Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Current Atherosclerosis Reports
Published in: Current Atherosclerosis Reports 12/2017

01-12-2017 | Cardiovascular Disease and Stroke (S. Prabhakaran, Section Editor)

Delayed Cerebral Ischemia after Subarachnoid Hemorrhage: Beyond Vasospasm and Towards a Multifactorial Pathophysiology

Authors: Joseph R. Geraghty, Fernando D. Testai

Published in: Current Atherosclerosis Reports | Issue 12/2017

Login to get access

Abstract

Purpose of Review

Delayed cerebral ischemia (DCI) is common after subarachnoid hemorrhage (SAH) and represents a significant cause of poor functional outcome. DCI was mainly thought to be caused by cerebral vasospasm; however, recent clinical trials have been unable to confirm this hypothesis. Studies in humans and animal models have since supported the notion of a multifactorial pathophysiology of DCI. This review summarizes some of the main mechanisms under investigation including cerebral vascular dysregulation, microthrombosis, cortical spreading depolarizations, and neuroinflammation.

Recent Findings

Recent guidelines have differentiated between DCI and angiographic vasospasm and have highlighted roles of the microvasculature, coagulation and fibrinolytic systems, cortical spreading depressions, and the contribution of the immune system to DCI. Many therapeutic interventions are underway in both preclinical and clinical studies to target these novel mechanisms as well as studies connecting these mechanisms to one another.

