Translational Stroke Research

, Volume 7, Issue 4, pp 284–293 | Cite as

Extending the Time Window for Endovascular and Pharmacological Reperfusion

  • Nils Henninger
  • Marc FisherEmail author
SI: Challenges and Controversies in Translational Stroke Research


Pharmacological and device-induced reperfusion therapies have demonstrated increasingly positive outcomes regarding both reperfusion efficacy and 90-day functional outcomes after acute ischemic stroke. However, presently, only a minority of patients are eligible for these treatments. Less than 10 % of all ischemic stroke patients receive intravenous thrombolysis in most centers and it has been projected that only approximately 7–15 % of ischemic stroke patients are eligible for acute endovascular intervention. Making these effective therapies safely available to a much larger number of patients is critical for expanding the benefits of acute ischemic stroke treatment. In this article, we summarize the key results from the clinical trials, challenges, and exciting novel opportunities to increase patient eligibility for these therapies as well as for better outcomes for stroke patients.


Animal modeling Endovascular Ischemic stroke Imaging Neuroprotection Recanalization Reperfusion injury Thrombolysis Tissue-type plasminogen activator Time window 


Compliance with Ethical Standards


This study was funded by institutional grants.

Conflict of Interest

The authors declare that they have no competing interests.

Ethical Approval

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

Disclosures and Study Funding



  1. 1.
    Puyal J, Ginet V, Clarke PG. Multiple interacting cell death mechanisms in the mediation of excitotoxicity and ischemic brain damage: a challenge for neuroprotection. Prog Neurobiol. 2013;105:24–48. doi: 10.1016/j.pneurobio.2013.03.002.CrossRefPubMedGoogle Scholar
  2. 2.
    Schabitz WR, Fisher M. Perspectives on neuroprotective stroke therapy. Biochem Soc Trans. 2006;34:1271–6. doi: 10.1042/BST0341271.CrossRefPubMedGoogle Scholar
  3. 3.
    Henninger N, Kumar R, Fisher M. Acute ischemic stroke therapy. Expert Rev Cardiovasc Ther. 2010;8:1389–98. doi: 10.1586/erc.10.128.CrossRefPubMedGoogle Scholar
  4. 4.
    Savitz SI, Fisher M. Future of neuroprotection for acute stroke: in the aftermath of the SAINT trials. Ann Neurol. 2007;61:396–402. doi: 10.1002/ana.21127.CrossRefPubMedGoogle Scholar
  5. 5.
    Stroke therapy academic industry roundtable (STAIR). Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke. 1999;30(12):2752–8.Google Scholar
  6. 6.
    Stroke therapy academic industry roundtable II (STAIR-II). Recommendations for clinical trial evaluation of acute stroke therapies. Stroke. 2001;32(7):1598–606.Google Scholar
  7. 7.
    Fisher M, Feuerstein G, Howells DW, Hurn PD, Kent TA, Savitz SI, et al. Update of the stroke therapy academic industry roundtable preclinical recommendations. Stroke. 2009;40:2244–50. doi: 10.1161/STROKEAHA.108.541128.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Saver JL, Jovin TG, Smith WS, Albers GW, Baron JC, Boltze J, et al. Stroke treatment academic industry roundtable: research priorities in the assessment of neurothrombectomy devices. Stroke. 2013;44:3596–601. doi: 10.1161/STROKEAHA.113.002769.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Sena E, van der Worp HB, Howells D, Macleod M. How can we improve the pre-clinical development of drugs for stroke? Trends Neurosci. 2007;30:433–9. doi: 10.1016/j.tins.2007.06.009.CrossRefPubMedGoogle Scholar
  10. 10.
