Translational Stroke Research

, Volume 7, Issue 4, pp 294–302 | Cite as

Improving Reperfusion Therapies in the Era of Mechanical Thrombectomy

  • Italo Linfante
  • Marilyn J. Cipolla
SI: Challenges and Controversies in Translational Stroke Research


Recent positive clinical trials using mechanical thrombectomy proved that endovascular recanalization is an effective treatment for patients with acute stroke secondary to large vessel occlusions. The trials offer definite evidence that in acute ischemia recanalization is a powerful predictor of good outcome. However, even in the era of rapid and effective recanalization using endovascular approaches, the percentage of patients with good outcomes varies between 33 and 71 %. In addition, the number of patients who are eligible for endovascular thrombectomy is small and usually based on having salvageable tissue on imaging. There is therefore room for improvement to both enhance the effectiveness of current practice and expand treatment to a larger subset of stroke patients. In this review, we highlight some of the most promising approaches to improve endovascular therapy by combining with strategies to enhance collateral perfusion and vascular protection.


Endovascular thrombectomy Acute stroke Neuroprotection Tissue plasminogen activator Intra-arterial delivery 


Compliance with Ethical Standards


M. J. C. is funded by the National Institutes of Health grants R01 NS045940, R01 NS093289, P01 HL095488, the Preeclampsia Foundation, and the Totman Medical Research Trust.

Conflict of Interest

I. L. is consultant for Medtronic/Covidien, Stryker, Codman, Penumbra, and stockholder for Surpass and InNeuroCo.

Ethical Approval

This article does not contain any studies with human participants or animals performed by the authors.