Summary

Clinical trials to date have been largely unsuccessful at preventing or treating DCI after SAH. The only successful pharmacologic intervention is the calcium channel antagonist, nimodipine. Recent studies have provided evidence that cerebral vasospasm is not the sole contributor to DCI and that additional mechanisms may play equal if not more important roles.
Literature
1.
Suarez JI, Tarr RW, Selman WR. Aneurysmal subarachnoid hemorrhage. N Engl J Med. 2006;354(4):387–96.PubMedCrossRef
2.
Rincon F, Rossenwasser RH, Dumont A. The epidemiology of admissions of nontraumatic subarachnoid hemorrhage in the United States. Neurosurgery. 2013;73(2):217,22. discussion 212-3CrossRef
3.
Hop JW, Rinkel GJ, Algra A, van Gijn J. Case-fatality rates and functional outcome after subarachnoid hemorrhage: a systematic review. Stroke. 1997;28(3):660–4.PubMedCrossRef
4.
Mackey J, Khoury JC, Alwell K, Moomaw CJ, Kissela BM, Flaherty ML, et al. Stable incidence but declining case-fatality rates of subarachnoid hemorrhage in a population. Neurology. 2016;87(21):2192–7.PubMedPubMedCentralCrossRef
5.
Lovelock CE, Rinkel GJ, Rothwell PM. Time trends in outcome of subarachnoid hemorrhage: population-based study and systematic review. Neurology. 2010;74(19):1494–501.PubMedPubMedCentralCrossRef
6.
Taufique Z, May T, Meyers E, Falo C, Mayer SA, Agarwal S, et al. Predictors of poor quality of life 1 year after subarachnoid hemorrhage. Neurosurgery. 2016;78(2):256–64.PubMedCrossRef
7.
Boerboom W, Heijenbrok-Kal MH, Khajeh L, van Kooten F, Ribbers GM. Differences in cognitive and emotional outcomes between patients with perimesencephalic and aneurysmal subarachnoid haemorrhage. J Rehabil Med. 2014;46(1):28–32.PubMedCrossRef
8.
Kreiter KT, Rosengart AJ, Claassen J, Fitzsimmons BF, Peery S, YE D, et al. Depressed mood and quality of life after subarachnoid hemorrhage. J Neurol Sci. 2013;335(1–2):64–71.PubMedCrossRef
9.
Wong GK, Lam SW, Ngai K, Wong A, Siu D, Poon WS, et al. Cognitive domain deficits in patients with aneurysmal subarachnoid haemorrhage at 1 year. J Neurol Neurosurg Psychiatry. 2013;84(9):1054–8.PubMedPubMedCentralCrossRef
10.
Fujii M, Yan J, Rolland WB, Soejima Y, Caner B, Zhang JH. Early brain injury, an evolving frontier in subarachnoid hemorrhage research. Transl Stroke Res. 2013;4(4):432–46.PubMedPubMedCentralCrossRef
11.
Foreman B. The pathophysiology of delayed cerebral ischemia. J Clin Neurophysiol. 2016;33(3):174–82.PubMedCrossRef
12.
13.
Macdonald RL, Kassell NF, Mayer S, Ruefenacht D, Schmiedek P, Weidauer S, et al. Clazosentan to overcome neurological ischemia and infarction occurring after subarachnoid hemorrhage (CONSCIOUS-1): randomized, double-blind, placebo-controlled phase 2 dose-finding trial. Stroke. 2008;39(11):3015–21.PubMedCrossRef
14.
Macdonald RL, Higashida RT, Keller E, Mayer SA, Molyneux A, Raabe A, et al. Randomized trial of clazosentan in patients with aneurysmal subarachnoid hemorrhage undergoing endovascular coiling. Stroke. 2012;43(6):1463–9.PubMedCrossRef
15.
Dorsch NW, King MTA. Review of cerebral vasospasm in aneurysmal subarachnoid haemorrhage part I: incidence and effects. J Clin Neurosci. 1994;1(1):19–26.PubMedCrossRef
16.
Pegoli M, Mandrekar J, Rabinstein AA, Lanzino G. Predictors of excellent functional outcome in aneurysmal subarachnoid hemorrhage. J Neurosurg. 2015;122(2):414–8.PubMedCrossRef
17.
de Rooij NK, Rinkel GJ, Dankbaar JW, Frijns CJ. Delayed cerebral ischemia after subarachnoid hemorrhage: a systematic review of clinical, laboratory, and radiological predictors. Stroke. 2013;44(1):43–54.PubMedCrossRef
18.
19.
Bouzat P, Payen JF, Crippa IA, Taccone FS. Noninvasive vascular methods for detection of delayed cerebral ischemia after subarachnoid hemorrhage. J Clin Neurophysiol. 2016;33(3):260–7.PubMedCrossRef
20.
Gaspard N. Current clinical evidence supporting the use of continuous EEG monitoring for delayed cerebral ischemia detection. J Clin Neurophysiol. 2016;33(3):211–6.PubMedCrossRef
21.
