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An introduction to the pathophysiology of aneurysmal subarachnoid hemorrhage

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Abstract

Pathophysiological processes following subarachnoid hemorrhage (SAH) present survivors of the initial bleeding with a high risk of morbidity and mortality during the course of the disease. As angiographic vasospasm is strongly associated with delayed cerebral ischemia (DCI) and clinical outcome, clinical trials in the last few decades focused on prevention of these angiographic spasms. Despite all efforts, no new pharmacological agents have shown to improve patient outcome. As such, it has become clear that our understanding of the pathophysiology of SAH is incomplete and we need to reevaluate our concepts on the complex pathophysiological process following SAH. Angiographic vasospasm is probably important. However, a unifying theory for the pathophysiological changes following SAH has yet not been described. Some of these changes may be causally connected or present themselves as an epiphenomenon of an associated process. A causal connection between DCI and early brain injury (EBI) would mean that future therapies should address EBI more specifically. If the mechanisms following SAH display no causal pathophysiological connection but are rather evoked by the subarachnoid blood and its degradation production, multiple treatment strategies addressing the different pathophysiological mechanisms are required. The discrepancy between experimental and clinical SAH could be one reason for unsuccessful translational results.

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References

  1. Akpinar G, Acikgoz B, Surucu S, Celik HH, Cagavi F (2005) Ultrastructural changes in the circumventricular organs after experimental subarachnoid hemorrhage. Neurol Res 27:580–585

    Article  PubMed  Google Scholar 

  2. Alkan T, Tureyen K, Ulutas M, Kahveci N, Goren B, Korfali E, Ozluk K (2001) Acute and delayed vasoconstriction after subarachnoid hemorrhage: local cerebral blood flow, histopathology, and morphology in the rat basilar artery. Arch Physiol Biochem 109:145–153

    Article  PubMed  CAS  Google Scholar 

  3. Asano T, Sano K (1977) Pathogenetic role of no-reflow phenomenon in experimental subarachnoid hemorrhage in dogs. J Neurosurg 46:454–466

    Article  PubMed  CAS  Google Scholar 

  4. Azarpazhooh MR, Velayati A, Chambers BR, Nejad HM, Nejad PS (2009) Microembolic signals in subarachnoid hemorrhage. J Clin Neurosci 16:390–393

    Article  PubMed  Google Scholar 

  5. Barth M, Capelle HH, Weidauer S, Weiss C, Munch E, Thome C, Luecke T, Schmiedek P, Kasuya H, Vajkoczy P (2007) Effect of nicardipine prolonged-release implants on cerebral vasospasm and clinical outcome after severe aneurysmal subarachnoid hemorrhage: a prospective, randomized, double-blind phase IIa study. Stroke 38:330–336

    Article  PubMed  CAS  Google Scholar 

  6. Bederson JB, Germano IM, Guarino L (1995) Cortical blood flow and cerebral perfusion pressure in a new noncraniotomy model of subarachnoid hemorrhage in the rat. Stroke 26:1086–1091 discussion 1091-1082

    Article  PubMed  CAS  Google Scholar 

  7. Bederson JB, Levy AL, Ding WH, Kahn R, DiPerna CA, Jenkins AL 3rd, Vallabhajosyula P (1998) Acute vasoconstriction after subarachnoid hemorrhage. Neurosurgery 42:352–360 discussion 360-352

    Article  PubMed  CAS  Google Scholar 

  8. Beseoglu K, Holtkamp K, Steiger HJ, Hanggi D (2013) Fatal aneurysmal subarachnoid haemorrhage: causes of 30-day in-hospital case fatalities in a large single-Centre historical patient cohort. Clin Neurol Neurosurg 115:77–81

    Article  PubMed  Google Scholar 

  9. Beseoglu K, Pannes S, Steiger HJ, Hanggi D (2010) Long-term outcome and quality of life after nonaneurysmal subarachnoid hemorrhage. Acta Neurochir 152:409–416

    Article  PubMed  Google Scholar 

  10. Bosche B, Graf R, Ernestus RI, Dohmen C, Reithmeier T, Brinker G, Strong AJ, Dreier JP, Woitzik J, Members of the Cooperative Study of Brain Injury D (2010) Recurrent spreading depolarizations after subarachnoid hemorrhage decreases oxygen availability in human cerebral cortex. Ann Neurol 67:607–617

    Article  PubMed  PubMed Central  Google Scholar 

  11. Brathwaite S, Macdonald RL (2014) Current management of delayed cerebral ischemia: update from results of recent clinical trials. Transl Stroke Res 5:207–226

    Article  PubMed  CAS  Google Scholar 

  12. Budohoski KP, Czosnyka M, Smielewski P, Kasprowicz M, Helmy A, Bulters D, Pickard JD, Kirkpatrick PJ (2012) Impairment of cerebral autoregulation predicts delayed cerebral ischemia after subarachnoid hemorrhage: a prospective observational study. Stroke 43:3230–3237

    Article  PubMed  Google Scholar 

  13. Budohoski KP, Czosnyka M, Smielewski P, Varsos GV, Kasprowicz M, Brady KM, Pickard JD, Kirkpatrick PJ (2013) Cerebral autoregulation after subarachnoid hemorrhage: comparison of three methods. J Cereb Blood Flow Metab 33:449–456

    Article  PubMed  Google Scholar 

  14. Cahill J, Calvert JW, Solaroglu I, Zhang JH (2006) Vasospasm and p53-induced apoptosis in an experimental model of subarachnoid hemorrhage. Stroke 37:1868–1874

    Article  PubMed  Google Scholar 

  15. Cahill J, Calvert JW, Zhang JH (2006) Mechanisms of early brain injury after subarachnoid hemorrhage. J Cereb Blood Flow Metab 26:1341–1353

    Article  PubMed  CAS  Google Scholar 

  16. Cai D, Mulle JG, Yue DT (1997) Inhibition of recombinant Ca2+ channels by benzothiazepines and phenylalkylamines: class-specific pharmacology and underlying molecular determinants. Mol Pharmacol 51:872–881

    Article  PubMed  CAS  Google Scholar 

  17. Caspers J, Rubbert C, Turowski B, Martens D, Reichelt DC, May R, Aissa J, Hanggi D, Etminan N, Mathys C (2015) Timing of mean transit time maximization is associated with neurological outcome after subarachnoid hemorrhage. Clin Neuroradiol

    Google Scholar 

  18. Chen S, Wu H, Tang J, Zhang J, Zhang JH (2015) Neurovascular events after subarachnoid hemorrhage: focusing on subcellular organelles. Acta Neurochir Suppl 120:39–46

    PubMed  PubMed Central  Google Scholar 

  19. Chen Y, Li Q, Tang J, Feng H, Zhang JH (2015) The evolving roles of pericyte in early brain injury after subarachnoid hemorrhage. Brain Res 1623:110–122

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Clark JF, Sharp FR (2006) Bilirubin oxidation products (BOXes) and their role in cerebral vasospasm after subarachnoid hemorrhage. J Cereb Blood Flow Metab 26:1223–1233