  1. 1.
    Berkhemer OA, Fransen PS, Beumer D, van den Berg LA, Lingsma HF, Yoo AJ, et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med. 2015;372:11–20.CrossRefPubMedGoogle Scholar
  2. 2.
    Goyal M, Demchuk AM, Menon BK, Eesa M, Rempel JL, Thornton J, et al. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med. 2015;372:1019–30.CrossRefPubMedGoogle Scholar
  3. 3.
    Campbell BC, Mitchell PJ, Kleinig TJ, Dewey HM, Churilov L, Yassi N, et al. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med. 2015;372:1009–18.CrossRefPubMedGoogle Scholar
  4. 4.
    Saver JL, Goyal M, Bonafe A, Diener HC, Levy EI, Pereira VM, et al. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med. 2015;372:2285–95.CrossRefPubMedGoogle Scholar
  5. 5.
    Jovin TG, Chamorro A, Cobo E, de Miquel MA, Molina CA, Rovira A, et al. Thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med. 2015;372:2296–306.CrossRefPubMedGoogle Scholar
  6. 6.
    Dirnagl U, Endres M. Found in translation: preclinical stroke research predicts human pathophysiology, clinical phenotypes, and therapeutic outcomes. Stroke. 2014;45:1510–8.CrossRefPubMedGoogle Scholar
  7. 7.
    Cumberland Consensus Working Group 1, Cheeran B, Cohen L, Dobkin B, Ford G, Greenwood R, et al. The future of restorative neurosciences in stroke: driving the translational research pipeline from basic science to rehabilitation of people after stroke. Neurorehabil Neural Repair. 2009;23:97–107.CrossRefGoogle Scholar
  8. 8.
    Fisher M, Bastan B. Identifying and utilizing the ischemic penumbra. Neurology. 2012;79:S79–85.CrossRefPubMedGoogle Scholar
  9. 9.
    Paciaroni M, Caso V, Agnelli G. The concept of ischemic penumbra in acute stroke and therapeutic opportunities. Eur Neurol. 2009;61:321–30.CrossRefPubMedGoogle Scholar
  10. 10.
    The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333:1581–7.CrossRefGoogle Scholar
  11. 11.
    Ciccone A, Valvassori L, Nichelatti M, Sgoifo A, Ponzio M, Sterzi R, et al. Endovascular treatment for acute ischemic stroke. N Engl J Med. 2013;368:2433–4.CrossRefPubMedGoogle Scholar
  12. 12.
    Broderick JP, Palesch YY, Demchuk AM, Yeatts SD, Khatri P, Hill MD, et al. Interventional Management of Stroke (IMS) III Investigators Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med. 2013;368:893–903.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Kidwell CS, Jahan R, Gornbein J, Alger JR, Nenov V, Ajani Z, et al. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med. 2013;368:914–23.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Liebeskind DS, Jahan R, Nogueira RG, Zaidat OO, Saver JL, SWIFT Investigators. Impact of collaterals on successful revascularization in solitaire FR with the intention for thrombectomy. Stroke. 2014;45:2036–40.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Lima FO, Furie KL, Silva GS, Lev MH, Camargo EC, Singhal AB, et al. The pattern of leptomeningeal collaterals on CT angiography is a strong predictor of long-term functional outcome in stroke patients with large vessel intracranial occlusion. Stroke. 2010;41:2316–22.Google Scholar
  16. 16.
    Bang OY, Saver JL, Kim SJ, Kim GM, Chung CS, Ovbiagele B, et al. Collateral flow predicts response to endovascular therapy for acute ischemic stroke. Stroke. 2011;42:693–9.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Sheth SA, Sanossian N, Hao Q, Starkman S, Ali LK, Kim D, et al. Collateral flow as causative of good outcomes in endovascular stroke therapy. J Neurointerv Surg. 2014. doi: 10.1136/neurintsurg-2014-011438.
  18. 18.