Alaraj A, Charbel FT, Amin-Hanjani S. Peri-operative measures for treatment and prevention of cerebral vasospasm following subarachnoid hemorrhage. Neurol Res. 2009;31(6):651–9.PubMedCrossRef
22.
23.
Allen GS, Ahn HS, Preziosi TJ, Battye R, Boone SC, Boone SC, et al. Cerebral arterial spasm—a controlled trial of nimodipine in patients with subarachnoid hemorrhage. N Engl J Med. 1983;308(11):619–24.PubMedCrossRef
24.
Hanggi D, Etminan N, Aldrich F, Steiger HJ, Mayer SA, Diringer MN, et al. 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. 2017;48(1):145–51.PubMedCrossRef
25.
•• Macdonald RL. Delayed neurological deterioration after subarachnoid haemorrhage. Nat Rev Neurol. 2014;10(1):44–58. Excellent review of delayed neurological injury after SAH including mechanisms, clinical trials and updated management schemes.PubMedCrossRef
26.
Dankbaar JW, Slooter AJ, Rinkel GJ, Schaaf IC. Effect of different components of triple-H therapy on cerebral perfusion in patients with aneurysmal subarachnoid haemorrhage: a systematic review. Crit Care. 2010;14(1):R23.PubMedPubMedCentralCrossRef
27.
Dorhout Mees SM, Rinkel GJ, Feigin VL, Algra A, van den Bergh WM, Vermeulen M, et al. Calcium antagonists for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev. 2007;3(3):CD000277.
28.
Dorhout Mees SM, van den Bergh WM, Algra A, Rinkel GJ. Antiplatelet therapy for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev. 2007;4(4):CD006184.
29.
Feigin VL, Anderson N, Rinkel GJ, Algra A, van Gijn J, Bennett DA. Corticosteroids for aneurysmal subarachnoid haemorrhage and primary intracerebral haemorrhage. Cochrane Database Syst Rev. 2005;3(3):CD004583.
30.
Golan E, Vasquez DN, Ferguson ND, Adhikari NK, Scales DC. Prophylactic magnesium for improving neurologic outcome after aneurysmal subarachnoid hemorrhage: systematic review and meta-analysis. J Crit Care. 2013;28(2):173–81.PubMedCrossRef
31.
Guo J, Shi Z, Yang K, Tian JH, Jiang L. Endothelin receptor antagonists for subarachnoid hemorrhage. Cochrane Database Syst Rev. 2012;(9):CD008354.
32.
Kramer AH, Fletcher JJ. Locally-administered intrathecal thrombolytics following aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. Neurocrit Care. 2011;14(3):489–99.PubMedCrossRef
33.
Liu GJ, Wang ZJ, Wang YF, LL X, Wang XL, Liu Y, et al. Systematic assessment and meta-analysis of the efficacy and safety of fasudil in the treatment of cerebral vasospasm in patients with subarachnoid hemorrhage. Eur J Clin Pharmacol. 2012;68(2):131–9.PubMedCrossRef
34.
Vergouwen MD, de Haan RJ, Vermeulen M, Roos YB. Effect of statin treatment on vasospasm, delayed cerebral ischemia, and functional outcome in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis update. Stroke. 2010;41(1):e47–52.PubMedCrossRef
35.
Zhang S, Wang L, Liu M, Wu B. Tirilazad for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev. 2010;(2):CD006778.
36.
Egge A, Waterloo K, Sjoholm H, Solberg T, Ingebrigtsen T, Romner B. Prophylactic hyperdynamic postoperative fluid therapy after aneurysmal subarachnoid hemorrhage: a clinical, prospective, randomized, controlled study. Neurosurgery. 2001;49(3):593,605. discussion 605-6
37.
Muench E, Horn P, Bauhuf C, Roth H, Philipps M, Hermann P, et al. Effects of hypervolemia and hypertension on regional cerebral blood flow, intracranial pressure, and brain tissue oxygenation after subarachnoid hemorrhage. Crit Care Med. 2007;35(8):1844,51. quiz 1852CrossRef
38.
Lennihan L, Mayer SA, Fink ME, Beckford A, Paik MC, Zhang H, et al. Effect of hypervolemic therapy on cerebral blood flow after subarachnoid hemorrhage : a randomized controlled trial. Stroke. 2000;31(2):383–91.PubMedCrossRef
39.
Gathier CS, Dankbaar JW, van der Jagt M, Verweij BH, Oldenbeuving AW, Rinkel GJ, et al. Effects of induced hypertension on cerebral perfusion in delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage: a randomized clinical trial. Stroke. 2015;46(11):3277–81.PubMedCrossRef
40.
Connolly ES Jr, 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(6):1711–37.PubMedCrossRef
41.
