; 83 per 1000 people) (Analysis 1.6). Similar (though non-significant) results were seen in the subgroup analysis of the three placebo controlled trials (RR 1.38, 95% CI 0.87 to 2.19) as well as in the three trials with CT scan or autopsy confirmed cerebral ischaemia (RR 1.34, 95% CI 0.88 to 2.03) (Analysis 1.7). In these analyses there was considerable heterogeneity between the results from the four older studies and the results from the most recent studies (Hillman 2002; Roos 2000a), in which specific treatments to prevent cerebral ischaemia were used (I² = 52%). In five trials hydrocephalus was reported. Antifibrinolytic treatment overall had no effect on the reported rates of hydrocephalus (RR 1.11, 95% CI 0.90 to 1.36) (Analysis 1.8). In the subgroup analysis on placebo versus open studies the RR of antifibrinolytic treatment for hydrocephalus was 1.19 (95% CI 0.95 to 1.48) in the placebo controlled studies, while it was 0.64 (95% CI 0.34 to 1.18) in the open label trials. The sensitivity analysis on one trial with CT scan or autopsy confirmed hydrocephalus showed no effect of therapy on hydrocephalus rate (RR 1.17, 95% CI 0.87 to 1.55) (Analysis 1.9). Ischaemia prevention did not appear to have an effect on hydrocephalus in the subgroup analysis of studies with and without ischaemia prevention according to duration of treatment. The RR of hydrocephalus in people receiving antifibrinolytic treatment during > 72 hours with cerebral ischaemia prevention was 1.17 (95% CI 0.87 to 1.55) and for people receiving antifibrinolytic treatment during > 72 hours without ischaemia prevention the RR was 1.03 (95% CI 0.74 to 1.43) (Analysis 1.10). In the subgroup analysis of studies with ischaemia prevention according to duration of treatment (< 72 hours versus > 72 hours), the RR for people receiving antifibrinolytic treatment during < 72 hours with cerebral ischaemia prevention was 0.85 (95% CI 0.64 to 1.14) for ‘poor outcome’ (Analysis 1.11) and 0.83 (95% CI 0.52 to 1.35) for ‘death from all causes’ (Analysis 1.12). Furthermore, cerebral ischaemia did not significantly increase with antifibrinolytic treatment in trials where participants received concomitant ischaemia preventative

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treatment (Hillman 2002 and Roos 2000a combined: RR 1.09, 95% CI 0.78 to 1.51) (Analysis 1.13).

DISCUSSION

Summary of main results Although this systematic review shows that antifibrinolytic treatment reduces the rate of rebleeding by approximately 35%, there is no evidence of benefit from antifibrinolytic treatment on case fatality or poor overall outcome. This analysis further shows that the lack of effect on clinical outcome, despite a reduction in rebleeding, may be caused by an increase in cerebral ischaemia with antifibrinolytic treatment, which was also shown in the sensitivity analysis in trials with data on the number of participants with CT or post-mortem 4 proven cerebral ischaemia (two double-blind, one with open control group). Any possible beneficial effect of the reduction in the rebleeding-rate on clinical outcome was offset by an increase in the rate of cerebral ischaemia. This was also seen in the most recent study (Hillman 2002) in which short-term antifibrinolytic therapy was given with ischaemia preventative measures, although permanent delayed neurological deficit was decreased with antifibrinolytic treatment. This finding could suggest that short-term antifibrinolytic treatment (compared to long-term treatment in the study by Roos 2000a) does not influence recovery from initial ischaemia or development of secondary ischaemia and may, therefore, lead to improved clinical outcome. However, confirmatory evidence is needed.

Overall completeness and applicability of evidence Trials in which people were included with symptoms and signs of SAH of suspected or proven aneurysmal cause, with confirmation of the diagnosis by the presence of subarachnoid blood on CT or on CSF examination were eligible for inclusion in the review. We chose this pragmatic approach and did not restrict our review to people with angiographically proven aneurysms, because in contrast to angiography, CT scan or CSF examination can be done instantaneously, independent of the clinical condition of the patient. One could argue that currently people with suspected aneurysmal SAH will undergo CT angiography (CTA) immediately to confirm the presence of an aneurysm. We chose not to limit our analysis to proven aneurysmal SAH,

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because CTA was not available at the time most of the trials were conducted. Moreover, CTA is not always available in referring hospitals without specialised units. Since antifibrinolytic treatment might be most beneficial when started as soon as possible, it is likely that treatment will start in the referring hospital without CTA confirmation of the presence of an aneurysm. An analysis on oral versus intravenous treatments or a comparison between treatment dosages could not be performed. Only one study used oral antifibrinolytic treatment, whereas other studies used intravenous therapy alone or a combination of intravenous and oral treatment in varying dosages. Furthermore, in the past decade treatment of cerebral aneurysms has changed considerably: whereas most studies were performed in the era where surgical treatment was the only method of occlusion of the aneurysm, currently endovascular coiling is an accepted alternative to surgical occlusion. Because no data on treatment modality were available from the included trials, an analysis according to aneurysm treatment modality was not possible. Such an analysis could, however, prove worthwhile in the future.

Quality of the evidence In this systematic review we only included true randomised controlled trials and performed a subgroup analysis on masked versus unmasked studies in an attempt to minimise allocation and performance bias. However, many of the included studies were older (1970s and 1980s) and most did not report on many sources of potential bias, such as how the randomisation sequence was generated and if participant outcome was assessed by individuals who were blinded to the intervention given. Therefore, we scored many potential sources of bias as ‘unclear risk’ as can be seen in Figure 2 and Figure 3. However, most of these studies were small and in total comprised 24% of all included participants. Most included participants originated from three large studies (Hillman 2002; Roos 2000a; Vermeulen 1984). For two of these studies, comprising 50% of all data, we could find no potential sources of bias so we rated them as low risk of bias for each source (Roos 2000a; Vermeulen 1984). For Hillman 2002, however, many potential sources of bias could not be scored and were unclear, such as sequence generation, allocation concealment, and blinded outcome assessment. Moreover, 15% of included participants were later excluded from the analysis and the baseline characteristics and outcome of these participants were not reported. Since this was the only study included in the subgroup

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analysis for treatment duration of less than 72 hours with ischaemia prevention these results are far from conclusive. We know of only one other case series that evaluated short-term antifibrinolytic treatment (Harrigan 2010). In this study all participants received antifibrinolytic treatment until occlusion of the aneurysm (average 56.5 hours after SAH ictus). Harrigan 2010 reported low rebleeding rates and permanent neurological deficit due to cerebral ischaemia (1.4% and 7.2% respectively). However, no follow-up was done to evaluate the participants’ clinical outcomes and no control group was available making it impossible to draw conclusions based on this study.

Potential biases in the review process We searched all major medical electronic databases and other sources, using sensitive and validated search strategies. However, it is possible that we did not 4 find all relevant publications. Furthermore, we only included studies that were published in medical literature and did not search the grey literature, such as government reports and unpublished information. Although all included trials met the predefined inclusion criteria, the studies differed considerably in participant selection, disease severity at baseline, start of treatment after diagnosis, dosage and type of trial medication, classification of events, and outcome and duration of follow-up. This clinical heterogeneity may in part account for the statistical heterogeneity found in the analyses on rebleeding and cerebral ischaemia.

Agreements and disagreements with other studies or reviews Our results are comparable to the results from a recent meta-analysis (Gaberel 2012). However, Gaberel 2012 included all studies in which antifibrinolytic treatment was compared with control treatment, including retrospective analyses and studies with historical control groups. Retrospective analyses are known to be much more susceptible to selection and reporting bias, since the decision to treat a patient is made subjectively. Moreover, the other review did not compare placebo controlled versus open studies, which is another potential source of bias, since all outcomes, except for death, are made on subjective clinical grounds and can be easily biased when the outcome assessor is not blinded to the treatment given. In our review we included only randomised clinical trials and performed several sensitivity analyses, which should yield less biased results. Since most studies did not describe

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whether outcomes were assessed blinded to treatment, sensitivity analyses are essential. Despite the fact that all authors reported that confirmation of rebleeding was sought, in most instances this was done by examination of the cerebrospinal fluid. Because CSF examination is an unreliable test to confirm rebleeding (Vermeulen 1983) the diagnosis of rebleeding could often not be regarded as proven. The sensitivity analyses we performed on reported versus confirmed (with confirmatory evidence on CT scan or at autopsy) rebleeding, cerebral ischaemia, or hydrocephalus showed similar results to the overall analyses. Lack of confirmatory evidence of these complications thus appears to be of minor importance in our analyses. The analyses we performed on trials with control treatment compared with those given placebo treatment showed similar reducing effects of antifibrinolytic treatment on rebleeding and similar increasing effects on cerebral ischaemia, whereas hydrocephalus trials with control treatment showed a tendency towards a beneficial effect compared with trials with placebo treatment, demonstrating a tendency towards increased hydrocephalus rates.

AUTHORS’ CONCLUSIONS

Implications for practice Antifibrinolytic treatment does not improve clinical outcome in people after SAH, although it does reduce the risk of rebleeding after SAH. Based on the currently available data, treatment with antifibrinolytic drugs cannot be recommended for people with subarachnoid haemorrhage from a presumed or proven aneurysmal origin.

Implications for research The available data suggest that short-term (less than 72 hours) antifibrinolytic treatment, combined with cerebral ischaemia preventative measures, may reduce rebleeding rates without an increase in the proportion of people with cerebral ischaemia. Thus, short-term treatment with antifibrinolytic therapy may be effective for people with aneurysmal SAH, but confirmatory evidence is lacking and a possible harmful effect can also not be excluded. Based on these findings new randomised trials of short-term antifibrinolytic agents versus control in people with SAH are needed. Recently, a new trial comparing

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ultra early and short antifibrinolytic treatment (less than 24 hours) with control treatment has been registered and is planned (Verbaan 2012).

ACKNOWLEDGEMENTS

Previous versions of this review were supported by research grants from the Netherlands Heart Foundation (Nederlandse Hart Stichting). We would like to thank Brenda Thomas for her help in developing the new electronic database search. We would like to thank Hazel Fraser for her editorial advice.

DATA AND ANALYSES 4

Comparison 1. Antifibrinolytic treatment versus control treatment with or without placebo Outcome or subgroup title No. of No. of Statistical method Effect size studies participants 1 Poor outcome (death, 4 1546 Risk Ratio (M-H, 1.02 vegetative or severe disability on Random, 95% CI) [0.91, 1.15] Glasgow Outcome Scale at end of follow-up): open versus blind studies 1.1 Trials with control 1 505 Risk Ratio (M-H, 0.85 treatment (open studies) Random, 95% CI) [0.64, 1.14] 1.2 Trials with placebo 3 1041 Risk Ratio (M-H, 1.06 treatment (blind studies) Random, 95% CI) [0.93, 1.21] 2 Death from all causes at end 10 1904 Risk Ratio (M-H, 1.00 of follow up: open versus blind Random, 95% CI) [0.85, 1.18] studies 2.1 Trials with control 4 709 Risk Ratio (M-H, 0.89 treatment (open studies) Random, 95% CI) [0.56, 1.42] 2.2 Trials with placebo 6 1195 Risk Ratio (M-H, 1.02 treatment (blind studies) Random, 95% CI) [0.87, 1.19] 3 Rebleeding reported at end 10 1904 Risk Ratio (M-H, 0.65 of follow up: open versus blind Random, 95% CI) [0.44, 0.97] studies 3.1 Trials with control 4 709 Risk Ratio (M-H, 0.66 treatment (open studies) Random, 95% CI) [0.25, 1.74] 3.2 Trials with placebo 6 1195 Risk Ratio (M-H, 0.64 treatment (blind studies) Random, 95% CI) [0.43, 0.97]

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Comparison 1. continued Outcome or subgroup title No. of No. of Statistical method Effect size studies participants 4 Confirmed rebleeding at end 4 1505 Risk Ratio (M-H, 0.44 of follow-up (sensitivity analysis): Random, 95% CI) [0.26, 0.75] open versus blind studies 4.1 Trials with control 2 564 Risk Ratio (M-H, 0.42 treatment (open studies) Random, 95% CI) [0.11, 1.59] 4.2 Trials with placebo 2 941 Risk Ratio (M-H, 0.46 treatment (blind studies) Random, 95% CI) [0.25, 0.86] 5 Rebleeding reported at end of 10 1904 Risk Ratio (M-H, 0.65 follow-up: trials with and without Random, 95% CI) [0.44, 0.97] ischaemia prevention according to treatment duration 5.1 Trials without ischaemia 8 937 Risk Ratio (M-H, 0.79 prevention, treatment Random, 95% CI) [0.47, 1.31] duration > 72 hours 5.2 Trials with ischaemia 1 462 Risk Ratio (M-H, 0.58 prevention treatment duration Random, 95% CI) [0.42, 0.80] > 72 hours 5.3 Trials with ischaemia 1 505 Risk Ratio (M-H, 0.22 prevention, treatment Random, 95% CI) [0.09, 0.52] duration < 72 hours 6 Cerebral ischaemia reported 6 1671 Risk Ratio (M-H, 1.41 at end of follow-up: open versus Random, 95% CI) [1.04, 1.91] blind studies 6.1 Trials with control 3 630 Risk Ratio (M-H, 1.46 treatment (open studies) Random, 95% CI) [0.99, 2.14] 6.2 Trials with placebo 3 1041 Risk Ratio (M-H, 1.38 treatment (blind studies) Random, 95% CI) [0.87, 2.19] 7 Confirmed cerebral ischaemia 3 1000 Risk Ratio (M-H, 1.34 at end of follow-up (sensitivity Random, 95% CI) [0.88, 2.03] analysis): open versus blind studies 7.1 Trials with control 1 59 Risk Ratio (M-H, 2.58 treatment (open studies) Random, 95% CI) [0.76, 8.77] 7.2 Trials with placebo 2 941 Risk Ratio (M-H, 1.24 treatment (blind studies) Random, 95% CI) [0.82, 1.89] 8 Hydrocephalus reported at end 5 1179 Risk Ratio (M-H, 1.11 of follow-up: open versus blind Random, 95% CI) [0.90, 1.36] studies 8.1 Trials with control 2 138 Risk Ratio (M-H, 0.64 treatment (open studies) Random, 95% CI) [0.34, 1.18] 8.2 Trials with placebo 3 1041 Risk Ratio (M-H, 1.19 treatment (blind studies) Random, 95% CI) [0.95, 1.48]

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Comparison 1. continued Outcome or subgroup title No. of No. of Statistical method Effect size studies participants 9 Confirmed hydrocephalus 1 462 Risk Ratio (M-H, 1.17 at end of follow up (sensitivity Random, 95% CI) [0.87, 1.55] analysis): open versus blind studies 9.1 Trials with control 0 0 Risk Ratio (M-H, 0.0 treatment (open studies) Random, 95% CI) [0.0, 0.0] 9.2 Trials with placebo 1 462 Risk Ratio (M-H, 1.17 treatment (blind studies) Random, 95% CI) [0.87, 1.55] 10 Hydrocephalus reported at 5 1179 Risk Ratio (M-H, 1.11 end of follow-up: trials with and Random, 95% CI) [0.90, 1.36] without ischaemia prevention according to treatment duration 10.1 Trials without ischaemia 4 717 Risk Ratio (M-H, 1.03 prevention, treatment Random, 95% CI) [0.74, 1.43] duration > 72 hours 10.2 Trials with ischaemia 1 462 Risk Ratio (M-H, 1.17 4 prevention, treatment Random, 95% CI) [0.87, 1.55] duration > 72 hours 10.3 Trials with ischaemia 0 0 Risk Ratio (M-H, 0.0 prevention, treatment Random, 95% CI) [0.0, 0.0] duration < 72 hours 11 Poor outcome (death, 4 1546 Risk Ratio (M-H, 1.02 vegetative or severe disability Random, 95% CI) [0.91, 1.15] on Glasgow Outcome Scale at end of follow-up): trials with and without ischaemia prevention according to treatment duration 11.1 Trials without cerebral 2 579 Risk Ratio (M-H, 1.03 ischaemia prevention, Random, 95% CI) [0.86, 1.22] treatment duration > 72 hours 11.2 Trials with ischaemia 1 462 Risk Ratio (M-H, 1.10 prevention, treatment Random, 95% CI) [0.91, 1.34] duration > 72 hours 11.3 Trials with cerebral 1 505 Risk Ratio (M-H, 0.85 ischaemia prevention, Random, 95% CI) [0.64, 1.14] treatment duration < 72 hours

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Comparison 1. continued Outcome or subgroup title No. of No. of Statistical method Effect size studies participants 12 Death from all causes at end 10 1904 Risk Ratio (M-H, 1.00 of follow-up: trials with and Random, 95% CI) [0.85, 1.18] without ischaemia prevention according to treatment duration 12.1 Trials without ischaemia 8 937 Risk Ratio (M-H, 1.03 prevention, treatment Random, 95% CI) [0.78, 1.35] duration > 72 hours 12.2 Trials with ischaemia 1 462 Risk Ratio (M-H, 1.03 prevention with treatment Random, 95% CI) [0.79, 1.34] duration > 72 hours 12.3 Trials with ischaemia 1 505 Risk Ratio (M-H, 0.83 prevention with treatment Random, 95% CI) [0.52, 1.35] duration < 72 hours 13 Cerebral ischaemia reported 6 1671 Risk Ratio (M-H, 1.41 at end of follow-up: trials Random, 95% CI) [1.04, 1.91] with and without ischaemia prevention according to treatment duration 13.1 Trials without ischaemia 4 704 Risk Ratio (M-H, 1.77 prevention, treatment Random, 95% CI) [1.30, 2.40] duration > 72 hours 13.2 Trials with ischaemia 1 462 Risk Ratio (M-H, 0.96 prevention, treatment Random, 95% CI) [0.75, 1.23] duration > 72 hours 13.3 Trials with ischaemia 1 505 Risk Ratio (M-H, 1.35 prevention, treatment Random, 95% CI) [0.89, 2.04] duration < 72 hours

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Analysis 1.1. Comparison 1 Antifibrinolytic treatment versus control treatment with or without placebo, Outcome 1 Poor outcome (death, vegetative of severe disability on Glasgow Outcome Scale at end of follow-up): open versus blind studies.

Analysis 1.2. Comparison 1 Antifibrinolytic treatment versus control treatment with or without placebo, Outcome 2 Death from all causes at end of follow-up: open versus blind studies.

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Analysis 1.3. Comparison 1 Antifibrinolytic treatment versus control treatment with or without placebo, Outcome 3 Rebleeding reported at end of follow-up: open versus blind studies.

Analysis 1.4. Comparison 1 Antifibrinolytic treatment versus control treatment with or without placebo, Outcome 4 Confirmed rebleeding at end of follow-up (sensitivity analysis): open versus blind studies.

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Analysis 1.5. Comparison 1 Antifibrinolytic treatment versus control treatment with or without placebo, Outcome 5 Rebleeding reported at end of follow-up: trials with and without ischaemia prevention according to treatment duration.

Analysis 1.6. Comparison 1 Antifibrinolytic treatment versus control treatment with or without placebo, Outcome 6 Cerebral ischaemia reported at end of follow-up: open versus blind studies.

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Analysis 1.7. Comparison 1 Antifibrinolytic treatment versus control treatment with or without placebo, Outcome 7 Confirmed cerebral ischaemia at end of follow-up (sensitivity analysis): open versus blind studies.

Analysis 1.8. Comparison 1 Antifibrinolytic treatment versus control treatment with or without placebo, Outcome 8 Hydrocephalus reported at end of follow-up: open versus blind studies.

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Analysis 1.9. Comparison 1 Antifibrinolytic treatment versus control treatment with or without placebo, Outcome 9 Confirmed hydrocephalus at end of follow-up (sensitivity analysis): open versus blind studies.

Analysis 1.10. Comparison 1 Antifibrinolytic treatment versus control treatment with or without placebo, Outcome 10 Hydrocephalus reported at end of follow-up: trials with and without ischaemia prevention according to treatment duration.

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Analysis 1.11. Comparison 1 Antifibrinolytic treatment versus control treatment with or without placebo, Outcome 11 Poor outcome (death, vegetative of severe disability on Glasgow Outcome Scale at end of follow-up): trials with and without ischaemia prevention according to treatment duration.

Analysis 1.12. Comparison 1 Antifibrinolytic treatment versus control treatment with or without placebo, Outcome 12 Death from all causes at end of follow-up: trials with and without ischaemia prevention according to treatment duration.

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Analysis 1.13. Comparison 1 Antifibrinolytic treatment versus control treatment with or without placebo, Outcome 13 Cerebral ischaemia reported at end of follow-up: trials with and without ischaemia prevention according to treatment duration.

APPENDICES

Appendix 1. MEDLINE search strategy 1. Subarachnoid Hemorrhage/ 2. intracranial hemorrhages/ or cerebral hemorrhage/ 3. Intracranial Aneurysm/ 4. Rupture, Spontaneous/ 5. 3 and 4 6. Aneurysm, Ruptured/ 7. exp brain/ or exp meninges/ 8. 6 and 7 9. ((subarachnoid or arachnoid) adj6 (haemorrhage$ or hemorrhage$ or bleed$ or blood$)).tw. 10. Vasospasm, Intracranial/ 11. ((cerebral or intracranial or cerebrovascular) adj6 (vasospasm or spasm)).tw. 12. sah.tw. 13. 1 or 2 or 5 or 8 or 9 or 10 or 11 or 12 14. exp Antifibrinolytic Agents/ 15. (anti-fibrinolytic$ or antifibrinolytic$ or antifibrinolysin$ or anti-fibrinolysin$ or antiplasmin$ or anti-plasmin$ or (plasmin adj3 inhibitor$)).tw. 16. (fibrinolysis adj3 (prevent$ or inhib$ or antag$)).tw. 17. tranexamic acid/ 18. (4 amino methylcyclohexane carboxylate or 4 aminomethylcyclohexanecarbonic acid or 4 aminomethylcyclohexanecarboxylic acid or amca or AMCHA or amchafibrin or amikapron or aminomethyl cyclohexane carboxylic acid or aminomethyl cyclohexanecarboxylic acid or aminomethylcyclohexane carbonic acid or aminomethylcyclohexane carboxylic acid or aminomethylcyclohexanecarbonic acid or aminomethylcyclohexanecarboxylic acid or aminomethylcyclohexanocarboxylic acid or aminomethylcyclohexanoic acid or amstat or anexan or antivoff or anvitoff orcaprilon or cis 4 aminomethylcyclohexanecarboxylic acid or cis

87 Chapter 4

aminomethyl cyclohexanecarboxylic acid or cl 65336 or cl65336 or cyclocapron or cyclokapron or cyklocapron or cyklokapron or exacyl or fibrinon or frenolyse or hemostan or hexacapron or hexakapron or kabi 2161 or kalnex or micranex or para aminomethylcyclohexane carboxylic acid or rikaparin or ronex or spotof or theranex or tramic or tranex or tranexam or tranexamic acid or tranexanic acid or tranexic or trans 1 aminomethylcyclohexane 4 carboxylic acid or trans 4 aminomethylcyclohexane 1 carboxylic acid or trans 4 aminomethylcyclohexane carboxylic acid or trans 4 aminomethylcyclohexanecarboxylic acid or trans achma or trans amcha or trans aminomethyl cyclohexane carboxylic acid or trans aminomethylcyclohexane carboxylic acid or trans aminomethylcyclohexanecarboxylic acid or transamin or transaminomethylcyclohexane carboxylic acid or transexamic acid or traxamic or trenaxin or ugurol).tw,nm. 19. exp Aminocaproic Acids/ 20. (acikaprin or afibrin or amicar or amino caproic acid or aminocaproic acid or aminohexanoic acid or capracid or capramol or caproamin or caprocid or caprogel or caprolest or caprolisin or caprolisine or caprolysin orcapromol or cl 10304 or cl10304 or cy 116 or cy116 or e aminocaproic acid or EACA or ecapron or ekaprol or epsamon or epsicaprom or epsicapron or epsikapron or epsilcapramin or epsilon amino caproate or epsilon amino caproic aci or depsilon aminocaproate or epsilon aminocaproic acid or epsilonaminocaproic acid or epsilonaminocapronsav or etha aminocaproic acid or ethaaminocaproic acid or gamma aminocaproic acidor gamma aminohexanoic acidor hemocaprol or hepin or hexalense or ipsilon or jd 177 or jd177 or neocaprol or nsc 26154 or nsc26154 or resplamin or tachostyptan).tw,nm. 21. Aprotinin/ 22. (9921 rp or antagosan or antilysin or antilysine or apronitin or apronitine or apronitrine or aprotimbin or aprotinin bovine or aprotinine or aprotonin or bayer a 128 or bayer a128 or bovine pancreatic secretory trypsin inhibitor or contrical or contrycal or contrykal or frey inhibitor or gordox or haemoprot or iniprol or kallikrein trypsin inhibitor or kazal type trypsin inhibitor or kontrikal or kontrycal or Kunitz inhibitor or Kunitz trypsin inhibitor or midran or pancreas antitrypsin or pancreas secretory trypsin inhibitor or pancreas trypsin inhibitor or pancreatic antitrypsin or pancreatic secretory trypsin inhibitor or pancreatic trypsin inhibitor or protinin orriker 52g or rivilina or rp 9921 or rp9921 or tracylol or trascolan or trasilol or traskolan or trasylol or trazylol or tumor associated trypsin inhibitor or zymofren).tw,nm. 23.( 4 aminomethylbenzoic acid or 4 amino methylbenzoic acid or alpha amino para toluic acid or amino methylbenzoic acid or aminomethyl benzoic acid or aminomethylbenzoic acid or PAMBA or para aminomethylbenzoic acid or para amino methylbenzoic acid or styptopur or styptosolut). tw,nm 24. Fibrinolysis/ai, de [Antagonists & Inhibitors, Drug Effects] 25. or/14-24 26. 13 and 25 27. exp animals/ not humans.sh. 28. 26 not 27