    Marks MP, Lansberg MG, Mlynash M, Olivot JM, Straka M, Kemp S, et al. Diffusion and perfusion imaging evaluation for understanding stroke evolution 2 investigators. Effect of collateral blood flow on patients undergoing endovascular therapy for acute ischemic stroke. Stroke. 2014;45:1035–9.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Bang OY, Saver JL, Buck BH, Alger JR, Starkman S, Ovbiagele B, et al. Impact of collateral flow on tissue fate in acute ischaemic stroke. J Neurol Neurosurg Psychiatry. 2008;79:625–9.CrossRefPubMedGoogle Scholar
  20. 20.
    Campbell BC, Christensen S, Tress BM, Churilov L, Desmond PM, Parsons MW, et al. Failure of collateral blood flow is associated with infarct growth in ischemic stroke. J Cereb Blood Flow Metab. 2013;33:1168–72.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Bang OY, Saver JL, Kim SJ, Kim GM, Chung CS, Ovbiagele B, et al. Collateral flow averts hemorrhagic transformation after endovascular therapy for acute ischemic stroke. Stroke. 2011;42:2235–9.CrossRefPubMedGoogle Scholar
  22. 22.
    Brozici M, van der Zwan A, Hillen B. Anatomy and functionality of leptomeningieal anastomoses: a review. Stroke. 2003;34:2750–62.CrossRefPubMedGoogle Scholar
  23. 23.
    Shuaib A, Butcher K, Mohammad AA, Saqqur M, Liebeskind DS. Collateral blood vessels in acute ischaemic stroke: a potential therapeutic target. Lancet Neurol. 2011;10:909–21.CrossRefPubMedGoogle Scholar
  24. 24.
    Zhang H, Prabhakar P, Sealock R, Faber JE. Wide genetic variation in the native pial collateral circulation is a major determinant of variation in severity of stroke. J Cereb Blood Flow Metab. 2010;30:923–34.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Chan S-L, Sweet JG, Bishop N, Cipolla MJ. Pial collateral reactivity during hypertension and aging: understanding the function of collaterals for stroke therapy. Stroke. 2016.Google Scholar
  26. 26.
    Hedera P, Bujdáková J, Traubner P, Pancák J. Stroke risk factors and development of collateral flow in carotid occlusive disease. Acta Neurol Scand. 1998;98:182–6.CrossRefPubMedGoogle Scholar
  27. 27.
    Letourneur A, Roussel S, Toutain J, Bernaudin M, Touzani O. Impact of genetic and renovascular chronic arterial hypertension on the acute spatiotemporal evolution of the ischemic penumbra: a sequential study with MRI in the rat. J Cereb Blood Flow Metab. 2011;31:504–13.CrossRefPubMedGoogle Scholar
  28. 28.
    McCabe C, Gallagher L, Gsell W, Graham D, Dominiczak AF, Macrae IM. Differences in the evolution of the ischemic penumbra in stroke-prone spontaneously hypertensive and Wistar-Kyoto rats. Stroke. 2009;40:3864–8.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Satoh K, Fukumoto Y, Shimokawa H. Rho-kinase: important new therapeutic target in cardiovascular diseases. Am J Physiol Heart Circ Physiol. 2011;301:H287–96.CrossRefPubMedGoogle Scholar
  30. 30.
    Faraci FM, Lamping KG, Modrick ML, Ryan MJ, Sigmund CD, Didion SP. Cerebral vascular effects of angiotensin II: new insights from genetic models. J Cereb Blood Flow Metab. 2006;26:449–55.CrossRefPubMedGoogle Scholar
  31. 31.
    Davies SP, Reddy H, Caivano M, Cohen P. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J. 2000;351:95–105.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Laufs U, Endres M, Stagliano N, Amin-Hanjani S, Chui DS, Yang SX, et al. Neuroprotection mediated by changes in the endothelial actin cytoskeleton. J Clin Invest. 2000;106:15–24.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Nishikawa Y, Doi M, Koji T, Watanabe M, Kimura S, Kawasaki S, et al. The role of rho and rho-dependent kinase in serotonin-induced contraction observed in bovine middle cerebral artery. Tohoku J Exp Med. 2003;201:239–49.CrossRefPubMedGoogle Scholar
  34. 34.