    Llovera G, Hofmann K, Roth S, Salas-Perdomo A, Ferrer-Ferrer M, Perego C, et al. Results of a preclinical randomized controlled multicenter trial (pRCT): anti-CD49d treatment for acute brain ischemia. Sci Transl Med. 2015;7:299ra121. doi: 10.1126/scitranslmed.aaa9853.CrossRefPubMedGoogle Scholar
  11. 11.
    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.Google Scholar
  12. 12.
    Hacke W, Kaste M, Bluhmki E, Brozman M, Davalos A, Guidetti D, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359:1317–29. doi: 10.1056/NEJMoa0804656.CrossRefPubMedGoogle Scholar
  13. 13.
    Emberson J, Lees KR, Lyden P, Blackwell L, Albers G, Bluhmki E, et al. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet. 2014;384:1929–35. doi: 10.1016/S0140-6736(14)60584-5.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Albers GW, Goyal M, Jahan R, Bonafe A, Diener HC, Levy EI, et al. Relationships between imaging assessments and outcomes in Solitaire with the intention for thrombectomy as primary endovascular treatment for acute ischemic stroke. Stroke. 2015;46:2786–94. doi: 10.1161/STROKEAHA.115.010710.CrossRefPubMedGoogle Scholar
  15. 15.
    Parsons M, Spratt N, Bivard A, Campbell B, Chung K, Miteff F, et al. A randomized trial of tenecteplase versus alteplase for acute ischemic stroke. N Engl J Med. 2012;366:1099–107. doi: 10.1056/NEJMoa1109842.CrossRefPubMedGoogle Scholar
  16. 16.
    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. doi: 10.1056/NEJMoa1411587.CrossRefPubMedGoogle Scholar
  17. 17.
    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. doi: 10.1056/NEJMoa1414905.CrossRefPubMedGoogle Scholar
  18. 18.
    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. doi: 10.1056/NEJMoa1415061.PubMedCentralGoogle Scholar
  19. 19.
    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. doi: 10.1056/NEJMoa1414792.CrossRefPubMedGoogle Scholar
  20. 20.
    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. doi: 10.1056/NEJMoa1503780.CrossRefPubMedGoogle Scholar
  21. 21.
    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. doi: 10.1056/NEJMoa1214300.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Shen Q, Ren H, Cheng H, Fisher M, Duong TQ. Functional, perfusion and diffusion MRI of acute focal ischemic brain injury. J Cereb Blood Flow Metab. 2005;25:1265–79. doi: 10.1038/sj.jcbfm.9600132.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Fisher M. The ischemic penumbra: a new opportunity for neuroprotection. Cerebrovasc Dis. 2006;21 Suppl 2:64–70. doi: 10.1159/000091705.CrossRefPubMedGoogle Scholar
  24. 24.
    Saver JL. Time is brain--quantified. Stroke. 2006;37:263–6. doi: 10.1161/01.STR.0000196957.55928.ab.CrossRefPubMedGoogle Scholar
  25. 25.
    Sandercock P, Wardlaw JM, Lindley RI, Dennis M, Cohen G, Murray G, et al. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial. Lancet. 2012;379:2352–63. doi: 10.1016/S0140-6736(12)60768-5.CrossRefPubMedGoogle Scholar
  26. 26.
    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. doi: 10.1056/NEJMoa1212793.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Nagakane Y, Christensen S, Brekenfeld C, Ma H, Churilov L, Parsons MW, et al. EPITHET: positive result after reanalysis using baseline diffusion-weighted imaging/perfusion-weighted imaging co-registration. Stroke. 2011;42:59–64. doi: 10.1161/STROKEAHA.110.580464.CrossRefPubMedGoogle Scholar
  28. 28.
    Wheeler HM, Mlynash M, Inoue M, Tipirneni A, Liggins J, Zaharchuk G, et al. Early diffusion-weighted imaging and perfusion-weighted imaging lesion volumes forecast final infarct size in DEFUSE 2. Stroke. 2013;44:681–5. doi: 10.1161/STROKEAHA.111.000135.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Lansberg MG, Cereda CW, Mlynash M, Mishra NK, Inoue M, Kemp S, et al. Response to endovascular reperfusion is not time-dependent in patients with salvageable tissue. Neurology. 2015;85:708–14. doi: 10.1212/WNL.0000000000001853.CrossRefPubMedGoogle Scholar