Appendix 2. EMBASE search strategy 1. Subarachnoid Hemorrhage/ 2. brain hemorrhage/ or brain artery aneurysm rupture/ 3. Brain Vasospasm/ 4. exp Intracranial Aneurysm/ 5. exp rupture/ 6. 4 and 5 7. Aneurysm Rupture/ 8. exp brain/ or exp meninx/ 9. 7 and 8 10. ((subarachnoid or arachnoid) adj6 (haemorrhage$ or hemorrhage$ or bleed$ or blood$)).tw. 11. ((cerebral or intracranial or cerebrovascular) adj6 (vasospasm or spasm)).tw. 12. sah.tw. 13. 1 or 2 or 3 or 6 or 9 or 10 or 11 or 12 14. exp antifibrinolytic agent/ 15. (anti-fibrinolytic$ or antifibrinolytic$ or antifibrinolysin$ or anti-fibrinolysin$ or antiplasmin$ or anti-plasmin$ or (plasmin adj3 inhibitor$)).tw. 16. (fibrinolysis adj3 (prevent$ or inhib$ or antag$)).tw. 17. tranexamic acid/

88 Antifibrinolytic therapy

18. (4 amino methylcyclohexane carboxylate or 4 aminomethylcyclohexanecarbonic acid or 4 aminomethylcyclohexanecarboxylic acid or amca or AMCHA or amchafibrin or amikapron or aminomethyl cyclohexane carboxylic acid or aminomethyl cyclohexanecarboxylic acid or aminomethylcyclohexane carbonic acid or aminomethylcyclohexane carboxylic acid or aminomethylcyclohexanecarbonic acid or aminomethylcyclohexanecarboxylic acid or aminomethylcyclohexanocarboxylic acid or aminomethylcyclohexanoic acid or amstat or anexan or antivoff or anvitoff orcaprilon or cis 4 aminomethylcyclohexanecarboxylic acid or cis aminomethyl cyclohexanecarboxylic acid or cl 65336 or cl65336 or cyclocapron or cyclokapron or cyklocapron or cyklokapron or exacyl or fibrinon or frenolyse or hemostan or hexacapron or hexakapron or kabi 2161 or kalnex or micranex or para aminomethylcyclohexane carboxylic acid or rikaparin or ronex or spotof or theranex or tramic or tranex or tranexam or tranexamic acid or tranexanic acid or tranexic or trans 1 aminomethylcyclohexane 4 carboxylic acid or trans 4 aminomethylcyclohexane 1 carboxylic acid or trans 4 aminomethylcyclohexane carboxylic acid or trans 4 aminomethylcyclohexanecarboxylic acid or trans achma or trans amcha or trans aminomethyl cyclohexane carboxylic acid or trans aminomethylcyclohexane carboxylic acid or trans aminomethylcyclohexanecarboxylic acid or transamin or transaminomethylcyclohexane carboxylic acid or transexamic acid or traxamic or trenaxin or ugurol).tw. 19. aminocaproic acid/ 20. (acikaprin or afibrin or amicar or amino caproic acid or aminocaproic acid or aminohexanoic acid or capracid or capramol or caproamin or caprocid or caprogel or caprolest or caprolisin or caprolisine or caprolysin orcapromol or cl 10304 or cl10304 or cy 116 or cy116 or e aminocaproic acid or EACA or ecapron or ekaprol or epsamon or epsicaprom or epsicapron or epsikapron or epsilcapramin 4 or epsilon amino caproate or epsilon amino caproic aci or depsilon aminocaproate or epsilon aminocaproic acid or epsilonaminocaproic acid or epsilonaminocapronsav or etha aminocaproic acid or ethaaminocaproic acid or gamma aminocaproic acidor gamma aminohexanoic acidor hemocaprol or hepin or hexalense or ipsilon or jd 177 or jd177 or neocaprol or nsc 26154 or nsc26154 or resplamin or tachostyptan).tw. 21. aprotinin/ 22. (9921 rp or antagosan or antilysin or antilysine or apronitin or apronitine or apronitrine or aprotimbin or aprotinin bovine or aprotinine or aprotonin or bayer a 128 or bayer a128 or bovine pancreatic secretory trypsin inhibitor or contrical or contrycal or contrykal or frey inhibitor or gordox or haemoprot or iniprol or kallikrein trypsin inhibitor or kazal type trypsin inhibitor or kontrikal or kontrycal or Kunitz inhibitor or Kunitz trypsin inhibitor or midran or pancreas antitrypsin or pancreas secretory trypsin inhibitor or pancreas trypsin inhibitor or pancreatic antitrypsin or pancreatic secretory trypsin inhibitor or pancreatic trypsin inhibitor or protinin orriker 52g or rivilina or rp 9921 or rp9921 or tracylol or trascolan or trasilol or traskolan or trasylol or trazylol or tumor associated trypsin inhibitor or zymofren).tw. 23. 4 aminomethylbenzoic acid/ 24. (4 aminomethylbenzoic acid or 4 amino methylbenzoic acid or alpha amino para toluic acid or amino methylbenzoic acid or aminomethyl benzoic acid or aminomethylbenzoic acid or PAMBA or para aminomethylbenzoic acid or para amino methylbenzoic acid or styptopur or styptosolut).tw. 25. fibrinolysis/pc [Prevention] 26. or/14-25 27. 13 and 26 28. limit 27 to human

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SOURCES OF SUPPORT

External sources Nederlandse Hartstichting (Netherlands Heart Foundation), Netherlands.

CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID]

Chandra 1978 Methods Single centre study Random allocation (method of randomisation not described) Double-blind treatment ITT analysis Participants Clinical diagnosis of aneurysmal SAH confirmed in CSF and on angiography Male:female: treatment group 11:9; placebo group 10:9 Mean age 51 years (range 20 to 65) Excluded: SAH > 7 days, ‘relevant associated illness’ Interventions Tranexamic acid (6 g per day iv in 6 doses) versus identical-appearing placebo treatment for a treatment duration of 3 weeks No report on surgical interventions Outcomes Outcome: deaths from all causes at 3-week follow-up Events: rebleeding: reported, not defined; cerebral ischaemia: not reported; hydrocephalus: not reported Notes No report on how many rebleeding were established on CT scan or at necropsy Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation Unclear risk In the text, participants were reported (selection bias) to be randomly allocated, but how this was achieved is not reported Allocation concealment Low risk Identical medication; however, unclear (selection bias) how medication was coded Blinding of participants and Low risk “Neither the investigators nor the personnel (performance bias) patients knew which subjects received All outcomes which substance” Blinding of outcome assessment Unclear risk Not described in text (detection bias) All outcomes Incomplete outcome data Low risk No missing data (attrition bias) All outcomes Selective reporting (reporting Unclear risk Unclear bias) Other bias Unclear risk More male than female participants included, which could point to some form of bias since people with SAH are more often female

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Fodstad 1981 Methods Single center study Random allocation (identical sequentially numbered sealed envelope) No blind treatment Not strictly ITT: 1 of the 30 control participants was excluded after randomisation because he had received tranexamic acid before admission Participants Clinical diagnosis of aneurysmal SAH verified with CSF, CT scan and angiography Male:female: treatment group 13:17; control group 12:17 Mean age: treatment group 50 years (range 19 to 72); control group 53 years (range 27 to 70) Excluded: SAH > 3 days and known thrombotic disease Interventions Tranexamic acid (6 g per day iv in 6 doses during the first week, 4 g in 4 doses iv in week 2 and 6 g orally in 4 doses in week 3 to 6) for a maximum duration of 6 weeks versus control group. Treatment continued until rebleeding, operation, discharge or death Outcomes Outcome: deaths from all causes at 6-week follow-up Events: rebleeding: reported, confirmed by CSF examination/ spectrophotometry, CT-scan or at necropsy; cerebral ischaemia: 4 reported, not defined; hydrocephalus: reported, not defined Notes Of the participants with rebleeding, 5 of 6 in the treatment group and 5 of 7 in the control group died. All had necropsy. In the remaining participants rebleeding was confirmed by CT. 6 of 8 participants with cerebral ischaemia in the treatment group and 2 of 3 in the control group died. All had necropsy, in the remaining participants cerebral ischaemia was established on CT Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation Unclear risk Not described in the text (selection bias) Allocation concealment (selection Unclear risk “Patients were assigned bias) randomly” and “the sealed envelope technique was used” It was not mentioned whether these envelopes were opaque or not Blinding of participants and personnel High risk Participants and personnel (performance bias) were not blinded (open All outcomes study) Blinding of outcome assessment High risk Part of recurrent (detection bias) haemorrhages were All outcomes confirmed by lumbar puncture Incomplete outcome data (attrition Low risk 1 participant was excluded bias) from final analysis All outcomes Selective reporting (reporting bias) Low risk Protocol was previously published Other bias Low risk None suspected based on study design and outcome

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Girvin 1973 Methods Single-centre study Random allocation (flip-of-a-coin) No blind treatment ITT Participants Clinical diagnosis of aneurysmal SAH probably confirmed on angiography Male:female ratio not described (“in control group were a relatively greater number of female patients”) Age distribution not described Excluded: SAH > 7 days Interventions Epsilon amino-caproic acid, dosage probably 24 g per day (6 times 4 g) orally versus control group, duration on average in treatment group 7.7 days versus 5.5 in control group Treatment continued until operation or death Outcomes Outcome: deaths from all causes (at unknown week) Events: rebleeding: reported, not defined; ischaemia: reported, not defined; hydrocephalus: not reported Notes Poor description of study methods, definitions and results Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation Low risk “The cases were (selection bias) randomised on admission, by the flip of a coin” Allocation concealment (selection Low risk See above bias) Blinding of participants and personnel High risk Participants and personnel (performance bias) were not blinded All outcomes Blinding of outcome assessment Unclear risk Not described in the text (detection bias) All outcomes Incomplete outcome data (attrition Low risk No missing data bias) All outcomes Selective reporting (reporting bias) Low risk Primary outcome described as “raison d’etre” of the study Other bias Low risk None suspected based on study design and outcome

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Hillman 2002 Methods Multi-centre study Random allocation (sequence generation not specified) with sealed envelopes (not specified if opaque or not) No blind treatment Not strictly ITT: 91 participants excluded after randomisation because no aneurysm was found Participants People suffering from CT-verified SAH within 48 hours prior to hospital admission Male:female ratio: 1.89 in both groups Age distribution similar in both groups Excluded: SAH > 48 hours, age < 15 years, pregnancy, and history of thromboembolic disease. People in whom no aneurysm was demonstrated on angiographic studies were excluded after randomisation Interventions Tranexamic acid (1 g iv immediately before transport, 1 g iv after 2 hours, and then 1 g every 6th hour until aneurysm occlusion up to 72 hours after SAH) versus control treatment Outcomes Outcome: Glasgow Outcome Scale at 6 months Events: rebleeding confirmed on CT or during operation until 72 hours 4 after admission; clinically established delayed ischaemic neurological deficit at 6 months, not confirmed by imaging Notes Poor description of delayed ischaemic neurological deficit and how this was scored No mention of follow-up for rebleeding after 72 hours Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation Unclear risk Sequence generation was (selection bias) not described in the text Allocation concealment (selection Unclear risk Sealed envelopes were bias) used that contained a randomisation document; however, it was not reported how these were ordered and if they were opaque or not Blinding of participants and personnel High risk Participants and personnel (performance bias) were not blinded (open All outcomes study) Blinding of outcome assessment Unclear risk Not described in the text (detection bias) All outcomes Incomplete outcome data (attrition High risk 15% of included bias) participants not evaluated All outcomes in final analysis, which might have resulted in an overestimation of the effect estimate Selective reporting (reporting bias) Unclear risk Previously published protocol was not mentioned, clinical outcome reported although not described in introduction or methods Other bias Low risk None suspected based on study design and outcome

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Kaste 1979 Methods Single-centre study Random allocation (identical sequentially numbered treatment boxes) Double-blind treatment Code broken after final evaluation ITT Participants Clinical diagnosis of aneurysmal SAH verified in the CSF Male:female: active treatment group 16:16; placebo group 14:18 Age distribution similar in both groups Excluded: SAH > 72 hours, myocardial infarction within 6 months, unconsciousness, coagulation disorders or thrombotic disease, renal failure and pregnancy Interventions Tranexamic acid (6 g per day iv in 6 doses) versus identical-appearing placebo treatment for a maximum treatment duration of 3 weeks Treatment discontinued at operation Outcomes Outcome: deaths from all causes at 3 months. Events: rebleeding: suspected when 2 of sudden deterioration of consciousness, increase of neck rigidity, headache or focal signs - rebleeding verified in CSF or at necropsy; ischaemia: reported, not defined; hydrocephalus: reported, not defined Notes No definition on cerebral ischaemia or hydrocephalus: ‘vasospasm and ventricular dilatation were seen on angiography’ Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation Unclear risk Sequence generation was not (selection bias) described in the text Allocation concealment (selection Low risk Tranexamic acid and placebo bias) were prepared in identical vials and were coded; the code was only broken after final evaluation of the trial Blinding of participants and personnel Low risk Tranexamic acid and placebo (performance bias) were prepared in identical vials All outcomes and were coded; the code was only broken after final evaluation of the trial Blinding of outcome assessment Low risk “The code identifying each (detection bias) substance was broken only after All outcomes the final evaluation of all 64 patients” Incomplete outcome data (attrition Low risk No missing data bias) All outcomes Selective reporting (reporting bias) Low risk Protocol was previously published Other bias Unclear risk Unconscious people not included causing the results to be less generalisable

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Maurice 1978 Methods Single-centre study Random allocation (identical sequentially numbered sealed envelop) No double-blind treatment Not published as ITT, but ITT analysis could be reconstructed Participants Clinical diagnosis of aneurysmal SAH probably verified in the CSF No description of age or sex ratios (‘treatment group matched in age and sex control group’) Excluded: SAH > 4 days, person > 65 years, unconsciousness Interventions Tranexamic acid (6 g per day iv in 6 doses during the first week, 6 g orally in 4 doses in week 2 until week 6) for a maximum duration of 6 weeks versus control group; treatment continued until operation or death Outcomes Outcome: deaths from all causes at 3 months Events: rebleeding: reported and defined; ‘confirmed in CSF or at necropsy’; ischaemia: reported, not defined; hydrocephalus: reported, not defined Notes Rebleeding ‘confirmed’ by CSF examination are not useable (see text), not reported how many rebleedings were established on CT scan or at necropsy 4 Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation Unclear risk Sequentially numbered, (selection bias) sealed envelopes were used, but no description was made of how these numbers were created Allocation concealment (selection Low risk Sequentially numbered, bias) sealed envelopes were used Blinding of participants and personnel High risk Participants and personnel (performance bias) were not blinded (open All outcomes study) Blinding of outcome assessment Unclear risk Not described in the text (detection bias) All outcomes Incomplete outcome data (attrition Low risk No missing data, ITT bias) analysis could be All outcomes reconstructed Selective reporting (reporting bias) Unclear risk Sequentially numbered, sealed envelopes were used, but no description was made of how these numbers were created Other bias Low risk Sequentially numbered, sealed envelopes were used

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Roos 2000a Methods Multicentre study Random allocation (identical sequentially numbered treatment boxes), blocked per centre Double-blind treatment: code broken after all events and outcomes had been recorded ITT Participants Clinical diagnosis of aneurysmal SAH verified on CT or in the CSF: if negative CT, angiography had to confirm an aneurysm before randomisation Male:female: treatment group 89:140; placebo group 73:160 Mean age: treatment group 56 years; placebo group 55 years Excluded: SAH > 96 hours or operation planned < 48 hours, coagulation disorders or thrombotic disease, renal failure, pregnancy, previous tranexamic acid treatment or people in whom death appeared imminent Interventions Tranexamic acid (6 g per day iv in 6 doses in week 1, and 6 g orally per day in 4 doses in week 2 and 3) versus identical-appearing placebo treatment for a maximum treatment duration of 3 weeks All participants received standard anti-ischaemic treatment with nimodipine and hypervolaemia Outcomes Outcome: Glasgow Outcome Scale at 3 months Events: rebleeding-definite: confirmed by CT scan or at necropsy; rebleeding-possible: sudden deterioration and death; infarction- definite: confirmed by CT scan or at necropsy; infarction-probable: gradual development of focal neurologic signs with or without deterioration in the level of consciousness; hydrocephalus: gradual deterioration of consciousness with on CT hydrocephalus and no other explanation Postoperative ischaemia: deterioration of consciousness or development of focal neurological signs immediately after recovery from anaesthesia compared to preoperative status, without rebleeding, infarction or hydrocephalus on CT or at autopsy Poor outcome caused by the initial bleeding: impaired consciousness or focal neurological signs from the time of the initial bleeding, without rebleeding, infarction or hydrocephalus on CT or at autopsy Notes Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation Low risk Sequence was generated (selection bias) by use of random number tables Allocation concealment (selection Low risk Identical, sequentially bias) numbered treatment boxes, blocked per centre were used and boxes were consecutively numbered and administered in the same order to each following participant Blinding of participants and personnel Low risk Identical and sequentially (performance bias) numbered treatment All outcomes boxes were used Blinding of outcome assessment Low risk “Only after recording of all (detection bias) events and outcomes, the All outcomes trial code was broken”

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Incomplete outcome data (attrition Low risk No missing data bias) All outcomes Selective reporting (reporting bias) Low risk Previously published protocol Other bias Low risk None suspected based on study design and outcome

Tsementzis 1990 Methods Single-centre study Random allocation (identical sequentially numbered medication boxes) Double-blind treatment Not strictly ITT: 4 participants excluded after randomisation who missed a few doses medication Participants Clinical diagnosis of aneurysmal SAH verified on CT or in the CSF Male:female: treatment group 20:30; placebo group 26:24 Age distribution similar in both groups Excluded: SAH > 72 hours, antihypertensives or medication known 4 to affect the fibrinolytic or coagulation systems, acute myocardial infarction, coagulation disorders or thrombotic disease, renal failure, pregnancy, previous tranexamic acid-treatment or people in whom death seemed imminent Interventions Tranexamic acid (9 g per day, iv in 6 doses in week 1, orally in 4 doses in week 2, 3 and 4) versus identical-appearing placebo treatment for a maximum treatment duration of 4 weeks# Treatment was discontinued if an operation for the aneurysm began or if deep vein thrombosis or pulmonary infarction developed Outcomes Outcome: Glasgow Outcome Scale at discharge, 1, 3 and 6 months Events: rebleeding: reported and defined - ‘clinical signs confirmed on CT, in the CSF or at necropsy’; ischaemia: reported and defined - ‘clinical signs combined with the absence of evidence of rebleeding on CT or CSF’; hydrocephalus: reported, not defined Notes No report of how many participants’ rebleedings or cerebral ischaemia were established on CT scan or at necropsy No definition on hydrocephalus other then ‘ventricular dilatation was seen on angiography’ Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation Unclear risk Sequence generation was (selection bias) not described Allocation concealment (selection Low risk Placebo controlled bias) trial with sequentially numbered boxes with trial medication was used Blinding of participants and personnel Low risk Boxes with either (performance bias) tranexamic acid or placebo All outcomes were used that were numbered consecutively by the pharmacist Blinding of outcome assessment Low risk Not reported in the text, (detection bias) but because of control All outcomes with placebo, not thought to have influenced results

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Incomplete outcome data (attrition Unclear risk 4 participants were bias) excluded and no mention All outcomes is made on their outcome Selective reporting (reporting bias) Unclear risk Not reported in the text Other bias Unclear risk 20 participants with protocol violations were excluded from the analysis after randomisation

Van Rossum 1977 Methods Multicentre study Random allocation (“drug or placebo randomly administered in a sequence prescribed by and only known to the statistician”) Double-blind treatment Not strictly ITT: 3 participants excluded, because of other diagnosis, after randomisation Participants Clinical diagnosis of aneurysmal SAH verified in the CSF Male:female ratio or age distribution not described Excluded: SAH > 14 days (in 94% of the participants, treatment started within 1 week) Interventions Tranexamic acid (4 g per day iv in 4 doses) versus identically appearing placebo treatment for a maximum treatment duration of 10 days Treatment was discontinued after the aneurysm operation Outcomes Outcome: all-cause mortality at 3 months Events: rebleeding: reported and defined - ‘clinical signs confirmed in the CSF or at necropsy’; ischaemia: not reported; hydrocephalus: not reported Notes Rebleeds ‘confirmed’ by CSF examination are not useable (see text), not reported how many rebleedings were established on CT scan or at necropsy Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation Low risk Sequence was generated (selection bias) by an independent statistician Allocation concealment (selection Low risk Sequence was only known bias) to the statistician and “it was impossible for medical staff or patients to distinguish between drug- and placebo-containing ampoules” Blinding of participants and personnel Low risk “It was impossible for (performance bias) medical staff or patients to All outcomes distinguish between drug- and placebo-containing ampoules” Blinding of outcome assessment Low risk Not reported in the text, (detection bias) but because of control All outcomes with placebo not thought to have influenced results

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Incomplete outcome data (attrition Unclear risk 3 participants were bias) excluded and not All outcomes mentioned further Selective reporting (reporting bias) Low risk Protocol was previously published Other bias Low risk None suspected based on study design and outcome

Vermeulen 1984 Methods Multicentre study Random allocation (identical sequentially numbered treatment boxes), blocked per centre Double-blind treatment Code broken after all events and outcomes had been recorded ITT Participants Clinical diagnosis of aneurysmal SAH verified on CT or in the CSF: if negative CT, angiography had to confirm an aneurysm before randomisation 4 Male:female: treatment group 95:146; placebo group 94:144 Mean age in both groups 50 years Excluded: SAH > 72 hours, coagulation disorders or thrombotic disease, renal failure, pregnancy, previous tranexamic acid-treatment or people in whom death appeared imminent Interventions Tranexamic acid (6 g per day iv in 6 doses in week 1 and 2, 4 g iv or 6 g orally per day in 4 doses in week 3 and 4) versus identical-appearing placebo treatment for a maximum treatment duration of 4 weeks Treatment was discontinued when an aneurysm-operation began, if the angiography was negative, if venous thrombosis or pulmonary infarction developed or another diagnosis than aneurysm was established Outcomes Outcome: Glasgow Outcome Scale at 3 months Events: rebleeding-definite: confirmed by CT scan or at necropsy; rebleeding-possible: sudden deterioration and death; infarction- definite: confirmed by CT scan or at necropsy; infarction-probable: gradual development of focal neurologic signs with or without deterioration in the level of consciousness; hydrocephalus: reported, not defined Notes No definition on hydrocephalus other than ‘requiring shunting’ Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation Low risk Random number tables (selection bias) were used Allocation concealment (selection Low risk Consecutively-numbered bias) boxes were used and were administered in that order to included participants Blinding of participants and personnel Low risk Placebo was used as (performance bias) control and the trial code All outcomes was unbroken until the trial was finished Blinding of outcome assessment Low risk “The trial code was broken (detection bias) in May 1983, after all All outcomes events and outcomes had been recorded”

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Incomplete outcome data (attrition Low risk No incomplete data bias) All outcomes Selective reporting (reporting bias) Low risk Protocol was previously published Other bias Low risk Not suspected based on study design and outcome

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion Adams 1981 Comparative trial between antifibrinolytic agents and blood pressure reduction or fluid restriction Ameen 1981 Not a randomised trial; historic control group used Brzecki 1974 All participants received epsikapron, while being randomised between trasylol or placebo; also historical control group Buchner 1985 Not a randomised trial; historical control group Chowdhary 1979 Not strictly randomised; allocation to treatment or placebo according to days of the week Chowdhary 1981 Comparative trial between tranexamic acid and EACA Chowdhary 1986 No clinical outcome reported, only data on rebleeding and cerebral ischaemia Fodstad 1978 No ITT analysis possible; too many participants (14 of a of total 60 randomised) excluded from final analysis after randomisation Gelmers 1980 Not strictly randomised; allocation to treatment or placebo according to days of the week Gibbs 1971 Not a randomised trial; significant treatment differences, for instance concerning the timing of surgery, between the EACA-treated participants and the control group Kassell 1984 Not a randomised trial; case-control study Knuckey 1982 Not a randomised trial; case-control study Marchel 1992 Not a randomised trial; historic control group used Nibbelink 1975 Not a randomised trial, no control group Profeta 1975 Not a randomised trial; historic control group used Rosenorn 1988 Not a randomised trial; case-control study Salaschek 1983 Not a randomised trial; historical control group Sengupta 1976 Not a randomised trial; physicians preferred allocation Shucart 1980 Not a randomised trial; physicians preferred allocation Starke 2008 Not a randomised trial; case control study Wijdicks 1989 Not a randomised trial; case-control study with historical control group

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Characteristics of ongoing studies [ordered by study ID]

Verbaan 2012 Trial name or title Ultra-early tranexamic acid after subarachnoid hemorrhage: a prospective, randomised multicenter study Methods Multicentre study Random allocation Open treatment with blind endpoint assessment Intention-to-treat Participants Clinical diagnosis of aneurysmal SAH verified with CT with inclusion within 24 hours of start of symptoms Excluded: no loss of consciousness after the haemorrhage with WFNS grade 1 or 2 on admission with a perimesencephalic hemorrhage; bleeding pattern on CT compatible with a traumatic SAH; treatment for deep vein thrombosis; history of a blood coagulation disorder; pregnancy or breastfeeding; severe renal (serum creatinine > 150 mmol/L) or liver failure (AST > 150 U/L or ALT >150 U/L or AF > 150 U/L or gamma-GT > 150 U/L); imminent death within 24 hours 4 Interventions Standard treatment with addition of 1 g tranexamic acid intravenously in 10 minutes, immediately after the diagnosis SAH, succeeded by continuous infusion of 1 g per 8 hours until a maximum of 24 hours Outcomes Primary outcome: Modified Rankin Scale score dichotomised as a favourable (mRS 0 to 3) or unfavourable (mRS 4 to 6) outcome at six months after SAH Seconday: case fatality, cause of poor outcome, rebleeding rate, thromboembolic complications, delayed cerebral ischemia, other complications (hydrocephalus, thromboembolic events, extracranial thrombosis or haemorrhagic complications), care cost Starting date January 2013 Contact information [email protected] Notes CT: computed tomography SAH: subarachnoid haemorrhage WFNS: World Federation of Neurosurgical Societies