    Shin HK, Huang PL, Ayata C. Rho-kinase inhibition improves ischemic perfusion deficit in hyperlipidemic mice. J Cereb Blood Flow Metab. 2014;34:284–7.CrossRefPubMedGoogle Scholar
  35. 35.
    Shin HK, Salomone S, Potts EM, Lee SW, Millican E, Noma K, et al. Rho-kinase inhibition acutely augments blood flow in focal cerebral ischemia via endothelial mechanisms. J Cereb Blood Flow Metab. 2007;27:998–1009.PubMedGoogle Scholar
  36. 36.
    Wang QM, Liao JK. ROCKs as immunomodulators of stroke. Expert Opin Ther Targets. 2012;16:1013–25.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Wu J, Li J, Hu H, Liu P, Fang Y, Wu D. Rho-kinase inhibitor, fasudil, prevents neuronal apoptosis via the Akt activation and PTEN inactivation in the ischemic penumbra of rat brain. Cell Mol Neurobiol. 2012;32:1187–97.CrossRefPubMedGoogle Scholar
  38. 38.
    Ishiguro M, Kawasaki K, Suzuki Y, Ishizuka F, Mishiro K, Egashira Y, et al. A Rho kinase (ROCK) inhibitor, fasudil, prevents matrix metalloproteinase-9-related hemorrhagic transformation in mice treated with tissue plasminogen activator. Neuroscience. 2012;220:302–12.CrossRefPubMedGoogle Scholar
  39. 39.
    Lee JH, Zheng Y, von Bornstadt D, Wei Y, Balcioglu A, Daneshmand A, et al. Selective ROCK2 inhibition in focal cerebral ischemia. Ann Clin Transl Neurol. 2014;1:2–14.CrossRefPubMedGoogle Scholar
  40. 40.
    Gibson CL, Srivastava K, Sprigg N, Bath PMW, Bayraktutan U. Inhibition of Rho-kinase protects cerebral barrier from ischaemia-evoked injury through modulations of endothelial cell oxidative stress and tight junctions. J Neurochem. 2014;129:816–26.CrossRefPubMedGoogle Scholar
  41. 41.
    Gokina N, Park KM, McElroy-Yaggy K, Osol G. Effects of Rho kinase inhibition on cerebral artery myogenic tone and reactivity. J Appl Physiol (1985). 2005;98:1940–8.CrossRefGoogle Scholar
  42. 42.
    Ledoux J, Werner ME, Brayden JE, Nelson MT. Calcium-activated potassium channels and the regulation of vascular tone. Physiology. 2006;21:69–79.Google Scholar
  43. 43.
    Marrelli SP, Eckmann MS, Hunte MS. Role of endothelial intermediate conductance Kca channels in cerebral EDHF-mediated dilations. Am J Physiol. 2003;285:H1590–9.Google Scholar
  44. 44.
    Cipolla MJ, Smith J, Kohlmeyer MM, Godfrey JA. SKCa and IKCa Channels, myogenic tone, and vasodilator responses in middle cerebral arteries and parenchymal arterioles: effect of ischemia and reperfusion. Stroke. 2009;40:1451–7.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Mishra RC, Belke D, Wulff H, Braun AP. SKA-31, a novel activator of SK(Ca) and IK(Ca) channels, increases coronary flow in male and female rat hearts. Cardiovasc Res. 2013;97:339–48.CrossRefPubMedGoogle Scholar
  46. 46.
    An H, Ford AL, Vo K, Eldeniz C, Ponisio R, Zhu H, et al. Early changes of tissue perfusion after tissue plasminogen activator in hyperacute ischemic stroke. Stroke. 2011;2:65–72.CrossRefGoogle Scholar
  47. 47.
    Soares BP, Tong E, Hom J, Cheng SC, Bredno J, Boussel L, et al. Reperfusion is a more accurate predictor of follow-up infarct volume than recanalization: a proof of concept using CT in acute ischemic stroke patients. Stroke. 2010;41:e34–40.CrossRefPubMedGoogle Scholar
  48. 48.
    Busch E, Krüger K, Allegrini PR, Kerskens CM, Gyngell ML, Hoehn-Berlage M, et al. Reperfusion after thrombolytic therapy of embolic stroke in the rat: magnetic resonance and biochemical imaging. J Cereb Blood Flow Metab. 1998;18:407–18.CrossRefPubMedGoogle Scholar
  49. 49.
    Garcia JH, Liu KF, Yoshida Y, Chen S, Lian J. Brain microvessels: factors altering their patency after the occlusion of a middle cerebral artery (Wistar rat). Am J Pathol. 1994;145:728–40.PubMedPubMedCentralGoogle Scholar
  50. 50.