  30. 30.
    Wintermark M, Flanders AE, Velthuis B, Meuli R, van Leeuwen M, Goldsher D, et al. Perfusion-CT assessment of infarct core and penumbra: receiver operating characteristic curve analysis in 130 patients suspected of acute hemispheric stroke. Stroke. 2006;37:979–85. doi: 10.1161/01.STR.0000209238.61459.39.CrossRefPubMedGoogle Scholar
  31. 31.
    Lin L, Bivard A, Levi CR, Parsons MW. Comparison of computed tomographic and magnetic resonance perfusion measurements in acute ischemic stroke: back-to-back quantitative analysis. Stroke. 2014;45:1727–32. doi: 10.1161/STROKEAHA.114.005419.CrossRefPubMedGoogle Scholar
  32. 32.
    Liebeskind DS, Jahan R, Nogueira RG, Jovin TG, Lutsep HL, Saver JL. Serial Alberta Stroke Program early CT score from baseline to 24 hours in Solitaire Flow Restoration with the Intention for Thrombectomy study: a novel surrogate end point for revascularization in acute stroke. Stroke. 2014;45:723–7. doi: 10.1161/STROKEAHA.113.003914.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Bratane BT, Cui H, Cook DJ, Bouley J, Tymianski M, Fisher M. Neuroprotection by freezing ischemic penumbra evolution without cerebral blood flow augmentation with a postsynaptic density-95 protein inhibitor. Stroke. 2011;42:3265–70. doi: 10.1161/STROKEAHA.111.618801.CrossRefPubMedGoogle Scholar
  34. 34.
    Henninger N, Bratane BT, Bastan B, Bouley J, Fisher M. Normobaric hyperoxia and delayed tPA treatment in a rat embolic stroke model. J Cereb Blood Flow Metab. 2009;29:119–29. doi: 10.1038/jcbfm.2008.104.CrossRefPubMedGoogle Scholar
  35. 35.
    Badhiwala JH, Nassiri F, Alhazzani W, Selim MH, Farrokhyar F, Spears J, et al. Endovascular thrombectomy for acute ischemic stroke: a meta-analysis. JAMA. 2015;314:1832–43. doi: 10.1001/jama.2015.13767.CrossRefPubMedGoogle Scholar
  36. 36.
    Meyers PM, Schumacher HC, Connolly Jr ES, Heyer EJ, Gray WA, Higashida RT. Current status of endovascular stroke treatment. Circulation. 2011;123:2591–601. doi: 10.1161/CIRCULATIONAHA.110.971564.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Cloft HJ, Rabinstein A, Lanzino G, Kallmes DF. Intra-arterial stroke therapy: an assessment of demand and available work force. AJNR Am J Neuroradiol. 2009;30:453–8. doi: 10.3174/ajnr.A1462.CrossRefPubMedGoogle Scholar
  38. 38.
    Wardlaw JM, Dennis MS. Thrombectomy for acute ischemic stroke. JAMA. 2015;314:1803–5. doi: 10.1001/jama.2015.14674.CrossRefPubMedGoogle Scholar
  39. 39.
    Kleindorfer D, Lindsell CJ, Brass L, Koroshetz W, Broderick JP. National US estimates of recombinant tissue plasminogen activator use: ICD-9 codes substantially underestimate. Stroke. 2008;39:924–8. doi: 10.1161/STROKEAHA.107.490375.CrossRefPubMedGoogle Scholar
  40. 40.
    Asplund K, Glader EL, Norrving B, Eriksson M. Effects of extending the time window of thrombolysis to 4.5 hours: observations in the Swedish stroke register (riks-stroke). Stroke. 2011;42:2492–7. doi: 10.1161/STROKEAHA.111.618587.CrossRefPubMedGoogle Scholar
  41. 41.
    Adeoye O, Hornung R, Khatri P, Kleindorfer D. Recombinant tissue-type plasminogen activator use for ischemic stroke in the United States: a doubling of treatment rates over the course of 5 years. Stroke. 2011;42:1952–5. doi: 10.1161/STROKEAHA.110.612358.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    O’Collins VE, Macleod MR, Donnan GA, Horky LL, van der Worp BH, Howells DW. 1,026 experimental treatments in acute stroke. Ann Neurol. 2006;59:467–77. doi: 10.1002/ana.20741.CrossRefPubMedGoogle Scholar