Shankar JJ, dos Santos MP, Deus-Silva L, Lum C. Angiographic evaluation of the effect of intra-arterial milrinone therapy in patients with vasospasm from aneurysmal subarachnoid hemorrhage. Neuroradiology. 2011;53(2):123–8.PubMedCrossRef
42.
Venkatraman A, Khawaja AM, Gupta S, Hardas S, Deveikis JP, Harrigan MR, et al. Intra-arterial vasodilators for vasospasm following aneurysmal subarachnoid hemorrhage: a meta-analysis. J Neurointerv Surg. 2017.
43.
Hollingworth M, Chen PR, Goddard AJ, Coulthard A, Soderman M, Bulsara KR. Results of an international survey on the investigation and endovascular management of cerebral vasospasm and delayed cerebral ischemia. World Neurosurg. 2015;83(6):1120,1126.e1.CrossRef
44.
Vergouwen MD, Vermeulen M, van Gijn J, Rinkel GJ, Wijdicks EF, Muizelaar JP, 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;41(10):2391–5.PubMedCrossRef
45.
Crowley RW, Medel R, Dumont AS, Ilodigwe D, Kassell NF, Mayer SA, et al. Angiographic vasospasm is strongly correlated with cerebral infarction after subarachnoid hemorrhage. Stroke. 2011;42(4):919–23.PubMedCrossRef
46.
Hijdra A, Van Gijn J, Stefanko S, Van Dongen KJ, Vermeulen M, Van Crevel H. Delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage: clinicoanatomic correlations. Neurology. 1986;36(3):329–33.PubMedCrossRef
47.
Vergouwen MD, Ilodigwe D, Macdonald RL. Cerebral infarction after subarachnoid hemorrhage contributes to poor outcome by vasospasm-dependent and -independent effects. Stroke. 2011;42(4):924–9.PubMedCrossRef
48.
Bederson JB, Connolly ES Jr, Batjer HH, Dacey RG, Dion JE, Diringer MN, 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. Stroke. 2009;40(3):994–1025.PubMedCrossRef
49.
Macdonald RL, Higashida RT, Keller E, Mayer SA, Molyneux A, Raabe A, et al. Clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid haemorrhage undergoing surgical clipping: a randomised, double-blind, placebo-controlled phase 3 trial (CONSCIOUS-2). Lancet Neurol. 2011;10(7):618–25.PubMedCrossRef
50.
Meyers PM, Connolly ES Jr. Stroke: disappointing results for clazosentan in CONSCIOUS-2. Nat Rev Neurol. 2011;7(12):660–1.PubMedCrossRef
51.
Budohoski KP, Guilfoyle M, Helmy A, Huuskonen T, Czosnyka M, Kirollos R, et al. The pathophysiology and treatment of delayed cerebral ischaemia following subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry. 2014;85(12):1343–53.PubMedCrossRef
52.
Friedrich B, Muller F, Feiler S, Scholler K, Plesnila N. Experimental subarachnoid hemorrhage causes early and long-lasting microarterial constriction and microthrombosis: an in-vivo microscopy study. J Cereb Blood Flow Metab. 2012;32(3):447–55.PubMedCrossRef
53.
Sabri M, Ai J, Lakovic K, Macdonald RL. Mechanisms of microthrombosis and microcirculatory constriction after experimental subarachnoid hemorrhage. Acta Neurochir Suppl. 2013;115:185–92.PubMed
54.
Sehba FA, Friedrich V. Cerebral microvasculature is an early target of subarachnoid hemorrhage. Acta Neurochir Suppl. 2013;115:199–205.PubMed
55.
Wellman GC, Koide M. Impact of subarachnoid hemorrhage on parenchymal arteriolar function. Acta Neurochir Suppl. 2013;115:173–7.PubMedPubMedCentral
56.
Wolf ME, Functional TCD. Regulation of cerebral hemodynamics—cerebral autoregulation, vasomotor reactivity, and neurovascular coupling. Front Neurol Neurosci. 2015;36:40–56.PubMedCrossRef
57.
Koide M, Bonev AD, Nelson MT, Wellman GC. Inversion of neurovascular coupling by subarachnoid blood depends on large-conductance Ca2+−activated K+ (BK) channels. Proc Natl Acad Sci U S A. 2012;109(21):E1387–95.PubMedPubMedCentralCrossRef
58.
Koide M, Bonev AD, Nelson MT, Wellman GC. Subarachnoid blood converts neurally evoked vasodilation to vasoconstriction in rat brain cortex. Acta Neurochir Suppl. 2013;115:167–71.PubMedPubMedCentral
59.
• Balbi M, Koide M, Wellman GC, Plesnila N. Inversion of neurovascular coupling after subarachnoid hemorrhage in vivo. J Cereb Blood Flow Metab. 2017;271678X16686595. Most recent report showing inversion of neurovascular coupling that occurs in a delayed fashion and progresses.
60.