    del Zoppo GJ, Mabuchi T. Cerebral microvessel responses to focal ischemia. J Cereb Blood Flow Metab. 2003;23:879–94.CrossRefPubMedGoogle Scholar
  51. 51.
    del Zoppo GJ, Poeck K, Pessin MS, Wolpert SM, Furlan AJ, Ferbert A, et al. Recombinant tissue plasminogen activator in acute thrombotic and embolic stroke. Ann Neurol. 1992;32:78–86.CrossRefPubMedGoogle Scholar
  52. 52.
    Alexandrov AV, Molina CA, Grotta JC, Garami Z, Ford SR, Alvarez-Sabin J, et al. Ultrasound-enhanced systemic thrombolysis for acute ischemic stroke. N Engl J Med. 2004;351:2170–8.CrossRefPubMedGoogle Scholar
  53. 53.
    Ribo M, Alvarez-Sabin J, Montaner J, Romero F, Delgado P, Rubiera M, et al. Temporal profile of recanalization after intravenous tissue plasminogen activator: selecting patients for rescue reperfusion techniques. Stroke. 2006;37:1000–4.CrossRefPubMedGoogle Scholar
  54. 54.
    Lee KY, Han SW, Kim SH, Nam HS, Ahn SW, Kim DJ, et al. Early recanalization after intravenous administration of recombinant tissue plasminogen activator as assessed by pre- and post-thrombolytic angiography in acute ischemic stroke patients. Stroke. 2007;38:192–3.CrossRefPubMedGoogle Scholar
  55. 55.
    Kimura K, Iguchi Y, Shibazaki K, Aoki J, Uemura J. Early recanalization rate of major occluded brain arteries after intravenous tissue plasminogen activator therapy using serial magnetic resonance angiography studies. Eur Neurol. 2009;62:287–92.CrossRefPubMedGoogle Scholar
  56. 56.
    Vanacker P, Lambrou D, Eskandari A, Maeder P, Meuli R, Ntaios G, et al. Improving prediction of recanalization in acute large vessel occlusive Stroke. J Thromb Haemost. 2014;12:814–21.CrossRefPubMedGoogle Scholar
  57. 57.
    Alexandrov AV, Hall CE, Labiche LA, Wojner AW, Grotta JC. Ischemic stunning of the brain: early recanalization without immediate clinical improvement in acute ischemic stroke. Stroke. 2004;35:449–52.CrossRefPubMedGoogle Scholar
  58. 58.
    del Zoppo GJ, Schmid-Schönbein GW, Mori E, Copeland BR, Chang CM. Polymorphonuclear leukocytes occlude capillaries following middle cerebral artery occlusion and reperfusion in baboons. Stroke. 1991;22:1276–83.CrossRefPubMedGoogle Scholar
  59. 59.
    Hallenbeck JM, Dutka AJ, Tanishima T, Kochanek PM, Kumaroo KK, Thompson CB, et al. Polymorphonuclear leukocyte accumulation in brain regions with low blood flow during the early postischemic period. Stroke. 1986;17:246–53.CrossRefPubMedGoogle Scholar
  60. 60.
    Faraci FM, Mayhan WG, Heistad DD. Segmental vascular responses to acute hypertension in cerebrum and brain stem. Am J Physiol. 1987;252:H738–42.PubMedGoogle Scholar
  61. 61.
    Faraci FM, Heistad DD. Regulation of large cerebral arteries and cerebral microvascular pressure. Circ Res. 1990;66:8–17.CrossRefPubMedGoogle Scholar
  62. 62.
    Faraci FM, Mayhan WG, Schmid PG, Heistad DD. Effects of arginine vasopressin on cerebral microvascular pressure. Am J Physiol. 1988;255:H70–6.PubMedGoogle Scholar
  63. 63.
    Cipolla MJ, Chan SL, Sweet J, Tavares MJ, Gokina N, Brayden JE. Postischemic reperfusion causes smooth muscle calcium sensitization and vasoconstriction of parenchymal arterioles. Stroke. 2014;45:2425–30.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Cipolla MJ, Sweet J, Chan SL, Tavares MJ, Gokina N, Brayden JE. Increased pressure-induced tone in rat parenchymal arterioles vs. middle cerebral arteries: role of ion channels and calcium sensitivity. J Appl Physiol (1985). 2014;117:53–9.CrossRefGoogle Scholar
  65. 65.
    Baumbach GL, Heistad DD. Regional, segmental, and temporal heterogeneity of cerebral vascular autoregulation. Ann Biomed Eng. 1985;13:303–10.CrossRefPubMedGoogle Scholar
  66. 66.
    Baumbach GL, Mayhan WG, Heistad DD. Protection of the blood–brain barrier by hypercapnia during acute hypertension. Am J Physiol. 1986;251:H282–7.PubMedGoogle Scholar