  43. 43.
    Minnerup J, Sutherland BA, Buchan AM, Kleinschnitz C. Neuroprotection for stroke: current status and future perspectives. Int J Mol Sci. 2012;13:11753–72. doi: 10.3390/ijms130911753.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Philip M, Benatar M, Fisher M, Savitz SI. Methodological quality of animal studies of neuroprotective agents currently in phase II/III acute ischemic stroke trials. Stroke. 2009;40:577–81. doi: 10.1161/STROKEAHA.108.524330.CrossRefPubMedGoogle Scholar
  45. 45.
    Tymianski M. Can molecular and cellular neuroprotection be translated into therapies for patients?: yes, but not the way we tried it before. Stroke. 2010;41:S87–90. doi: 10.1161/STROKEAHA.110.595496.CrossRefPubMedGoogle Scholar
  46. 46.
    Mehra M, Henninger N, Hirsch JA, Chueh J, Wakhloo AK, Gounis MJ. Preclinical acute ischemic stroke modeling. J Neurointerv Surg. 2012;4:307–13. doi: 10.1136/neurintsurg-2011-010101.CrossRefPubMedGoogle Scholar
  47. 47.
    Henninger N, Sicard KM, Schmidt KF, Bardutzky J, Fisher M. Comparison of ischemic lesion evolution in embolic versus mechanical middle cerebral artery occlusion in Sprague Dawley rats using diffusion and perfusion imaging. Stroke. 2006;37:1283–7. doi: 10.1161/01.STR.0000217223.72193.98.CrossRefPubMedGoogle Scholar
  48. 48.
    Manning NW, Campbell BC, Oxley TJ, Chapot R. Acute ischemic stroke: time, penumbra, and reperfusion. Stroke. 2014;45:640–4. doi: 10.1161/STROKEAHA.113.003798.CrossRefPubMedGoogle Scholar
  49. 49.
    Marosfoi MG, Korin N, Gounis MJ, Uzun O, Vedantham S, Langan ET, et al. Shear-activated nanoparticle aggregates combined with temporary endovascular bypass to treat large vessel occlusion. Stroke. 2015. doi: 10.1161/STROKEAHA.115.011063.Google Scholar
  50. 50.
    Henninger N, Bouley J, Nelligan JM, Sicard KM, Fisher M. Normobaric hyperoxia delays perfusion/diffusion mismatch evolution, reduces infarct volume, and differentially affects neuronal cell death pathways after suture middle cerebral artery occlusion in rats. J Cereb Blood Flow Metab. 2007;27:1632–42. doi: 10.1038/sj.jcbfm.9600463.CrossRefPubMedGoogle Scholar
  51. 51.
    Kim HY, Singhal AB, Lo EH. Normobaric hyperoxia extends the reperfusion window in focal cerebral ischemia. Ann Neurol. 2005;57:571–5. doi: 10.1002/ana.20430.CrossRefPubMedGoogle Scholar
  52. 52.
    Ip HL, Liebeskind DS. The future of ischemic stroke: flow from prehospital neuroprotection to definitive reperfusion. Interv Neurol. 2014;2:105–17. doi: 10.1159/000357164.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Jung JE, Kim GS, Chen H, Maier CM, Narasimhan P, Song YS, et al. Reperfusion and neurovascular dysfunction in stroke: from basic mechanisms to potential strategies for neuroprotection. Mol Neurobiol. 2010;41:172–9. doi: 10.1007/s12035-010-8102-z.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Bardutzky J, Meng X, Bouley J, Duong TQ, Ratan R, Fisher M. Effects of intravenous dimethyl sulfoxide on ischemia evolution in a rat permanent occlusion model. J Cereb Blood Flow Metab. 2005;25:968–77. doi: 10.1038/sj.jcbfm.9600095.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Henninger N, Fisher M. Stimulating circle of Willis nerve fibers preserves the diffusion-perfusion mismatch in experimental stroke. Stroke. 2007;38:2779–86. doi: 10.1161/STROKEAHA.107.485581.CrossRefPubMedGoogle Scholar
  56. 56.