    Article  PubMed  CAS  Google Scholar 

  21. Cook DJ, Kan S, Ai J, Kasuya H, Macdonald RL (2012) Cisternal sustained release dihydropyridines for subarachnoid hemorrhage. Curr Neurovasc Res 9:139–148

    Article  PubMed  CAS  Google Scholar 

  22. Crowley RW, Medel R, Dumont AS, Ilodigwe D, Kassell NF, Mayer SA, Ruefenacht D, Schmiedek P, Weidauer S, Pasqualin A, Macdonald RL (2011) Angiographic vasospasm is strongly correlated with cerebral infarction after subarachnoid hemorrhage. Stroke 42:919–923

    Article  PubMed  Google Scholar 

  23. Dehdashti AR, Mermillod B, Rufenacht DA, Reverdin A, de Tribolet N (2004) Does treatment modality of intracranial ruptured aneurysms influence the incidence of cerebral vasospasm and clinical outcome? Cerebrovasc Dis 17:53–60

    Article  PubMed  Google Scholar 

  24. Diochot S, Richard S, Baldy-Moulinier M, Nargeot J, Valmier J (1995) Dihydropyridines, phenylalkylamines and benzothiazepines block N-, P/Q- and R-type calcium currents. Pflugers Arch 431:10–19

    Article  PubMed  CAS  Google Scholar 

  25. Dorhout Mees SM, Kerr RS, Rinkel GJ, Algra A, Molyneux AJ (2012) Occurrence and impact of delayed cerebral ischemia after coiling and after clipping in the international subarachnoid aneurysm trial (ISAT). J Neurol 259:679–683

    Article  PubMed  Google Scholar 

  26. Dorhout Mees SM, Rinkel GJ, Feigin VL, Algra A, van den Bergh WM, Vermeulen M, van Gijn J (2007) Calcium antagonists for aneurysmal subarachnoid haemorrhage. The Cochrane database of systematic reviews:CD000277

  27. Dorhout Mees SM, van den Bergh WM, Algra A, Rinkel GJ (2007) Antiplatelet therapy for aneurysmal subarachnoid haemorrhage. The Cochrane database of systematic reviews:CD006184

  28. Dorsch N (2011) A clinical review of cerebral vasospasm and delayed ischaemia following aneurysm rupture. Acta Neurochir Suppl 110:5–6

    PubMed  Google Scholar 

  29. Dreier JP (2011) The role of spreading depression, spreading depolarization and spreading ischemia in neurological disease. Nat Med 17:439–447

    Article  PubMed  CAS  Google Scholar 

  30. Dreier JP, Ebert N, Priller J, Megow D, Lindauer U, Klee R, Reuter U, Imai Y, Einhaupl KM, Victorov I, Dirnagl U (2000) Products of hemolysis in the subarachnoid space inducing spreading ischemia in the cortex and focal necrosis in rats: a model for delayed ischemic neurological deficits after subarachnoid hemorrhage? J Neurosurg 93:658–666

    Article  PubMed  CAS  Google Scholar 

  31. Dreier JP, Korner K, Ebert N, Gorner A, Rubin I, Back T, Lindauer U, Wolf T, Villringer A, Einhaupl KM, Lauritzen M, Dirnagl U (1998) Nitric oxide scavenging by hemoglobin or nitric oxide synthase inhibition by N-nitro-L-arginine induces cortical spreading ischemia when K+ is increased in the subarachnoid space. J Cereb Blood Flow Metab 18:978–990

    Article  PubMed  CAS  Google Scholar 

  32. Dreier JP, Major S, Manning A, Woitzik J, Drenckhahn C, Steinbrink J, Tolias C, Oliveira-Ferreira AI, Fabricius M, Hartings JA, Vajkoczy P, Lauritzen M, Dirnagl U, Bohner G, Strong AJ, group Cs (2009) Cortical spreading ischaemia is a novel process involved in ischaemic damage in patients with aneurysmal subarachnoid haemorrhage. Brain 132:1866–1881

    Article  PubMed  PubMed Central  Google Scholar 

  33. Dreier JP, Petzold G, Tille K, Lindauer U, Arnold G, Heinemann U, Einhaupl KM, Dirnagl U (2001) Ischaemia triggered by spreading neuronal activation is inhibited by vasodilators in rats. J Physiol 531:515–526

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Dreier JP, Woitzik J, Fabricius M, Bhatia R, Major S, Drenckhahn C, Lehmann TN, Sarrafzadeh A, Willumsen L, Hartings JA, Sakowitz OW, Seemann JH, Thieme A, Lauritzen M, Strong AJ (2006) Delayed ischaemic neurological deficits after subarachnoid haemorrhage are associated with clusters of spreading depolarizations. Brain 129:3224–3237

    Article  PubMed  Google Scholar 

  35. Ebel H, Rust DS, Leschinger A, Ehresmann N, Kranz A, Hoffmann O, Boker DK (1996) Vasomotion, regional cerebral blood flow and intracranial pressure after induced subarachnoid haemorrhage in rats. Zentralbl Neurochir 57:150–155

    PubMed  CAS  Google Scholar 

  36. Ecker A, Riemenschneider PA (1951) Arteriographic demonstration of spasm of the intracranial arteries, with special reference to saccular arterial aneurysms. J Neurosurg 8:660–667

    Article  PubMed  CAS  Google Scholar 

  37. Etminan N, Beseoglu K, Heiroth HJ, Turowski B, Steiger HJ, Hanggi D (2013) Early perfusion computerized tomography imaging as a radiographic surrogate for delayed cerebral ischemia and functional outcome after subarachnoid hemorrhage. Stroke 44:1260–1266

    Article  PubMed  Google Scholar 

  38. Etminan N, Vergouwen MD, Ilodigwe D, Macdonald RL (2011) Effect of pharmaceutical treatment on vasospasm, delayed cerebral ischemia, and clinical outcome in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. J Cereb Blood Flow Metab 31:1443–1451

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Fabricius M, Jensen LH, Lauritzen M (1993) Microdialysis of interstitial amino acids during spreading depression and anoxic depolarization in rat neocortex. Brain Res 612:61–69

    Article  PubMed  CAS  Google Scholar 

  40. Feigin VL, Lawes CM, Bennett DA, Barker-Collo SL, Parag V (2009) Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. Lancet Neurol 8:355–369

    Article  PubMed  Google Scholar 

  41. Fisher CM, Kistler JP, Davis JM (1980) Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by computerized tomographic scanning. Neurosurgery 6:1–9

    Article  PubMed  CAS  Google Scholar 

  42. Fisher CM, Roberson GH, Ojemann RG (1977) Cerebral vasospasm with ruptured saccular aneurysm--the clinical manifestations. Neurosurgery 1:245–248

    Article  PubMed  CAS  Google Scholar 

  43. Foreman B (2016) The pathophysiology of delayed cerebral ischemia. J Clin Neurophysiol 33:174–182

    Article  PubMed  Google Scholar 

  44. Fountas KN, Tasiou A, Kapsalaki EZ, Paterakis KN, Grigorian AA, Lee GP, Robinson JS Jr (2009) Serum and cerebrospinal fluid C-reactive protein levels as predictors of vasospasm in aneurysmal subarachnoid hemorrhage. Clinical article Neurosurg Focus 26:E22