Ostergaard L, Aamand R, Karabegovic S, Tietze A, Blicher JU, Mikkelsen IK, et al. The role of the microcirculation in delayed cerebral ischemia and chronic degenerative changes after subarachnoid hemorrhage. J Cereb Blood Flow Metab. 2013;33(12):1825–37.PubMedPubMedCentralCrossRef
61.
Vergouwen MD, Vermeulen M, Coert BA, Stroes ES, Roos YB. Microthrombosis after aneurysmal subarachnoid hemorrhage: an additional explanation for delayed cerebral ischemia. J Cereb Blood Flow Metab. 2008;28(11):1761–70.PubMedCrossRef
62.
Roos YB, Levi M, Carroll TA, Beenen LF, Vermeulen M. Nimodipine increases fibrinolytic activity in patients with aneurysmal subarachnoid hemorrhage. Stroke. 2001;32(8):1860–2.PubMedCrossRef
63.
Suzuki S, Suzuki M, Iwabuchi T, Kamata Y. Role of multiple cerebral microthrombosis in symptomatic cerebral vasospasm: with a case report. Neurosurgery. 1983;13(2):199–203.PubMedCrossRef
64.
Sabri M, Ai J, Lakovic K, D’abbondanza J, Ilodigwe D, Macdonald RL. Mechanisms of microthrombi formation after experimental subarachnoid hemorrhage. Neuroscience. 2012;224:26–37.PubMedCrossRef
65.
Pisapia JM, Xu X, Kelly J, Yeung J, Carrion G, Tong H, et al. Microthrombosis after experimental subarachnoid hemorrhage: time course and effect of red blood cell-bound thrombin-activated pro-urokinase and clazosentan. Exp Neurol. 2012;233(1):357–63.PubMedCrossRef
66.
Boluijt J, Meijers JC, Rinkel GJ, Vergouwen MD. Hemostasis and fibrinolysis in delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage: a systematic review. J Cereb Blood Flow Metab. 2015;35(5):724–33.PubMedPubMedCentralCrossRef
67.
• Frontera JA, Provencio JJ, Sehba FA, McIntyre TM, Nowacki AS, Gordon E, et al. The role of platelet activation and inflammation in early brain injury following subarachnoid hemorrhage. Neurocrit Care. 2017;26(1):48–57. Demonstrates association of platelet activation and inflammation in EBI, DCI, and long-term outcomes after SAH.PubMedCrossRef
68.
• El Amki M, Dubois M, Lefevre-Scelles A, Magne N, Roussel M, Clavier T, et al. Long-lasting cerebral vasospasm, microthrombosis, apoptosis and paravascular alterations associated with neurological deficits in a mouse model of subarachnoid hemorrhage. Mol Neurobiol. 2017. Demonstrates utility of a model of SAH in studying mechanisms of vasospasm, microthrombosis, and neuronal loss.
69.
Vergouwen MD, Bakhtiari K, van Geloven N, Vermeulen M, Roos YB, Meijers JC. Reduced ADAMTS13 activity in delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. J Cereb Blood Flow Metab. 2009;29(10):1734–41.PubMedCrossRef
70.
Shen J, Huang KY, Zhu Y, Pan JW, Jiang H, Weng YX, et al. Effect of statin treatment on vasospasm-related morbidity and functional outcome in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. J Neurosurg. 2016;1–11.
71.
Kramer AH, Gurka MJ, Nathan B, Dumont AS, Kassell NF, Bleck TP. Statin use was not associated with less vasospasm or improved outcome after subarachnoid hemorrhage. Neurosurgery. 2008;62(2):422,7. discussion 427-30CrossRef
72.
Vergouwen MD, Knaup VL, Roelofs JJ, de Boer OJ, Meijers JC. Effect of recombinant ADAMTS-13 on microthrombosis and brain injury after experimental subarachnoid hemorrhage. J Thromb Haemost. 2014;12(6):943–7.PubMedCrossRef
73.
Muroi C, Fujioka M, Mishima K, Irie K, Fujimura Y, Nakano T, et al. Effect of ADAMTS-13 on cerebrovascular microthrombosis and neuronal injury after experimental subarachnoid hemorrhage. J Thromb Haemost. 2014;12(4):505–14.PubMedCrossRef
74.
Amin-Hanjani S, Ogilvy CS, Barker FG 2nd. Does intracisternal thrombolysis prevent vasospasm after aneurysmal subarachnoid hemorrhage? A meta-analysis Neurosurgery. 2004;54(2):326,34. discussion 334-5
75.
Etminan N, Beseoglu K, Eicker SO, Turowski B, Steiger HJ, Hanggi D. Prospective, randomized, open-label phase II trial on concomitant intraventricular fibrinolysis and low-frequency rotation after severe subarachnoid hemorrhage. Stroke. 2013;44(8):2162–8.PubMedCrossRef
76.
LEAO AA. Further observations on the spreading depression of activity in the cerebral cortex. J Neurophysiol. 1947;10(6):409–14.PubMed