    Bratane BT, Bouley J, Schneider A, Bastan B, Henninger N, Fisher M. Granulocyte-colony stimulating factor delays PWI/DWI mismatch evolution and reduces final infarct volume in permanent-suture and embolic focal cerebral ischemia models in the rat. Stroke. 2009;40:3102–6. doi: 10.1161/STROKEAHA.109.553958.CrossRefPubMedGoogle Scholar
  57. 57.
    Saver JL, Starkman S, Eckstein M, Stratton SJ, Pratt FD, Hamilton S, et al. Prehospital use of magnesium sulfate as neuroprotection in acute stroke. N Engl J Med. 2015;372:528–36. doi: 10.1056/NEJMoa1408827.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Ebinger M, Winter B, Wendt M, Weber JE, Waldschmidt C, Rozanski M, et al. Effect of the use of ambulance-based thrombolysis on time to thrombolysis in acute ischemic stroke: a randomized clinical trial. JAMA. 2014;311:1622–31. doi: 10.1001/jama.2014.2850.CrossRefPubMedGoogle Scholar
  59. 59.
    Audebert HJ, Saver JL, Starkman S, Lees KR, Endres M. Prehospital stroke care: new prospects for treatment and clinical research. Neurology. 2013;81:501–8. doi: 10.1212/WNL.0b013e31829e0fdd.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Korin N, Kanapathipillai M, Matthews BD, Crescente M, Brill A, Mammoto T, et al. Shear-activated nanotherapeutics for drug targeting to obstructed blood vessels. Science. 2012;337:738–42. doi: 10.1126/science.1217815.CrossRefPubMedGoogle Scholar
  61. 61.
    van der Worp HB, Macleod MR, Bath PM, Demotes J, Durand-Zaleski I, Gebhardt B, et al. EuroHYP-1: European multicenter, randomized, phase III clinical trial of therapeutic hypothermia plus best medical treatment vs. best medical treatment alone for acute ischemic stroke. Int J Stroke. 2014;9:642–5. doi: 10.1111/ijs.12294.CrossRefPubMedGoogle Scholar
  62. 62.
    Horn CM, Sun CH, Nogueira RG, Patel VN, Krishnan A, Glenn BA, et al. Endovascular Reperfusion and Cooling in Cerebral Acute Ischemia (ReCCLAIM I). J Neurointerv Surg. 2014;6:91–5. doi: 10.1136/neurintsurg-2013-010656.CrossRefPubMedGoogle Scholar
  63. 63.
    van der Worp HB, Sena ES, Donnan GA, Howells DW, Macleod MR. Hypothermia in animal models of acute ischaemic stroke: a systematic review and meta-analysis. Brain. 2007;130:3063–74. doi: 10.1093/brain/awm083.CrossRefPubMedGoogle Scholar
  64. 64.
    Donnino MW, Andersen LW, Berg KM, Reynolds JC, Nolan JP, Morley PT, et al. Temperature management after cardiac arrest: an advisory statement by the Advanced Life Support Task Force of the International Liaison Committee on Resuscitation and the American Heart Association Emergency Cardiovascular Care Committee and the Council on Cardiopulmonary, Critical Care. Perioper Resuscitation Circ. 2015. doi: 10.1161/CIR.0000000000000313.Google Scholar
  65. 65.
    Kuliha M, Roubec M, Jonszta T, Krajca J, Czerny D, Krajina A, et al. Safety and efficacy of endovascular sonolysis using the EkoSonic endovascular system in patients with acute stroke. AJNR Am J Neuroradiol. 2013;34:1401–6. doi: 10.3174/ajnr.A3416.CrossRefPubMedGoogle Scholar
  66. 66.
    Schellinger PD, Alexandrov AV, Barreto AD, Demchuk AM, Tsivgoulis G, Kohrmann M, et al. Combined lysis of thrombus with ultrasound and systemic tissue plasminogen activator for emergent revascularization in acute ischemic stroke (CLOTBUST-ER): design and methodology of a multinational phase 3 trial. Int J Stroke. 2015;10:1141–8. doi: 10.1111/ijs.12536.CrossRefPubMedGoogle Scholar
  67. 67.
    Fisher M, Saver JL. Future directions of acute ischaemic stroke therapy. Lancet Neurol. 2015;14:758–67. doi: 10.1016/S1474-4422(15)00054-X.CrossRefPubMedGoogle Scholar
  68. 68.