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REFERENCE LIST

References to studies included in this review Chandra 1978 {published data only} Chandra B. Treatment of subarachnoid hemorrhage from ruptured intracranial aneurysm with tranexamic acid: a double-blind clinical trial. Annals of Neurology 1978;3: 502-504. [MEDLINE: 1978233972] Fodstad 1981 {published data only} Fodstad H, Forssell A, Liliequist B, Schannong M. Antifibrinolysis with tranexamic acid in aneurysmal subarachnoid hemorrhage: a consecutive controlled clinical trial. Neurosurgery 1981;8: 158-165. [MEDLINE: 1981149180] Girvin 1973 {published and unpublished data} Girvin JP. The use of antifibrinolytic agents in the preoperative treatment of ruptured intracranial aneurysms. Transactions of the American Neurological Association 1973;98: 150- 152. [MEDLINE: 1974127393] Hillman 2002 {published data only} Hillman J, Fridriksson S, Nillson O, Yu Z, Saveland H, Jakobsson KE. Immediate administration of tranexamic acid and reduced incidence of early rebleeding after aneurysmal subarachnoid hemorrhage: a prospective randomized study. Journal of Neurosurgery 2002;97: 771-778. [MEDLINE: 12405362] Kaste 1979 {published data only} Kaste M, Ramsay M. Tranexamic acid in subarachnoid hemorrhage. A double-blind study. Stroke 1979;10: 519-522. [MEDLINE: 1980059548] Maurice 1978 {published data only} Maurice-Williams RS. Prolonged antifibrinolysis: an effective non-surgical treatment for ruptured intracranial aneurysms? British Medical Journal 1978;1: 945-947. [MEDLINE: 1978145585] Roos 2000a {published and unpublished data} Roos Y, for the STAR-study group. Antifibrinolytic treatment in aneurysmal subarachnoid haemorrhage: a randomized placebo-controlled trial. Neurology 2000;54: 77-82. [MEDLINE: 10636129] Tsementzis 1990 {published data only} Tsementzis SA, Hitchcock ER, Meyer CH. Benefits and risks of antifibrinolytic therapy in the management of ruptured intracranial aneurysms. A double-blind placebo-controlled study. Acta Neurochirurgica 1990;102: 1-10. [MEDLINE: 1990164043] Tsementzis SA, Honan WP, Nightingale S, Hitchcock ER, Meyer CH. Fibrinolytic activity after subarachnoid haemorrhage and the effect of tranexamic acid. Acta Neurochirurgica 1990;103: 116-21. Van Rossum 1977 {published data only} Van Rossum J, Wintzen AR, Endtz LJ, Schoen JH, de Jonge H. Effect of tranexamic acid on rebleeding after subarachnoid hemorrhage: a double-blind controlled clinical trial. Annals of Neurology 1977;2: 238-242. [MEDLINE: 1979081173] Vermeulen 1984 {published data only} Vermeulen M, Lindsay KW, Murray GD, Cheah F, Hijdra A, Muizelaar JP, et al. Antifibrinolytic treatment in subarachnoid hemorrhage. New England Journal of Medicine 1984;311: 432-437. [MEDLINE: 1984270539]

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References to studies excluded from this review Adams 1981 {published data only} Adams HP Jr, Nibbelink DW, Torner JC, Sahs AL. Antifibrinolytic therapy in patients with aneurysmal subarachnoid hemorrhage. A report of the cooperative aneurysm study. Archives of Neurology 1981;38: 25-29. [MEDLINE: 1981109034] Ameen 1981 {published data only} Ameen AA, Illingworth R. Anti-fibrinolytic treatment in the pre-operative management of subarachnoid haemorrhage caused by ruptured intracranial aneurysm. Journal of Neurology, Neurosurgery and Psychiatry 1981;44: 220-226. [MEDLINE: 1981193689] Brzecki 1974 {published data only} Brzecki A, Misztal S. Results of Trasylol treatment of subarachnoid hemorrhage [Wyniki leczenia Trasylolem krwotoku podpajeczynowkowego]. Polski Tygodnik Lekarski 1974;29(2): 53-55. [MEDLINE: 4595123] Buchner 1985 {published data only} Buchner H, Hacke W, Kugel I, Zeumer H, Ferbert A. Antifibrinolytic therapy following an aneurysmal subarachnoid hemorrhage [Antifibrinolytika in der konservativen Therapie der aneurysmatischen Subarachnoidalblutung]. Intensivmed 1985;22: 424-427. Chowdhary 1979 {published data only} 4 Chowdhary UM, Carey PC, Hussein MM. Prevention of early recurrence of spontaneous subarachnoid haemorrhage by epsilon-aminocaproic acid. Lancet 1979;1:741-743. [MEDLINE: 1979155678] Chowdhary 1981 {published data only} Chowdhary UM, Sayed K. Comparative clinical trial of epsilon amino-caproic acid and tranexamic acid in the prevention of early recurrence of subarachnoid haemorrhage. Journal of Neurology, Neurosurgery and Psychiatry 1981;44:810-3. [MEDLINE: 1982077145] Chowdhary 1986 {published data only} Chowdhary UM, Sayed K. Prevention of early recurrence of aneurysmal subarachnoid haemorrhage by tranexamic acid: a controlled clinical trial. Vascular Surgery 1986;1: 8-13. [EMBASE: 1986195828] Fodstad 1978 {published data only} Fodstad H, Liliequist B, Schannong M, Thulin CA. Tranexamic acid in the preoperative management of ruptured intracranial aneurysms. Surgical Neurology 1978;10:9-15. [MEDLINE: 1978250737] Gelmers 1980 {published data only} Gelmers HJ. Prevention of recurrence of spontaneous subarachnoid haemorrhage by tranexamic acid. Acta Neurochirurgica 1980;52: 45-50. [MEDLINE: 1980194959] Gibbs 1971 {published data only} Gibbs JR, Corkill AG. Use of an anti-fibrinolytic agent (tranexamic acid) in the management of ruptured intracranial aneurysms. Postgraduate Medical Journal 1971;47: 199-200. [MEDLINE: 1971190989] Kassell 1984 {published data only} Kassell NF, Torner JC, Adams HP. Antifibrinolytic therapy in the acute period following aneurysmal subarachnoid hemorrhage. Preliminary observations from the Cooperative Aneurysm Study. Journal of Neurosurgery 1984;61: 225-230. [MEDLINE: 6737046] Knuckey 1982 {published data only} Knuckey NW, Stokes BA. Medical management of patients following a ruptured cerebral aneurysm, with epsilon-aminocaproic acid, kanamycin, and reserpine. Surgical Neurology 1982;17: 181-185. [MEDLINE: 7079936] Marchel 1992 {published data only} Marchel A. Antifibrinolytic treatment after subarachnoid hemorrhage. Neurologia i Neurochirurgia Polska 1992;26: 502-510. [MEDLINE: 1993133362]

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Nibbelink 1975 {published data only} Nibbelink DW, Torner JC, Henderson WG. Intracranial aneurysms and subarachnoid hemorrhage. A cooperative study. Antifibrinolytic therapy in recent onset subarachnoid hemorrhage. Stroke 1975;6: 622-629. [MEDLINE: 1976082089] Profeta 1975 {published data only} Profeta G, Castellano F, Guarnieri L, Cigliano A, Amborsio A. Antifibrinolytic therapy in the treatment of subarachnoid haemorrhage caused by arterial aneurysms. Journal of Neurosurgical Sciences 1975;19:77-78. [MEDLINE: 1976145501] Rosenorn 1988 {published data only} Rosenorn J, Eskesen V, Espersen JO, Haase J, Schmidt K. Antifibrinolytic therapy in patients with aneurysmal subarachnoid haemorrhage. British Journal of Neurosurgery 1988;2:447-453. [MEDLINE: 3267328] Salaschek 1983 {published data only} Salaschek M, Weinrich W. Epsilon aminocaproic acid (FACA) in the treatment of spontaneous subarachnoid haemorrhage [Antifibrinolytische behandlung spontaner subarachnoidalblutungen mit epsilon-aminocapronaure]. Aktuelle Neurologie 1983;10: 65- 68. [EMBASE: 1983183434] Sengupta 1976 {published data only} Sengupta RP, So SC, Villarejo Ortega FJ. Use of epsilon aminocaproic acid (EACA) in the preoperative management of ruptured intracranial aneurysms. Journal of Neurosurgery 1976;44: 479-484. [MEDLINE: 1976145471] Shucart 1980 {published data only} Shucart WA, Hussain SK, Cooper PR. Epsilon-aminocaproic acid and recurrent subarachnoid hemorrhage: a clinical trial. Journal of Neurosurgery 1980;53: 28-31. [MEDLINE: 1981008738] Starke 2008 {published data only} Starke RM, Kim GH, Fernandez A, Komotar RJ, Hickman ZL, Otten ML, et al. Impact of a protocol for acute antifibrinolytic therapy on aneurysm rebleeding after subarachnoid hemorrhage. Stroke 2008;39: 2617-2621. [MEDLINE: 18658042] Wijdicks 1989 {published data only} Wijdicks EF, Hasan D, Lindsay KW, Brouwers PJ, Hatfield R, Murray GD, et al. Short-term tranexamic acid treatment in aneurysmal subarachnoid hemorrhage. Stroke 1989;20: 1674- 1679. [MEDLINE: 2595729]

References to ongoing studies Verbaan 2012 {published data only} Verbaan D. Ultra-early tranexamic acid after subarachnoid hemorrhage. Netherlands Trial Register 2012.

Additional references Adams 1982 Adams HP. Current status of antifibrinolytic therapy for treatment of patients with aneurysmal subarachnoid hemorrhage. Stroke 1982;13: 256-259. [MEDLINE: 7039006] Adams 1987 Adams HP. Antifibrinolytics in aneurysmal subarachnoid hemorrhage. Do they have a role? Maybe. Archives of Neurology 1987;44: 114-115. [MEDLINE: 3800711] Biller 1988 Biller J, Godersky JC, Adams HP. Management of aneurysmal subarachnoid hemorrhage. Stroke 1988;19: 1300-1305. [MEDLINE: 3176090] Carley 2005 Carley S, Sen A. Best evidence topic report. Antifibrinolytics for the initial management of sub arachnoid haemorrhage. Emergency Medicine Journal 2005;22: 274-275. [MEDLINE: 15788831]

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Chawjol 2008 Chawjol M, Starke RM, Kim GH, Majer SA, Connolly ES. Antifibrinolytic therapy to prevent early rebleeding after subarachnoid hemorrhage. Neurocritical Care 2008;8: 418-426. [MEDLINE: 18386187] Connolly 2012 Connolly ES, Rabinstein AA, Carhuapoma JR, Derdeyn CP, Dion J, Higashida RT, 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: 1711-1737. [MEDLINE: 22556195] Fodstad 1982 Fodstad H. Antifibrinolytic treatment in subarachnoid haemorrhage: present state. Acta Neurochirurgica 1982;63: 233-244. [MEDLINE: 1982253415] Gaberel 2012 Gaberel T, Magheru C, Emery E, Derlon J. Antifibrinolytic therapy in the management of aneurismal subarachnoid hemorrhage revisited. A meta-analysis. Acta Neurochirurgica 2012;154: 1-9. [MEDLINE: 22002504] Gibbs 1967 Gibbs JR, O’Gorman P. Fibrinolysis in subarachnoid haemorrhage. Postgraduate Medical Journal 1967;43(506): 779-784. [MEDLINE: 1968120575] 4 Guo 2011 Guo L, Zhou H, Xu J, Wang Y, Qiu Y, Jiang J. Risk factors related to aneurysmal rebleeding. World Neurosurgery 2011;76: 292-298. [MEDLINE: 21986427] Harrigan 2010 Harrigan MR, Rajneesh KF, Ardelt AA, Fisher WS. Short-term antifibrinolytic therapy before early aneurysm treatment in subarachnoid hemorrhage: effects on rehemorrhage, cerebral ischemia, and hydrocephalus. Neurosurgery 2010;67: 935-939. [MEDLINE: 20881558] Higgins 2011 Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www. cochrane-handbook.org. Lindsay 1987 Lindsay KW. Antifibrinolytic agents in subarachnoid haemorrhage. Journal of Neurology 1987;234: 1-8. [MEDLINE: 1987140160] Locksley 1966 Locksley HB. Natural history of subarachnoid hemorrhage, intracranial aneurysms and arteriovenous malformations. Journal of Neurosurgery 1966;25: 321-368. [MEDLINE: 1967021605] Maira 2006 Maira G, Albanese A, Pentimalli L, Tirpakova B. Treatment of intracranial aneurysms. Clinical and Experimental Hypertension 2006;28: 371-376. [MEDLINE: 16833048] Mayberg 1994 Mayberg MR, Batjer HH, Dacey R, Diringer M, Haley EC, Heros RC, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage. A statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Circulation 1994;90: 2592-2605. [MEDLINE: 7955232] Naidech 2005 Naidech AM, Janjua N, Kreiter KT, Ostapkovich ND, Fitzsimmons BF, Parra A, et al. Predictors and impact of aneurysm rebleeding after subarachnoid hemorrhage. Archives of Neurology 2005;62: 410-416. Ramirez 1981 Ramirez-Lassepas M. Antifibrinolytic therapy in subarachnoid hemorrhage caused by ruptured intracranial aneurysm. Neurology 1981;31: 316-322. [MEDLINE: 1981149246]

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RevMan 2012 The NordicCochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). 5.2. Copenhagen: The NordicCochrane Centre, The Cochrane Collaboration, 2012. Rinkel 2008 Rinkel GJ. Medical management of patients with aneurysmal subarachnoid haemorrhage. International Journal of Stroke 2008;3: 193-204. [MEDLINE: 18705899] Roos 2000b Roos YB, de Haan RJ, Beenen LF, Groen RJ, Albrecht KW, Vermeulen M. Complications and outcome in patients with aneurysmal subarachnoid haemorrhage: a prospective hospital based cohort study in the Netherlands. Journal of Neurology, Neurosurgery and Psychiatry 2000;68: 337-341. [MEDLINE: 10675216] Van Gijn 2001 Van Gijn J, Rinkel GJ. Subarachnoid haemorrhage: diagnosis, causes and management. Brain 2001;124: 249-278. [MEDLINE: 11157554] Van Gijn 2007 Van Gijn J, Kerr RS, Rinkel GJ. Subarachnoid haemorrhage. Lancet 2007;369: 306-318. [MEDLINE: 17258671; : ] Vermeulen 1980 Vermeulen M, Muizelaar JP. Do antifibrinolytic agents prevent rebleeding after rupture of a cerebral aneurysm? A review. Clinical Neurology and Neurosurgery 1980;82: 25-30. [MEDLINE: 1981112901] Vermeulen 1983 Vermeulen M, van Gijn J, Blijenberg BG. Spectrophotometric analysis of CSF after subarachnoid hemorrhage: limitations in the diagnosis of rebleeding. Neurology 1983;33: 112-114. [MEDLINE: 1983089354] Vermeulen 1996 Vermeulen M. Subarachnoid haemorrhage: diagnosis and treatment. Journal of Neurology 1996;243: 496-501. [MEDLINE: 8836937] Weaver 1994 Weaver JP, Fisher M. Subarachnoid hemorrhage: an update of pathogenesis, diagnosis and management. Journal of the Neurological Sciences 1994;125: 119-131. [MEDLINE: 7807157] Weir 1987 Weir B. Antifibrinolytics in subarachnoid hemorrhage. Do they have a role? No. Archives of Neurology 1987;44:116-118. [MEDLINE: 3800712]

References to other published versions of this review Roos 1998 Roos YB, Vermeulen M, Rinkel GJ, Algra A, Van Gijn J, Algra A. Systematic review of antifibrinolytic treatment in aneurysmal subarachnoid haemorrhage. Journal of Neurology, Neurosurgery and Psychiatry 1998;65: 942-943. [MEDLINE: 9854979] Roos 2003 Roos YB, Rinkel GJE, Vermeulen M, Algra A, van Gijn J. Antifibrinolytic therapy for aneurysmal subarachnoid haemorrhage. Cochrane Database of Systematic Reviews 2003, Issue 2. [DOI: 10.1002/14651858.CD001245]

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Chapter 5

Ultra-early tranexamic acid after subarachnoid hemorrhage (ULTRA): study protocol for a randomized controlled trial

M.R. Germans, MD R. Post, MD B.A. Coert, MD, PhD G.J.E. Rinkel, MD, PhD W.P. Vandertop, MD, PhD D. Verbaan, PhD

Trials (2013) 14: 143 Chapter 5

ABSTRACT

Introduction: A frequent complication in patients with subarachnoid hemorrhage (SAH) is a recurrent bleeding from the aneurysm. The risk is highest within the first six hours after the initial hemorrhage. Securing the aneurysm within this timeframe is difficult due to logistical delays. The rate of recurrent bleeding can also be reduced by ultra-early administration of antifibrinolytics, which probably improves functional outcome. The aim of this study is to investigate whether ultra-early and short-term administration of the antifibrinolytic agent tranexamic acid (TXA), as add-on to standard SAH management, leads to better functional outcome.

Methods/design: This is a multicenter, prospective, randomized open-label trial with blinded endpoint assessment (PROBE-design). Adult patients with the diagnosis of non-traumatic SAH, as proven by CT within 24 hours after the onset of headache, are randomly assigned to the treatment group or the control group. Patients in the treatment group receive standard treatment with addition of a bolus of 1 gram TXA intravenously immediately after randomization, followed by continuous infusion of 1 gram per eight hours until start of aneurysm treatment, or a maximum of 24 hours after start of medication. Patients in the control group receive standard treatment without TXA. The primary outcome measure is favourable functional outcome, defined as a score of 0-3 on the modified Rankin Scale, at six months after SAH. Primary outcome will be determined by a trial nurse blinded for treatment allocation. We aim to include 950 patients in three years.

Discussion: Strengths of this study are 1) the ultra-early and short-term administration of TXA, resulting in a lower dose as compared to previous studies, should reduce the risk for delayed cerebral ischemia (DCI), which is an important risk factor in the long-term treatment with antifibrinolytics; 2) the power calculation is based on functional outcome and calculated with use of recent study results of our own population, supported by data from prominent studies; 3) the participation of several specialized SAH centers, and their referring hospitals, in the Netherlands with comparative treatment protocols.

Trial Registration: Start of study will be in April 2013. Nederlands Trial Register (Dutch Trial Registry) number NTR3272.

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INTRODUCTION

Subarachnoid hemorrhage (SAH) from a ruptured aneurysm occurs in relatively young patients (mean age 55 years) and accounts for 5% of all strokes, with an incidence of about 9 per 100.000 person-years1, 2. The case fatality rate is approximately 35%, 25% of the survivors has a favourable outcome, and only a small group recovers completely3. A frequent complication in patients with a SAH is a recurrent bleeding from the aneurysm, which happens primarily within the first few hours after the initial hemorrhage and occurs in 10-22% of patients who present to a hospital4-9. Besides the primary hemorrhage, recurrent bleeding is still one of the major causes of death and disability10. Rebleeding can be prevented by early aneurysm occlusion, but in daily clinical practice, treatment is often delayed by logistical factors, such as delay in diagnosis or transfer between hospitals11-13. Therefore, early aneurysm treatment alone is not sufficient to prevent all recurrent bleedings, and other strategies have to be explored. An alternative to reduce the risk of rebleeding 5 is the administration of an antifibrinolytic agent, which slows down the breakdown of the blood clot, prior to aneurysm occlusion14. Long-term administration of antifibrinolytics has been found to effectively reduce the risk of recurrent bleeding by approximately 40%, but patient outcome was not improved due to a concurrent increase in delayed cerebral ischemia (DCI)14. Recent studies using early and short-term antifibrinolytic therapy have also shown reduction of recurrent rebleeding but without an increase in DCI7, 8, 14, 15. However, the only randomized controlled trial (RCT) that was performed was underpowered to show an effect on functional outcome7. The aim of this RCT is therefore, to investigate whether treatment with ultra- early and short-term administration of the antifibrinolytic agent tranexamic acid (TXA), as add-on to standard, state-of-the-art SAH management leads to a significantly higher percentage of patients with a favourable functional outcome, defined as a score of 0 to 3 on the modified Rankin Scale (mRS), assessed at six months after SAH.

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METHODS/DESIGN

Design The ULtra-early TRAnexamic acid after subarachnoid hemorrhage (ULTRA) study is performed as a multicenter, prospective, randomized open-label trial with blinded endpoint assessment (PROBE design).

Setting The protocol of this study was approved by the Medical Ethics Committee (MEC) of the Academic Medical Center, Amsterdam (AMC). It is registered at the Nederlands Trial Register (Dutch Trial Registry) under number NTR3272. At the start of the study in April 2013, a total of 26 participating hospitals, including three specialized SAH centers (from now on called study centers) and their referring hospitals, will start randomization for the ULTRA-study. It is expected that four additional study centers and their referring hospitals will start randomization in the near future.

Participants All patients presenting with a proven SAH are checked for eligibility by the treating physician. Inclusion criteria: adult patients (≥ 18 years) with the diagnosis SAH as proven by CT within 24 hours after the last hemorrhage. Exclusion criteria are 1) no loss of consciousness after the hemorrhage with World Federation of Neurological Surgeons (WFNS) grade 1 or 2 on admission in combination with a perimesencephalic bleeding pattern; 2) history and bleeding pattern on CT compatible with a traumatic SAH; 3) ongoing treatment for deep vein thrombosis or pulmonary embolism; 4) history of a hypercoagulability disorder; 5) pregnancy; 6) severe renal (serum creatinin >150 mmol/L) or liver (AST > 150 U/l or ALT > 150 U/l or AF > 150 U/l or γ-GT > 150 U/l) failure; 7) expected death within 24 hours; 8) participation in another SAH intervention study.

Randomization On-line randomization will be performed by the treating physician in the study center using permuted blocks and with stratification by study center (i.e. equal number of patients in both study arms at each study center).

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Interventions All participating patients are treated according to state-of-the-art SAH management, comparable with recent published international guidelines2, 16. Subjects with CT-confirmed SAH who are randomly assigned to the treatment group receive additional administration of TXA. This treatment consists of a bolus of TXA (1 gram i.v.) as soon as possible after randomisation (also at the referring hospital when applicable), continued by continuous infusion of 1 gram per eight hours, until a maximum of 24 hours after start of medication. If aneurysm treatment is initiated within 24 hours after the TXA-bolus, the medication infusion will be discontinued at the time-out procedure before start of the aneurysm treatment (endovascular or surgical). The continuous infusion of the study medication will be cancelled immediately if, after inclusion 1) no aneurysm appears to be present on CT-angiography (CT-a) and/or Digital Subtraction Angiography (DSA); 2) other intracranial pathology than an aneurysm is responsible for the SAH; or 3) the aneurysm which is visualised is not held responsible for the hemorrhage, based on the bleeding pattern on CT. 5 Patients randomly assigned to the control group do not receive TXA treatment. The procedures which are performed during the study are outlined in figure 1.

Consent procedure As this study evaluates the impact of a treatment initiated as soon as possible in an emergency situation, and because a major part of the patients will not be able to give informed consent at admission, the informed consent procedure for this study will be delayed in a so-called ‘emergency-procedure’. For patients who are randomized for TXA administration, the medication will be administrated as soon as possible after randomization. Information about the study will be given to the patients or their legal representatives as soon as possible in the study center. Permission will be asked about participation in the study by signing an “informed consent”. If patients or legal representatives decline to participate, study medication will be stopped immediately (if randomized for treatment and TXA is still administered) and the patient will be excluded from the study.

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Fig. 1 Flow chart of procedures

Primary outcome The primary endpoint, defined as a favourable functional outcome on the modified Rankin Scale17 (mRS score 0-3), is assessed at six months after the SAH by a trial nurse who is blinded for treatment allocation during a standardized, validated telephone interview18.

Secondary outcomes Secondary outcome measures are: case fatality rate, cause of poor outcome, rebleeding rate, complication rate (including delayed ischemic stroke, thromboembolic events, hydrocephalus, extracranial thrombosis or hemorrhagic complications), discharge location, (micro)infarctions on MR imaging at six months after endovascular treatment, quality of life at six months

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after SAH (with EQ-5D questionnaire19) and health-care use and health-care related costs until six months after SAH.

Sample size calculation The primary endpoint analysis of this study is based on the difference in percentage of patients with favourable outcome (mRS score 0-3) at six months after SAH between patients with and without TXA treatment. This expected difference between the TXA and control group was estimated with the results of renowned SAH studies and our own data (293 consecutive aneurysmal SAH patients, added with angiogram-negative SAH patients, treated in the AMC between 2008 and 2011): The percentage of SAH patients (including angiogram-negative patients) who reach the hospital have a favourable outcome in 69% (own data), and the rebleeding rate is 17%, which is consistent with numbers reported in previous studies (11%-22%)6-8. Of patients with a recurrent bleeding, an estimated 20% will have a favourable 5 outcome (0.17*0.20= 3.4% of the total control group). Consequently, the percentage of patients with a favourable outcome in patients without a recurrent bleeding is 79% (total of patients without a recurrent bleeding with a favourable outcome: 69-3.4= 65.6%; total of patients without a recurrent bleeding: 100-17=83%; 65.6/83= 0.79). In the TXA group, the reduction in recurrent bleeding is expected to be 77%7, 8(Hillman et al. 771-78;Starke et al. 2617-21), which reduces the rate of rebleeding to 3.9% (0.17*0.77= 13.1%; 17%-13.1%= 3.9%). Furthermore, TXA is anticipated to improve the percentage of favourable outcome in patients with a recurrent bleeding from 20% to 30%7. Therefore, in the TXA group, 3.9% will have a recurrent bleeding, of which 30% will have a favourable outcome (0.039*0.3= 1.2% of the total TXA group). Patients without a recurrent bleeding will have a favourable outcome in 79%, which is 75.9% of the total TXA group (total of patients without a recurrent bleeding: 100-3.9=96.1; 0.961*0.79=75.9%). In the TXA group, the total of patients with a favourable outcome is 77.1% (75.9%+1.2%). Based on these assumptions it is expected that TXA administration will increase the proportion of patients with a favourable outcome from 69% to 77.1%. A two group Chi-square test with a 0.05 two- sided significance level will have 80% power to detect the difference between a control group proportion of 0.69 and a treatment group proportion of 0.771

115 Chapter 5

(odds ratio of 1.513) when the sample size in each group is 470 (940 patients in total). The plan is to include a total of 950 patients. The aim is to include these patients within 3 years. Analysis of the results is planned in 2016.

Statistical analysis The statistical analysis will be by intention-to-treat. The occurrence of the primary outcome, mRS score 0-3 at six months, will be compared between the two randomization groups. The secondary outcome analyses compare the above described variables between randomization groups. Subgroup analyses will be performed to evaluate whether rate of recurrent bleeding and percentage of favourable outcome differ between gender and groups with different WFNS grade at admission. Subsequently, the association between favourable outcome and time interval from last hemorrhage to first TXA administration will be evaluated. Group differences for continuous variables will be calculated using an independent T-test for continuous variables with a parametric distribution or Mann-Whitney U test for continuous variables with a non-parametric distribution. Group differences for categorical variables will be calculated using chi-square statistics. Chi-square statistics will be used to calculate an odds ratio, risk ratio, or risk difference. Adjustments for factors that differ at randomization will be made using regression or multi-level models. A p-value <0.05 will be considered significant. For the cost-effectiveness analysis, the mRS score at six months is the effect measure. The costs during admission and the costs from discharge to six months after SAH are summed up resulting in one value for overall direct and indirect costs. The incremental cost-effectiveness ratio and its 95% CI will be estimated with bootstrapping.

Data safety analysis An interim analysis will be performed by a Data Safety Monitoring Board (DSMB) when half of the patients (n=475) are enrolled. In this analysis unblinded data are assessed and the DSMB can advise to adjust the conduct, design or sample size, or to terminate the study according to predefined stopping rules. These are, 1) clear evidence that TXA administration is harmful for the patients, or 2) superiority in functional outcome (mRS 0-3) in the treatment group after six months, evaluated with the Peto analysis20 with a p-value of 0.001.

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DISCUSSION

Antifibrinolytic therapy after aneurysmal SAH reduces rebleeding by approximately 40%14, but outcome is not improved, due to a concurrent increase in DCI. Recent studies of early, short-term antifibrinolytic therapy have shown better results, with a tendency for improved functional outcome, but were judged to be biased and in case of the only RCT, underpowered7, 8, 15. These results raise the expectation that a reduction of rebleeding without an increase of DCI will improve functional outcome at six months. We have developed an RCT for ultra-early and short-term treatment with TXA, with the sample size calculation based on the expected improvement in functional outcome. Our study has several strengths: TXA can be administrated as soon as possible after randomization since the emergency procedure for delayed informed consent is used in this study; the risk for DCI is reduced to a minimum by the short-term and low total dose TXA. In addition, our dosing regimen is 5 considered safe because the maximum dose is lower than in previous studies and administration regimen in concordance with the CRASH-2 trial21; the power calculation is based on functional outcome and calculated with use of recent study results of our own population, supported by data from prominent studies; a significant proportion of the ten specialized SAH centers throughout The Netherlands, including their referring hospitals, is willing to participate; and both coordinating centers (AMC and University Medical Center Utrecht (UMCU)) are experienced in coordinating clinical trials in SAH. There are some limitations in our protocol: firstly, patients and personnel are not blinded for treatment allocation, which could potentially lead to a detection bias. However, because of the PROBE design the assessor of the primary endpoint is blinded for treatment allocation, which prevents detection bias. Secondly, the maximum duration of TXA administration will be 24 hours. Theoretically, this could be too short for those patients who are treated later than 24 hours after the diagnosis. The risk for a rebleeding however, is strongly decreased after 24 hours6, and the antifibrinolytic function of TXA in blood serum remains for 7-8 hours when several doses have been given. In addition, our own data (not shown) show that 74% of patients are treated within 24 hours, with a median time of 18 hours. So, with the early aneurysm treatment nowadays, low risk for rebleeding after 24 hours and remaining antifibrinolytic

117 Chapter 5

function, we expect to expose patients to a minimal risk for rebleeding when terminating TXA therapy after a maximum of 24 hours. In conclusion, we have developed a protocol for a randomized, open-label study with administration of TXA in SAH patients. In contrast with earlier studies the treatment will start ultra-early to reduce as many recurrent bleedings as possible and treatment will be continued to a maximum of 24 hours to prevent an increase in DCI. Because functional outcome assessed at six months is taken as the primary endpoint, this study will provide an answer whether an increase of favourable outcome can be reached in patients with ultra-early and short- term TXA treatment after SAH.

TRIAL COMMITTEES Executive committee D. Verbaan, Ph.D. (PI, clinical epidemiologist, AMC), M.R. Germans, M.D. (study coordinator (SC), AMC), B.A. Coert, M.D., Ph.D. (SC, AMC), R. Post, M.D. (SC, AMC), prof. W.P. Vandertop, M.D. (PI, AMC, VUMC), prof. G.J.E. Rinkel, M.D. (PI, UMCU), N.M. Fleitour (trial nurse).

Steering committee D. Verbaan, clinical epidemiologist (AMC), M.R. Germans, neurosurgeon (AMC), B.A. Coert, neurosurgeon (AMC), R. Post, resident neurosurgery (AMC), prof. W.P. Vandertop, neurosurgeon (AMC, VUMC), Y.B.W.E.M. Roos, neurologist (AMC), R. van den Berg, neuroradiologist (AMC), prof. C.B.L.M. Majoie, neuroradiologist (AMC), J. Horn, neurointensivist (AMC), prof. G.J.E. Rinkel, neurologist (UMCU). New members may be added if more centers join the study.

Data Safety Monitoring Board Prof. B.M.J. Uitdehaag, clinical neuroepidemiologist (VUMC), prof. A.R.J. Girbes, intensivist (VUMC), N. van Geloven, statistician (AMC)

Statistical analysis D. Verbaan, clinical epidemiologist (AMC), M.R. Germans, neurosurgeon (AMC), R. Post, resident neurosurgery (AMC), prof. R.J. de Haan, clinical epidemiologist (AMC).

Trial status The study start date is 15 May 2013. The estimated study duration will be three years.

Funding This project is funded by Fonds NutsOhra (project number 1202-031).

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REFERENCE LIST

(1) de Rooij NK, Linn FH, van der Plas JA, Algra A, Rinkel GJ. Incidence of subarachnoid haemorrhage: a systematic review with emphasis on region, age, gender and time trends. J Neurol Neurosurg Psychiatry 2007 December;78(12):1365-72. (2) Steiner T, Juvela S, Unterberg A, Jung C, Forsting M, Rinkel G. European Stroke Organization Guidelines for the Management of Intracranial Aneurysms and Subarachnoid Haemorrhage. Cerebrovasc Dis 2013 February 7;35(2):93-112. (3) Wermer MJ, Kool H, Albrecht KW, Rinkel GJ. Subarachnoid hemorrhage treated with clipping: long-term effects on employment, relationships, personality, and mood. Neurosurgery 2007 January;60(1):91-7. (4) Beck J, Raabe A, Szelenyi A, Berkefeld J, Gerlach R, et al. Sentinel headache and the risk of rebleeding after aneurysmal subarachnoid hemorrhage. Stroke 2006 November;37(11):2733-7. (5) Brisman JL, Song JK, Newell DW. Cerebral aneurysms. N Engl J Med 2006 August 31;355(9):928-39. (6) Guo LM, Zhou HY, Xu JW, Wang Y, Qiu YM, Jiang JY. Risk factors related to aneurysmal rebleeding. World Neurosurg 2011 September;76(3-4):292-8. (7) Hillman J, Fridriksson S, Nilsson O, Yu Z, Saveland H, Jakobsson KE. Immediate administration of tranexamic acid and reduced incidence of early rebleeding after aneurysmal subarachnoid hemorrhage: a prospective randomized study. J Neurosurg 2002 October;97(4):771-8. (8) Starke RM, Kim GH, Fernandez A, Komotar RJ, Hickman ZL, et al. Impact of a protocol for acute antifibrinolytic therapy on aneurysm rebleeding after subarachnoid hemorrhage. Stroke 2008 September;39(9):2617-21. (9) Starke RM, Connolly ES, Jr. Rebleeding After Aneurysmal Subarachnoid Hemorrhage. Neurocrit 5 Care 2011 October;15(2):241-6. (10) Roos YB, Beenen LF, Groen RJ, Albrecht KW, Vermeulen M. Timing of surgery in patients with aneurysmal subarachnoid haemorrhage: rebleeding is still the major cause of poor outcome in neurosurgical units that aim at early surgery. J Neurol Neurosurg Psychiatry 1997 October;63(4):490-3. (11) Laidlaw JD, Siu KH. Ultra-early surgery for aneurysmal subarachnoid hemorrhage: outcomes for a consecutive series of 391 patients not selected by grade or age. J Neurosurg 2002 August;97(2):250-8. (12) Phillips TJ, Dowling RJ, Yan B, Laidlaw JD, Mitchell PJ. Does treatment of ruptured intracranial aneurysms within 24 hours improve clinical outcome? Stroke 2011 July;42(7):1936-45. (13) Lamb JN, Crocker M, Tait MJ, Anthony BB, Papadopoulos MC. Delays in treating patients with good grade subarachnoid haemorrhage in London. Br J Neurosurg 2011 April;25(2):243-8. (14) Roos YB, Rinkel GJ, Vermeulen M, Algra A, van Gijn J. Antifibrinolytic therapy for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev 2003;(2):CD001245. (15) Gaberel T, Magheru C, Emery E, Derlon JM. Antifibrinolytic therapy in the management of aneurismal subarachnoid hemorrhage revisited. A meta-analysis. Acta Neurochir (Wien ) 2011 October 15. (16) Connolly ES, Jr., Rabinstein AA, Carhuapoma JR, Derdeyn CP, Dion J, 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 June;43(6):1711-37. (17) Rankin J. Cerebral vascular accidents in patients over the age of 60. II. Prognosis. Scott Med J 1957 May;2(5):200-15. (18) Janssen PM, Visser NA, Dorhout Mees SM, Klijn CJ, Algra A, Rinkel GJ. Comparison of telephone and face-to-face assessment of the modified Rankin Scale. Cerebrovasc Dis 2010 January;29(2):137-9. (19) Ronne-Engstrom E, Enblad P, Lundstrom E. Outcome after spontaneous subarachnoid hemorrhage measured with the EQ-5D. Stroke 2011 November;42(11):3284-6. (20) Schulz KF, Grimes DA. Multiplicity in randomised trials II: subgroup and interim analyses. Lancet 2005 May 7;365(9471):1657-61. (21) Roberts I, Perel P, Prieto-Merino D, Shakur H, Coats T, et al. Effect of tranexamic acid on mortality in patients with traumatic bleeding: prespecified analysis of data from randomised controlled trial. BMJ 2012;345:e5839.

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Part 2

Evaluation of the spinal axis in non-aneurysmal subarachnoid hemorrhage

Chapter 6

Spinal vascular malformations in non-perimesencephalic subarachnoid hemorrhage

M.R. Germans, MD F.A. Pennings, MD, PhD M.E.S. Sprengers, MD, PhD W.P. Vandertop, MD, PhD

Journal of Neurology (2008) 255(12): 1910-1915 Chapter 6

ABSTRACT

Introduction: In patients with non-traumatic subarachnoid hemorrhage (SAH) and no evidence for a cerebral aneurysm on angiography, a frequent cause of the hemorrhage is perimesencephalic hemorrhage or other cerebral vascular pathology. In some patients no cause is found. The exact incidence of a spinal vascular malformation (SVM) as the origin for the SAH is not known. We assessed the occurrence of SVM in angiogram-negative non-perimesencephalic subarachnoid hemorrhage (NPSAH).

Methods: 47 patients (from a consecutive cohort of 632) were identified with an angiogram-negative, non-perimesencephalic subarachnoid hemorrhage and 42 of these were analysed by performing MR-imaging of the complete spinal neuraxis with additional spinal angiography on indication.

Results: In four patients a spinal vascular malformation was identified as the cause of the SAH, indicating an incidence of 9% of SVM in NPSAH, and an incidence of 1% of SVM in all patients with SAH.

Conclusions: Systematic analysis of angiogram-negative, non- perimesencephalic subarachnoid hemorrhage by MR-imaging of the complete spinal neuraxis yields a higher incidence of SVM than previously documented. We recommend MR-imaging of the complete spinal neuraxis in patients with a non-perimesencephalic subarachnoid haemorrhage in whom no cause for the hemorrhage has been found.

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INTRODUCTION

Acute non-traumatic subarachnoid hemorrhage (SAH) is most frequently caused by a ruptured saccular aneurysm. However, in an overall mean of 15%1-7, an initial cerebral angiography fails to demonstrate an aneurysm: the “angiogram- negative SAH”8. A consistent part of this group, about two thirds, can be ascribed to a so-called perimesencephalic hemorrhage, which generally has a good clinical outcome6. In the remaining patients with a non-perimesencephalic angiogram-negative SAH, complications as in aneurysmal SAH such as rebleed, hydrocephalus and symptoms of focal ischemia8, 9 are known to occur, suggesting that another, less benign, cause for the hemorrhage could be present. In these patients therefore, efforts have to be made to rule out every possible cause, such as an initially not visualised aneurysm (e.g. due to an intramural thrombus or compression by an intraparenchymal hematoma), vertebral or carotid artery dissection, brain arteriovenous malformation (bAVM), trauma, mycotic aneurysm, vasculitis, pregnancy-induced hypertension, cocaine abuse, sickle cell disease, coagulation disorders/anticoagulant use, pituitary apoplexy and spinal vascular malformations (SVM)8, 10. Some of these causes can only be diagnosed with additional evaluation, such as laboratory investigations, a second cerebral 6 angiography or MR-imaging of the complete neuraxis. The incidence of spinal vascular malformations (SVM) as a cause of SAH is unknown and remains largely anecdotal6, 11-24 25-31. Short and long term complications, such as rebleed, spinal cord edema and hydrocephalus can be quite significant32. To determine the incidence of SVM in angiogram-negative, non- perimesencephalic SAH (NPSAH), we retrospectively reviewed our experience with this rare phenomenon.

METHODS

Patient population From January 2000 to December 2007, 632 patients with a SAH, verified by computed tomography or a positive lumbar puncture, were admitted to the department of Neurosurgery of the Academic Medical Center (Amsterdam, The Netherlands). Of these, 20 patients were excluded because of a traumatic

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cause (18 cases) or pituitary apoplexy (2 cases), and in 16 patients no diagnostic angiography was performed at all. The remaining 596 patients with a spontaneous SAH were eligible for further analysis.

Study protocol Based on the first angiography (four-vessel cerebral angiography including both posterior inferior cerebellar arteries), patients were divided into three groups as to the cause of their SAH: 1) aneurysmal origin (n=478), 2) arterial dissection (n=9; with two times a dissection in combination with an aneurysm) or brain AVM (n=7) and 3) angiogram-negative SAH (n=104). In this last group, cases with a perimesencephalic bleeding pattern on computed tomography in combination with a compatible history and physical examination were called perimesencephalic SAH. This group contained 57 patients (55% of angiogram- negatives; 10% of all spontaneous SAH). Because of the known favourable prognosis, these were excluded from additional investigations to detect a cause for the hemorrhage. The remaining 47 angiogram-negative cases (mean age 53.0 years (95% CI 49.0-57.0), M:F 19:28) form the basis of this study and are called NPSAH. In this group, second cerebral angiography, additional MR-imaging of the spinal neuraxis and, in selected cases, spinal angiography were performed (table 1).

Case reports The patients with an SVM are described shortly with respect to clinical characteristics, additional investigations, diagnosis and treatment.

RESULTS

Study population Twenty-seven of 47 (57%) cases of NPSAH underwent a second cerebral angiography, and 42 (89%) additional MR-imaging of the spinal neuraxis. The reason not to perform a second angiography was a reliable brain MRI/MRA, imminent death or transfer to another hospital. No additional MR-imaging was performed in five cases; once because the patient died due to meningitis, in one patient the diagnosis was clear after second angiography, one patient was transferred to another hospital before performing MR-imaging and two times

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due to an unknown cause. These additional investigations resulted in one more patient with an aneurysm on each PICA (completed after a third angiography), 4 SVM (9% of NPSAH; 1% of total SAH) and 19 cases of “SAH of unknown origin” (40% of NPSAH; 3% of total SAH) as previously described in the literature2-5, 7, 33- 39. The remaining 23 cases (49%) did not receive both additional investigations and are considered as a separate group (table 1). All SVM were diagnosed on MR-imaging of the spinal neuraxis, three times followed by spinal angiography to detect the origin of the malformation.

Table 1 Organigram of study

Case reports Patient 1 A 22-year-old female presented with severe head- and neck pain, nausea and vomiting. Neurological examination was unremarkable and lumbar puncture was positive for blood pigments. Computed tomography (CT), performed 24 hours after onset of complaints, had shown no SAH or hydrocephalus. Cerebral digital subtraction angiography (DSA) was negative for an aneurysm, AVM or fistula. An MR-imaging of the complete spinal neuraxis showed intramedullary flow voids at Th9-10 (figure 1a) and a selective angiogram confirmed an intradural spinal cord AVM at Th9-10 (figure 1b,c) (according

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to the classification of spinal cord arteriovenous shunts by Rodesch and Lasjuanias40). The patient underwent two partial embolisations with minimal residual neurological complaints.

Fig. 1a Patient 1: T2-weighted MR-image of intramedullary AVM at Th9-10 with intramedullary flow voids and venous drainage through a thickened radiculomedullary vein

Patient 2 A 38-year-old male presented with sudden onset of neck pain evolving to intractable headache within minutes (previously described elsewhere23). On examination, no focal neurological deficit was found. Within a few hours, a CT was performed which showed subtle blood in the perimesencephalic cisterns, beneath the tentorium and in the fourth ventricle. Cerebral digital subtraction angiography (DSA) was negative. Because he subsequently developed a remarkably opisthotonic posture an MR-imaging of the spinal neuraxis was performed, showing intradural, extramedullary flow voids at the conus medullaris. Diagnostic DSA confirmed an intradural AVM of the conus medullaris. The patient underwent a partial embolisation without neurological side-effects.

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B C

6 Fig. 1b, c Selective angiogram: Th9 left shows filling of an intramedullary AVM through the anterior spinal artery with main feeding vessels at Th9 on the left (b) and Th10 right and L1 left (c)

Patient 3 A 66-year-old male presented with pain in the back of the head with nausea, preceded by sudden low back pain. His medical history was positive for cardiac disease and osteoporosis. He was desoriented in time with nuchal rigidity, subtle rightsided muscle weakness and symmetrical reflexes. The CT was negative for blood, and subsequently the SAH was diagnosed by lumbar puncture. A cerebral DSA was negative for an aneurysm, AVM or fistula. MR- imaging of the spinal neuraxis showed a hemorrhage around the conus medullaris and cauda equina. Additionally, a small round lesion was detected with different signal intensities on T1- and T2-weigthed MR-images adjacent to the spinal cord at level Th11 without dilated vessels. Its appearance was suggestive for an cavernous hemangioma, so additional spinal DSA was not performed. Ventricular drainage was necessary for several days because he developed a hydrocephalus two days after admission. Finally, the patient was

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discharged without complaints or neurological deficit.

Patient 4 A 21-year-old female presented at the emergency department with an tonic clonic seizure. At neurological investigation she did not react to painful stimuli with pupils equal and reactive to light, fixed eyes to the left, tongue bite and urinary incontinence. A subsequent CT showed subtle SAH in the perimesencephalic cisterns and the fourth ventricle with diffuse cerebral swelling (figure 2a). The cerebral DSA showed no intracranial cause for the SAH. An MR-imaging of the cervical and thoracic spine revealed intra- and extramedullary flow voids, suggestive of an AVM (figure 2b). Additional spinal DSA confirmed the intramedullary AVM with a nidus at Th8-10 and a small venous pouch at Th9 (figure 2c,d). After an uncomplicated embolisation through the Th8 radicular artery, the patient had a complete recovery without neurological deficit.

A B

Fig. 2a Patient 4: Computed tomography at admission with subtle subarachnoid hemorrhage in the perimesencephalic cisterns and the fourth ventricle with diffuse cerebral swelling

Fig. 2b T2-weighted MR-imaging shows an intramedullary AVM at Th8-10

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C D

Fig. 2c, d Angiogram: the major part of the AVM is filled through the right Th8, left Th9 and left Th11 radicular arteries. The right Th8 radiculopial artery fills an intranidal venous pouch (c) and a large part of the nidus (d) 6

DISCUSSION

In this retrospective, single institution series over a period of eight years, we found that 9% of all angiogram-negative, non-perimesencephalic subarachnoid hemorrhages (NPSAH) is caused by a Spinal Vascular Malformation (SVM). Although still being a rare cause for spontaneous SAH (1%), this incidence is considerably higher than could be expected by reports in the literature. Unlike a spinal cause for SAH would be expected to give signs and symptoms of spinal pathology, we described in our case reports (case 1 and 4) that medical history and neurological investigation is not always suggestive for spinal pathology.

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SVM incidence in SAH In the literature, only several case reports have described the presence of dural or perimedullary arteriovenous fistulas (DAVF)11, 13, 18, 20, 23, 24, 41-44 and cavernous malformations14, 17, 25-31 as a cause of angiogram-negative SAH. The incidence of a spinal origin of SAH has been reported on in only three articles: Walton45 described three cases, including one spinal AVM in 312 angiogram- negative SAH, resulting in a incidence of SVM of less than 1% of total SAH. Van Calenbergh6 found two cases of spinal AVM in 68 initial angiogram-negative patients with SAH (3%), but provided no further information about clinical history, way of diagnosing or additional investigations in other angiogram- negative SAH. Recently, Little found one cervical AVM with additional cervical MR scans in a group of 84 patients with NPSAH (1%). He suggested not to perfom MR investigation, “unless patients exhibit signs and symptoms suggestive of spinal pathology.” In this same study, only 12 out of 84 patients with NPSAH underwent an MRI of the thoracolumbar spine, with no evidence of spinal vascular malformations. Our prospective series compiled over eight consecutive years in a large neurosurgical academic referral center seems very representative. Our rate of 17% negative first angiography in all patients admitted with a spontaneous SAH and our rate of 10% perimesencephalic hemorrhage is in line with those reported by others9, 46. In this representative population, it is remarkable that we found a much higher incidence of spinal vascular malformations in NPSAH patients than previously reported. A probable explanation would be that this is the first series in which MR-imaging of the complete spinal neuraxis was performed consecutively in the large majority of patients with NPSAH. Because 11% of the patients in our study group did not undergo additional MR-imaging of the spinal neuraxis, this high percentage (9% spinal vascular malformations) could even be understated. MR-imaging of the spinal neuraxis after an angiogram-negative NPSAH is easy and safe and can provide a treatable cause for the hemorrhage in a sizeable subset of these patients. This is especially meaningful as the short- and longterm prognosis of these patients is not always as good as in the ‘true’ perimesencephalic hemorrhages.

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SAH of unknown origin SAH of unknown origin can only be diagnosed when all other causes for angiogram-negative SAH are excluded, as already stated by others8. Important in this respect is that all cerebral vessels are adequately visualised and that a second (or even third) angiography can be necessary to detect initially occult aneurysms (as occurred once in our patient population). In the literature, the incidence of angiogram-negative SAH is generally reported to be higher than the 8% found in our study1-7, 34, 36, 38, 39, 47. Nevertheless, three dimensional rotational angiography has recently been shown to be more sensitive in detecting aneurysms, leading to a rate of 4% of angiogram-negative SAH48 which could explain our lower incidence. Flaherty46 evaluated 352 SAH which revealed 285 cases of aneurysmatic origin and 24 times a perimesencephalic SAH (PMSAH), whereas 43 (12%) had a nonaneurysmal hemorrhage not of the PMSAH pattern. This percentage would be in line with our incidence of 8%, but unfortunately, a systematic analysis of this last group, including MR-imaging of the complete neuraxis, was not performed. In conclusion, one percent of spontaneous SAH, and 9% of NPSAH, was caused by a spinal vascular malformation in our series. According to this result, we recommend MR-imaging of the complete spinal neuraxis in patients with a 6 non-perimesencephalic subarachnoid haemorrhage in whom no cause for the hemorrhage has been found after first reliable cerebral angiography.

ACKNOWLEDGEMENTS

The authors would like to thank C.B.L.M. Majoie and W.J. van Rooij for performing the angiographies and endovascular treatments and G.J.E. Rinkel for his critical review of an earlier version of this manuscript.