77.
Charles AC, Baca SM. Cortical spreading depression and migraine. Nat Rev Neurol. 2013;9(11):637–44.PubMedCrossRef
78.
•• Dreier JP, Reiffurth C. The stroke-migraine depolarization continuum. Neuron. 2015;86(4):902–22. Excellent review of the pathophysiology of spreading depolarizations, similarities and differences in migraine and stroke, and recent developments in the field.PubMedCrossRef
79.
Dreier JP. The role of spreading depression, spreading depolarization and spreading ischemia in neurological disease. Nat Med. 2011;17(4):439–47.PubMedCrossRef
80.
Sanchez-Porras R, Zheng Z, Santos E, Scholl M, Unterberg AW, Sakowitz OW. The role of spreading depolarization in subarachnoid hemorrhage. Eur J Neurol. 2013;20(8):1121–7.PubMedCrossRef
81.
Kramer DR, Fujii T, Ohiorhenuan I, Liu CY. Cortical spreading depolarization: pathophysiology, implications, and future directions. J Clin Neurosci. 2016;24:22–7.PubMedCrossRef
82.
Hubschmann OR, Kornhauser D. Cortical cellular response in acute subarachnoid hemorrhage. J Neurosurg. 1980;52(4):456–62.PubMedCrossRef
83.
Dreier JP, Woitzik J, Fabricius M, Bhatia R, Major S, Drenckhahn C, et al. Delayed ischaemic neurological deficits after subarachnoid haemorrhage are associated with clusters of spreading depolarizations. Brain. 2006;129(Pt 12):3224–37.PubMedCrossRef
84.
Woitzik J, Dreier JP, Hecht N, Fiss I, Sandow N, Major S, et al. Delayed cerebral ischemia and spreading depolarization in absence of angiographic vasospasm after subarachnoid hemorrhage. J Cereb Blood Flow Metab. 2012;32(2):203–12.PubMedCrossRef
85.
Winkler MK, Chassidim Y, Lublinsky S, Revankar GS, Major S, Kang EJ, et al. Impaired neurovascular coupling to ictal epileptic activity and spreading depolarization in a patient with subarachnoid hemorrhage: possible link to blood-brain barrier dysfunction. Epilepsia. 2012;53(Suppl 6):22–30.PubMedPubMedCentralCrossRef
86.
Aiba I, Shuttleworth CW. Sustained NMDA receptor activation by spreading depolarizations can initiate excitotoxic injury in metabolically compromised neurons. J Physiol. 2012;590(22):5877–93.PubMedPubMedCentralCrossRef
87.
Zarcone D, Corbetta S. Shared mechanisms of epilepsy, migraine and affective disorders. Neurol Sci. 2017;38(Suppl 1):73–6.PubMedCrossRef
88.
Tozzi A, de Iure A, Di Filippo M, Costa C, Caproni S, Pisani A, et al. Critical role of calcitonin gene-related peptide receptors in cortical spreading depression. Proc Natl Acad Sci U S A. 2012;109(46):18985–90.PubMedPubMedCentralCrossRef
89.
Engelhardt B, Vajkoczy P, Weller RO. The movers and shapers in immune privilege of the CNS. Nat Immunol. 2017;18(2):123–31.PubMedCrossRef
90.
91.
Carr KR, Zuckerman SL, Mocco J. Inflammation, cerebral vasospasm, and evolving theories of delayed cerebral ischemia. Neurol Res Int. 2013;2013:506584.PubMedPubMedCentral
92.
Peng J, Wu Y, Tian X, Pang J, Kuai L, Cao F, et al. High-throughput sequencing and co-expression network analysis of lncRNAs and mRNAs in early brain injury following experimental subarachnoid haemorrhage. Sci Rep. 2017;7:46577.PubMedPubMedCentralCrossRef
93.
Muroi C, Hugelshofer M, Seule M, Tastan I, Fujioka M, Mishima K, et al. Correlation among systemic inflammatory parameter, occurrence of delayed neurological deficits, and outcome after aneurysmal subarachnoid hemorrhage. Neurosurgery. 2013;72(3):367,75. discussion 375CrossRef
94.
McMahon CJ, Hopkins S, Vail A, King AT, Smith D, Illingworth KJ, et al. Inflammation as a predictor for delayed cerebral ischemia after aneurysmal subarachnoid haemorrhage. J Neurointerv Surg. 2013;5(6):512–7.PubMedCrossRef
95.
Da Silva IR, Gomes JA, Wachsman A, de Freitas GR, Provencio JJ. Hematologic counts as predictors of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. J Crit Care. 2017;37:126–9.PubMedCrossRef
96.
Chamling B, Gross S, Stoffel-Wagner B, Schubert GA, Clusmann H, Coburn M, et al. Early diagnosis of delayed cerebral ischemia: possible relevance for inflammatory biomarkers in routine clinical practice? World Neurosurg. 2017.