    dela Pena IC, Yoo A, Tajiri N, Acosta SA, Ji X, Kaneko Y, et al. Granulocyte colony-stimulating factor attenuates delayed tPA-induced hemorrhagic transformation in ischemic stroke rats by enhancing angiogenesis and vasculogenesis. J Cereb Blood Flow Metab. 2015;35:338–46. doi: 10.1038/jcbfm.2014.208.CrossRefGoogle Scholar
  69. 69.
    Iadecola C, Anrather J. The immunology of stroke: from mechanisms to translation. Nat Med. 2011;17:796–808. doi: 10.1038/nm.2399.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Sanderson TH, Reynolds CA, Kumar R, Przyklenk K, Huttemann M. Molecular mechanisms of ischemia-reperfusion injury in brain: pivotal role of the mitochondrial membrane potential in reactive oxygen species generation. Mol Neurobiol. 2013;47:9–23. doi: 10.1007/s12035-012-8344-z.CrossRefPubMedGoogle Scholar
  71. 71.
    Warach S, Latour LL. Evidence of reperfusion injury, exacerbated by thrombolytic therapy, in human focal brain ischemia using a novel imaging marker of early blood-brain barrier disruption. Stroke. 2004;35:2659–61. doi: 10.1161/01.STR.0000144051.32131.09.CrossRefPubMedGoogle Scholar
  72. 72.
    Leigh R, Jen SS, Hillis AE, Krakauer JW, Barker PB. Pretreatment blood-brain barrier damage and post-treatment intracranial hemorrhage in patients receiving intravenous tissue-type plasminogen activator. Stroke. 2014;45:2030–5. doi: 10.1161/STROKEAHA.114.005249.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Berger C, Fiorelli M, Steiner T, Schabitz WR, Bozzao L, Bluhmki E, et al. Hemorrhagic transformation of ischemic brain tissue: asymptomatic or symptomatic? Stroke. 2001;32:1330–5.CrossRefPubMedGoogle Scholar
  74. 74.
    Kent DM, Hinchey J, Price LL, Levine SR, Selker HP. In acute ischemic stroke, are asymptomatic intracranial hemorrhages clinically innocuous? Stroke. 2004;35:1141–6. doi: 10.1161/01.STR.0000125712.02090.6e.CrossRefPubMedGoogle Scholar
  75. 75.
    Lei C, Wu B, Liu M, Chen Y. Asymptomatic hemorrhagic transformation after acute ischemic stroke: is it clinically innocuous? J Stroke Cerebrovasc Dis. 2014;23:2767–72. doi: 10.1016/j.jstrokecerebrovasdis.2014.06.024.CrossRefPubMedGoogle Scholar
  76. 76.
    Park JH, Ko Y, Kim WJ, Jang MS, Yang MH, Han MK, et al. Is asymptomatic hemorrhagic transformation really innocuous? Neurology. 2012;78:421–6. doi: 10.1212/WNL.0b013e318245d22c.CrossRefPubMedGoogle Scholar
  77. 77.
    Dzialowski I, Pexman JH, Barber PA, Demchuk AM, Buchan AM, Hill MD. Asymptomatic hemorrhage after thrombolysis may not be benign: prognosis by hemorrhage type in the Canadian Alteplase for Stroke Effectiveness Study registry. Stroke. 2007;38:75–9. doi: 10.1161/01.STR.0000251644.76546.62.CrossRefPubMedGoogle Scholar
  78. 78.
    Zhu Z, Fu Y, Tian D, Sun N, Han W, Chang G, et al. Combination of the immune modulator fingolimod with alteplase in acute ischemic stroke: a pilot trial. Circulation. 2015;132:1104–12. doi: 10.1161/CIRCULATIONAHA.115.016371.CrossRefPubMedGoogle Scholar
  79. 79.
    Schwamm LH, Holloway RG, Amarenco P, Audebert HJ, Bakas T, Chumbler NR, et al. A review of the evidence for the use of telemedicine within stroke systems of care: a scientific statement from the American Heart Association/American Stroke Association. Stroke. 2009;40:2616–34. doi: 10.1161/STROKEAHA.109.192360.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Department of NeurologyUniversity of Massachusetts Medical SchoolWorcesterUSA
  2. 2.Department of PsychiatryUniversity of Massachusetts Medical SchoolWorcesterUSA
  3. 3.Department of NeurologyBeth Israel Deaconess Medical Center, Harvard Medical SchoolBostonUSA
  4. 4.Division of Stroke and Cerebrovascular Diseases, Department of Neurology, Beth Israel Deaconess Medical CenterHarvard Medical SchoolBostonUSA

Personalised recommendations