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REFERENCE LIST

(1) Kassell NF, Adams HP, Jr., Torner JC, Sahs AL. Influence of timing of admission after aneurysmal subarachnoid hemorrhage on overall outcome. Report of the cooperative aneurysm study. Stroke 1981 September;12(5):620-3. (2) Kawamura S, Yasui N. Clinical and long-term follow-up study in patients with spontaneous subarachnoid haemorrhage of unknown aetiology. Acta Neurochir (Wien) 1990;106(3-4):110-4. (3) Ronkainen A, Hernesniemi J. Subarachnoid haemorrhage of unknown aetiology. Acta Neurochir (Wien ) 1992;119(1-4):29-34. (4) Spallone A, Ferrante L, Palatinsky E, Santoro A, Acqui M. Subarachnoid haemorrhage of unknown origin. Acta Neurochir (Wien ) 1986;80(1-2):12-7. (5) Suzuki S, Kayama T, Sakurai Y, Ogawa A, Suzuki J. Subarachnoid hemorrhage of unknown cause. Neurosurgery 1987 September;21(3):310-3. (6) Van Calenbergh F, Plets C, Goffin J, Velghe L. Nonaneurysmal subarachnoid hemorrhage: prevalence of perimesencephalic hemorrhage in a consecutive series. Surg Neurol 1993 April;39(4):320-3. (7) Velghe LE, De WP. Cryptogenic spontaneous subarachnoid haemorrhage. Clin Neurol Neurosurg 1983;85(3):139-44. (8) Rinkel GJ, van Gijn J, Wijdicks EF. Subarachnoid hemorrhage without detectable aneurysm. A review of the causes. Stroke 1993 September;24(9):1403-9. (9) Schwartz TH, Solomon RA. Perimesencephalic nonaneurysmal subarachnoid hemorrhage: review of the literature. Neurosurgery 1996 September;39(3):433-40. (10) Little AS, Garrett M, Germain R, Farhataziz N, Albuquerque FC, et al. Evaluation of patients with spontaneous subarachnoid hemorrhage and negative angiography. Neurosurgery 2007 December;61(6):1139-50. (11) Aviv RI, Shad A, Tomlinson G, Niemann D, Teddy PJ, et al. Cervical dural arteriovenous fistulae manifesting as subarachnoid hemorrhage: report of two cases and literature review. AJNR Am J Neuroradiol 2004 May;25(5):854-8. (12) Caglar YS, Torun F, Pait G, Bagdatoglu C, Sancak T. Ruptured aneurysm of the posterior spinal artery of the conus medullaris. J Clin Neurosci 2005 June;12(5):603-5. (13) Do HM, Jensen ME, Cloft HJ, Kallmes DF, Dion JE. Dural arteriovenous fistula of the cervical spine presenting with subarachnoid hemorrhage. AJNR Am J Neuroradiol 1999 February;20(2):348-50. (14) Kim CH, Kim HJ. Cervical subarachnoid floating cavernous malformation presenting with recurrent subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry 2002 May;72(5):668. (15) Koch C. Spinal dural arteriovenous fistula. Curr Opin Neurol 2006 February;19(1):69-75. (16) Logue V. Angiomas of the spinal cord: review of the pathogenesis, clinical features, and results of surgery. J Neurol Neurosurg Psychiatry 1979 January;42(1):1-11. (17) Mocco J, Laufer I, Mack WJ, Winfree CJ, Libien J, Connolly ES, Jr. An extramedullary foramen magnum cavernous malformation presenting with acute subarachnoid hemorrhage: case report and literature review. Neurosurgery 2005 February;56(2):E410. (18) Morimoto T, Yoshida S, Basugi N. Dural arteriovenous malformation in the cervical spine presenting with subarachnoid hemorrhage: case report. Neurosurgery 1992 July;31(1):118-20. (19) Mourier KL, Gobin YP, George B, Lot G, Merland JJ. Intradural perimedullary arteriovenous fistulae: results of surgical and endovascular treatment in a series of 35 cases. Neurosurgery 1993 June;32(6):885-91. (20) Ohmori Y, Hamada J, Morioka M, Yoshida A. Spinal aneurysm arising from the feeding pedicle of a thoracic perimedullary arteriovenous fistula: case report. Surg Neurol 2005 November;64(5):468-70. (21) Rosenblum B, Oldfield EH, Doppman JL, Di CG. Spinal arteriovenous malformations: a comparison of dural arteriovenous fistulas and intradural AVM’s in 81 patients. J Neurosurg 1987 December;67(6):795-802. (22) Shephard RH. Spinal arteriovenous malformations and subarachnoid haemorrhage. Br J Neurosurg 1992;6(1):5-12. (23) van Santbrink H, de Witt Hamer PC. Spinal AV malformation. Lancet 2003 May 24;361(9371):1766. (24) Vates GE, Quinones-Hinojosa A, Halbach VV, Lawton MT. Conus perimedullary arteriovenous fistula with intracranial drainage: case report. Neurosurgery 2001 August;49(2):457-61.

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(25) Acciarri N, Padovani R, Pozzati E, Gaist G, Manetto V. Spinal cavernous angioma: a rare cause of subarachnoid hemorrhage. Surg Neurol 1992 June;37(6):453-6. (26) Bruni P, Massari A, Greco R, Hernandez R, Oddi G, Chiappetta F. Subarachnoid hemorrhage from cavernous angioma of the cauda equina: case report. Surg Neurol 1994 March;41(3):226-9. (27) Casado N, I, Sancho RJ, Martin GR, Cerda M, Soler J. Recurrent subarachnoid haemorrhage due to spinal haemangioma. J Neurol Neurosurg Psychiatry 1987 December;50(12):1722-3. (28) Heimberger K, Schnaberth G, Koos W, Pendl G, Auff E. Spinal cavernous haemangioma (intradural- extramedullary) underlying repeated subarachnoid haemorrhage. J Neurol 1982;226(4):289-93. (29) Marconi F, Parenti G, Giorgetti V, Puglioli M. Spinal cavernous angioma producing subarachnoid hemorrhage. Case report. J Neurosurg Sci 1995 March;39(1):75-80. (30) Mori K, Ishii H, Tomita Y, Nakajima K, Morimoto K, Maeda M. Intradural-extramedullary spinal cavernous angioma--case report. Neurol Med Chir (Tokyo) 1991 September;31(9):593-6. (31) Ueda S, Saito A, Inomori S, Kim I. Cavernous angioma of the cauda equina producing subarachnoid hemorrhage. Case report. J Neurosurg 1987 January;66(1):134-6. (32) Canhao P, Ferro JM, Pinto AN, Melo TP, Campos JG. Perimesencephalic and nonperimesencephalic subarachnoid haemorrhages with negative angiograms. Acta Neurochir (Wien ) 1995;132(1-3):14-9. (33) Beguelin C, Seiler R. Subarachnoid hemorrhage with normal cerebral panangiography. Neurosurgery 1983 October;13(4):409-11. (34) Cioffi F, Pasqualin A, Cavazzani P, Da Pian R. Subarachnoid haemorrhage of unknown origin: clinical and tomographical aspects. Acta Neurochir (Wien ) 1989;97(1-2):31-9. (35) Congia S, Carta S, Coraddu M. Subarachnoid hemorrhage of unknown origin. A 44 cases study. Acta Neurol (Napoli) 1994 August;16(4):177-83. (36) Duong H, Melancon D, Tampieri D, Ethier R. The negative angiogram in subarachnoid haemorrhage. Neuroradiology 1996 January;38(1):15-9. (37) Giombini S, Bruzzone MG, Pluchino F. Subarachnoid hemorrhage of unexplained cause. Neurosurgery 1988 February;22(2):313-6. (38) Oder W, Kollegger H, Zeiler K, Dal-Bianco P, Wessely P, Deecke L. Subarachnoid hemorrhage of unknown etiology: early prognostic factors for long-term functional capacity. J Neurosurg 1991 6 April;74(4):601-5. (39) Ruelle A, Lasio G, Boccardo M, Gottlieb A, Severi P. Long-term prognosis of subarachnoid hemorrhages of unknown etiology. J Neurol 1985;232(5):277-9. (40) Rodesch G, Lasjaunias P. Spinal cord arteriovenous shunts: from imaging to management. Eur J Radiol 2003 June;46(3):221-32. (41) Hashimoto H, Iida J, Shin Y, Hironaka Y, Sakaki T. Spinal dural arteriovenous fistula with perimesencephalic subarachnoid haemorrhage. J Clin Neurosci 2000 January;7(1):64-6. (42) Koch C, Gottschalk S, Giese A. Dural arteriovenous fistula of the lumbar spine presenting with subarachnoid hemorrhage. Case report and review of the literature. J Neurosurg 2004 April;100(4 Suppl Spine):385-91. (43) Willinsky R, terBrugge K, Lasjaunias P, Montanera W. The variable presentations of craniocervical and cervical dural arteriovenous malformations. Surg Neurol 1990 August;34(2):118-23. (44) Kai Y, Hamada J, Morioka M, Yano S, Mizuno T, Kuratsu J. Arteriovenous fistulas at the cervicomedullary junction presenting with subarachnoid hemorrhage: six case reports with special reference to the angiographic pattern of venous drainage. AJNR Am J Neuroradiol 2005 September;26(8):1949-54. (45) Walton JN. Subarachnoid Hemorrhage. Edinburgh: E. S. Livingstone; 1956. (46) Flaherty ML, Haverbusch M, Kissela B, Kleindorfer D, Schneider A, et al. Perimesencephalic Subarachnoid Hemorrhage: Incidence, Risk Factors, and Outcome. J Stroke Cerebrovasc Dis 2005;14(6):267-71. (47) Schaller C, Raueiser B, Rohde V, Hassler W. Cerebral vasospasm after subarachnoid haemorrhage of unknown aetiology: a clinical and transcranial Doppler study. Acta Neurochir (Wien ) 1996;138(5):560-8. (48) Ishihara H, Kato S, Akimura T, Suehiro E, Oku T, Suzuki M. Angiogram-negative subarachnoid hemorrhage in the era of three dimensional rotational angiography. J Clin Neurosci 2007 March;14(3):252-5.

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Chapter 7

Spinal axis imaging in non- aneurysmal subarachnoid hemorrhage: a prospective cohort study

M.R. Germans, MD B.A. Coert, MD, PhD C.B.L.M. Majoie, MD, PhD R. van den Berg, MD, PhD D. Verbaan, PhD W.P. Vandertop, MD, PhD

Journal of Neurology (2014) 261(11): 2199-2203 Chapter 7

ABSTRACT

Introduction: In 15% of all spontaneous subarachnoid hemorrhages (SAH) no intracranial vascular pathology is found. Those non-aneurysmal hemorrhages are categorized into perimesencephalic SAH (PMSAH) and non- perimesencephalic SAH (NPSAH). Searching for spinal pathology might reveal a cause for the hemorrhage in some patients. Our goal was to assess the yield of magnetic resonance (MR) imaging of the complete spinal axis in search for a spinal origin in non-aneurysmal SAH.

Methods: In a prospective, observational study at a tertiary SAH referral center we assessed clinical and radiological characteristics of patients who consecutively presented with spontaneous non-aneurysmal SAH, diagnosed by computed tomography (CT) or lumbar puncture, and negative CT- angiography and digital subtraction angiography (DSA). Eligible patients were enrolled for investigation of the complete spinal axis by standard T1- and T2- weighted MR-imaging.

Results: Ninety-seven non-aneurysmal SAH patients were included in the study. Baseline characteristics were comparable between PMSAH and NPSAH patients. DSA and spinal MR-imaging were performed in 95% and 91% of patients, respectively. This revealed one lumbar ependymoma in a 43-year-old male who was diagnosed by LP (yield 1%). No spinal origin for the SAH was found in 51 PMSAH patients.

Conclusions: The yield of MR-imaging of the complete spinal axis in spontaneous non-aneurysmal SAH patients is low. Routine radiological investigation of the spinal axis in non-aneurysmal SAH patients is therefore not recommended.

138 Spinal axis imaging in non-aneurysmal SAH

INTRODUCTION

In about 15% of all spontaneous subarachnoid hemorrhages (SAH) no aneurysm is found at initial radiological investigations1. This group of non-aneurysmal SAH consists of patients who have a perimesencephalic hemorrhage (PMSAH) and patients with an aneurysmal or no hemorrhage pattern on the initial computed tomography (CT) investigation, the so called non-perimesencephalic SAH (NPSAH). In NPSAH patients, additional investigations are recommended, such as repeat digital subtraction angiography (DSA) and/or CT angiography (CTA), in order to definitively rule out an intracranial cause of the hemorrhage and to assess the course of the disease, treatment options and prognosis2-6. Patients with a PMSAH, on the other hand, have a type of hemorrhage of which the exact pathogenic mechanism is still unclear. Ruptures of small venous anomalies, capillary teleangiectasias or aneurysms of perforating arteries have been discussed as possible explanations but also atypical venous drainage patterns or a dissection of the basilar artery have been seen6-9. Moreover, a spinal vascular malformation has been reported as a cause of PMSAH, but its incidence is unknown10-12. As no intracranial cause for non-aneurysmal SAH is found and the exact pathogenic mechanism is still unclear, it might be warranted to search for a spinal origin not only in NPSAH but also in PMSAH. A spinal origin of SAH is rare11, 13, but the failure to diagnose it can lead to severe complications, such as acute spinal hemorrhage or slowly progressive symptoms due to myelopathy, 7 which often leads to a delay in establishment of the diagnosis14. Reviews investigating a spinal cause for non-aneurysmal SAH do not report different hemorrhage patterns and the studies that systematically searched for a spinal origin of the hemorrhage lack important aspects in order to calculate a reliable incidence10, 11, 13, 15. Our goal was to assess the yield of standard MR-imaging of the complete spinal axis in search for a spinal origin in non-aneurysmal SAH, which contains PMSAH and NPSAH.

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MATERIALS AND METHODS

Patient population We prospectively collected data of patients who were consecutively admitted to the Academic Medical Center (AMC) in Amsterdam, the Netherlands, a tertiary referral center for patients with SAH, from April 2009 to October 2012. Patients with clinical features and subsequent diagnosis of SAH, based on hemorrhage pattern on the initial CT scan or a positive LP, and no identifiable intracranial vascular pathology on the CTA, DSA or both, were eligible. The data collection continued until 100 patients were enrolled. One patient was included in the database, but his initial positive LP appeared to be negative, i.e. false-positive, after re-evaluation of the results, so he was excluded afterwards. Of the remaining 99 patients, two were excluded because they were diagnosed with an aneurysm after the second DSA. This resulted in 97 patients who were included in this study. There was no objection of the Medical Ethics Committee of the AMC to perform this study.

Data collection The data collection included patient demographics; clinical condition on admission according to the World Federation of Neurological Surgeons (WFNS) grade16; focal neurological deficits, loss of consciousness after the hemorrhage, neck and thoracolumbar pain; date of initial hemorrhage; results of CT (no hemorrhage, aneurysmal, perimesencephalic or other pattern), CTA, DSA and spinal cord MR investigations.

Clinical management All patients who presented with SAH were initially treated according to a standardized aneurysmal SAH protocol which closely follows international guidelines19, 20. Nimodipine was withheld in patients with a PMSAH and they were discharged as soon as their pain was under control or else transferred back to the referring hospital. The patients with NPSAH were observed for at least seven days to monitor for any delayed complications.

Radiological evaluation All patients underwent a plain CT and CTA of the brain, performed on a 64-slice scanner with administration of intravenous contrast. A PMSAH was defined as

140 Spinal axis imaging in non-aneurysmal SAH

the presence of subarachnoid blood that was strictly confined to the cisterns around the midbrain with the center of the bleeding immediately anterior to the midbrain. The maximal extension of the hemorrhage was allowed to reach the medial one-third of the Sylvian fissures or the anterior part of the interhemispheric fissure. Some sedimentation of blood in the posterior horns of the lateral ventricles may occur, but no frank intraventricular hemorrhage or extension of the hemorrhage into the brain17. Patients with an aneurysmal SAH pattern, or no blood on the initial CT with confirmation of the diagnosis by LP, and absence of intracranial vascular pathology, were classified as NPSAH. A DSA of the intracranial and extracranial vessels was subsequently performed, unless it was deemed clinically not relevant and the complication risk of the DSA would outweigh the benefit. Acquisition of images was done by four vessel 2D and 3D-DSA using a single-plane angiographic unit (Integris Allura Neuro; Philips Medical Systems, Best, the Netherlands) following institutional protocol. 2D-DSA was performed with selective vertebral artery or internal and external carotid artery injection of iodinated contrast (Visipaque; GE Healthcare, Cork, Ireland), typically administered at 4 mL/sec; 3D-DSA was acquired during a 6 seconds’ run with 15-21 mL of contrast, administered at 3 mL/sec and started 3 seconds after contrast injection. A second DSA was performed in a delayed fashion when indicated after multidisciplinary discussion. When absence of intracranial vascular pathology was confirmed by the neuroradiologist, patients were planned to undergo MR-imaging of the complete spinal axis. The minimal requirements for the MR-imaging were T1- and T2-weigthed 7 sequences in the sagittal plane, which has a high sensitivity for screening for spinal vascular malformations18. All images were interpreted by the attending neuroradiologist with knowledge of the patient’s clinical status.

Statistical analysis The WFNS-scale was dichotomized into groups with a good (WFNS-grade 1-3) or poor (WFNS-grade 4-5) grade. Normal distributed variables were expressed as means with standard deviations (SD) and the Student’s T test was used for a two-group comparison. Categorical variables were compared using the Chi- square test. The yield of MR-imaging was calculated by dividing the number of patients with a spinal origin by the number of patients who received MR- imaging of the spinal axis and given as proportion with corresponding 95% confidence interval (CI). A p-value <0.05 was considered significant.

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RESULTS

Patient characteristics The mean (± SD) age of non-aneurysmal SAH patients was 53 (± 12) years and 45% was female. Patients presented in a good WFNS grade in 98%, loss of consciousness after the hemorrhage occurred in 3% of patients (all of them were NPSAH) and 6% presented with focal neurological deficits (see table 1). No significant differences in baseline characteristics were seen between the groups of PMSAH and NPSAH patients.

Table 1 Baseline characteristics of 97 non-aneurysmal subarachnoid hemorrhage patients Patient characteristics PMSAH NPSAH Total (n=54) (n=43) (n=97) Age, years 52 ± 11 55 ± 14 53 ± 12 Female 23 (43) 21 (49) 44 (45) WFNS at first presentation 1-3 54 (100) 41 (95) 95 (98) 4-5 0 2 (5) 2 (2) Focal neurological deficits yes 2 (4) 4 (9) 6 (6) no 52 (96) 39 (91) 91 (94) Loss of consciousness yes 0 3 (7) 3 (3) no 54 (100) 40 (93) 94 (97) Pain in neck yes 33 (61) 22 (51) 55 (57) no 13 (24) 11 (26) 24 (24) unknown 8 (15) 10 (23) 18 (19) Thoracolumbar pain yes 3 (6) 1 (2) 4 (4) no 36 (67) 28 (65) 64 (66) unknown 15 (28)a 14 (33) 29 (30) Data are shown as n (%), or medians ± standard deviation PMSAH Perimesencephalic subarachnoid hemorrhage; NPSAH Non-perimesencephalic subarachnoid hemorrhage; WFNS World Federation of Neurological Surgeons a sum of percentages is not 100% due to rounding off

Radiological evaluation The initial CT investigation showed a PMSAH pattern in 56%, whereas 21% showed an aneurysmal hemorrhage pattern; the initial CT showed no hemorrhage in 24%, and these SAH were diagnosed by LP. The initial CT scan was not retrievable in one patient and the radiology report mentioned SAH, but was not clear about the pattern of hemorrhage. This scan was performed more

142 Spinal axis imaging in non-aneurysmal SAH

than 48 hours after the initial hemorrhage and the patient was categorized as an NPSAH. The initial CT was performed within 24 hours after hemorrhage in 74%, and 90% of these showed SAH (see table 2). The patients whose SAH was diagnosed by LP (i.e. without hemorrhage on CT) presented significantly more often later than 24 hours after the hemorrhage (p<0.05).

Table 2 Radiological assessment of 97 non-aneurysmal subarachnoid hemorrhage patients Patient characteristics PMSAH NPSAH Total (n=54) (n=43) (n=97) No hemorrhage on CT / 0 23 (53) 23 (24) diagnosis by LP

Time interval between onset of symptoms and first CT 47 (87) 72 (74) < 24 hours 0 25 (58) 3 (3) 24-48 hours 7 (13) 3 (7) 22 (23) >48 hours 15 (35) CT angiography negative 53 (98) 40 (93) 93 (96) dubious pathology 0 3 (7) 3 (3) not performed 1 (2) 0 1 (1) DSA negative 50 (93) 38 (88) 88 (91) dubious pathology a 2 (4) 3 (7) 5 (5) not performed 2 (4)b 2 (5) 4 (4) MR spinal axis negative 51 (94) 36 (84) 87 (90) spinal origin 0 1 (2) 1 (1) not performed 3 (6) 6 (14) 9 (9) Data are shown as n (%) 7 PMSAH Perimesencephalic subarachnoid hemorrhage; NPSAH Non-perimesencephalic subarachnoid hemorrhage; CT Computed tomography; LP Lumbar puncture; DSA Digital subtraction angiography; MR Magnetic resonance a all dubious pathologies were negative at second DSA b sum of percentages is not 100% due to rounding off

All patients except one received a CTA. The patient who was not investigated with a CTA was 17 weeks pregnant and therefore underwent MR/MRA-imaging, which showed PMSAH without evidence for an aneurysm. A DSA was performed in 93 patients (96%) with dubious evidence for intracranial vascular pathology in five patients (5%); all of them were negative at the second DSA. Five patients did not undergo a DSA because the neuroradiologist was able to rule out an aneurysm based on a reliable repeat CTA/MRA and decided that the added value of a repeat DSA was minimal. An MR investigation of the spinal axis was performed in 88 patients (91%). Reasons not to undergo an MR investigation

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were claustrophobia (n=1), patient refusal (n=1), or unknown cause (n=7). Six of those were categorized as NPSAH, including two who were diagnosed by LP. Routine MR-imaging of the spinal axis in 88 non-aneurysmal SAH patients revealed one spinal origin for the SAH (yield 1%, 95% CI -1.1-3.4); this 43-year old male was diagnosed by LP and appeared to have a lumbar ependymoma with evidence of hemorrhage. The tumor was resected without complications. On analysis of the different hemorrhage patterns on the initial CT, the yield of spinal MR-imaging in NPSAH patients became 2% (1/43; 95% CI -2.2-6.8), which increased to 4% (1/23; 95% CI -4.0-12.7) if only the patients without blood on the initial CT were included. No spinal origin for the hemorrhage was found in 51 PMSAH patients.

DISCUSSION

This prospective cohort study assessed the yield of MR-imaging of the complete spinal axis in 97 non-aneurysmal SAH patients. One patient (1%), with no hemorrhage on his initial CT, was diagnosed with a lumbar ependymoma that caused the hemorrhage. This is the first report of a prospectively studied group of patients who consecutively presented with non-aneurysmal SAH, consisting of NPSAH including an aneurysmal hemorrhage pattern and no blood on the initial CT scan as well as patients with a perimesencephalic SAH. In two other studies the incidence of a spinal origin in non-aneurysmal patients was estimated to be in between 0.05 and 1%13, 15. The first study, i.e. the review on spinal arteriovenous shunts causing SAH, was a retrospective study and the rate of patients with a PMSAH was underrepresented13. The other study reported results of 100 angiogram-negative SAH patients with MR-imaging of the cervical and thoracolumbar spine in 85% and 14%, respectively15. They found one cervical cavernous malformation (1%) in a patient who presented with an aneurysmal SAH pattern, so their yield of MR-imaging is comparable with our results. It is remarkable that the distribution of blood showed a perimesencephalic pattern in only 16%, whereas an unexpectedly high percentage of patients had blood at the convexity (25%). The limitations of that study are the retrospective design and the lack of MR-imaging of the thoracolumbar spine in 86%. Several studies have shown that non-aneurysmal SAH can also be caused by a spinal lesion in

144 Spinal axis imaging in non-aneurysmal SAH

the thoracolumbar spine11, 19-21, which is supported by our study. Therefore, investigation of the complete spinal axis is necessary when the decision is made to perform spinal MR-imaging. As we performed MR-imaging of the complete spinal axis in 91% of all our consecutively admitted non-aneurysmal SAH patients, this study reports the most reliable yield of spinal MR-imaging in this patient population. Our patient with a spinal origin of his hemorrhage was diagnosed by LP. The absence of intracranial blood on his initial CT could be a result from a very small amount of SAH which was undetectable or a washout of SAH, because the CT was performed after more than 48 hours. Therefore, it cannot be excluded that this patient might have had some blood on his CT if he was assessed earlier. On the other hand, with a presumably small and low pressure hemorrhage from his spinal lesion, the SAH might not have caused any intracranial hemorrhage at all. Despite this uncertainty, we categorized this patient as NPSAH and calculated the yield of spinal MR-imaging among all non-aneurysmal SAH patients who underwent MR-imaging. Moreover, the yield of spinal MR- imaging in the group of patients who were diagnosed by LP is much higher (4%). Two other studies, including one review and our retrospective study assessing spinal arteriovenous malformations in SAH, showed that 22% and 50% of patients with a spinal origin had an LP-proven SAH11, 13. As only 3-7% of all SAH patients are diagnosed by LP1, 22, it might indicate that a spinal origin of SAH is more commonly found in patients who have no SAH on their initial CT. The clinical relevance of diagnosing a spinal origin of the SAH in our patient 7 remains debatable, as a benign tumor in the lumbar spine will probably not lead to a complication, such as acute recurrent hemorrhage or myelopathy. Because both the yield of MR-imaging of the complete spinal axis and the clinical relevance of the finding is low we would not advocate for routine investigation of the spinal axis in all non-aneurysmal SAH patients. The absence of a spinal origin for the hemorrhage in 51 PMSAH patients is comparable with the result of one other study that did not find a lesion after performing MR-imaging of the cervical spine in 15 of their 16 PMSAH patients15. Nevertheless, they did not investigate the complete spinal axis in 88% of their PMSAH patients, so a reliable conclusion could not be drawn from their results. On the other hand, some case reports have mentioned a spinal origin for the hemorrhage in patients with a PMSAH pattern, although a consistent part had an atypical course of their disease10-12. To our knowledge, our study contains

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the largest group of PMSAH patients who underwent MR-imaging of the complete spinal axis. This study has limitations. First, 4% of patients did not receive a DSA, so we did not use the gold-standard to diagnose non-aneurysmal SAH in all patients. Second, 9% did not receive MR-imaging of the spinal axis. If a spinal origin for the hemorrhage was found in those patients, our yield is underestimated. On the other hand, if those patients were included as having no spinal origin in the calculation of the yield for the complete non-aneurysmal group, the percentage would be unchanged. Third, the minimal requirements for MR- imaging were sagittal T1- and T2-weighted imaging only. It is possible that small arteriovenous fistulas would have been detected if contrast-enhanced MR angiography had been performed. In conclusion, the yield of MR-imaging of the complete spinal axis in search for a spinal origin for the hemorrhage in non-aneurysmal SAH patients is so low that routine MR-imaging of the spinal axis in all non-aneurysmal SAH patients is not recommended, but it might be warranted in NPSAH patients. We propose that further research should be aimed at routine spinal MR-imaging and the clinical relevance of the findings in patients with NPSAH.

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REFERENCE LIST (1) van Gijn J, Rinkel GJ. Subarachnoid haemorrhage: diagnosis, causes and management. Brain 2001 February;124(Pt 2):249-78. (2) Agid R, Andersson T, Almqvist H, Willinsky RA, Lee SK, et al. Negative CT angiography findings in patients with spontaneous subarachnoid hemorrhage: When is digital subtraction angiography still needed? AJNR Am J Neuroradiol 2010 April;31(4):696-705. (3) Andaluz N, Zuccarello M. Yield of further diagnostic work-up of cryptogenic subarachnoid hemorrhage based on bleeding patterns on computed tomographic scans. Neurosurgery 2008 May;62(5):1040-6. (4) Dalyai R, Chalouhi N, Theofanis T, Jabbour PM, Dumont AS, et al. Subarachnoid hemorrhage with negative initial catheter angiography: a review of 254 cases evaluating patient clinical outcome and efficacy of short- and long-term repeat angiography. Neurosurgery 2013 April;72(4):646-52. (5) Jung JY, Kim YB, Lee JW, Huh SK, Lee KC. Spontaneous subarachnoid haemorrhage with negative initial angiography: a review of 143 cases. J Clin Neurosci 2006 December;13(10):1011-7. (6) Khan AA, Smith JD, Kirkman MA, Robertson FJ, Wong K, et al. Angiogram negative subarachnoid haemorrhage: outcomes and the role of repeat angiography. Clin Neurol Neurosurg 2013 August;115(8):1470-5. (7) Beseoglu K, Pannes S, Steiger HJ, Hanggi D. Long-term outcome and quality of life after nonaneurysmal subarachnoid hemorrhage. Acta Neurochir (Wien ) 2010 March;152(3):409-16. (8) Schievink WI, Wijdicks EF. Pretruncal subarachnoid hemorrhage: an anatomically correct description of the perimesencephalic subarachnoid hemorrhage. Stroke 1997 December;28(12):2572. (9) Wijdicks EF, Schievink WI. Perimesencephalic nonaneurysmal subarachnoid hemorrhage: first hint of a cause? Neurology 1997 August;49(2):634-6. (10) Fassett DR, Rammos SK, Patel P, Parikh H, Couldwell WT. Intracranial subarachnoid hemorrhage resulting from cervical spine dural arteriovenous fistulas: literature review and case presentation. Neurosurg Focus 2009 January;26(1):E4. (11) Germans MR, Pennings FA, Sprengers ME, Vandertop WP. Spinal vascular malformations in non- perimesencephalic subarachnoid hemorrhage. J Neurol 2008 December;255(12):1910-5. (12) Hashimoto H, Iida J, Shin Y, Hironaka Y, Sakaki T. Spinal dural arteriovenous fistula with perimesencephalic subarachnoid haemorrhage. J Clin Neurosci 2000 January;7(1):64-6. (13) van Beijnum J, Straver DC, Rinkel GJ, Klijn CJ. Spinal arteriovenous shunts presenting as intracranial subarachnoid haemorrhage. J Neurol 2007 August;254(8):1044-51. (14) Jellema K, Canta LR, Tijssen CC, van Rooij WJ, Koudstaal PJ, van Gijn J. Spinal dural arteriovenous fistulas: clinical features in 80 patients. J Neurol Neurosurg Psychiatry 2003 October;74(10):1438-40. 7 (15) Little AS, Garrett M, Germain R, Farhataziz N, Albuquerque FC, et al. Evaluation of patients with spontaneous subarachnoid hemorrhage and negative angiography. Neurosurgery 2007 December;61(6):1139-50. (16) Teasdale GM, Drake CG, Hunt W, Kassell N, Sano K, et al. A universal subarachnoid hemorrhage scale: report of a committee of the World Federation of Neurosurgical Societies. J Neurol Neurosurg Psychiatry 1988 November;51(11):1457. (17) Rinkel GJ, Wijdicks EF, Vermeulen M, Ramos LM, Tanghe HL, et al. Nonaneurysmal perimesencephalic subarachnoid hemorrhage: CT and MR patterns that differ from aneurysmal rupture. AJNR Am J Neuroradiol 1991 September;12(5):829-34. (18) Toossi S, Josephson SA, Hetts SW, Chin CT, Kralik S, et al. Utility of MRI in spinal arteriovenous fistula. Neurology 2012 July 3;79(1):25-30. (19) Bruni P, Massari A, Greco R, Hernandez R, Oddi G, Chiappetta F. Subarachnoid hemorrhage from cavernous angioma of the cauda equina: case report. Surg Neurol 1994 March;41(3):226-9. (20) Koch C, Gottschalk S, Giese A. Dural arteriovenous fistula of the lumbar spine presenting with subarachnoid hemorrhage. Case report and review of the literature. J Neurosurg 2004 April;100(4 Suppl Spine):385-91. (21) Vates GE, Quinones-Hinojosa A, Halbach VV, Lawton MT. Conus perimedullary arteriovenous fistula with intracranial drainage: case report. Neurosurgery 2001 August;49(2):457-61. (22) Bakker NA, Groen RJ, Foumani M, Uyttenboogaart M, Eshghi OS, et al. Appreciation of CT-negative, lumbar puncture-positive subarachnoid haemorrhage: risk factors for presence of aneurysms and diagnostic yield of imaging. J Neurol Neurosurg Psychiatry 2013 December 19.

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Chapter 8

Yield of spinal imaging in non-aneurysmal, non- perimesencephalic subarachnoid hemorrhage

M.R. Germans, MD B.A. Coert, MD, PhD C.B.L.M. Majoie, MD, PhD R. van den Berg, MD, PhD G. Lycklama à Nijeholt, MD, PhD G.J.E. Rinkel, MD, PhD D. Verbaan, PhD W.P. Vandertop, MD, PhD

Neurology; accepted for publication Chapter 8

ABSTRACT

Introduction: We studied the yield of MR-imaging of the spinal neuraxis in non- perimesencephalic SAH patients (NPSAH).

Methods: In a prospective, multicenter study we performed T1-weighted and T2-weighted MR-imaging of the spinal axis in a consecutive series of patients with a spontaneous NPSAH without intracranial vascular pathology on intracranial vascular imaging.

Results: A spinal origin of the hemorrhage was found in three of 75 patients (4%; 95% CI 0-8.4). The lesions were one lumbar ependymoma and two cervical cavernous malformations. All three patients presented without focal neurological deficits and two had a CT negative SAH but positive LP. Patients with a spinal origin were younger than patients without a spinal origin (38 vs. 56 years; p<0.05), which was the only significant difference between groups.

Conclusions: The yield and clinical relevance of MR-imaging of the spinal axis in patients who present with NPSAH is low. We do not recommend routine MR- imaging of the spinal axis in this patient population, but it might be justified in a subgroup of patients.

150 Spinal axis imaging in NPSAH

INTRODUCTION

In 15% of patients with spontaneous subarachnoid hemorrhage (SAH) no aneurysm or other vascular lesion is demonstrated at initial radiological investigations1. This group consists of patients with a perimesencephalic subarachnoid hemorrhage (PMSAH) and non-perimesencephalic SAH (NPSAH)2. Spinal lesions may give rise to a NPSAH and can lead to recurrence and other complications2-4. In a retrospective study we found 9% of patients having a spinal origin for NPSAH5. This study prospectively assesses the yield of spinal MR-imaging in NPSAH patients.

METHODS

Patient population Patients with a clinical history and diagnosis of SAH without intracranial vascular pathology, admitted to three centers from April 2009 to October 2012, were prospectively included. Patients with a hemorrhage pattern consistent with a perimesencephalic hemorrhage2 were excluded. Sample size calculation was based on the results of a retrospective study in one of the participating centers, where a spinal vascular malformation was found in 9% of NPSAH patients5.

Standard protocol approvals The Medical Ethics Committee of the Academic Medical Center Amsterdam approved the study protocol. 8 Data collection Patient demographics, clinical characteristics and radiological investigations were recorded in a web-based database.

Radiological evaluation All patients underwent a plain CT and a CT-angiography, performed on 64-slice scanners. Digital subtraction angiography (DSA) images were acquired by four vessel 2D-DSA and 3D-DSA when indicated by the treatment team. When intracranial vascular pathology was ruled out, patients underwent MR-imaging of the complete spinal axis. The minimal requirements for the MR-imaging were T1- and T2-weighted sequences in the sagittal plane.

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Statistical analysis Wilcoxon rank sum test was used for a two-group comparison for not normal distributed variables. Categorical variables were compared using Fisher’s exact test. The yield of the MR-imaging was calculated in patients who received the investigation and given as proportion with corresponding 95% confidence interval. A p-value <0.05 was considered statistically significant.

RESULTS

Patient characteristics Ninety NPSAH patients, from a total cohort of 1,650 SAH patients, were included in this study (see table 1 for baseline characteristics). The initial CT-scan was negative for SAH in 39 patients (43%), of whom 27 (69%) were investigated later than 24 hours after onset of symptoms.

Radiological evaluation At least one DSA was performed in 78 patients (87%). Hemorrhage patterns not suggestive for aneurysmal rupture were small intraventricular hemorrhages (n=2) and isolated cortical hemorrhages (n=2); in one patient movement artifacts hampered a good evaluation of the CT. Fifteen patients (17%) did not receive MR-imaging because of claustrophobia (n=1), patient refusal (n=1), patient’s transfer to another hospital (n=1), or unknown reasons (n=12). Thus, the yield of MR-imaging of the spinal axis was based on 75 patients. In three patients MR-imaging revealed a spinal origin of the hemorrhage (yield 4%; 95% CI 0-8.4): a lumbar ependymoma in one patient and a cervical cavernous malformation in two patients. An overview of the pattern of SAH on the primary CT in the 75 patients and findings at MR-imaging of the spinal axis are presented in figure 1.

Clinical characteristics of patients with a spinal origin Patients with a spinal origin of their hemorrhage were significantly younger than patients without a spinal origin. Otherwise, no statistically significant differences were seen between those groups. One patient with a cervical cavernous malformation had an aneurysmal SAH pattern on CT, whereas the other two patients had no blood on the initial CT, of which one had onset of symptoms more than 48 hours before presentation.

152 Spinal axis imaging in NPSAH

Fig. 1 Flow diagram of radiological investigations in 75 non-perimesencephalic subarachnoid hemorrhage patients without intracranial vascular pathology

DISCUSSION

Our results are in line with a review that revealed that spinal arteriovenous shunts causing SAH are rare and occur more commonly in males and in younger patients4. The types of spinal origins for the SAH in our study are rare, but very similar to those reported elsewhere4, 6-8. In two patients the CT-scan was negative and the SAH diagnosed by LP, which is in line with the rate of 50% of patients in our previously published study5. The lack of SAH found on brain CT- scan is probably explained by the etiology of the hemorrhages, as cavernous malformations and lumbar ependymomas tend to leak with low pressure, opposed to arterial bleeding, which could have hindered the hemorrhage to disperse against gravity to the intracranial compartment but did cause a SAH and its related symptoms. The goal of spinal axis investigation in SAH patients is to search for the source of the hemorrhage to assess the risk of recurrence and other complications. However, the clinical course of a cavernous malformation, like in two of our 8 patients, is usually favorable9, leaving the clinical relevance of the search for this pathology debatable. Our retrospective assessment of spinal vascular malformations in NPSAH patients in a single center showed an incidence of almost 9% which would support routine imaging5. Our current prospective multicenter study, however, does not confirm this high rate of a spinal origin as a cause for the SAH, although it is still higher than previously reported in the literature4, 7. This higher percentage could be attributable to 1) the relatively high number of patients with a negative CT-scan, 2) standard evaluation in the majority of patients, even in absence of clinical cues for spinal pathology, and 3) investigation of the

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complete spinal axis. One study with a proportion of CT negative SAH patients comparable to our study found a 2% incidence of a spinal origin in NPSAH. This number might have been underestimated because the complete spinal axis was not investigated in all patients7, especially because SAH can also result from spinal pathology originating lower than the cervicothoracic spine4, 5. We would currently not recommend routine MR-imaging of the spinal axis in all NPSAH patients, because both the yield of the investigation and clinical relevance of the findings are low. Nevertheless, in a subgroup of patients it might be justified, e.g. in patients younger than 50 years who were diagnosed by LP, as MR-imaging of the spinal axis in these patients revealed a cause in 10% of cases. But, due to the low reliability of post-hoc analysis we cannot draw a reliable conclusion in which group routine MR-imaging would be justified. In contrary to the 9% we used for our sample calculation, it appeared that the yield of spinal MR-imaging in NPSAH patients much lower. Future studies, therefore, need to include a large number of SAH patients to draw reliable conclusions. A first limitation is the small number of patients with a spinal origin, which hampered a good comparison of their characteristics with the other patients. Second, only 87% of all patients received a DSA, so we cannot be completely sure that all patients had no intracranial vascular pathology. Third, 17% of patients did not receive spinal MR-imaging. The yield of MR-imaging of the complete spinal axis in NPSAH patients is 4%. We do not recommend routine MR-imaging of the complete spinal axis in all NPSAH patients, but it might be justified in young patients with CT negative SAH. Future studies investigating NPSAH subgroups need to include a large number of patients to draw a reliable conclusion.

ACKNOWLEDGEMENTS

We thank Paut Greebe for collecting the patients who were eligible for the study at the University Medical Center Utrecht.

FUNDING

This study received institutional funding of the “Stichting ter Bevordering van Neurochirurgische Ontwikkeling”.

154 Spinal axis imaging in NPSAH

REFERENCE LIST

(1) van Gijn J, Rinkel GJ. Subarachnoid haemorrhage: diagnosis, causes and management. Brain 2001 February;124(Pt 2):249-78. (2) Rinkel GJ, Wijdicks EF, Vermeulen M, Ramos LM, Tanghe HL, et al. Nonaneurysmal perimesencephalic subarachnoid hemorrhage: CT and MR patterns that differ from aneurysmal rupture. AJNR Am J Neuroradiol 1991 September;12(5):829-34. (3) Jellema K, Canta LR, Tijssen CC, van Rooij WJ, Koudstaal PJ, van Gijn J. Spinal dural arteriovenous fistulas: clinical features in 80 patients. J Neurol Neurosurg Psychiatry 2003 October;74(10):1438-40. (4) van Beijnum J, Straver DC, Rinkel GJ, Klijn CJ. Spinal arteriovenous shunts presenting as intracranial subarachnoid haemorrhage. J Neurol 2007 August;254(8):1044-51. (5) Germans MR, Pennings FA, Sprengers ME, Vandertop WP. Spinal vascular malformations in non- perimesencephalic subarachnoid hemorrhage. J Neurol 2008 December;255(12):1910-5. (6) Acciarri N, Padovani R, Pozzati E, Gaist G, Manetto V. Spinal cavernous angioma: a rare cause of subarachnoid hemorrhage. Surg Neurol 1992 June;37(6):453-6. (7) Little AS, Garrett M, Germain R, Farhataziz N, Albuquerque FC, et al. Evaluation of patients with spontaneous subarachnoid hemorrhage and negative angiography. Neurosurgery 2007 December;61(6):1139-50. (8) Nicastro N, Schnider A, Leemann B. Anaplastic medullary ependymoma presenting as subarachnoid hemorrhage. Case Rep Neurol Med 2013;2013:701820. (9) Kim KM, Chung CK, Huh W, Lee WJ, Park SB, et al. Clinical outcomes of conservative management of spinal cord cavernous angiomas. Acta Neurochir (Wien ) 2013 July;155(7):1209-14.

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Chapter 9

General discussion and future considerations Chapter 9

GENERAL DISCUSSION

Patients who have suffered an aneurysmal subarachnoid hemorrhage (aSAH) have an increased risk for poor outcome if the aneurysm rebleeds. Therefore, physicians continuously try to reduce the rate of rebleeds. About 20 years ago, timing of aneurysm treatment was advanced from a minimum waiting period of 10 days after the hemorrhage1, 2, in order not to operate during the period of ‘vasospasm’, to “early treatment” within three days after hemorrhage3-5. Since the advent of coiling procedures, most centers strive to secure the aneurysm within 48 hours6-11. The optimal timing for securing the aneurysm has not yet been elucidated, but recent guidelines advise treatment as early as feasible and at least within the first 72 hours12-14. Factors that interfere with early aneurysm treatment are a delay in diagnosis, patient transfer to the treatment center and the inability to treat aneurysms 24 hours a day, seven days a week15-18. The latter factor was clearly illustrated in a recent study in the greater London area, which showed that only 27% of aneurysms were treated within 48 hours due to the lack of routine weekend clipping or coiling and a two-day a week routine coiling service15. As a result, the rate of rebleeds is still higher than desirable and current management on early aneurysm obliteration therefore, needs optimization to achieve a further reduction in rebleeds. In other emergency diseases, such as myocardial infarction (MI) and ischemic stroke, specialists have been able to dramatically reduce the time to treatment by determining and improving factors that delay the treatment19-21. This approach might also be appropriate for aSAH management. One important difference is that early aSAH management is aimed at the prevention of a sudden devastating event which is related to a worse outcome22-24, whereas early treatment of MI and ischemic stroke forces to stop the ongoing devastating event and therefore directly improves patients’ outcome.

Having a spontaneous SAH without identifiable cause is not only very frustrating for physicians, but also leads to a lot of anxiety in patients, as they fear another hemorrhage25. The current diagnostic approach rules out treatable intracranial causes in these type of hemorrhages, but leaves the spinal axis out of consideration. Missing a spinal cause for the hemorrhage can potentially lead to a rebleed and future neurological deterioration, like in the case of a

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spinal vascular malformation26-28. A thorough assessment of the spinal axis in non-aneurysmal SAH, therefore, seems warranted to assess the incidence of a spinal origin for the hemorrhage.

Early management aimed at reduction of rebleeds Multiple studies have shown that the rate of rebleeds is reduced when patients are treated within 24 hours (i.e. “ultra-early”) after the onset of symptoms11, 29, 30. Despite this ultra-early treatment however, the rebleed rate is still 7-22%, which is higher than desirable7, 31-34. The study in Chapter 2 confirms this high percentage and even shows that most rebleeds occur while the patients are waiting for their aneurysm to be secured at the treatment center. The current strategy of ultra-early treatment is apparently not good enough to prevent ultra-early rebleeds. So, a further reduction in rebleeds is necessary, and should be possible. This might be achieved by improved prehospital management of SAH patients but especially by optimization of in-hospital logistics. The question remains how we can improve a system that already treats patients within 24 hours? According to the significantly shorter time interval to treatment of approximately 10 hours in patients who suffered a rebleed, compared to the average time interval of 20 hours, it would seem possible to treat patients early. So, what detain physicians from treating all patients within 10 hours? The study in Chapter 3 was conducted to answer this question and concludes that primary presentation to a referring center and admissions later in the day are independent factors that contribute to delay. This implies again that factors before and after admission to the treatment center need to be improved to optimize ultra-early aneurysm treatment. One major improvement can be achieved by approaching aSAH patients as a medical emergency, and thus to treat them in line with the “time-is-brain” concept which has so successfully been implemented in acute ischemic stroke care19, 21. When adapting to this approach, in-hospital management has to change into performing aneurysm 9 treatment 24 hours a day, 7 days a week, and immediately after admission to the treatment center. One must bear in mind however, that ultra-early aneurysm treatment might also be harmful to the patients due to a higher risk for aneurysmal rerupture at early angiography35 and surgical difficulties in patients who have had a very recent SAH, especially in poor grade patients8, 29. The other part, namely expediting prehospital care, appears difficult to achieve because of many influencing factors19. In acute ischemic stroke management

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this has been achieved by mass communication campaigns, and population- and physician-based education19. But, because of the low incidence of SAH it is probably not cost-effective and therefore very unlikely to be implemented. So, other options need to be explored that reduce the risk for a rebleed before the patient is transferred to the treatment center for early aneurysm treatment. Already decades ago, researchers have proven that antifibrinolytic agents successfully reduce the rate of rebleeds. Unfortunately, the agents themselves increased other SAH-related complications, i.c. delayed cerebral ischemia (DCI), so finally no improvement in outcome was seen. An important issue is that these agents were started many hours, or even days, after the initial hemorrhage and continued for several days to weeks. According to the current knowledge that most of the rebleeds occur in the first few hours after the initial hemorrhage, the timing of administration was possibly not early enough. Moreover, the current widespread use of nimodipine has improved overall outcome, and the optimization of intensive care treatment has reduced the rate of SAH-related complications, like DCI36-38. Supported by more recent studies, showing no increased risk for DCI with short-term use of antifibrinolytic agents7, 39, we now think that ultra-early and short- term antifibrinolytic agents should be able to improve overall outcome, as the rebleed rate should be reduced without a simultaneous increase in DCI34. Based on these assumptions, antifibrinolytic agents are considered as a treatment option in certain SAH patients in the guidelines, but no conclusive evidence has been published yet12, 14. The ongoing trial of ultra-early tranexamic acid in SAH (ULTRA-study, Chapter 5) will provide evidence, but the results need to be awaited before a revival of antifibrinolytic agents in SAH patients can take place. The strength of the ULTRA-study is that it assesses not merely the rebleed rate, but especially the functional outcome after aSAH, which was not addressed in the above-mentioned studies. The ULTRA-study therefore, should answer the most important question: can ultra-early prevention of rebleeds lead to an improvement of overall outcome? One study examining the outcome in 459 patients showed that aneurysm treatment within 24 hours leads to a reduction in rebleeds and an improved clinical outcome30. This result was more pronounced for endovascular treatment than for surgery, which can explain the lack of a significantly improved outcome in other studies which were able to reduce rebleeds by ultra-early surgical treatment11, 29. As a rebleed is an independent prognostic indicator for poor outcome22, 24 and ultra-early

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treatment improves outcome in some studies11, 30, one can postulate that a further reduction of the rebleed rate should improve outcome, especially as nowadays more and more aneurysms are treated endovascularly40. A discussion point in the studies regarding time intervals in this thesis is the reliability of the time-points and the diagnosis rebleed, because those were retrieved retrospectively. This may have led to information bias due to misclassification of some time-points and a false diagnosis of a rebleed. We tried to overcome these problems by reviewing and approximating the time data by at least two investigators. In addition, the possible occurrence of rebleeds was reviewed by two experienced neurosurgeons.

Evaluation of the spinal axis in non-aneurysmal SAH patients Studies that looked outside the cranium in search for a cause of non-aneurysmal SAH are scarce41-43, and most of them were aimed at spinal arteriovenous shunts and did not look beyond the cervical spine41-43. Some case reports have mentioned other causes than spinal arteriovenous shunts, e.g. a cavernous hemangioma or ependymoma, and SAH that originated from lesions in the thoracolumbar spine26-28, 44-47. This raised the question whether a spinal origin of the hemorrhage is missed in some non-aneurysmal SAH patients, and that was the basis for the studies regarding the evaluation of the spinal axis in this thesis. The study in Chapter 6 shows that non-aneurysmal SAH can indeed be caused by thoracolumbar spinal vascular malformations with a remarkably high incidence of 9%. This study however, lacked the investigation of the PMSAH population, leaving a consistent part of the non-aneurysmal population out of consideration. Only one previous study did include PMSAH patients who underwent routine imaging of the spinal axis, but only 13% of these patients underwent MR-imaging of the thoracolumbar spine42. To clarify the above-mentioned points of concern, an additional prospective study was developed with the goal of investigating the yield of MR-imaging in the 9 complete non-aneurysmal SAH population. The strength of this study is that all non-aneurysmal patients were enrolled to undergo MR-imaging of the complete spinal axis, independent from the patient having a NPSAH or PMSAH. Weaknesses of this study are the lack of spinal MR-imaging in some patients due to various reasons and the fact that a routine T1- and T2-weighted screening MRI cannot definitively rule out a spinal origin for the hemorrhage, although the reported sensitivity is high48. As a result, the yield of spinal MR-imaging

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among the patients who did receive the imaging was used to approximate the incidence of spinal malformations in non-aneurysmal patients. With an incidence of 1% in all non-aneurysmal patients, and 4% in solely NPSAH patients without intracranial vascular pathology found in our studies, routine MR-imaging of the spinal axis in these groups remains debatable. The studies in this thesis confirm that MR-imaging of the spinal axis in patients with SAH without intracranial vascular pathology can establish a cause for the hemorrhage. This can help to reduce patients’ anxiety. On the other hand, a spinal lesion does not always need treatment, such as in cavernous malformations that do not cause focal neurological deficits28, leaving the patient with the knowledge of an abnormality in which treatment is not indicated. This in itself can lead to a reduced quality of life, as described in patients with unruptured intracranial aneurysms49. Secondly, cost-effectiveness of MR-imaging is becoming more and more important nowadays and spinal MR-imaging is a relatively expensive investigation. A simple triage model for diagnostic imaging in degenerative spine patients led to a notable reduction in imaging costs50. So, the costs of routine spinal MR-imaging in non-aneurysmal patients can probably also be reduced with the development of an algorithm. Such an algorithm should include the expected yield in subgroups of patients and the advice in which patients MR-imaging would be cost-effective. Taking the above considerations into account, it is not recommended to routinely perform spinal MR-imaging in all non-aneurysmal SAH patients. Especially in PMSAH patients it seems redundant, as concluded from the study in Chapter 7. This does not mean that a PMSAH cannot be caused by a spinal origin, as illustrated in the second case of Chapter 6, and a review regarding spinal arteriovenous shunts43. Nonetheless, spinal MR-imaging might still be simultaneous to a carefully selected group of non-aneurysmal SAH patients. Selection of the right patients will not only lead to an increased chance of finding a clinically significant spinal origin of the hemorrhage, but will also reduce unnecessary investigations in many patients and therefore reduce health-care costs. An decision tree for spinal MR investigation is presented below, to illustrate in which patients the additional imaging might be indicated.

162 General discussion and future considerations

Decision tree for MR-imaging of the spinal neuraxis, based on the results of this thesis

FUTURE CONSIDERATIONS

Despite improved emergency and specialized care, 7-22% of patients still have a rebleed in the first 24 hours after the initial hemorrhage7, 31-34 and this number has not changed much over the last decades51. One explanation for the lack of improvement in rebleed rate has been the increased awareness that aSAH patients need to be managed early. In this way a consistent part of rebleeds is prevented, but on the other hand, due to the earlier management more patients with an ultra-early rebleed are admitted to the hospital who would have died at the hemorrhage site in the past, leaving the rebleed rate somewhat unchanged. This thesis proposes ultra-early management strategies, including improved prehospital management and in-hospital logistics, in order to reduce the number of rebleeds. A prospective database, including time intervals in SAH treatment, rebleeds and outcome assessment, will be an important step towards optimization of SAH management. These prospective data can be compared with the results of the current thesis in terms of time intervals and 9 rebleed rates, to evaluate whether the proposed strategies indeed lead to optimization of care. One important notice is that it still needs to be elucidated whether optimization of care leads to an improvement of outcome. The ULTRA study assesses functional outcome, but it will take several years before the results are known. So, in the meantime it needs to be investigated whether optimization of ultra-early aneurysm treatment improves outcome. Due to the already ultra-early treatment of aneurysms and expected difficulty to expedite

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prehospital care, a large reduction in time interval between initial hemorrhage and treatment will be hard to achieve, especially when some physicians are not convinced about the relevance of performing aneurysm treatment 24 hours a day, 7 days a week52. Consequently, large patient groups are needed to conclude whether optimization of care leads to an improved outcome. One way to overcome this problem is to use data of national and international collaborations. A recent study performed such analysis and concluded that treatment within 24 hours lead to a worse outcome than treatment between 24 to 72 hours13. However, their results do not provide information about outcome when patients are treated immediately in comparison to an ultra- early treatment protocol (i.e. treatment within 24 hours). Secondly, due to the retrospective, non-randomized design of the study, the results need to be interpreted with care. On the other hand, databases with prospective data on time intervals from initial hemorrhage to treatment and outcome are currently available and include data from multiple clinical trials and prospective observational databases53, 54. With the high number of patients in these databases, one can assess more reliable whether earlier aneurysm treatment indeed leads to improved outcome. The results of this analysis would be very helpful to assess whether optimization of ultra-early aneurysm treatment is something to strive for. An important limitation of this database however, is the heterogeneity between centers and studies, both in prehospital transfer times and in-hospital logistics. Another way to overcome the problem of large patient groups is to avoid inclusion of a high number of patients by optimizing care in a subgroup, like patients who benefit most from ultra-early aneurysm treatment, such as patients with an increased risk for a rebleed. Unfortunately, it is not completely clear which patients should be included in this group and although analyzing subgroups might reduce the number of patients, it will still take a long time to include enough patients for a properly powered study.

The results of the second part of this thesis support that additional MR-imaging of the spinal axis is not recommended in all non-aneurysmal patients, but that it might be indicated in a subgroup of patients. According to the studies in this thesis, these subgroups might include younger patients with specific hemorrhage patterns on the initial CT. It would be of additional value to investigate the clinical relevance and cost-effectiveness of routine spinal MR- imaging in non-aneurysmal SAH patients younger than 50 years old, whose

164 General discussion and future considerations

initial CT was either negative or showed an aneurysmal hemorrhage pattern. These results may provide useful information to develop an algorithm for spinal MR investigations in non-aneurysmal SAH patients.

In conclusion, optimization of ultra-early management of aSAH patients will reduce the number of rebleeds which might result in an improved outcome. To achieve this, multiple factors need to be addressed, such as delay in diagnosis and treatment, and rebleeds in the few first hours. Expediting the transport to a SAH treatment center, improvement of in-hospital logistics aimed at ultra- early aneurysm treatment and ultra-early and short antifibrinolytic treatment are ways to optimize ultra-early management. It still needs to be determined whether a reduction in rebleeds indeed leads to an improved outcome. Routine MR-imaging of the spinal axis in all non-aneurysmal SAH patients is not recommended. Specifically in PMSAH patients it is redundant. Nonetheless, it can be justified to a subgroup of non-aneurysmal SAH patients and further studies need to be performed with the goal to create an algorithm for spinal investigations in non-aneurysmal patients.

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REFERENCE LIST

(1) Ross N, Hutchinson PJ, Seeley H, Kirkpatrick PJ. Timing of surgery for supratentorial aneurysmal subarachnoid haemorrhage: report of a prospective study. J Neurol Neurosurg Psychiatry 2002 April;72(4):480-4. (2) Taneda M. The significance of early operation in the management of ruptured intracranial aneurysms--an analysis of 251 cases hospitalized within 24 hours after subarachnoid haemorrhage. Acta Neurochir (Wien ) 1982;63(1-4):201-8. (3) Roos YB, Beenen LF, Groen RJ, Albrecht KW, Vermeulen M. Timing of surgery in patients with aneurysmal subarachnoid haemorrhage: rebleeding is still the major cause of poor outcome in neurosurgical units that aim at early surgery. J Neurol Neurosurg Psychiatry 1997 October;63(4):490-3. (4) Whitfield PC, Moss H, O’Hare D, Smielewski P, Pickard JD, Kirkpatrick PJ. An audit of aneurysmal subarachnoid haemorrhage: earlier resuscitation and surgery reduces inpatient stay and deaths from rebleeding. J Neurol Neurosurg Psychiatry 1996 March;60(3):301-6. (5) Whitfield PC, Kirkpatrick PJ. Timing of surgery for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev 2001;(2):CD001697. (6) Gu DQ, Zhang X, Luo B, Long XA, Duan CZ. Impact of ultra-early coiling on clinical outcome after aneurysmal subarachnoid hemorrhage in elderly patients. Acad Radiol 2012 January;19(1):3-7. (7) Hillman J, Fridriksson S, Nilsson O, Yu Z, Saveland H, Jakobsson KE. Immediate administration of tranexamic acid and reduced incidence of early rebleeding after aneurysmal subarachnoid hemorrhage: a prospective randomized study. J Neurosurg 2002 October;97(4):771-8. (8) Laidlaw JD, Siu KH. Poor-grade aneurysmal subarachnoid hemorrhage: outcome after treatment with urgent surgery. Neurosurgery 2003 December;53(6):1275-80. (9) Luo YC, Shen CS, Mao JL, Liang CY, Zhang Q, He ZJ. Ultra-early versus delayed coil treatment for ruptured poor-grade aneurysm. Neuroradiology 2014 October 17. (10) Siddiq F, Chaudhry SA, Tummala RP, Suri MF, Qureshi AI. Factors and outcomes associated with early and delayed aneurysm treatment in subarachnoid hemorrhage patients in the United States. Neurosurgery 2012 September;71(3):670-7. (11) Wong GK, Boet R, Ng SC, Chan M, Gin T, et al. Ultra-early (within 24 hours) aneurysm treatment after subarachnoid hemorrhage. World Neurosurg 2012 February;77(2):311-5. (12) Connolly ES, Jr., Rabinstein AA, Carhuapoma JR, Derdeyn CP, Dion J, 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 June;43(6):1711- 37. (13) Oudshoorn SC, Rinkel GJ, Molyneux AJ, Kerr RS, Dorhout Mees SM, et al. Aneurysm treatment <24 versus 24-72 h after subarachnoid hemorrhage. Neurocrit Care 2014 August;21(1):4-13. (14) Steiner T, Juvela S, Unterberg A, Jung C, Forsting M, Rinkel G. European Stroke Organization Guidelines for the Management of Intracranial Aneurysms and Subarachnoid Haemorrhage. Cerebrovasc Dis 2013 February 7;35(2):93-112. (15) Lamb JN, Crocker M, Tait MJ, Anthony BB, Papadopoulos MC. Delays in treating patients with good grade subarachnoid haemorrhage in London. Br J Neurosurg 2011 April;25(2):243-8. (16) Larsen CC, Eskesen V, Hauerberg J, Olesen C, Romner B, Astrup J. Considerable delay in diagnosis and acute management of subarachnoid haemorrhage. Dan Med Bull 2010 April;57(4):A4139. (17) Nuno M, Patil CG, Lyden P, Drazin D. The effect of transfer and hospital volume in subarachnoid hemorrhage patients. Neurocrit Care 2012 December;17(3):312-23. (18) O’Kelly CJ, Spears J, Urbach D, Wallace MC. Proximity to the treating centre and outcomes following subarachnoid hemorrhage. Can J Neurol Sci 2011 January;38(1):36-40. (19) Bouckaert M, Lemmens R, Thijs V. Reducing prehospital delay in acute stroke. Nat Rev Neurol 2009 September;5(9):477-83. (20) Herlitz J, Wireklintsundstrom B, Bang A, Berglund A, Svensson L, Blomstrand C. Early identification and delay to treatment in myocardial infarction and stroke: differences and similarities. Scand J Trauma Resusc Emerg Med 2010;18:48.

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(21) Lindley RI. Improving onset to needle time: knowledge is not enough. Stroke 2008 June;39(6):1667. (22) Broderick JP, Brott TG, Duldner JE, Tomsick T, Leach A. Initial and recurrent bleeding are the major causes of death following subarachnoid hemorrhage. Stroke 1994 July;25(7):1342-7. (23) Naidech AM, Janjua N, Kreiter KT, Ostapkovich ND, Fitzsimmons BF, et al. Predictors and impact of aneurysm rebleeding after subarachnoid hemorrhage. Arch Neurol 2005 March;62(3):410-6. (24) Roos YB, Beenen LF, Groen RJ, Albrecht KW, Vermeulen M. Timing of surgery in patients with aneurysmal subarachnoid haemorrhage: rebleeding is still the major cause of poor outcome in neurosurgical units that aim at early surgery. J Neurol Neurosurg Psychiatry 1997 October;63(4):490-3. (25) Al-Khindi T, Macdonald RL, Schweizer TA. Cognitive and functional outcome after aneurysmal subarachnoid hemorrhage. Stroke 2010 August;41(8):e519-e536. (26) Casado N, I, Sancho RJ, Martin GR, Cerda M, Soler J. Recurrent subarachnoid haemorrhage due to spinal haemangioma. J Neurol Neurosurg Psychiatry 1987 December;50(12):1722-3. (27) Heimberger K, Schnaberth G, Koos W, Pendl G, Auff E. Spinal cavernous haemangioma (intradural- extramedullary) underlying repeated subarachnoid haemorrhage. J Neurol 1982;226(4):289-93. (28) Kim CH, Kim HJ. Cervical subarachnoid floating cavernous malformation presenting with recurrent subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry 2002 May;72(5):668. (29) Laidlaw JD, Siu KH. Ultra-early surgery for aneurysmal subarachnoid hemorrhage: outcomes for a consecutive series of 391 patients not selected by grade or age. J Neurosurg 2002 August;97(2):250-8. (30) Phillips TJ, Dowling RJ, Yan B, Laidlaw JD, Mitchell PJ. Does treatment of ruptured intracranial aneurysms within 24 hours improve clinical outcome? Stroke 2011 July;42(7):1936-45. (31) Cha KC, Kim JH, Kang HI, Moon BG, Lee SJ, Kim JS. Aneurysmal rebleeding : factors associated with clinical outcome in the rebleeding patients. J Korean Neurosurg Soc 2010 February;47(2):119-23. (32) Fujii Y, Takeuchi S, Sasaki O, Minakawa T, Koike T, Tanaka R. Ultra-early rebleeding in spontaneous subarachnoid hemorrhage. J Neurosurg 1996 January;84(1):35-42. (33) Guo LM, Zhou HY, Xu JW, Wang Y, Qiu YM, Jiang JY. Risk factors related to aneurysmal rebleeding. World Neurosurg 2011 September;76(3-4):292-8. (34) Starke RM, Connolly ES, Jr. Rebleeding after aneurysmal subarachnoid hemorrhage. Neurocrit Care 2011 September;15(2):241-6. (35) Kusumi M, Yamada M, Kitahara T, Endo M, Kan S, et al. Rerupture of cerebral aneurysms during angiography--a retrospective study of 13 patients with subarachnoid hemorrhage. Acta Neurochir (Wien ) 2005 August;147(8):831-7. (36) Diringer MN, Bleck TP, Claude HJ, III, Menon D, Shutter L, et al. Critical care management of patients following aneurysmal subarachnoid hemorrhage: recommendations from the Neurocritical Care Society’s Multidisciplinary Consensus Conference. Neurocrit Care 2011 September;15(2):211-40. (37) Dorhout Mees SM, van den Bergh WM, Algra A, Rinkel GJ. Antiplatelet therapy for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev 2007;(4):CD006184. (38) Lovelock CE, Rinkel GJ, Rothwell PM. Time trends in outcome of subarachnoid hemorrhage: Population-based study and systematic review. Neurology 2010 May 11;74(19):1494-501. (39) Starke RM, Kim GH, Fernandez A, Komotar RJ, Hickman ZL, et al. Impact of a protocol for acute antifibrinolytic therapy on aneurysm rebleeding after subarachnoid hemorrhage. Stroke 2008 September;39(9):2617-21. (40) Payner TD, Melamed I, Ansari S, Leipzig TJ, Scott JA, et al. Trends over time in the management of 9 2253 patients with cerebral aneurysms: A single practice experience. Surg Neurol Int 2011;2:110. (41) Fassett DR, Rammos SK, Patel P, Parikh H, Couldwell WT. Intracranial subarachnoid hemorrhage resulting from cervical spine dural arteriovenous fistulas: literature review and case presentation. Neurosurg Focus 2009 January;26(1):E4. (42) Little AS, Garrett M, Germain R, Farhataziz N, Albuquerque FC, et al. Evaluation of patients with spontaneous subarachnoid hemorrhage and negative angiography. Neurosurgery 2007 December;61(6):1139-50. (43) van Beijnum J, Straver DC, Rinkel GJ, Klijn CJ. Spinal arteriovenous shunts presenting as intracranial subarachnoid haemorrhage. J Neurol 2007 August;254(8):1044-51. (44) Acciarri N, Padovani R, Pozzati E, Gaist G, Manetto V. Spinal cavernous angioma: a rare cause of subarachnoid hemorrhage. Surg Neurol 1992 June;37(6):453-6.

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(45) Bruni P, Massari A, Greco R, Hernandez R, Oddi G, Chiappetta F. Subarachnoid hemorrhage from cavernous angioma of the cauda equina: case report. Surg Neurol 1994 March;41(3):226-9. (46) Marconi F, Parenti G, Giorgetti V, Puglioli M. Spinal cavernous angioma producing subarachnoid hemorrhage. Case report. J Neurosurg Sci 1995 March;39(1):75-80. (47) Nicastro N, Schnider A, Leemann B. Anaplastic medullary ependymoma presenting as subarachnoid hemorrhage. Case Rep Neurol Med 2013;2013:701820. (48) Toossi S, Josephson SA, Hetts SW, Chin CT, Kralik S, et al. Utility of MRI in spinal arteriovenous fistula. Neurology 2012 July 3;79(1):25-30. (49) Buijs JE, Greebe P, Rinkel GJ. Quality of life, anxiety, and depression in patients with an unruptured intracranial aneurysm with or without aneurysm occlusion. Neurosurgery 2012 April;70(4):868-72. (50) Kim JS, Dong JZ, Brener S, Coyte PC, Rampersaud YR. Cost-effectiveness analysis of a reduction in diagnostic imaging in degenerative spinal disorders. Healthc Policy 2011 November;7(2):e105-e121. (51) Nibbelink DW, Torner JC, Henderson WG. Intracranial aneurysms and subarachnoid hemorrhage. A cooperative study. Antifibrinolytic therapy in recent onset subarachnoid hemorrhage. Stroke 1975 November;6(6):622-9. (52) van Rooij WJ, Bechan RS, Sluzewski M. Interventional Neuroradiology on Call: The Need for Emergency Coiling of Ruptured Intracranial Aneurysms. AJNR Am J Neuroradiol 2014 September 18. (53) Macdonald RL, Cusimano MD, Etminan N, Hanggi D, Hasan D, et al. Subarachnoid Hemorrhage International Trialists data repository (SAHIT). World Neurosurg 2013 March;79(3-4):418-22. (54) Schatlo B, Fung C, Fathi AR, Sailer M, Winkler K, et al. Introducing a nationwide registry: the Swiss study on aneurysmal subarachnoid haemorrhage (Swiss SOS). Acta Neurochir (Wien ) 2012 December;154(12):2173-8.

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Chapter 10

Summary Chapter 10

SUMMARY

A general introduction to this thesis is written in Chapter 1. This chapter describes that a spontaneous subarachnoid hemorrhage (SAH) has an incidence of 9 per 100.000 persons per year1. Eighty-five percent of hemorrhages is caused by a ruptured intracranial aneurysm. Approximately three quarters of aneurysmal SAH (aSAH) patients have a classic presentation and complain of an acute onset headache (“worst of their life”), often accompanied by nausea, vomiting and loss of consciousness. When no aneurysm is found, the hemorrhage pattern can be consistent with a perimesencephalic hemorrhage (PMSAH) or non- perimesencephalic hemorrhage (NPSAH), which consists of patients with an aneurysmal hemorrhage pattern or no hemorrhage pattern on the initial CT- scan.

This thesis encompasses both aneurysmal and non-aneurysmal patients and has therefore been split into two parts. The first part of this thesis examined the risk for aneurysm rerupture (“rebleed”) in the early phase after aSAH and options that can reduce this risk. The second part assessed whether routine MR-imaging of the spinal axis is justified in non-aneurysmal SAH patients to identify a treatable cause of the hemorrhage.

Part 1: Early rebleed risk and reduction of rebleeds A spontaneous SAH is a severe disease with a high risk for permanent invalidity or death. One of the most severe early complications is recurrent hemorrhage (“rebleed”) of the aneurysm, which leads to an increased risk for poor outcome. A spontaneous SAH is considered as a medical emergency and patients need to be transported to a specialized treatment center as soon as possible. Despite this awareness, a consistent part still suffers from a rebleed that might have been prevented. In order to develop management strategies that can reduce rebleeds, one has to understand when and where the rebleeds occur. The study in Chapter 2 was done to assess the time interval between the initial hemorrhage and rebleed and the location of the patient at time of the rebleed. A retrospective database of admissions to a single center was created to study the above mentioned parameters. The results of 293 patients show that 16% suffer from a rebleed at a median time interval of 180 minutes, and 83% of the rebleeds occur within

172 Summary

12 hours after the initial hemorrhage. Most remarkable, 60% of patients have their rebleed at the treatment hospital, when waiting for the aneurysm to be secured. This implicates that a consistent part of rebleeds can be prevented by immediate treatment of the aneurysm when the patient arrives at the treatment center. Thus, further reduction in rebleeds can be achieved by expediting the transport of patients, optimizing in-hospital logistics or other options that can reduce the risk for a rebleed, like antifibrinolytic therapy. This same study also showed that aneurysm treatment was started siginificantly earlier in patients with a rebleed compared with patients without a rebleed. So, early treatment can be achieved, but this is apparently delayed in patients who did not have a rebleed yet. Chapter 3 was done to elucidate causes for delay in the start of aneurysm treatment and reports the time intervals between hemorrhage and start of treatment and factors that influence this time interval. The median time interval from hemorrhage to diagnosis is only 169 minutes and the median time to treatment is 1,057 minutes, or 17,6 hours. Delaying factors were transfer of a patients between hospitals and admission at a later time-point in the day. Proposed strategies to improve the time interval to treatment are immediate transport to the treatment center when there is suspicion of an aSAH and the preparation of a treatment plan as soon as a patient is transported from another hospital. This can be achieved by education of general practitioners and ambulance employees, and improvement of in-hospital logistics, such as availability for aneurysm treatment 24 hours a day, 7 days a week. The article in Chapter 4 reports a major update of a Cochrane review on antifibrinolytic therapy in SAH patients to examine if this treatment reduces rebleeds in order to improve outcome. Two authors idependently screened 1,045 records, which resulted in ten randomized controlled trials relevant for the study. These ten trials showed that antifibrinolytic therapy significantly reduces rebleeds (relative risk (RR) 0.65, 95% confidence interval (CI) 0.44-0.97). Unfortunately, a reduction in rebleeds did not improve overall outcome in the pooled analysis, because of a simultaneous increase in delayed cerebral ischemia (DCI). A subgroup analysis of studies with ischemia prevention and 10 duration of therapy shorter than 72 hours was performed because current guidelines recommend the use of nimodipine to reduce DCI and aneurysm treatment within 72 hours2, 3. The only eligible study had a high risk for bias4, but showed a trend towards improved outcome (RR for ‘poor outcome’ 0.83,

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95% CI 0.52-1.35). These results implicate that, with the standard use of nimodipine nowadays, short-term antifibrinolytic therapy may be effective for SAH patients. With the knowledge that the majority of rebleeds occur within the first few hours after the initial hemorrage and that short-term antifibrinolytic therapy may be effective, a study protocol was developed. This protocol is presented in Chapter 5 and encompasses a multicenter randomized controlled trial where patients receive tranexamic acid (TXA), an antifibrinolytic agent, as early as possible and started within the first 24 hours after the initial hemorrhage for a duration of maximum 24 hours, or no TXA at all. Otherwise, patients are treated according to protocols that are in comparison with recent guidelines. The primary outcome measure is functional outcome at six months after SAH. A total of 950 patients need to be included and the study is currently enrolling patients (see www.ultrastudie.nl) with an estimated end of study in 2018.

Part 2: Evaluation of the spinal axis in non-aneurysmal subarachnoid hemorrhage patients A small part of spontaneous SAH is non-aneurysmal, which means that no aneurysmal origin for the hemorrhage is found5. In about two-thirds of those patients, the hemorrhage pattern is consistent with a perimesencephalic hemorrhage (PMSAH). The etiology of this hemorrhage is not exactly known, but the functional outcome is generally favorable with a low risk for complications. When there is no evidence for an aneurysm and the hemorrhage pattern is not consistent with a PMSAH, or when no hemorrhage is seen on the initial CT- scan and the SAH has been diagnosed by lumbar puncture (LP), the patient is categorized into a separate group: the non-aneurysmal non-perimesencephalic SAH (NPSAH). The current diagnostic approach for non-aneurysmal SAH aims for treatable intracranial causes, but leaves the spinal axis out of consideration. Some case reports mention a spinal cause of both PMSAH and NPSAH6, 7. Missing a spinal cause for the hemorrhage can potentially lead to a rebleed and neurological deterioration8, 9. A thorough assessment of the spinal axis in non-aneurysmal SAH, therefore, seems warranted to assess the incidence of a spinal origin for the hemorrhage. A retrospective single-center study was performed to investigate the occurrence of spinal vascular malformations in NPSAH patients. This study (Chapter 6) revealed four spinal vascular malformations in a group of 47 NPSAH patients

174 Summary

(9% of NPSAH) and the cases in question are described. Based on this study, we advised MR-imaging of the spinal neuraxis in all NPSAH patients. To verify the results of this retrospective study, a prospective database was created with the goal to assess the usefulness of MR-imaging of the spinal neuraxis in non-aneurysmal SAH patients. Because of the lack of PMSAH in the retrospective study, these patients were included too. A total of 97 consecutive non-aneurysmal SAH patients, enrolled in a period of 3.5 years, were included in the study of Chapter 7. Ninety-six percent of patients received at least one digital subtraction angiography (DSA) of the intracranial arteries and 91% received MR-imaging of the spinal neuraxis. One patient appeared to have a spinal origin for the hemorrhage (yield of MR-imaging: 1%). The SAH was in this male diagnosed by LP and the origin appeared to be a lumbar tumor. No spinal origin for the hemorrhage was found in 54 PMSAH patients. The results of this study led to the conclusion that routine MR-imaging of the spinal neuraxis can not be recommended in all non-aneurysmal SAH patients, especially not in PMSAH patients, and that further research should be aimed at NPSAH patients. In the context of this conclusion, a second study was done to assess the yield of MR-imaging of the spinal neuraxis in a large, multicenter group of NPSAH patients (Chapter 8). The same prospective database was used and 90 NPSAH patients, from a total cohort of 1,650 SAH patients, were eligible for the study. Eighty-seven percent of these patients received at least one DSA of the intracranial arteries. Not all NPSAH patients received their MR-imaging due to various reasons, so the yield of MR-imaging was calculated in 75 patients. Three patients had a spinal origin for their hemorrhage, consisting of one lumbar tumor and two cervical cavernous malformations, resulting in a yield of 4% (95% CI 0-8.4). These three patients were male and significantly younger than the other NPSAH patients with otherwise no distinctive factors. Because the yield of both the MR-imaging and the clinical relevance of the findings is low, we would not recommend to perform MR-imaging in all NPSAH patients. Nevertheless, it might be justified in young NPSAH patients with a aneurysmal hemorrhage pattern or those who are diagnosed by LP. Further studies aimed at these subgroups need a high number of patients to draw reliable conclusions. 10 In Chapter 9 early management options that can reduce rebleeds are described and their relevance to improve functional outcome are discussed. The studies regarding evaluation of the spinal neuraxis were combined to create a decision analysis for MR-imaging of the spinal neuraxis in non-aneurysmal patients. The final part of this chapter describes considerations for future research projects.

175 Chapter 10

REFERENCE LIST

(1) de Rooij NK, Linn FH, van der Plas JA, Algra A, Rinkel GJ. Incidence of subarachnoid haemorrhage: a systematic review with emphasis on region, age, gender and time trends. J Neurol Neurosurg Psychiatry 2007 December;78(12):1365-72. (2) Connolly ES, Jr., Rabinstein AA, Carhuapoma JR, Derdeyn CP, Dion J, 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 June;43(6):1711- 37. (3) Steiner T, Juvela S, Unterberg A, Jung C, Forsting M, Rinkel G. European Stroke Organization Guidelines for the Management of Intracranial Aneurysms and Subarachnoid Haemorrhage. Cerebrovasc Dis 2013 February 7;35(2):93-112. (4) Hillman J, Fridriksson S, Nilsson O, Yu Z, Saveland H, Jakobsson KE. Immediate administration of tranexamic acid and reduced incidence of early rebleeding after aneurysmal subarachnoid hemorrhage: a prospective randomized study. J Neurosurg 2002 October;97(4):771-8. (5) van Gijn J, Rinkel GJ. Subarachnoid haemorrhage: diagnosis, causes and management. Brain 2001 February;124(Pt 2):249-78. (6) Hashimoto H, Iida J, Shin Y, Hironaka Y, Sakaki T. Spinal dural arteriovenous fistula with perimesencephalic subarachnoid haemorrhage. J Clin Neurosci 2000 January;7(1):64-6. (7) van Beijnum J, Straver DC, Rinkel GJ, Klijn CJ. Spinal arteriovenous shunts presenting as intracranial subarachnoid haemorrhage. J Neurol 2007 August;254(8):1044-51. (8) Kim CH, Kim HJ. Cervical subarachnoid floating cavernous malformation presenting with recurrent subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry 2002 May;72(5):668. (9) Koch C, Gottschalk S, Giese A. Dural arteriovenous fistula of the lumbar spine presenting with subarachnoid hemorrhage. Case report and review of the literature. J Neurosurg 2004 April;100(4 Suppl Spine):385-91.

176

Chapter 11

Samenvatting Chapter 11

SAMENVATTING

Een algemene introductie van dit proefschrift is geschreven in Hoofdstuk 1. Hierin wordt beschreven dat een spontane subarachnoïdale bloeding (SAB, Engels: “subarachnoid hemorrhage” (SAH)) een incidentie heeft van 9 per 100.000 personen per jaar1. Vijfentachtig procent van de bloedingen wordt veroorzaakt door een gescheurd intracranieel aneurysma. Ongeveer driekwart van de aneurysmatische SAB patiënten heeft een klassieke presentatie en klaagt over een peracute hoofdpijn (“ergste hoofdpijn ooit”), vaak gepaard gaande met misselijkheid, braken en bewustzijnsverlies. Wanneer er geen aneurysma wordt gevonden, dan kan het bloedingspatroon overeenkomen met een perimesencefale bloeding (PMSAH) of niet-perimesencephale bloeding (NPSAH), waarbij de laatste zowel patiënten met een aneurysmatisch bloedingspatroon als zonder bloedingspatroon op de initiële CT-scan bevat.

Dit proefschrift omvat zowel SAB patiënten met en zonder aantoonbaar aneurysma en is daarom opgesplitst in twee delen. Het eerste deel van dit proefschrift onderzocht het risico op een volgende bloeding (“rebleed”) in de vroege fase na een aneurysmatische SAB en opties die dit risico kunnen verlagen. Het tweede deel stelde vast of routine MRI onderzoek van de spinale as (ofwel wervelkolom en ruggenmerg) nuttig zou zijn in niet-aneurysmatische SAB patiënten teneinde een behandelbare oorzaak voor de bloeding te vinden.

Deel 1: Vroeg rebleed risico en vermindering van rebleeds Een spontane SAB is een ernstige ziekte met een hoog risico voor permanente invaliditeit of overlijden. Een van de meest ernstige vroege complicaties is een volgende bloeding (“rebleed”) van het aneurysma, dat leidt tot een verhoogd risico voor een slechte uitkomst. Een spontane SAB wordt gezien als een spoedeisende aandoening en patiënten dienen zo spoedig mogelijk getransporteerd te worden naar een centrum dat is gespecialiseerd in de behandeling van deze patiënten. Ondanks dit besef krijgt een significant deel alsnog een rebleed wat voorkomen zou kunnen worden. Teneinde strategieën te ontwikkelen die rebleeds kunnen verminderen dient men inzicht te hebben in het tijdsinterval tot een rebleed en de locatie van de patiënt ten tijde van de rebleed. De studie in Hoofdstuk 2 werd gedaan om het tijdsinterval tussen de initiële bloeding en rebleed, alsmede de locatie van

180 Samenvatting

de patiënt ten tijde van de rebleed vast te stellen. Een retrospectieve database werd opgezet om de bovenstaande parameters te onderzoeken. De resultaten van 293 patiënten toonden aan dat 16% van de patiënten een rebleed heeft na een mediane tijdsinterval van 180 minuten en dat 83% van de rebleeds binnen 12 uur na de initiële bloeding plaatsvindt. Meest opvallend is dat 60% van de rebleeds optreedt in het behandelcentrum, wanneer de patiënt wacht op behandeling van het aneurysma. Dit impliceert dat een significant deel van de rebleeds voorkomen kan worden door onmiddellijke behandeling van het aneurysma na aankomst van de patiënt in het behandelcentrum. Aldus kan een verdere vermindering van rebleeds worden bewerkstelligd door het transport van patiënten te versnellen, het optimaliseren van de logistiek in het behandelcentrum of alternatieve opties, zoals behandeling met antifibrinolytica. De studie in Hoofdstuk 2 toonde ook aan dat significant sneller werd gestart met de behandeling van het aneurysma bij patiënten met een rebleed in vergelijking met patiënten zonder rebleed. Dus, vroege behandeling kan worden bereikt, maar dit is schijnbaar vertraagd bij patiënten die geen rebleed hebben gehad.

Hoofdstuk 3 werd gedaan om oorzaken voor vertraging in de behandeling van het aneurysma te achterhalen en beschrijft de tijdsintervallen tussen de initiële bloeding en de start van de behandeling van het aneurysma, en factoren die dit tijdsinterval beïnvloeden. Het mediane tijdsinterval tussen initiële bloeding en diagnose is slechts 169 minuten en de mediane tijd tot behandeling is 1.057 minuten, ofwel 17,6 uur. Factoren die het tijdsinterval tot behandeling vertraagden waren overplaatsing van een patiënt en opname op een later tijdstip op de dag. Voorgestelde strategieën om het tijdsinterval tot behandeling te verbeteren zijn het onmiddellijk transporteren van de patiënt naar het behandelcentrum als er verdenking is op een SAB en vaststellen van een behandelplan op het moment dat een patiënt overgeplaatst wordt. Dit kan worden bereikt door aanvullende training van huisartsen en ambulancemedewerkers en verbetering van logistiek in het ziekenhuis, zoals de beschikbaarheid van de behandeling voor het aneurysma 24 uur per dag, 7 dagen per week. Het artikel in Hoofdstuk 4 beschrijft een belangrijke update van een Cochrane review over antifibrinolytische therapie bij SAB patiënten om te onderzoeken of deze therapie rebleeds vermindert teneinde de uitkomst te verbeteren. Twee 11

181 Chapter 11

auteurs screenden 1.045 artikelen onafhankelijk van elkaar, wat resulteerde in tien gerandomiseerde en gecontroleerde studies die relevant waren voor de review. Deze tien studies toonden aan dat antifibrinolytische therapie het aantal rebleeds significant vermindert (relatief risico (RR) 0,65, 95% betrouwbaarheidsinterval (BI) 0,44-0,97). Helaas leidt een reductie in rebleeds niet tot een verbetering van functionele uitkomst in de samengestelde analyse als gevolg van een tegelijkertijdige toename van late ischemie. Een subgroep analyse van studies met ischemie preventie en een duur van behandeling korter dan 72 uur werd uitgevoerd omdat huidige richtlijnen adviseren om nimodipine te gebruiken om late ischemie te reduceren en het aneurysma binnen 72 uur te behandelen2, 3. De enige in aanmerking komende studie had een hoog risico op bias4, maar toonde een trend naar een verbeterde uitkomst (RR voor ‘slechte uitkomst’ 0,83, 95% BI 0,52-1,35). Deze resultaten impliceren dat, met de huidige standaard behandeling van nimodipine, kortdurende antifibrinolytische therapie effectief kan zijn voor SAB patiënten. Met de kennis dat het grootste deel van de rebleeds binnen de eerste uren na de initiële bloeding plaatsvindt, en dat kortdurende antifibrinolytische therapie nuttig kan zijn, werd een studie protocol ontwikkeld. Dit protocol is te lezen in Hoofdstuk 5 en beschrijft een multicenter gerandomiseerde en gecontroleerde studie waar patiënten tranexaminezuur (TXA), een antifibrinolytisch medicijn, zo vroeg mogelijk krijgen en gestart binnen de eerste 24 uur na de initiële bloeding gedurende maximaal 24 uur, tegenover geen TXA. Verder worden patiënten behandeld volgens protocollen die vergelijkbaar zijn met recente richtlijnen. De primaire uitkomstmaat is functionele uitkomst na zes maanden na de bloeding. De studie is momenteel bezig met de inclusie van 950 patiënten (zie www.ultrastudie.nl) en heeft een verwachte einddatum in 2018.

Deel 2: Evaluatie van de spinale as bij patiënten met een niet- aneurysmatische subarachnoïdale bloeding Een klein deel van de spontane SABs is niet-aneurysmatisch, wat betekent dat er geen aneurysmatische oorzaak voor de bloeding wordt gevonden5. In ongeveer tweederde van de gevallen is het bloedingspatroon overeenkomstig met een perimesencefale bloeding (PMSAH). De etiologie van deze bloeding is niet bekend, maar de functionele uitkomst is in het algemeen goed met lage risico’s voor complicaties. Wanneer er geen aneurysma aantoonbaar is en het bloedingspatroon niet overeenkomt met een PMSAH, of wanneer helemaal

182 Samenvatting

geen bloed op de CT-scan te zien is en de bloeding is gediagnosticeerd met een ruggenprik (ofwel lumbaal punctie: LP) , dan wordt de patiënt ingedeeld in een afzonderlijke groep, namelijk de niet-aneurysmatische, niet-perimesencefale SAB (NPSAH). Het huidige diagnostisch proces voor een niet-aneurysmatische SAB onderzoekt behandelbare intracraniële afwijkingen, maar laat de spinale as buiten beschouwing. Enkele case reports melden een spinale oorzaak voor zowel een PMSAH als een NPSAH6, 7. Het missen van een spinale oorzaak kan leiden tot een rebleed en neurologische verslechtering8, 9. Een grondige evaluatie van de spinale as in niet-aneurysmatische patiënten lijkt daarom relevant om de incidentie van een spinale oorzaak voor de bloeding vast te stellen. Een retrospectieve studie met data van één centrum werd uitgevoerd om het optreden van spinale vasculaire afwijkingen in NPSAH patiënten te onderzoeken. Deze studie (Hoofdstuk 6) vond vier spinale vasculaire afwijkingen in een groep van 47 NPSAH patiënten (9% van NPSAH) en de desbetreffende casus werden beschreven. Gebaseerd op deze studie werd geadviseerd een MRI van de spinale as in alle NPSAH patiënten te vervaardigen. Om de resultaten van deze retrospectieve studie te verifiëren werd een prospectieve database opgezet om het nut van MRI van de spinale as in niet- aneurysmatische patiënten vast te stellen. Vanwege het ontbreken van PMSAH patiënten in de retrospectieve studie werden deze patiënten ook geïncludeerd in de database. Een totaal van 97 opeenvolgende niet-aneurysmatische patiënten, geïncludeerd in een tijdsbestek van drieëneenhalf jaar, werd geïncludeerd in de studie van Hoofdstuk 7. Zesennegentig procent van deze patiënten onderging tenminste één digitale subtractie angiografie (DSA) van de hersenvaten en 91% een MRI van de spinale as. Eén patiënt bleek een spinale oorzaak voor de bloeding te hebben (opbrengst van MRI: 1%). De SAB was bij deze man gediagnostiseerd met een LP en de oorzaak bleek een lumbale tumor te zijn. Er werd geen spinale oorzaak voor de bloeding gevonden in 54 PMSAH patiënten. Met deze resultaten werd geconcludeerd dat routine MRI van de spinale as niet kan worden geadviseerd in alle niet-aneurysmatische patiënten, en in het bijzonder niet in PMSAH patiënten, en dat verder onderzoek gericht moet zijn naar NPSAH patiënten. In het kader van deze conclusie werd een tweede onderzoek verricht om de opbrengst van MRI van de spinale as in een grote, multicenter groep van NPSAH patiënten vast te stellen (Hoofdstuk 8). Dezelfde prospectieve database werd gebruikt en 90 NPSAH patiënten, 11

183 Chapter 11

uit een cohort van 1.650 SAB patiënten, waren geschikt voor het onderzoek. Zevenentachtig procent van deze patiënten onderging tenminste één DSA van de hersenvaten. Niet alle patiënten ondergingen een MRI vanwege verscheidene redenen, zodoende werd de opbrengst berekend op basis van 75 patiënten. Drie patiënten hadden een spinale oorzaak voor de bloeding, waaronder één lumbale tumor en twee cervicale caverneuze malformaties, resulterend in een opbrengst van 4% (95% BI 0-8,4). Deze drie patiënten waren allen man en significant jonger dan de overige NPSAH patiënten zonder overige onderscheidende factoren. Omdat zowel de opbrengst van de MRI en de klinische relevantie van de bevindingen laag waren, zouden we routine MRI in alle NPSAH patiënten niet adviseren. Desalniettemin, een MRI van de spinale as zou nuttig kunnen zijn in jonge NPSAH patiënten met een aneurysmatische bloedingspatroon of die gediagnostiseerd zijn met een LP. Verdere studies die gericht zijn op deze subgroepen hebben een groot aantal patiënten nodig om betrouwbare conclusies te kunnen trekken. In Hoofdstuk 9 worden vroege management opties die rebleeds kunnen verminderen besproken en hun relevantie voor een verbeterde functionele uitkomst bediscussieerd. Hierin zijn ook de resultaten van de studies betreffende evaluatie van de spinale as gecombineerd tot een flowdiagram voor besluitvorming voor MRI van de spinale as bij niet-aneurysmatische patiënten. Het laatste deel van dit hoofdstuk beschrijft overwegingen voor toekomstige studie projecten.

184 Samenvatting

REFERENTIELIJST

(1) de Rooij NK, Linn FH, van der Plas JA, Algra A, Rinkel GJ. Incidence of subarachnoid haemorrhage: a systematic review with emphasis on region, age, gender and time trends. J Neurol Neurosurg Psychiatry 2007 December;78(12):1365-72. (2) Connolly ES, Jr., Rabinstein AA, Carhuapoma JR, Derdeyn CP, Dion J, 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 June;43(6):1711- 37. (3) Steiner T, Juvela S, Unterberg A, Jung C, Forsting M, Rinkel G. European Stroke Organization Guidelines for the Management of Intracranial Aneurysms and Subarachnoid Haemorrhage. Cerebrovasc Dis 2013 February 7;35(2):93-112. (4) Hillman J, Fridriksson S, Nilsson O, Yu Z, Saveland H, Jakobsson KE. Immediate administration of tranexamic acid and reduced incidence of early rebleeding after aneurysmal subarachnoid hemorrhage: a prospective randomized study. J Neurosurg 2002 October;97(4):771-8. (5) van Gijn J, Rinkel GJ. Subarachnoid haemorrhage: diagnosis, causes and management. Brain 2001 February;124(Pt 2):249-78. (6) Hashimoto H, Iida J, Shin Y, Hironaka Y, Sakaki T. Spinal dural arteriovenous fistula with perimesencephalic subarachnoid haemorrhage. J Clin Neurosci 2000 January;7(1):64-6. (7) van Beijnum J, Straver DC, Rinkel GJ, Klijn CJ. Spinal arteriovenous shunts presenting as intracranial subarachnoid haemorrhage. J Neurol 2007 August;254(8):1044-51. (8) Kim CH, Kim HJ. Cervical subarachnoid floating cavernous malformation presenting with recurrent subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry 2002 May;72(5):668. (9) Koch C, Gottschalk S, Giese A. Dural arteriovenous fistula of the lumbar spine presenting with subarachnoid hemorrhage. Case report and review of the literature. J Neurosurg 2004 April;100(4 Suppl Spine):385-91.

185 LIST OF ABBREVIATIONS

AMC Academic Medical Center aSAH aneurysmal subarachnoid hemorrhage AVM arteriovenous malformation CI confidence interval CSF cerebrospinal fluid CT computed tomography CTA computed tomography angiography DCI delayed cerebral ischemia DSA digital subtraction angiography DSMB data safety monitoring board EACA epsilon amino-caproic acid Fig. figure IQR interquartile range ITT intention-to-treat iv intravenously LP lumbar puncture MI myocardial infarction MR magnetic resonance MRA magnetic resonance angiography mRS modified Rankin Scale NPSAH non-perimesencephalic subarachnoid hemorrhage OR odds ratio PICA posterior inferior cerebellar artery PMSAH perimesencephalic hemorrhage PROBE prospective, randomized open-label trial with blinded endpoint assessment RCT randomized controlled trial RR risk ratio SAH subarachnoid hemorrhage SD standard deviation SVM spinal vascular malformation TXA tranexamic acid ULTRA ultra-early tranexamic acid in subarachnoid hemorrhage UMCU University Medical Center Utrecht VUMC VU Medical Center WFNS World Federation of Neurosurgical Societies

186 LIST OF PUBLICATIONS

This thesis: Germans MR, Coert BA, Majoie CBLM, van den Berg R, Verbaan D, Vandertop WP. Spinal axis imaging in non-aneurysmal subarachnoid hemorrhage: a prospective cohort study. Journal of Neurology 2014;261(11): 2199-2203

Germans MR, Coert BA, Vandertop WP, Verbaan D. Time intervals from subarachnoid hemorrhage to rebleed. Journal of Neurology 2014;261(7): 1425- 1431

Germans MR, Hoogmoed J, van Straaten HAS, Coert BA, Vandertop WP, Verbaan D. Time intervals from aneurysmal subarachnoid hemorrhage to treatment and factors contributing to delay. Journal of Neurology 2014;261(3): 473-479

Baharoglu MI, Germans MR, Rinkel GJE, Algra A, Vermeulen M, van Gijn J, Roos YBWEM. Antifibrinolytic therapy for aneurysmal subarachnoid hemorrhage. Cochrane Database of Systematic Reviews 2013;30(8): CD001245

Germans MR, Post R, Coert BA, Rinkel GJE, Vandertop WP, Verbaan D. Ultra-early tranexamic acid after subarachnoid hemorrhage (ULTRA): study protocol for a randomized controlled trial. Trials 2013;16(14): 43

Germans MR, Pennings FA, Sprengers MES, Vandertop WP. Spinal vascular malformations in non-perimesencephalic hemorrhage. Journal of Neurology 2008;255(12): 1910-5

Germans MR, Coert BA, Majoie CBLM, van den Berg R, Lycklama à Nijeholt G, Rinkel GJE, Verbaan D, Vandertop WP. Yield of spinal imaging in non-aneurysmal, non-perimesencephalic hemorrage. Neurology; accepted for publication

Other publications: De Oliviera Manoel AL, Turkel-Parella D, Germans MR, Kouzmina E, da Silva Almendra P, Marotta T, Spears J, Abrahamson S. Safety of early pharmacological thromboprophylaxis after subarachnoid hemorrhage. Canadian Journal of Neurological Sciences. 2014;41(05): 554-561

187 List of publications

Germans MR, Regli L. Posterior auricular artery as an alternative donor vessel for extracranial-intracranial bypass surgery. Acta Neurochirurgica (Wien) 2014;156(11): 2095-2101

Alotaibi NM, Witiw CD, Germans MR, Macdonald RL. Spontaneous subdural fluid collection following aneurysmal subarachnoid hemorrhage: subdural hygroma or external hydrocephalus? Neurocritical Care 2014;21(2): 312-315

Germans MR, Macdonald RL. Is a Sylvian Fissure Hematoma Caused by Leaking Vessels? World Neurosurgery 2013;26: S1878-8750(13)01235-7

Germans MR, Macdonald RL. Clip or Coil – Is Some of the Effect on Outcome Related to the Risk of Delayed Cerebral Ischemia? World Neurosurgery 2013;24: S1878-8750(13)01212-6

Schoenmaker N, Germans MR, Troost D, Richard E. A remarkable pattern of subcortical vessel wall enhancement in granulomatous angiitis of the central nervous system. Journal of Rheumatology 2012;39(10): 2051-2053 van den Munckhof P, Germans MR, Schouten-van Meeteren AY, Oldenburger F, Troost D, Vandertop WP, Recurring intracranial malignant peripheral nerve sheath tumor: case report and systematic review of literature. Neurosurgery 2011;68(4): E1152-8

Müller MC, Lagarde SM, Germans MR, Juffermans N. Cerebral air embolism after arthrography of the ankle. Medical Science Monitor 2010;16(7): CS92-94

Germans MR, de Witt Hamer PC, van Boven LJ, Zwinderman KA, Bouma GJ. Blood volume measurement with indocyanine green pulse spectrophotometry: dose and site of dye administration. Acta Neurochirurgica (Wien) 2010;152(2): 251-5 van de Kerkhove MP, Germans MR, Deurholt T, Hoekstra R, Joziasse DH, van Wijk AC, van Gulik TM, Chamuleau RA, Roos A. Evidence for Galalpha(1-3)Gal expression on primary porcine hepatocytes: implications for bioartificial liver systems. Journal of Hepatology 2005;42(4): 541-547

188 DANKWOORD

Graag wil ik de volgende personen bedanken die hebben bijgedragen aan de totstandkoming van dit proefschrift:

Mijn promotoren en co-promotoren: Prof. dr. W.P. Vandertop, beste Peter, ik ben je zeer dankbaar dat je me de mogelijkheid hebt gegeven om naast mijn opleiding tot neurochirurg ook wetenschappelijk onderzoek te laten verrichten. Jouw kennis en kunde hebben een grote stempel gedrukt op mijn ontwikkeling tot neurochirurg met wetenschappelijke interesse. In het bijzonder jouw wetenschappelijke expertise, overstijgende blik, “duwtjes in de goede richting” en altijd snelle en gestructureerde commentaren op mijn manuscripten hebben een belangrijk aandeel gehad in mijn wetenschappelijke ontwikkeling.

Prof. dr. G.J.E. Rinkel, beste Gabriël, promoveren met onderzoek naar subarachnoïdale bloedingen met jou als promotor is een grote eer. Jouw ervaring met prospectieve studies en multicenter trials was een waardevolle toevoeging voor de ontwikkeling van de SPINES-database en ULTRA trial. Een deel van deze resultaten zijn al gepubliceerd in dit proefschrift en hopelijk zal verdere samenwerking leiden tot nog mooiere resultaten.

Dr. D. Verbaan, beste Dagmar, sinds jouw komst op de afdeling neurochirurgie van het AMC hebben we vele uren overleg gehad, zowel mondeling als via de honderden e-mails. Samen met jouw scherpe inzicht en epidemiologische ervaring heeft dit geleid heeft tot zeer goede artikelen, en nog belangrijker, ik heb er ontzettend veel van geleerd! Jouw tomeloze inzet voor de ULTRA trial is onbeschrijfelijk, zonder jou was het nooit wat geworden.

Dr. B.A. Coert, beste Bert, de discussies met jouw over wetenschappelijke en klinische vraagstukken hebben mij vaak geholpen om dingen ook eens vanuit een ander perspectief te bekijken. Jouw begeleiding in mijn onderzoek en opleiding in de neurochirurgie, en in het bijzonder de neurovasculaire operaties, hebben een onvergetelijke invloed gehad op mijn carrière als neurochirurg met neurovasculaire interesse.

189 Dankwoord

Alle andere mede-auteurs van artikelen in dit proefschrift: Ale Algra, Irem Baharoglu, René van den Berg, Jan van Gijn, Jantien Hoogmoed, Geert Lycklama à Nijeholt, Charles Majoie, Frits Pennings, René Post, Yvo Roos, Marieke Sprengers, Stéphanie van Straaten en Rien Vermeulen.

De leden van de promotiecommissie: Prof. dr. C.M.F. Dirven, prof. dr. R.J. de Haan, prof. dr. C.B.L.M. Majoie, prof. dr. M.B. Vroom en dr. A. van der Zwan.

Overige personen die hun bijdrage hebben geleverd: Nan van Geloven, Janneke Horn, Paut Greebe en Willem-Jan van Rooij; maar ook het secretariaat en de verpleegafdeling neurochirurgie; de arts- assistenten - in opleiding zijnde of niet - ; mijn paranimfen Ivo Bisschops en Jantien Hoogmoed, voor hun steun en toeverlaat; en mijn (stief- en schoon-) ouders voor het begrip dat ik er regelmatig niet bij kon zijn “omdat ik aan mijn onderzoek moet werken”.

En natuurlijk mijn lieve Lotte. Jouw steun en urenlange discussies over frustraties, begrip voor mijn uren computerwerk tijdens onze spaarzame vrije tijd en het altijd klaar staan voor me, zijn wel de grootste bijdragen geweest voor het feit dat ik zover ben gekomen.

190 CURRICULUM VITAE

The author of this thesis was born on November 17th, 1978 in Geleen, the Netherlands. He grew up in the community of Meerssen, where he finished his secondary school (Gymnasium) in 1997. In 1997 he started his study Medical Biology and in 1998 he entered medical school. In 2003 he received the degrees of both studies on the same day. After becoming medical doctor in 2005 he started as a resident-not-in-training at the department of neurosurgery at the Academic Medical Center (AMC) and VU University Medical Center (VUMC) in Amsterdam. In November 2006 he started his neurosurgical training at the AMC and VUMC in Amsterdam (prof. dr. W.P. Vandertop, dr. G.J. Bouma and dr. S.M. Peerdeman). His training also included one year of neurology (prof. dr. J. Stam and prof. dr. M. Vermeulen), four months of intensive care (prof. dr. M.B. Vroom) and six months of spinal surgery (dr. G.J. Bouma). Because of his specific interest in neurovascular surgery he followed a differentiation training in neurovascular surgery at the University Medical Center in Utrecht (prof. L. Regli). During his residency he performed scientific research and officially started as a PhD student in 2010. Currently, he is a member of the steering committee of the ULTRA trial, of which he developed the study protocol. After becoming a neurosurgeon in November 2012 he worked as a staff member neurosurgery at the University Hospital in Zürich, Switzerland (prof. L. Regli). Afterwards, he expanded his vascular experience by following a clinical fellowship in neurovascular surgery at the St. Michael’s Hospital in Toronto, Canada (prof. R.L. Macdonald). During this year he also performed scientific research aimed at subarachnoid hemorrhage, leading to various publications. His areas of interest in neurosurgery are neurovascular surgery, with specific expertise in subarachnoid hemorrhage, skull-base surgery and spine. He is married to Lotte Verweij and their daughter Fenne Germans was born during their stay in Canada.

191 You can view a page turn PDF at:

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