    Article  PubMed  Google Scholar 

  45. Friedrich B, Muller F, Feiler S, Scholler K, Plesnila N (2012) Experimental subarachnoid hemorrhage causes early and long-lasting microarterial constriction and microthrombosis: an in-vivo microscopy study. J Cereb Blood Flow Metab 32:447–455

    Article  PubMed  CAS  Google Scholar 

  46. Friedrich V, Flores R, Muller A, Sehba FA (2010) Luminal platelet aggregates in functional deficits in parenchymal vessels after subarachnoid hemorrhage. Brain Res 1354:179–187

    Article  PubMed  CAS  Google Scholar 

  47. Friedrich V, Flores R, Sehba FA (2012) Cell death starts early after subarachnoid hemorrhage. Neurosci Lett 512:6–11

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Fu P, Hu Q (2016) 3,4-Dihydroxyphenylethanol alleviates early brain injury by modulating oxidative stress and Akt and nuclear factor-kappaB pathways in a rat model of subarachnoid hemorrhage. Exp Ther Med 11:1999–2004

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Gioia AE, White RP, Bakhtian B, Robertson JT (1985) Evaluation of the efficacy of intrathecal nimodipine in canine models of chronic cerebral vasospasm. J Neurosurg 62:721–728

    Article  PubMed  CAS  Google Scholar 

  50. Gomis P, Graftieaux JP, Sercombe R, Hettler D, Scherpereel B, Rousseaux P (2010) Randomized, double-blind, placebo-controlled, pilot trial of high-dose methylprednisolone in aneurysmal subarachnoid hemorrhage. J Neurosurg 112:681–688

    Article  PubMed  CAS  Google Scholar 

  51. Grafstein B (1956) Mechanism of spreading cortical depression. J Neurophysiol 19:154–171

    Article  PubMed  CAS  Google Scholar 

  52. Grote E, Hassler W (1988) The critical first minutes after subarachnoid hemorrhage. Neurosurgery 22:654–661

    Article  PubMed  CAS  Google Scholar 

  53. Handa Y, Kubota T, Kaneko M, Tsuchida A, Kobayashi H, Kawano H, Kubota T (1995) Expression of intercellular adhesion molecule 1 (ICAM-1) on the cerebral artery following subarachnoid haemorrhage in rats. Acta Neurochir 132:92–97

    Article  PubMed  CAS  Google Scholar 

  54. Hanggi D, Eicker S, Beseoglu K, Behr J, Turowski B, Steiger HJ (2009) A multimodal concept in patients after severe aneurysmal subarachnoid hemorrhage: results of a controlled single Centre prospective randomized multimodal phase I/II trial on cerebral vasospasm. Cent Eur Neurosurg 70:61–67

    Article  PubMed  CAS  Google Scholar 

  55. Hanggi D, Etminan N, Aldrich F, Steiger HJ, Mayer SA, Diringer MN, Hoh BL, Mocco J, Faleck HJ, Macdonald RL, Investigators N (2017) Randomized, open-label, phase 1/2a study to determine the maximum tolerated dose of intraventricular sustained release nimodipine for subarachnoid hemorrhage (NEWTON [nimodipine microparticles to enhance recovery while reducing toxicity after subarachnoid hemorrhage]). Stroke 48:145–151

    Article  PubMed  CAS  Google Scholar 

  56. Hanggi D, Etminan N, Macdonald RL, Steiger HJ, Mayer SA, Aldrich F, Diringer MN, Hoh BL, Mocco J, Strange P, Faleck HJ, Miller M (2015) NEWTON: nimodipine microparticles to enhance recovery while reducing toxicity after subarachnoid hemorrhage. Neurocrit Care 23:274–284

    Article  PubMed  CAS  Google Scholar 

  57. Hanggi D, Perrin J, Eicker S, Beseoglu K, Etminan N, Kamp MA, Heiroth HJ, Bege N, Macht S, Frauenknecht K, Sommer C, Kissel T, Steiger HJ (2012) Local delivery of nimodipine by prolonged-release microparticles-feasibility, effectiveness and dose-finding in experimental subarachnoid hemorrhage. PLoS One 7:e42597

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Hart MN (1980) Morphometry of brain parenchymal vessels following subarachnoid hemorrhage. Stroke 11:653–655

    Article  PubMed  CAS  Google Scholar 

  59. Hijdra A, Van Gijn J, Stefanko S, Van Dongen KJ, Vermeulen M, Van Crevel H (1986) Delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage: clinicoanatomic correlations. Neurology 36:329–333

    Article  PubMed  CAS  Google Scholar 

  60. Honda M, Sase S, Yokota K, Ichibayashi R, Yoshihara K, Sakata Y, Masuda H, Uekusa H, Seiki Y, Kishi T (2012) Early cerebral circulatory disturbance in patients suffering subarachnoid hemorrhage prior to the delayed cerebral vasospasm stage: xenon computed tomography and perfusion computed tomography study. Neurol Med Chir (Tokyo) 52:488–494

    Article  Google Scholar 

  61. Hop JW, Rinkel GJ, Algra A, van Gijn J (1997) Case-fatality rates and functional outcome after subarachnoid hemorrhage: a systematic review. Stroke 28:660–664

    Article  PubMed  CAS  Google Scholar 

  62. Horstmann S, Su Y, Koziol J, Meyding-Lamade U, Nagel S, Wagner S (2006) MMP-2 and MMP-9 levels in peripheral blood after subarachnoid hemorrhage. J Neurol Sci 251:82–86

    Article  PubMed  CAS  Google Scholar 

  63. Huang L, Wan J, Chen Y, Wang Z, Hui L, Li Y, Xu D, Zhou W (2013) Inhibitory effects of p38 inhibitor against mitochondrial dysfunction in the early brain injury after subarachnoid hemorrhage in mice. Brain Res 1517:133–140

    Article  PubMed  CAS  Google Scholar 

  64. Ishiguro M, Wellman GC (2008) Cellular basis of vasospasm: role of small diameter arteries and voltage-dependent Ca2+ channels. Acta Neurochir Suppl 104:95–98

    Article  PubMed  CAS  Google Scholar 

  65. Ishiguro M, Wellman TL, Honda A, Russell SR, Tranmer BI, Wellman GC (2005) Emergence of a R-type Ca2+ channel (CaV 2.3) contributes to cerebral artery constriction after subarachnoid hemorrhage. Circ Res 96:419–426

    Article  PubMed  CAS  Google Scholar 

  66. Iuliano BA, Pluta RM, Jung C, Oldfield EH (2004) Endothelial dysfunction in a primate model of cerebral vasospasm. J Neurosurg 100:287–294

    Article  PubMed  Google Scholar 

  67. Jaeger M, Schuhmann MU, Soehle M, Nagel C, Meixensberger J (2007) Continuous monitoring of cerebrovascular autoregulation after subarachnoid hemorrhage by brain tissue oxygen pressure reactivity and its relation to delayed cerebral infarction. Stroke 38:981–986