  67. 67.
    Ronaldson PT, Davis TP. Blood–brain barrier integrity and glial support: mechanisms that can be targeted for novel therapeutic approaches in stroke. Curr Pharm Des. 2012;18:3624–44.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Ergul A, Kelly-Cobbs A, Abdalla M, Fagan SC. Cerebrovascular complications of diabetes: focus on stroke. Endocr Metab Immune Disord Drug Targets. 2012;12(2):148–58.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Cipolla MJ, Huang Q, Sweet JG. Inhibition of protein kinase Cβ reverses increased blood–brain barrier permeability during hyperglycemic stroke and prevents edema formation in vivo. Stroke. 2011;42:3252–7.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Kumai Y, Ooboshi H, Ibayashi S, Ishikawa E, Sugimori H, Kamouchi M, et al. Postischemic gene transfer of soluble Flt-1 protects against brain ischemia with marked attenuation of blood–brain barrier permeability. J Cereb Blood Flow Metab. 2007;27(6):1152–60.CrossRefPubMedGoogle Scholar
  71. 71.
    Lyden PD. Hemorrhagic transformation during thrombolytic therapy and reperfusion: effects of age, blood pressure, and matrix metalloproteinases. J Stroke Cerebrovasc Dis. 2013;22(4):532–8.CrossRefPubMedGoogle Scholar
  72. 72.
    Wang M, Joshi S, Emerson RG. Comparison of intracarotid and intravenous propofol for electrocerebral silence in rabbits. Anesthesiology. 2003;99:904–10.CrossRefPubMedGoogle Scholar
  73. 73.
    Yamashita J, Handa H, Tokuriki Y, Ha YS, Otsuka SI, Suda K, et al. Intra-arterial ACNU therapy for malignant brain tumors. Experimental studies and preliminary clinical results. J Neurosurg. 1983;59:424–30.CrossRefPubMedGoogle Scholar
  74. 74.
    Joshi S, Young WL, Pile-Spellman J, Duong DH, Vang MC, Hacein-Bey L, et al. The feasibility of intracarotid adenosine for the manipulation of human cerebrovascular resistance. Anesth Analg. 1998;87:1291–8.PubMedGoogle Scholar
  75. 75.
    Joshi S, Meyers PM, Ornstein E. Intracarotid delivery of drugs: the potential and the pitfalls. Anesthesiology. 2008;109:543–64.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Chen H, Yoshioka H, Kim GS, Jung JE, Okami N, Sakata H, et al. Oxidative stress in ischemic brain damage: mechanisms of cell death and potential molecular targets for neuroprotection. Antioxid Redox Signal. 2011;14:1505–17.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Duong H, Hacein-Bey L, Vang MC, Pile-Spellman J, Joshi S, Young WL. Management of cerebral arterial occlusion during endovascular treatment of cerebrovascular disease. Problems in Anesthesia. 1997;9:99–111.Google Scholar
  78. 78.
    Hillen B. The variability of the circle of Willis: univariate and bivariate analysis. Acta Morphol Neerl Scand. 1986;24:87–101.PubMedGoogle Scholar
  79. 79.
    Hillen B, Hoogstraten HW, Van Overbeeke JJ, Van der Zwan A. Functional anatomy of the circulus arteriosus cerebri (WillisII). Bull Assoc Anat. 1991;75:123–6.Google Scholar
  80. 80.
    Hillen B, Drinkenburg BA, Hoogstraten HW, Post L. Analysis of flow and vascular resistance in a model of the circle of Willis. J Biomechan. 1988;21:807–14.CrossRefGoogle Scholar
  81. 81.
    Dedrick RL. Arterial drug infusion: pharmacokinetic problems and pitfalls. J Natl Cancer Inst. 1988;80:84–9.CrossRefPubMedGoogle Scholar
  82. 82.
    Cipolla MJ. The cerebral circulation. In: Integrated systems physiology—from molecule to function. Morgan & Claypool Life Sciences Publishers:San Rafael, 2009Google Scholar
  83. 83.
    Butt AM. Effect of inflammatory agents on electrical resistance across the blood–brain barrier in pial microvessels of anaesthetized rats. Brain Res. 1995;696:145–50.CrossRefPubMedGoogle Scholar
  84. 84.
    Giraud M, Cho TH, Nighoghossian N, Maucort-Boulch D, Deiana G, Østergaard L, et al. Early blood brain barrier changes in acute ischemic stroke: a sequential MRI study. J Neuroimaging. 2015;25:959–63.CrossRefPubMedGoogle Scholar
  85. 85.
    Prasad S, Sajja RK, Naik P, Cucullo L. Diabetes mellitus and blood–brain barrier dysfunction: an overview. J Pharmacovigil. 2014;2:125.PubMedPubMedCentralGoogle Scholar
  86. 86.
    Won SJ, Tang XN, Suh SW, Yenari MA, Swanson RA. Hyperglycemia promotes tissue plasminogen activator-induced hemorrhage by increasing superoxide production. Ann Neurol. 2011;70:583–90.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Tang XN, Cairns B, Kim JY, Yenari MA. NADPH oxidase in stroke and cerebrovascular disease. Neurol Res. 2012;34:338–45.CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Obrist WD, Thompson Jr HK, Wang HS, Wilkinson WE. Regional cerebral blood flow estimated by 133xenon inhalation. Stroke. 1975;6:245–56.CrossRefPubMedGoogle Scholar
  89. 89.
    Obrist WD, Dolinskas CA, Jaggi JL, Cruz J, Steiman DL. Serial cerebral blood flow studies in acute head injury: application of the intravenous 133 Xe method. 1983. p. 145–50.Google Scholar
  90. 90.
    Sanelli PC, Nicola G, Tsiouris AJ, Ougorets I, Knight C, Frommer B, et al. Reproducibility of post processing of quantitative CT perfusion maps. AJR Am J Roentgenol. 2007;188:213–8.CrossRefPubMedGoogle Scholar
  91. 91.
    Morales Palomares S, Cipolla MJ. Vascular protection following ischemia and reperfusion. J Neurol Neurophysiol. 2011;20:S1–4.Google Scholar
  92. 92.
    Cipolla MJ, McCall A, Lessov N, Porter J. Reperfusion decreases myogenic reactivity and alters middle cerebral artery function after focal cerebral ischemia in rats. Stroke. 1997;28:176–80.CrossRefPubMedGoogle Scholar
  93. 93.
    Linfante I, Walker GR, Castonguay AC, Dabus G, Starosciak AK, Yoo AJ, et al. Predictors of mortality in acute ischemic stroke intervention: analysis of the north American solitaire acute stroke registry. Stroke. 2015;46:2305–8.CrossRefPubMedGoogle Scholar
  94. 94.
    Linfante I, Starosciak AK, Walker GR, Dabus G, Castonguay AC, Gupta R, et al. Predictors of poor outcome despite recanalization: a multiple regression analysis of the NASA registry. J NeuroIntervent Surg. 2015;8(3):1–6. doi: 10.1136/neurintsurg-2014-011525.Google Scholar
  95. 95.
    Wardlaw JM, Murray V, Berge E, del Zoppo G, Sandercock P, Lindley RL, et al. Recombinant tissue plasminogen activator for acute ischaemic stroke:an updated systematic review and meta-analysis. Lancet. 2012;379:2364–72.Google Scholar
  96. 96.
    Saver JL, Fonarow GC, Smith EE, Reeves MJ, Grau-Sepulveda MV, Pan W, et al. Time to treatment with intravenous plasminogen activator and outcome from acute ischemic stroke. JAMA. 2013;309:2480–8.Google Scholar
  97. 97.
    Broderick JP, Palesch YY, Demchuk AM, Yeatts SD, Khatri P, Hill MD, et al. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med. 2013;368:893–903.Google Scholar
  98. 98.
    Hussein HM, Georgiadis AL, Vazquez G, Miley JT, Memon MZ, Mohammad YM, et al. Occurrence and predictorsof futile recanalization following endovascular treatment among patients with acute ischemic stroke. AJNR Am J Neuroradiol. 2010;31:454–458.Google Scholar

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© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Miami Cardiac and Vascular Institute and Neuroscience CenterBaptist HospitalMiamiUSA
  2. 2.Department of Neurological Sciences and PharmacologyUniversity of Vermont College of MedicineBurlingtonUSA

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