97.
Lucke-Wold BP, Logsdon AF, Manoranjan B, Turner RC, McConnell E, Vates GE, et al. Aneurysmal subarachnoid hemorrhage and neuroinflammation: a comprehensive review. Int J Mol Sci. 2016;17(4):497.PubMedPubMedCentralCrossRef
98.
• Schallner N, Pandit R, LeBlanc R 3rd, Thomas AJ, Ogilvy CS, Zuckerbraun BS, et al. Microglia regulate blood clearance in subarachnoid hemorrhage by heme oxygenase-1. J Clin Invest. 2015;125(7):2609–25. Evidence of a mechanism by which microglia act in hemoglobin clearance after SAH.PubMedPubMedCentralCrossRef
99.
Kantor E, Bayir H, Ren D, Provencio JJ, Watkins L, Crago E, et al. Haptoglobin genotype and functional outcome after aneurysmal subarachnoid hemorrhage. J Neurosurg. 2014;120(2):386–90.PubMedCrossRef
100.
Ma C, Zhou W, Yan Z, Qu M, Bu X. Toll-like receptor 4 (TLR4) is correlated with delayed cerebral ischemia (DCI) and poor prognosis in aneurysmal subarachnoid hemorrhage. J Neurol Sci. 2015;359(1–2):67–71.PubMedCrossRef
101.
Haruma J, Teshigawara K, Hishikawa T, Wang D, Liu K, Wake H, et al. Anti-high mobility group box-1 (HMGB1) antibody attenuates delayed cerebral vasospasm and brain injury after subarachnoid hemorrhage in rats. Sci Rep. 2016;6:37755.PubMedPubMedCentralCrossRef
102.
• Schneider UC, Davids AM, Brandenburg S, Muller A, Elke A, Magrini S, et al. Microglia inflict delayed brain injury after subarachnoid hemorrhage. Acta Neuropathol. 2015;130(2):215–31. Explores role of microglia in delayed neuronal and axonal injury in an animal model of SAH.PubMedCrossRef
103.
Kooijman E, Nijboer CH, van Velthoven CT, Mol W, Dijkhuizen RM, Kesecioglu J, et al. Long-term functional consequences and ongoing cerebral inflammation after subarachnoid hemorrhage in the rat. PLoS One. 2014;9(6):e90584.PubMedPubMedCentralCrossRef
104.
Hanafy KA. The role of microglia and the TLR4 pathway in neuronal apoptosis and vasospasm after subarachnoid hemorrhage. J Neuroinflammation. 2013;10:83,2094–10-83.CrossRef
105.
Doorn KJ, Breve JJ, Drukarch B, Boddeke HW, Huitinga I, Lucassen PJ, et al. Brain region-specific gene expression profiles in freshly isolated rat microglia. Front Cell Neurosci. 2015;9:84.PubMedPubMedCentralCrossRef
106.
Penn DL, Witte SR, Komotar RJ, Sander Connolly E Jr. Pathological mechanisms underlying aneurysmal subarachnoid haemorrhage and vasospasm. J Clin Neurosci. 2015;22(1):1–5.PubMedCrossRef
107.
• Kooijman E, Nijboer CH, van Velthoven CT, Kavelaars A, Kesecioglu J, Heijnen CJ. The rodent endovascular puncture model of subarachnoid hemorrhage: mechanisms of brain damage and therapeutic strategies. J Neuroinflammation. 2014;11:2,2094-11-2. Review of rodent SAH models, current therapies and targets being tested.CrossRef
108.
Provencio JJ, Swank V, Lu H, Brunet S, Baltan S, Khapre RV, et al. Neutrophil depletion after subarachnoid hemorrhage improves memory via NMDA receptors. Brain Behav Immun. 2016;54:233–42.PubMedPubMedCentralCrossRef
109.
Maddahi A, Povlsen GK, Edvinsson L. Regulation of enhanced cerebrovascular expression of proinflammatory mediators in experimental subarachnoid hemorrhage via the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathway. J Neuroinflammation. 2012;9:274,2094–9-274.CrossRef
110.
You W, Wang Z, Li H, Shen H, Xu X, Jia G, et al. Inhibition of mammalian target of rapamycin attenuates early brain injury through modulating microglial polarization after experimental subarachnoid hemorrhage in rats. J Neurol Sci. 2016;367:224–31.PubMedCrossRef
111.
Xie Y, Guo H, Wang L, Xu L, Zhang X, Yu L, et al. Human albumin attenuates excessive innate immunity via inhibition of microglial Mincle/Syk signaling in subarachnoid hemorrhage. Brain Behav Immun. 2017;60:346–60.PubMedCrossRef
112.
Chen T, Wang W, Li JR, HZ X, Peng YC, Fan LF, et al. PARP inhibition attenuates early brain injury through NF-kappaB/MMP-9 pathway in a rat model of subarachnoid hemorrhage. Brain Res. 2016;1644:32–8.PubMedCrossRef
113.