    Article  PubMed  Google Scholar 

  68. Jaeger M, Soehle M, Schuhmann MU, Meixensberger J (2012) Clinical significance of impaired cerebrovascular autoregulation after severe aneurysmal subarachnoid hemorrhage. Stroke 43:2097–2101

    Article  PubMed  Google Scholar 

  69. Jakubowski J, Bell BA, Symon L, Zawirski MB, Francis DM (1982) A primate model of subarachnoid hemorrhage: change in regional cerebral blood flow, autoregulation carbon dioxide reactivity, and central conduction time. Stroke 13:601–611

    Article  PubMed  CAS  Google Scholar 

  70. Jung CS, Iuliano BA, Harvey-White J, Espey MG, Oldfield EH, Pluta RM (2004) Association between cerebrospinal fluid levels of asymmetric dimethyl-L-arginine, an endogenous inhibitor of endothelial nitric oxide synthase, and cerebral vasospasm in a primate model of subarachnoid hemorrhage. J Neurosurg 101:836–842

    Article  PubMed  CAS  Google Scholar 

  71. Kacira T, Kemerdere R, Atukeren P, Hanimoglu H, Sanus GZ, Kucur M, Tanriverdi T, Gumustas K, Kaynar MY (2007) Detection of caspase-3, neuron specific enolase, and high-sensitivity C-reactive protein levels in both cerebrospinal fluid and serum of patients after aneurysmal subarachnoid hemorrhage. Neurosurgery 60:674–679 discussion 679-680

    Article  PubMed  Google Scholar 

  72. Kamiya K, Kuyama H, Symon L (1983) An experimental study of the acute stage of subarachnoid hemorrhage. J Neurosurg 59:917–924

    Article  PubMed  CAS  Google Scholar 

  73. Kamp MA, Dibue M, Etminan N, Steiger HJ, Schneider T, Hanggi D (2013) Evidence for direct impairment of neuronal function by subarachnoid metabolites following SAH. Acta Neurochir 155:255–260

    Article  PubMed  Google Scholar 

  74. Kamp MA, Dibue M, Schneider T, Steiger HJ, Hanggi D (2012) Calcium and potassium channels in experimental subarachnoid hemorrhage and transient global ischemia. Stroke Res Treat 2012:382146

    PubMed  PubMed Central  Google Scholar 

  75. Kamp MA, Dibue M, Sommer C, Steiger HJ, Schneider T, Hanggi D (2014) Evaluation of a murine single-blood-injection SAH model. PLoS One 9:e114946

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Kamp MA, Heiroth HJ, Beseoglu K, Turowski B, Steiger HJ, Hanggi D (2012) Early CT perfusion measurement after aneurysmal subarachnoid hemorrhage: a screening method to predict outcome? Acta Neurochir Suppl 114:329–332

    Article  PubMed  Google Scholar 

  77. Kamp MA, van Lieshout JH, Dibué-Adjei M, Weber JK, Schneider T, Restin T, Fischer I, Steiger H-J (2017) A systematic and meta-analysis of mortality in experimental mouse models analyzing delayed cerebral ischemia after subarachnoid hemorrhage. Transl Stroke Res:in press

  78. Kasuya H (2011) Clinical trial of nicardipine prolonged-release implants for preventing cerebral vasospasm: multicenter cooperative study in Tokyo. Acta Neurochir Suppl 110:165–167

    PubMed  CAS  Google Scholar 

  79. Kasuya H, Onda H, Sasahara A, Takeshita M, Hori T (2005) Application of nicardipine prolonged-release implants: analysis of 97 consecutive patients with acute subarachnoid hemorrhage. Neurosurgery 56:895–902 discussion 895-902

    PubMed  Google Scholar 

  80. Kasuya H, Onda H, Takeshita M, Okada Y, Hori T (2002) Efficacy and safety of nicardipine prolonged-release implants for preventing vasospasm in humans. Stroke 33:1011–1015

    Article  PubMed  CAS  Google Scholar 

  81. Kawamata T, Aoki N, Sakai T, Arai K (1993) Symptomatic cerebral vasospasm manifested 18 days after aneurysmal subarachnoid haemorrhage. Neurol Res 15:209–211

    Article  PubMed  CAS  Google Scholar 

  82. Kaynar MY, Tanriverdi T, Kafadar AM, Kacira T, Uzun H, Aydin S, Gumustas K, Dirican A, Kuday C (2004) Detection of soluble intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in both cerebrospinal fluid and serum of patients after aneurysmal subarachnoid hemorrhage. J Neurosurg 101:1030–1036

    Article  PubMed  CAS  Google Scholar 

  83. Keep RF, Andjelkovic AV, Stamatovic SM, Shakui P, Ennis SR (2005) Ischemia-induced endothelial cell dysfunction. Acta Neurochir Suppl 95:399–402

    Article  PubMed  CAS  Google Scholar 

  84. Kim GH, Kellner CP, Hahn DK, Desantis BM, Musabbir M, Starke RM, Rynkowski M, Komotar RJ, Otten ML, Sciacca R, Schmidt JM, Mayer SA, Connolly ES Jr (2008) Monocyte chemoattractant protein-1 predicts outcome and vasospasm following aneurysmal subarachnoid hemorrhage. J Neurosurg 109:38–43

    Article  PubMed  CAS  Google Scholar 

  85. Korja M, Kaprio J (2016) Controversies in epidemiology of intracranial aneurysms and SAH. Nat Rev Neurol 12:50–55

    Article  PubMed  Google Scholar 

  86. Korja M, Lehto H, Juvela S, Kaprio J (2016) Incidence of subarachnoid hemorrhage is decreasing together with decreasing smoking rates. Neurology 87:1118–1123

    Article  PubMed  PubMed Central  Google Scholar 

  87. Kow LM, van Harreveld A (1972) Ion and water movements in isolated chicken retinas during spreading depression. Neurobiology 2:61–69

    PubMed  CAS  Google Scholar 

  88. Kraig RP, Nicholson C (1978) Extracellular ionic variations during spreading depression. Neuroscience 3:1045–1059

    Article  PubMed  CAS  Google Scholar 

  89. Kreiter KT, Mayer SA, Howard G, Knappertz V, Ilodigwe D, Sloan MA, Macdonald RL (2009) Sample size estimates for clinical trials of vasospasm in subarachnoid hemorrhage. Stroke 40:2362–2367

    Article  PubMed  Google Scholar 

  90. Kubo Y, Ogasawara K, Kakino S, Kashimura H, Tomitsuka N, Sugawara A, Ogawa A (2008) Serum inflammatory adhesion molecules and high-sensitivity C-reactive protein correlates with delayed ischemic neurologic deficits after subarachnoid hemorrhage. Surg Neurol 69:592–596 discussion 596

    Article  PubMed  Google Scholar 

  91. Kummer TT, Magnoni S, MacDonald CL, Dikranian K, Milner E, Sorrell J, Conte V, Benetatos JJ, Zipfel GJ, Brody DL (2015) Experimental subarachnoid haemorrhage results in multifocal axonal injury. Brain 138:2608–2618

    Article  PubMed  PubMed Central  Google Scholar 

  92. Kunkler PE, Hulse RE, Schmitt MW, Nicholson C, Kraig RP (2005) Optical current source density analysis in hippocampal organotypic culture shows that spreading depression occurs with uniquely reversing currents. J Neurosci 25:3952–3961

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Kusaka G, Ishikawa M, Nanda A, Granger DN, Zhang JH (2004) Signaling pathways for early brain injury after subarachnoid hemorrhage. J Cereb Blood Flow Metab 24:916–925

    Article  PubMed  CAS  Google Scholar 

  94. Lauritzen M, Dreier JP, Fabricius M, Hartings JA, Graf R, Strong AJ (2011) Clinical relevance of cortical spreading depression in neurological disorders: migraine, malignant stroke, subarachnoid and intracranial hemorrhage, and traumatic brain injury. J Cereb Blood Flow Metab 31:17–35

    Article  PubMed  Google Scholar 

  95. Leao A (1944) Spreading depression of activity in cerebral cortex. J Neurophysiol 7:359–390

    Article  Google Scholar 

  96. Lee JY, He Y, Sagher O, Keep R, Hua Y, Xi G (2009) Activated autophagy pathway in experimental subarachnoid hemorrhage. Brain Res 1287:126–135

    Article  PubMed  CAS  Google Scholar 

  97. Lewis PJ, Weir BK, Nosko MG, Tanabe T, Grace MG (1988) Intrathecal nimodipine therapy in a primate model of chronic cerebral vasospasm. Neurosurgery 22:492–500

    Article  PubMed  CAS  Google Scholar 

  98. Link TE, Murakami K, Beem-Miller M, Tranmer BI, Wellman GC (2008) Oxyhemoglobin-induced expression of R-type Ca2+ channels in cerebral arteries. Stroke 39:2122–2128

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Longstreth WT Jr, Nelson LM, Koepsell TD, van Belle G (1993) Clinical course of spontaneous subarachnoid hemorrhage: a population-based study in King County, Washington. Neurology 43:712–718

    Article  PubMed  Google Scholar 

  100. Lovelock CE, Rinkel GJ, Rothwell PM (2010) Time trends in outcome of subarachnoid hemorrhage: population-based study and systematic review. Neurology 74:1494–1501

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Ma J, Wang Z, Liu C, Shen H, Chen Z, Yin J, Zuo G, Duan X, Li H, Chen G (2016) Pramipexole-induced hypothermia reduces early brain injury via PI3K/AKT/GSK3beta pathway in subarachnoid hemorrhage rats. Sci Rep 6:23817

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Macdonald RL (2014) Delayed neurological deterioration after subarachnoid haemorrhage. Nat Rev Neurol 10:44–58

    Article  PubMed  CAS  Google Scholar 

  103. Macdonald RL (2016) Origins of the concept of vasospasm. Stroke 47:e11–e15

    Article  PubMed  Google Scholar 

  104. Macdonald RL, Kassell NF, Mayer S, Ruefenacht D, Schmiedek P, Weidauer S, Frey A, Roux S, Pasqualin A, Investigators C (2008) Clazosentan to overcome neurological ischemia and infarction occurring after subarachnoid hemorrhage (CONSCIOUS-1): randomized, double-blind, placebo-controlled phase 2 dose-finding trial. Stroke 39:3015–3021

    Article  PubMed  CAS  Google Scholar 

  105. Mack WJ, Mocco J, Hoh DJ, Huang J, Choudhri TF, Kreiter KT, Lozier A, Opperman M, Poisik A, Yorgason J, Solomon RA, Mayer SA, Connolly ES (2002) Outcome prediction with serum intercellular adhesion molecule-1 levels after aneurysmal subarachnoid hemorrhage. J Neurosurg 96:71–75

    Article  PubMed  CAS  Google Scholar 

  106. Manno EM, Gress DR, Ogilvy CS, Stone CM, Zervas NT (1997) The safety and efficacy of cyclosporine a in the prevention of vasospasm in patients with fisher grade 3 subarachnoid hemorrhages: a pilot study. Neurosurgery 40:289–293

    Article  PubMed  CAS  Google Scholar 

  107. Mathys C, Martens D, Reichelt DC, Caspers J, Aissa J, May R, Hanggi D, Antoch G, Turowski B (2013) Long-term impact of perfusion CT data after subarachnoid hemorrhage. Neuroradiology 55:1323–1331

    Article  PubMed  Google Scholar 

  108. Matz PG, Fujimura M, Lewen A, Morita-Fujimura Y, Chan PH (2001) Increased cytochrome c-mediated DNA fragmentation and cell death in manganese-superoxide dismutase-deficient mice after exposure to subarachnoid hemolysate. Stroke 32:506–515

    Article  PubMed  CAS  Google Scholar 

  109. Mayberg MR, Batjer HH, Dacey R, Diringer M, Haley EC, Heros RC, Sternau LL, Torner J, Adams HP Jr, Feinberg W et al (1994) 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 90:2592–2605

    Article  PubMed  CAS  Google Scholar 

  110. Miller BA, Turan N, Chau M, Pradilla G (2014) Inflammation, vasospasm, and brain injury after subarachnoid hemorrhage. Biomed Res Int 2014:384342

    PubMed  PubMed Central  Google Scholar 

  111. Mocco J, Mack WJ, Kim GH, Lozier AP, Laufer I, Kreiter KT, Sciacca RR, Solomon RA, Mayer SA, Connolly ES Jr (2002) Rise in serum soluble intercellular adhesion molecule-1 levels with vasospasm following aneurysmal subarachnoid hemorrhage. J Neurosurg 97:537–541

    Article  PubMed  CAS  Google Scholar 

  112. Moghaddam B, Schenk JO, Stewart WB, Hansen AJ (1987) Temporal relationship between neurotransmitter release and ion flux during spreading depression and anoxia. Can J Physiol Pharmacol 65:1105–1110

    Article  PubMed  CAS  Google Scholar 

  113. Mutch WA, Hansen AJ (1984) Extracellular pH changes during spreading depression and cerebral ischemia: mechanisms of brain pH regulation. J Cereb Blood Flow Metab 4:17–27

    Article  PubMed  CAS  Google Scholar 

  114. Nikitina E, Kawashima A, Takahashi M, Zhang ZD, Shang X, Ai J, Macdonald RL (2010) Alteration in voltage-dependent calcium channels in dog basilar artery after subarachnoid hemorrhage. Laboratory investigation J Neurosurg 113:870–880

    PubMed  CAS  Google Scholar 

  115. Nornes H (1973) The role of intracranial pressure in the arrest of hemorrhage in patients with ruptured intracranial aneurysm. J Neurosurg 39:226–234

    Article  PubMed  CAS  Google Scholar 

  116. Nornes H (1978) Cerebral arterial flow dynamics during aneurysm haemorrhage. Acta Neurochir 41:39–48

    Article  PubMed  CAS  Google Scholar 

  117. Ohkuma H, Itoh K, Shibata S, Suzuki S (1997) Morphological changes of intraparenchymal arterioles after experimental subarachnoid hemorrhage in dogs. Neurosurgery 41:230–235 discussion 235-236

    Article  PubMed  CAS  Google Scholar 

  118. Ohno K, Masaoka H, Suzuki R, Monma S, Matsushima Y (1991) Symptomatic cerebral vasospasm of unusually late onset after aneurysm rupture. Acta Neurochir 108:163–166

    Article  PubMed  CAS  Google Scholar 

  119. Ohta H, Ito Z (1981) Cerebral infraction due to vasospasm, revealed by computed tomography (author's transl). Neurol Med Chir (Tokyo) 21:365–372

    Article  CAS  Google Scholar 

  120. Ostergaard L, Aamand R, Karabegovic S, Tietze A, Blicher JU, Mikkelsen IK, Iversen NK, Secher N, Engedal TS, Anzabi M, Jimenez EG, Cai C, Koch KU, Naess-Schmidt ET, Obel A, Juul N, Rasmussen M, Sorensen JC (2013) The role of the microcirculation in delayed cerebral ischemia and chronic degenerative changes after subarachnoid hemorrhage. J Cereb Blood Flow Metab 33:1825–1837

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Park S, Yamaguchi M, Zhou C, Calvert JW, Tang J, Zhang JH (2004) Neurovascular protection reduces early brain injury after subarachnoid hemorrhage. Stroke 35:2412–2417

    Article  PubMed  CAS  Google Scholar 

  122. Paschen W, Mengesdorf T (2005) Cellular abnormalities linked to endoplasmic reticulum dysfunction in cerebrovascular disease--therapeutic potential. Pharmacol Ther 108:362–375

    Article  PubMed  CAS  Google Scholar 

  123. Pasparakis M (2009) Regulation of tissue homeostasis by NF-kappaB signalling: implications for inflammatory diseases. Nat Rev Immunol 9:778–788

    Article  PubMed  CAS  Google Scholar 

  124. Prunell GF, Mathiesen T, Diemer NH, Svendgaard NA (2003) Experimental subarachnoid hemorrhage: subarachnoid blood volume, mortality rate, neuronal death, cerebral blood flow, and perfusion pressure in three different rat models. Neurosurgery 52:165–175 discussion 175-166

    PubMed  Google Scholar 

  125. Prunell GF, Svendgaard NA, Alkass K, Mathiesen T (2005) Delayed cell death related to acute cerebral blood flow changes following subarachnoid hemorrhage in the rat brain. J Neurosurg 102:1046–1054

    Article  PubMed  Google Scholar 

  126. Prunell GF, Svendgaard NA, Alkass K, Mathiesen T (2005) Inflammation in the brain after experimental subarachnoid hemorrhage. Neurosurgery 56:1082–1092 discussion 1082-1092

    PubMed  Google Scholar 

  127. Rasmussen G, Hauerberg J, Waldemar G, Gjerris F, Juhler M (1992) Cerebral blood flow autoregulation in experimental subarachnoid haemorrhage in rat. Acta Neurochir 119:128–133

    Article  PubMed  CAS  Google Scholar 

  128. Reilly C, Amidei C, Tolentino J, Jahromi BS, Macdonald RL (2004) Clot volume and clearance rate as independent predictors of vasospasm after aneurysmal subarachnoid hemorrhage. J Neurosurg 101:255–261

    Article  PubMed  Google Scholar 

  129. Romano JG, Forteza AM, Concha M, Koch S, Heros RC, Morcos JJ, Babikian VL (2002) Detection of microemboli by transcranial Doppler ultrasonography in aneurysmal subarachnoid hemorrhage. Neurosurgery 50:1026–1030 discussion 1030-1021

    PubMed  Google Scholar 

  130. Romano JG, Rabinstein AA, Arheart KL, Nathan S, Campo-Bustillo I, Koch S, Forteza AM (2008) Microemboli in aneurysmal subarachnoid hemorrhage. J Neuroimaging 18:396–401

    Article  PubMed  Google Scholar 

  131. Roos YB, de Haan RJ, Beenen LF, Groen RJ, Albrecht KW, Vermeulen M (2000) Complications and outcome in patients with aneurysmal subarachnoid haemorrhage: a prospective hospital based cohort study in the Netherlands. J Neurol Neurosurg Psychiatry 68:337–341

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Rothoerl RD, Axmann C, Pina AL, Woertgen C, Brawanski A (2006) Possible role of the C-reactive protein and white blood cell count in the pathogenesis of cerebral vasospasm following aneurysmal subarachnoid hemorrhage. J Neurosurg Anesthesiol 18:68–72

    Article  PubMed  Google Scholar 

  133. Ryba M, Pastuszko M, Iwanska K, Bidzinski J, Dziewiecki C (1991) Cyclosporine a prevents neurological deterioration of patients with SAH--a preliminary report. Acta Neurochir 112:25–27

    Article  PubMed  CAS  Google Scholar 

  134. Sabri M, Ai J, Knight B, Tariq A, Jeon H, Shang X, Marsden PA, Loch Macdonald R (2011) Uncoupling of endothelial nitric oxide synthase after experimental subarachnoid hemorrhage. J Cereb Blood Flow Metab 31:190–199

    Article  PubMed  CAS  Google Scholar 

  135. Sabri M, Ai J, Lakovic K, D'Abbondanza J, Ilodigwe D, Macdonald RL (2012) Mechanisms of microthrombi formation after experimental subarachnoid hemorrhage. Neuroscience 224:26–37

    Article  PubMed  CAS  Google Scholar 

  136. Sabri M, Ai J, Lakovic K, Macdonald RL (2013) Mechanisms of microthrombosis and microcirculatory constriction after experimental subarachnoid hemorrhage. Acta Neurochir Suppl 115:185–192

    PubMed  Google Scholar 

  137. Sabri M, Jeon H, Ai J, Tariq A, Shang X, Chen G, Macdonald RL (2009) Anterior circulation mouse model of subarachnoid hemorrhage. Brain Res 1295:179–185

    Article  PubMed  CAS  Google Scholar 

  138. Sanelli PC, Jou A, Gold R, Reichman M, Greenberg E, John M, Cayci Z, Ugorec I, Rosengart A (2011) Using CT perfusion during the early baseline period in aneurysmal subarachnoid hemorrhage to assess for development of vasospasm. Neuroradiology 53:425–434

    Article  PubMed  Google Scholar 

  139. Sarkar FH, Li Y, Wang Z, Kong D (2008) NF-kappaB signaling pathway and its therapeutic implications in human diseases. Int Rev Immunol 27:293–319

    Article  PubMed  CAS  Google Scholar 

  140. Schmieder K, Moller F, Engelhardt M, Scholz M, Schregel W, Christmann A, Harders A (2006) Dynamic cerebral autoregulation in patients with ruptured and unruptured aneurysms after induction of general anesthesia. Zentralbl Neurochir 67:81–87

    Article  PubMed  CAS  Google Scholar 

  141. Schneider UC, Davids AM, Brandenburg S, Muller A, Elke A, Magrini S, Atangana E, Turkowski K, Finger T, Gutenberg A, Gehlhaar C, Bruck W, Heppner FL, Vajkoczy P (2015) Microglia inflict delayed brain injury after subarachnoid hemorrhage. Acta Neuropathol 130:215–231

    Article  PubMed  Google Scholar 

  142. Schubert GA, Seiz M, Hegewald AA, Manville J, Thome C (2009) Acute hypoperfusion immediately after subarachnoid hemorrhage: a xenon contrast-enhanced CT study. J Neurotrauma 26:2225–2231

    Article  PubMed  Google Scholar 

  143. Sehba FA, Friedrich V (2013) Cerebral microvasculature is an early target of subarachnoid hemorrhage. Acta Neurochir Suppl 115:199–205

    PubMed  Google Scholar 

  144. Sehba FA, Hou J, Pluta RM, Zhang JH (2012) The importance of early brain injury after subarachnoid hemorrhage. Prog Neurobiol 97:14–37

    Article  PubMed  PubMed Central  Google Scholar 

  145. Sehba FA, Pluta RM, Zhang JH (2011) Metamorphosis of subarachnoid hemorrhage research: from delayed vasospasm to early brain injury. Mol Neurobiol 43:27–40

    Article  PubMed  CAS  Google Scholar 

  146. Smith CM, Chen Y, Sullivan ML, Kochanek PM, Clark RS (2011) Autophagy in acute brain injury: feast, famine, or folly? Neurobiol Dis 43:52–59

    Article  PubMed  CAS  Google Scholar 

  147. Somjen GG (2001) Mechanisms of spreading depression and hypoxic spreading depression-like depolarization. Physiol Rev 81:1065–1096

    Article  PubMed  CAS  Google Scholar 

  148. Stegmayr B, Eriksson M, Asplund K (2004) Declining mortality from subarachnoid hemorrhage: changes in incidence and case fatality from 1985 through 2000. Stroke 35:2059–2063

    Article  PubMed  Google Scholar 

  149. Steiger HJ, Beez T, Beseoglu K, Hanggi D, Kamp MA (2015) Perioperative measures to improve outcome after subarachnoid hemorrhage-revisiting the concept of secondary brain injury. Acta Neurochir Suppl 120:211–216

    PubMed  Google Scholar 

  150. Stein SC, Browne KD, Chen XH, Smith DH, Graham DI (2006) Thromboembolism and delayed cerebral ischemia after subarachnoid hemorrhage: an autopsy study. Neurosurgery 59:781–787 discussion 787-788

    Article  PubMed  Google Scholar 

  151. Stephens GJ, Page KM, Burley JR, Berrow NS, Dolphin AC (1997) Functional expression of rat brain cloned alpha1E calcium channels in COS-7 cells. Pflugers Arch 433:523–532

    Article  PubMed  CAS  Google Scholar 

  152. Suzuki S, Kimura M, Souma M, Ohkima H, Shimizu T, Iwabuchi T (1990) Cerebral microthrombosis in symptomatic cerebral vasospasm--a quantitative histological study in autopsy cases. Neurol Med Chir (Tokyo) 30:309–316

    Article  CAS  Google Scholar 

  153. Takano T, Tian GF, Peng W, Lou N, Lovatt D, Hansen AJ, Kasischke KA, Nedergaard M (2007) Cortical spreading depression causes and coincides with tissue hypoxia. Nat Neurosci 10:754–762

    Article  PubMed  CAS  Google Scholar 

  154. Tanriverdi T, Sanus GZ, Ulu MO, Tureci E, Uzun H, Aydin S, Kaynar MY (2005) Serum and cerebrospinal fluid concentrations of E-selectin in patients with aneurysmal subarachnoid hemorrhage. Braz J Med Biol Res 38:1703–1710

    Article  PubMed  CAS  Google Scholar 

  155. Tateyama K, Kobayashi S, Murai Y, Teramoto A (2013) Assessment of cerebral circulation in the acute phase of subarachnoid hemorrhage using perfusion computed tomography. J Nippon Med Sch 80:110–118

    Article  PubMed  Google Scholar 

  156. Thome C, Seiz M, Schubert GA, Barth M, Vajkoczy P, Kasuya H, Schmiedek P (2011) Nicardipine pellets for the prevention of cerebral vasospasm. Acta Neurochir Suppl 110:209–211

    PubMed  Google Scholar 

  157. Trojanowski T (1982) Experimental subarachnoid haemorrhage. Part I a new approach to subarachnoid blood injection in cats Acta Neurochir (Wien) 62:171–175

    CAS  Google Scholar 

  158. Trojanowski T (1982) Experimental subarachnoid haemorrhage. Part II: extravasation volume and dynamics of subarachnoid arterial bleeding in cats. Acta Neurochir 64:103–108

    Article  PubMed  CAS  Google Scholar 

  159. Tsuang FY, Chen JY, Lee CW, Li CH, Lee JE, Lai DM, Hu FC, Tu YK, Hsieh ST, Wang KC (2012) Risk profile of patients with poor-grade aneurysmal subarachnoid hemorrhage using early perfusion computed tomography. World Neurosurg 78:455–461

    Article  PubMed  Google Scholar 

  160. Turowski B, Haenggi D, Wittsack J, Beck A, Moedder U (2007) Cerebral perfusion computerized tomography in vasospasm after subarachnoid hemorrhage: diagnostic value of MTT. Rofo 179:847–854

    Article  PubMed  CAS  Google Scholar 

  161. van der Schaaf I, Wermer MJ, van der Graaf Y, Hoff RG, Rinkel GJ, Velthuis BK (2006) CT after subarachnoid hemorrhage: relation of cerebral perfusion to delayed cerebral ischemia. Neurology 66:1533–1538

    Article  PubMed  Google Scholar 

  162. van Gijn J, Kerr RS, Rinkel GJ (2007) Subarachnoid haemorrhage. Lancet 369:306–318

    Article  PubMed  Google Scholar 

  163. Van Harreveld A, Fifkova E (1970) Glutamate release from the retina during spreading depression. J Neurobiol 2:13–29

    Article  PubMed  CAS  Google Scholar 

  164. Vergouwen MD, Etminan N, Ilodigwe D, Macdonald RL (2011) Lower incidence of cerebral infarction correlates with improved functional outcome after aneurysmal subarachnoid hemorrhage. J Cereb Blood Flow Metab 31:1545–1553

    Article  PubMed  PubMed Central  Google Scholar 

  165. Vergouwen MD, Participants in the International Multi-Disciplinary Consensus Conference on the Critical Care Management of Subarachnoid H (2011) Vasospasm versus delayed cerebral ischemia as an outcome event in clinical trials and observational studies. Neurocrit Care 15:308–311

    Article  PubMed  Google Scholar 

  166. Vergouwen MD, Vermeulen M, Coert BA, Stroes ES, Roos YB (2008) Microthrombosis after aneurysmal subarachnoid hemorrhage: an additional explanation for delayed cerebral ischemia. J Cereb Blood Flow Metab 28:1761–1770

    Article  PubMed  Google Scholar 

  167. Vergouwen MD, Vermeulen M, van Gijn J, Rinkel GJ, Wijdicks EF, Muizelaar JP, Mendelow AD, Juvela S, Yonas H, Terbrugge KG, Macdonald RL, Diringer MN, Broderick JP, Dreier JP, Roos YB (2010) 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 41:2391–2395

    Article  PubMed  Google Scholar 

  168. Voldby B (1988) Pathophysiology of subarachnoid haemorrhage. Experimental and clinical data. Acta Neurochir Suppl (Wien) 45:1–6

    Article  CAS  Google Scholar 

  169. Voldby B, Enevoldsen EM (1982) Intracranial pressure changes following aneurysm rupture. Part 3: recurrent hemorrhage. J Neurosurg 56:784–789

    Article  PubMed  CAS  Google Scholar 

  170. Voldby B, Petersen OF, Buhl M, Jakobsen P, Ostergaard R (1984) Reversal of cerebral arterial spasm by intrathecal administration of a calcium antagonist (nimodipine). Acta Neurochir 70:243–254

    Article  PubMed  CAS  Google Scholar 

  171. von Bornstadt D, Houben T, Seidel JL, Zheng Y, Dilekoz E, Qin T, Sandow N, Kura S, Eikermann-Haerter K, Endres M, Boas DA, Moskowitz MA, Lo EH, Dreier JP, Woitzik J, Sakadzic S, Ayata C (2015) Supply-demand mismatch transients in susceptible peri-infarct hot zones explain the origins of spreading injury depolarizations. Neuron 85:1117–1131

    Article  CAS  Google Scholar 

  172. Vora YY, Suarez-Almazor M, Steinke DE, Martin ML, Findlay JM (1999) Role of transcranial Doppler monitoring in the diagnosis of cerebral vasospasm after subarachnoid hemorrhage. Neurosurgery 44:1237–1247 discussion 1247-1238

    PubMed  CAS  Google Scholar 

  173. Wang F, Yin YH, Jia F, Jiang JY (2010) Antagonism of R-type calcium channels significantly improves cerebral blood flow after subarachnoid hemorrhage in rats. J Neurotrauma 27:1723–1732

    Article  PubMed  Google Scholar 

  174. Weiergraber M, Henry M, Sudkamp M, de Vivie ER, Hescheler J, Schneider T (2005) Ablation of Ca(v)2.3 / E-type voltage-gated calcium channel results in cardiac arrhythmia and altered autonomic control within the murine cardiovascular system. Basic Res Cardiol 100:1–13

    Article  PubMed  CAS  Google Scholar 

  175. Weir B, Grace M, Hansen J, Rothberg C (1978) Time course of vasospasm in man. J Neurosurg 48:173–178

    Article  PubMed  CAS  Google Scholar 

  176. Westermaier T, Jauss A, Eriskat J, Kunze E, Roosen K (2009) Acute vasoconstriction: decrease and recovery of cerebral blood flow after various intensities of experimental subarachnoid hemorrhage in rats. J Neurosurg 110:996–1002

    Article  PubMed  Google Scholar 

  177. Westermaier T, Jauss A, Eriskat J, Kunze E, Roosen K (2009) Time-course of cerebral perfusion and tissue oxygenation in the first 6 h after experimental subarachnoid hemorrhage in rats. J Cereb Blood Flow Metab 29:771–779

    Article  PubMed  Google Scholar 

  178. Windmuller O, Lindauer U, Foddis M, Einhaupl KM, Dirnagl U, Heinemann U, Dreier JP (2005) Ion changes in spreading ischaemia induce rat middle cerebral artery constriction in the absence of NO. Brain 128:2042–2051

    Article  PubMed  Google Scholar 

  179. Yanamoto H, Kikuchi H, Sato M, Shimizu Y, Yoneda S, Okamoto S (1992) Therapeutic trial of cerebral vasospasm with the serine protease inhibitor, FUT-175, administered in the acute stage after subarachnoid hemorrhage. Neurosurgery 30:358–363

    Article  PubMed  CAS  Google Scholar 

  180. Yatsushige H, Ostrowski RP, Tsubokawa T, Colohan A, Zhang JH (2007) Role of c-Jun N-terminal kinase in early brain injury after subarachnoid hemorrhage. J Neurosci Res 85:1436–1448

    Article  PubMed  CAS  Google Scholar 

  181. Yemisci M, Gursoy-Ozdemir Y, Vural A, Can A, Topalkara K, Dalkara T (2009) Pericyte contraction induced by oxidative-nitrative stress impairs capillary reflow despite successful opening of an occluded cerebral artery. Nat Med 15:1031–1037

    Article  PubMed  CAS  Google Scholar 

  182. Zabramski J, Spetzler RF, Bonstelle C (1986) Chronic cerebral vasospasm: effect of calcium antagonists. Neurosurgery 18:129–135

    Article  PubMed  CAS  Google Scholar 

  183. Zhang J, Yang J, Zhang C, Jiang X, Zhou H, Liu M (2012) Calcium antagonists for acute ischemic stroke. The Cochrane database of systematic reviews 5:CD001928

    Google Scholar 

  184. Zhou N, Gordon GR, Feighan D, MacVicar BA (2010) Transient swelling, acidification, and mitochondrial depolarization occurs in neurons but not astrocytes during spreading depression. Cereb Cortex 20:2614–2624

    Article  PubMed  Google Scholar 

  185. Zubkov AY, Tibbs RE, Clower B, Ogihara K, Aoki K, Zhang JH (2002) Morphological changes of cerebral arteries in a canine double hemorrhage model. Neurosci Lett 326:137–141

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Neurosurgery, Medical Faculty, Heinrich-Heine-University Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany

    Jasper H. van Lieshout, Maxine Dibué-Adjei, Jan F. Cornelius, Philipp J. Slotty, Hans-Jakob Steiger, Athanasios K. Petridis & Marcel A. Kamp

  2. Institute for Neurophysiology, Medical Faculty, University of Cologne, Robert-Koch-Str. 39, 50931, Köln, Germany

    Toni Schneider

  3. Zurich Centre for Integrative Human Physiology, Institute of Physiology, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland

    Tanja Restin

  4. Institute of Anesthesiology, Medical Faculty, University Hospital Zurich, Rämistrasse 100, 8091, Zurich, Switzerland

    Tanja Restin

  5. Department of Neurosurgery, Medical Faculty, Radboud University Nijmegen, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, the Netherlands

    Hieronymus D. Boogaarts

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  1. Jasper H. van Lieshout
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TRs position is funded through the MD-PhD program of the Swiss National Science Foundation (SNSF), Bern, Switzerland (323530_158128).

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Dr. Maxine Dibué-Adjei is employed by LivaNova PLC. All other authors declare that they have no conflict of interest.

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Athanasios K. Petridis and Marcel A. Kamp contributed equally to this article.

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van Lieshout, J.H., Dibué-Adjei, M., Cornelius, J.F. et al. An introduction to the pathophysiology of aneurysmal subarachnoid hemorrhage. Neurosurg Rev 41, 917–930 (2018). https://doi.org/10.1007/s10143-017-0827-y

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