Li H, JS Y, Zhang DD, Yang YQ, Huang LT, Yu Z, et al. Inhibition of the receptor for advanced glycation end-products (RAGE) attenuates neuroinflammation while sensitizing cortical neurons towards death in experimental subarachnoid hemorrhage. Mol Neurobiol. 2017;54(1):755–67.PubMedCrossRef
114.
Xu HL, Pelligrino DA, Paisansathan C, Testai FD. Protective role of fingolimod (FTY720) in rats subjected to subarachnoid hemorrhage. J Neuroinflammation. 2015;12:16,015–0234-7.CrossRef
115.
116.
Nassiri F, Ibrahim GM, Badhiwala JH, Witiw CD, Mansouri A, Alotaibi NM, et al. A propensity score-matched study of the use of non-steroidal anti-inflammatory agents following aneurysmal subarachnoid hemorrhage. Neurocrit Care. 2016;25(3):351–8.PubMedCrossRef
117.
Singh N, Hopkins SJ, Hulme S, Galea JP, Hoadley M, Vail A, et al. The effect of intravenous interleukin-1 receptor antagonist on inflammatory mediators in cerebrospinal fluid after subarachnoid haemorrhage: a phase II randomised controlled trial. J Neuroinflammation. 2014;11:1,2094–11-1.
118.
• Galea J, Ogungbenro K, Hulme S, Patel H, Scarth S, Hoadley M, et al. Reduction of inflammation after administration of interleukin-1 receptor antagonist following aneurysmal subarachnoid hemorrhage: results of the subcutaneous interleukin-1Ra in SAH (SCIL-SAH) study. J Neurosurg. 2017;1–9. Important study showing safety and levels of inflammation after administration of IL-1Ra.
119.
• Shibata M, Suzuki N. Exploring the role of microglia in cortical spreading depression in neurological disease. J Cereb Blood Flow Metab. 2017;37(4):1182–91. Review connecting microglia and neuroinflammation to cortical spreading depression, referencing how these two phenomena may be related.PubMedPubMedCentralCrossRef
120.
Gaberel T, Gakuba C, Goulay R, Martinez De Lizarrondo S, Hanouz JL, Emery E, et al. Impaired glymphatic perfusion after strokes revealed by contrast-enhanced MRI: a new target for fibrinolysis? Stroke. 2014;45(10):3092–6.PubMedCrossRef
121.
Golanov EV, Bovshik EI, Wong KK, Pautler RG, Foster CH, Federley RG, et al. Subarachnoid hemorrhage—induced block of cerebrospinal fluid flow: role of brain coagulation factor III (tissue factor). J Cereb Blood Flow Metab. 2017;271678X17701157.
122.
Goulay R, Flament J, Gauberti M, Naveau M, Pasquet N, Gakuba C, et al. Subarachnoid hemorrhage severely impairs brain parenchymal cerebrospinal fluid circulation in nonhuman primate. Stroke 2017.
123.
• Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, et al. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015;523(7560):337–41. Landmark study demonstrating the existence of CNS lymphatics lining dural sinuses and draining to deep cervical lymph nodes.PubMedPubMedCentralCrossRef
124.
Metadata
Title
Delayed Cerebral Ischemia after Subarachnoid Hemorrhage: Beyond Vasospasm and Towards a Multifactorial Pathophysiology
Authors
Joseph R. Geraghty
Fernando D. Testai
Publication date
01-12-2017
Publisher
Springer US
Published in
Current Atherosclerosis Reports / Issue 12/2017
Print ISSN: 1523-3804
Electronic ISSN: 1534-6242
DOI
https://doi.org/10.1007/s11883-017-0690-x

Other articles of this Issue 12/2017

Current Atherosclerosis Reports 12/2017 Go to the issue

Cardiovascular Disease and Stroke (Shyam Prabhakaran, Section Editor)

Improving Regional Stroke Systems of Care

Lipid and Metabolic Effects of Gastrointestinal Surgery (R. Cohen, Section Editor)

Cardiovascular Risk Factors After Single Anastomosis Duodeno-Ileal Bypass with Sleeve Gastrectomy (SADI-S): a New Effective Therapeutic Approach?

Nonstatin Drugs (E. deGoma, Section Editor)

Novel Approaches for HDL-Directed Therapies

Lipid and Metabolic Effects of Gastrointestinal Surgery (R. Cohen, Section Editor)

Is Mini-Gastric Bypass a Rational Approach for Type-2 Diabetes?

Vascular Biology (J. Hamilton, Section Editor)

Atherosclerosis, Periodontal Disease, and Treatment with Resolvins

Genetics and Genomics (Ali Marian, Section Editor)

PCSK9 Mutations in Familial Hypercholesterolemia: from a Groundbreaking Discovery to Anti-PCSK9 Therapies
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits