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Sonothrombolysis in Ischemic Stroke

  • CRITICAL CARE NEUROLOGY (KN SHETH, SECTION EDITOR)
  • Published:
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Opinion statement

Acute ischemic stroke remains one of the most devastating diseases when it comes to morbidity and mortality, not to mention the personal and economic burden that occurs in long-term. Intravenous thrombolysis with tissue plasminogen activator (tPA) is the only effective acute stroke therapy that improves outcome if given up to 4.5 hours from symptom onset. However, recanalization rates are meager and the majority of treated patients still have residual disability after stroke, emphasizing the need for further treatment options that may facilitate or even rival the only approved therapy. Sonothrombolysis, the adjuvant continuous ultrasound sonication of an intra-arterial occlusive thrombus during thrombolysis, enhances the clot-dissolving capabilities of intravenous tPA presumably by delivering acoustic pressure to the target brain vessel. Higher recanalization rates produce a trend towards better functional outcomes that could be safely achieved with the combination of high-frequency ultrasound and intravenous tPA. However, data on ultrasound targeting of intracranial proximal occlusive lesions other than those in the middle cerebral arteries are sparse. Moreover, recent sonothrombolysis trials were exclusively conducted with operator-dependent hand-held technology hindering its further testing in clinical sonothrombolysis trials. An operator-independent 2-MHz transcranial Doppler device has been developed allowing health care professionals not formally trained in ultrasound apparatus to provide therapeutic ultrasound as needed. Currently, this operator-independent device covering 12 proximal intracranial segments that most commonly contain thrombo-embolic occlusions enters testing in a pivotal multicenter sonothrombolysis efficacy trial. If this trial demonstrates safety and efficacy, adjuvants, such as gaseous microbubbles that further potentiate the thrombolytic effect of intravenous tPA, could be tested along with this device.

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References and Recommended Reading

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  1. Roger VL, Go AS, Lloyd-Jones DM, American Heart Association Statistics Committee and Stroke Statistics Subcommittee, et al. Heart disease and stroke statistics–2012 update: a report from the American Heart Association. Circulation. 2012;125:e2–e220.

    Article  PubMed  Google Scholar 

  2. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995;333:1581–7.

    Google Scholar 

  3. Hacke W, Kaste M, Bluhmki E, et al. ECASS Investigators: thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359:1317–29.

    Article  PubMed  CAS  Google Scholar 

  4. Sandercock P, Wardlaw JM, Lindley RI, et al. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischemic stroke (the third international stroke trial [IST-3]): a randomized controlled trial. Lancet. 2012;379:2352–63.

    Article  PubMed  Google Scholar 

  5. Grotta JC, Welch KM, Fagan SC, et al. Clinical deterioration following improvement in the NINDS rt-PA Stroke Trial. Stroke. 2001;32:661–8.

    Article  PubMed  CAS  Google Scholar 

  6. Alexandrov AV, Grotta JC. Arterial reocclusion in stroke patients treated with intravenous tissue plasminogen activator. Neurology. 2002;59:862–7.

    Article  PubMed  CAS  Google Scholar 

  7. Alexandrov AV. Ultrasound identification and lysis of clots. Stroke. 2004;35:2722–5.

    Article  PubMed  Google Scholar 

  8. Barreto AD, Alexandrov AV. Adjunctive and alternative approaches to current reperfusion therapy. Stroke. 2012;43:591–8. This review appraises novel adjunctive or alternative approaches to current reperfusion strategies being tested in all ischemic stroke trial phases.

    Article  PubMed  Google Scholar 

  9. Balucani C, Grotta JC. Selecting stroke patients for intra-arterial therapy. Neurology. 2012;78:755–61.

    Article  PubMed  CAS  Google Scholar 

  10. Hacke W, Furlan AJ, Al-Rawi Y, et al. Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomized, double-blind, placebo-controlled study. Lancet Neurol. 2009;8:141–50.

    Article  PubMed  CAS  Google Scholar 

  11. Adams Jr HP, Effron MB, Torner J, et al. Emergency administration of abciximab for treatment of patients with acute ischemic stroke: results of an international phase III trial: Abciximab in Emergency Treatment of Stroke Trial (AbESTT-II). Stroke. 2008;39:87–99.

    Article  PubMed  CAS  Google Scholar 

  12. National Institute of Neurological Disorders and Stroke. National Institutes of Health. Interventional Management of Stroke III Trial (IMS III). Available at: http://www.ninds.nih.gov/disorders/clinical_trials/NCT00359424.htm. Accessed November 02, 2012.

  13. Miller DL, Smith NB, Bailey MR, et al. Overview of therapeutic ultrasound applications and safety considerations. J Ultrasound Med. 2012;31:623–34.

    PubMed  Google Scholar 

  14. Voigt J, Wendelken M, Driver V, Alvarez OM. Low-frequency ultrasound (20–40 kHz) as an adjunctive therapy for chronic wound healing: a systematic review of the literature and meta-analysis of 8 randomized controlled trials. Int J Low Extrem Wounds. 2011;10:190–9.

    Article  PubMed  Google Scholar 

  15. Alexandrov AV, Barlinn K. Taboos and opportunities in sonothrombolysis for stroke. Int J Hyperthermia. 2012;28:397–404. This review summarizes our current knowledge about potentially harmful (taboos) directions and what we think are promising venues for sonothrombolysis in acute ischemic stroke.

    Article  PubMed  CAS  Google Scholar 

  16. Mahon BR, Nesbit GM, Barnwell SL, et al. North American clinical experience with the EKOS MicroLysUS infusion catheter for the treatment of embolic stroke. Am J Neuroradiol. 2003;24:534–8.

    PubMed  Google Scholar 

  17. Tomsick T, Broderick J, Carrozella J, et al. Revascularization results in the interventional management of stroke II trial. Am J Neuroradiol. 2008;29:582–7.

    Article  PubMed  CAS  Google Scholar 

  18. Meairs S, Culp W. Microbubbles for thrombolysis of acute ischemic stroke. Cerebrovasc Dis. 2009;27 Suppl 2:55–6.

    Article  PubMed  Google Scholar 

  19. Cintas P, Le Traon AP, Larrue V. High rate of recanalization of middle cerebral artery occlusion during 2-MHz transcranial color-coded Doppler continuous monitoring without thrombolytic drug. Stroke. 2002;33:626–8.

    Article  PubMed  Google Scholar 

  20. Baker KG, Robertson VJ, Duck FA. A review of therapeutic ultrasound: biophysical effects. Phys Ther. 2001;81:1351–8.

    PubMed  CAS  Google Scholar 

  21. Pfaffenberger S, Devcic-Kuhar B, Kollmann C, et al. Can a commercial diagnostic ultrasound device accelerate thrombolysis? An in vitro skull model. Stroke. 2005;36:124–8.

    Article  PubMed  Google Scholar 

  22. Pfaffenberger S, Vyskocil E, Kollmann C, et al. Transtemporal ultrasound application potentially elevates brain temperature: results of an Anthropomorphic Skull Model. Ultraschall Med. 2012; doi:10.1055/s-0032-1313083

  23. Sakharov DV, Hekkenberg RT, Rijken DC. Acceleration of fibrinolysis by high frequency ultrasound: the contribution of acoustic streaming and temperature rise. Thromb Res. 2000;100:333–40.

    Article  PubMed  CAS  Google Scholar 

  24. Tsivgoulis G, Eggers J, Ribo M, et al. Safety and efficacy of ultrasound-enhanced thrombolysis: a comprehensive review and meta-analysis of randomized and nonrandomized studies. Stroke. 2010;41:280–7. This paper constitutes the first meta-analysis of all relevant clinical sonothrombolysis studies in acute ischemic stroke. Conclusively, the exposure to any diagnostic high-frequency ultrasound is safe and yields higher recanalization rates compared with intravenous tPA alone.

    Article  PubMed  Google Scholar 

  25. Everbach EC, Francis CW. Cavitational mechanisms in ultrasound-accelerated thrombolysis at 1 MHz. Ultrasound Med Biol. 2000;26:1153–60.

    Article  PubMed  CAS  Google Scholar 

  26. Datta S, Coussios CC, McAdory LE, et al. Correlation of cavitation with ultrasound enhancement of thrombolysis. Ultrasound Med Biol. 2006;32:1257–67.

    Article  PubMed  Google Scholar 

  27. Francis CW, Blinc A, Lee S, Cox C. Ultrasound accelerates transport of recombinant tissue plasminogen activator into clots. Ultrasound Med Biol. 1995;21:419–24.

    Article  PubMed  CAS  Google Scholar 

  28. Barlinn K, Tsivgoulis G, Molina CA, et al. Exploratory analysis of estimated peak rarefaction pressure, recanalization, and outcome in the Transcranial Ultrasound in Clinical SONothrombolysis (TUCSON) Trial. J Clin Ultrasound. 2012; doi:10.1002/jcu.21978. A mathematical estimation of the acoustic peak rarefaction pressure achieved in the TUCSON trial and its association with recanalization and functional outcome.

  29. Baron C, Aubry JF, Tanter M, et al. Simulation of intracranial acoustic fields in clinical trials of sonothrombolysis. Ultrasound Med Biol. 2009;35:1148–58.

    Article  PubMed  Google Scholar 

  30. Sakharov DV, Rijken DC. The effect of flow on lysis of plasma clots in a plasma environment. Thromb Haemost. 2000;83:469–74.

    PubMed  CAS  Google Scholar 

  31. Siddiqi F, Blinc A, Braaten J, Francis CW. Ultrasound increases flow through fibrin gels. Thromb Haemost. 1995;73:495–8.

    PubMed  CAS  Google Scholar 

  32. Suchkova VN, Baggs RB, Sahni SK, Francis CW. Ultrasound improves tissue perfusion in ischemic tissue through a nitric oxide dependent mechanism. Thromb Haemost. 2002;88:865–70.

    PubMed  Google Scholar 

  33. Sugita Y, Mizuno S, Nakayama N, et al. Nitric oxide generation directly responds to ultrasound exposure. Ultrasound Med Biol. 2008;34:487–93.

    Article  PubMed  Google Scholar 

  34. Daffertshofer M, Gass A, Ringleb P, et al. Transcranial low-frequency ultrasound-mediated thrombolysis in brain ischemia: increased risk of hemorrhage with combined ultrasound and tissue plasminogen activator: results of a phase II clinical trial. Stroke. 2005;36:1441–6.

    Article  PubMed  Google Scholar 

  35. Schneider F, Gerriets T, Walberer M, et al. Brain edema and intracerebral necrosis caused by transcranial low-frequency 20-kHz ultrasound: a safety study in rats. Stroke. 2006;37:1301–6.

    Article  PubMed  Google Scholar 

  36. Reinhard M, Hetzel A, Kruger S, et al. Blood-brain barrier disruption by low frequency ultrasound. Stroke. 2006;37:1546–8.

    Article  PubMed  Google Scholar 

  37. Alexandrov AV, Burgin WS, Demchuk AM, et al. Speed of intracranial clot lysis with intravenous tissue plasminogen activator therapy: sonographic classification and short-term improvement. Circulation. 2001;103:2897–902.

    Article  PubMed  CAS  Google Scholar 

  38. Alexandrov AV, Tsivgoulis G. Body weight, not thrombus-burden tissue plasminogen activator dosing: but still. Stroke. 2010;41:2723–4.

    Article  PubMed  Google Scholar 

  39. Saqqur M, Uchino K, Demchuk AM, et al. Site of arterial occlusion identified by transcranial Doppler predicts the response to intravenous thrombolysis for stroke. Stroke. 2007;38:948–54.

    Article  PubMed  Google Scholar 

  40. Rha JH, Saver JL. The impact of recanalization on ischemic stroke outcome: a meta-analysis. Stroke. 2007;38:967–73.

    Article  PubMed  Google Scholar 

  41. Alexandrov AV, Barlinn K, Strong R, Alexandrov AW, Aronowski J. Low-power 2-MHz pulsed-wave transcranial ultrasound reduces ischemic brain damage in rats. Transl Stroke Res. 2011; 10.1007/s12975–011–0080–6.41.

  42. Tachibana K. Enhancement of fibrinolysis with ultrasound energy. J Vasc Interv Radiol. 1992;3:299–303.

    Article  PubMed  CAS  Google Scholar 

  43. Suchkova V, Siddiqi FN, Carstensen EL, et al. Enhancement of fibrinolysis with 40-kHz ultrasound. Circulation. 1998;98:1030–5.

    Article  PubMed  CAS  Google Scholar 

  44. Daffertshofer M, Huang Z, Fatar M, et al. Efficacy of sonothrombolysis in a rat model of embolic ischemic stroke. Neurosci Lett. 2004;361:115–9.

    Article  PubMed  CAS  Google Scholar 

  45. Lauer CG, Burge R, Tang DB, et al. Effect of ultrasound on tissue-type plasminogen activator-induced thrombolysis. Circulation. 1992;86:1257–64.

    Article  PubMed  CAS  Google Scholar 

  46. Behrens S, Daffersthofer M, Spiegel D, Hennerici M. Low-frequency, low-intensity ultrasound accelerates thrombolysis through the skull. Ultrasound Med Biol. 1999;25:269–73.

    Article  PubMed  CAS  Google Scholar 

  47. Blinc A, Francis CW, Trudnowski JL, Carstensen EL. Characterization of ultrasound-potentiated fibrinolysis in vitro. Blood. 1993;81:2636–43.

    PubMed  CAS  Google Scholar 

  48. Holland CK, Vaidya SS, Datta S, Coussios CC, Shaw GJ. Ultrasound-enhanced tissue plasminogen activator thrombolysis in an in vitro porcine clot model. Thromb Res. 2008;121:663–73.

    Article  PubMed  CAS  Google Scholar 

  49. Saguchi T, Onoue H, Urashima M, et al. Effective and safe conditions of low-frequency transcranial ultrasound thrombolysis for acute ischemic stroke. Neurologic and histologic evaluation in a rat middle cerebral artery stroke model. Stroke. 2008;39:1007–11.

    Article  PubMed  Google Scholar 

  50. Wilhelm-Schwenkmezger T, Pittermann P, Zajonz K, et al. Therapeutic application of 20-kHz transcranial ultrasound in an embolic middle cerebral artery occlusion model in rats: safety concerns. Stroke. 2007;38:1031–5.

    Article  PubMed  Google Scholar 

  51. Nedelmann M, Reuter P, Walberer M, et al. Detrimental effects of 60 kHz sonothrombolysis in rats with middle cerebral artery occlusion. Ultrasound Med Biol. 2008;34:2019–27.

    Article  PubMed  Google Scholar 

  52. Ricci S, Dinia L, Del Sette M, et al. Sonothrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev. 2012;10:CD008348. The results of this Cochrane Review add to the growing scientific body of evidence that sonothrombolysis with high-frequency ultrasound could be a promising option for acute ischemic stroke patients.

    PubMed  Google Scholar 

  53. Saqqur M, Tsivgoulis G, Molina CA, et al. Symptomatic intracerebral hemorrhage and recanalization after IV rt-PA: a multicenter study. Neurology. 2008;71:1304–12.

    Article  PubMed  CAS  Google Scholar 

  54. Barlinn K, Barreto A, Liebeskind DS, et al. CLOTBUST-hands free operator independent ultrasound device: initial safety testing in healthy volunteers. Stroke. 2011;42:e111–350. For the first time, an operator-independent ultrasound TCD technology has been safely tested in stroke-free volunteers.

    Article  Google Scholar 

  55. Hitchcock KE, Holland CK. Ultrasound-assisted thrombolysis for stroke therapy: better thrombus break-up with bubbles. Stroke. 2010;41:S50–3.

    Article  PubMed  Google Scholar 

  56. Moehring MA, Klepper JR. Pulse Doppler ultrasound detection, characterization and size estimation of emboli in flowing blood. IEEE Trans Biomed Eng. 1994;41:35–44.

    Article  PubMed  CAS  Google Scholar 

  57. Alexandrov AV, Tsivgoulis G, Rubiera M, TUCSON Investigators, et al. End-diastolic velocity increase predicts recanalization and neurological improvement in patients with ischemic stroke with proximal arterial occlusions receiving reperfusion therapies. Stroke. 2010;41:948–52.

    Article  PubMed  Google Scholar 

  58. Sharma VK, Tsivgoulis G, Lao AY, et al. Noninvasive detection of diffuse intracranial disease. Stroke. 2007;38:3175–81.

    Article  PubMed  Google Scholar 

  59. Molina CA, Barreto AD, Tsivgoulis G, et al. Transcranial ultrasound in clinical sonothrombolysis (TUCSON) trial. Ann Neurol. 2009;66:28–38.

    Article  PubMed  CAS  Google Scholar 

  60. Molina CA, Ribo M, Rubiera M, et al. Microbubble administration accelerates clot lysis during continuous 2-MHz ultrasound monitoring in stroke subjects treated with intravenous tissue plasminogen activator. Stroke. 2006;37:425–9.

    Article  PubMed  CAS  Google Scholar 

  61. The IMS II Trial Investigators. The Interventional Management of Stroke (IMS) II study. Stroke. 2007;38:2127–35.

    Article  Google Scholar 

  62. Alexandrov AV, Sloan MA, Tegeler CH, et al. Practice standards for Transcranial Doppler (TCD) Ultrasound. Part II. Clinical indications and expected outcomes. J Neuroimaging. 2012;22:215–24.

    Article  PubMed  Google Scholar 

  63. Alberts MJ, Latchaw RE, Selman WR, et al. Recommendations for comprehensive stroke centers: a consensus statement from the brain attack coalition. Stroke. 2005;36:1597–618.

    Article  PubMed  Google Scholar 

  64. Schulz KF, Altman DG, Moher D, for the CONSORT Group. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomized trials. Ann Int Med. 2010;152.

  65. Alexandrov AV, Molina CA, Grotta JC, et al. Ultrasound-enhanced systemic thrombolysis for acute ischemic stroke. N Engl J Med. 2004;351:2170–8.

    Article  PubMed  CAS  Google Scholar 

  66. Alexandrov AV, Mikulik R, Sharma VK, et al. A pilot randomized clinical safety study of sonothrombolysis augmentation with ultrasound- activated perflutren-lipid microspheres (μS) for acute ischemic stroke. Stroke. 2008;39:1464–9.

    Article  PubMed  CAS  Google Scholar 

  67. NCRP (National Council on Radiation Protection and Measurements) Report No. 140. Exposure criteria for medical diagnostic ultrasound: II. Criteria based on all known mechanisms. Issued December 31, 2002. Available at: http://www.ncrponline.org/Publications/Press_Releases/140press.html. Accessed October 31, 2010.

  68. Tanne D, Kasner SE, Demchuk AM, et al. Markers of increased risk of intracerebral hemorrhage after intravenous recombinant tissue plasminogen activator therapy for acute ischemic stroke in clinical practice: the multicenter rt-PA Stroke Survey. Circulation. 2002;105:1679–85.

    Article  PubMed  CAS  Google Scholar 

  69. Fischer U, Arnold M, Nedeltchev K, et al. NIHSS score and arteriographic findings in acute ischemic stroke. Stroke. 2005;36:2121–5.

    Article  PubMed  Google Scholar 

  70. Lewandowski CA, Frankel M, Tomsick TA, et al. Combined intravenous and intra-arterial r-TPA versus intra-arterial therapy of acute ischemic stroke: Emergency Management of Stroke (EMS) bridging trial. Stroke. 1999;30:2598–605.

    Article  PubMed  CAS  Google Scholar 

  71. Kristian Barlinn, Andrei V. Alexandrov. Transcranial Doppler sonography. In: AbuRahma AF, Bandyk DF, editors. Noninvasive vascular diagnosis. A practical guide to therapy. Springer London Ltd. 2012. p. 133–55.

  72. Larrue V, Viguier A, Arnaud C, et al. Transcranial ultrasound combined with intravenous microbubbles and tissue plasminogen activator for acute ischemic stroke: a randomized controlled study. Stroke. 2007;38:472.

    Google Scholar 

  73. Eggers J, Koenig IR, Koch B, et al. Sonothrombolysiswith transcranial color-coded sonography and recombinant tissue-type plasminogen activator in acute middle cerebral artery main stem occlusion: results from a randomized study. Stroke. 2008;39:1470–5.

    Article  PubMed  CAS  Google Scholar 

  74. Perren F, Loulidi J, Poglia D, et al. Microbubble potentiated transcranial duplex ultrasound enhances IV thrombolysis in acute stroke. J Thromb Thrombolysis. 2008;25:19–23.

    Article  Google Scholar 

  75. Eggers J, Seidel J, Koch B, Konig I. Sonothrombolysis in acute ischemic stroke for patients ineligible for rt-PA. Neurology. 2005;64:1052–4.

    Article  PubMed  Google Scholar 

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Disclosure

Dr. Barlinn was supported through NINDS SPOTRIAS grant (PI – Grotta, MD, University of Texas-Houston), project CLOTBUST-Hands Free, phase I/II studies of an operator-independent device for sonothrombolysis in stroke. Dr. Alexandrov serves as consultant to Cerevast Therapeutics, Inc. and holds a US patent 6733450 “Therapeutic Method and Apparatus for Use of Sonication to Enhance Perfusion of Tissues”, assignee – Texas Board of Regents.

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  1. Comprehensive Stroke Center, University of Alabama Hospital, RWUH M226 619 19th St South, Birmingham, AL, 35249-3280, USA

    Kristian Barlinn MD & Andrei V. Alexandrov MD

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  1. Kristian Barlinn MD
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  2. Andrei V. Alexandrov MD
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Correspondence to Andrei V. Alexandrov MD.

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Barlinn, K., Alexandrov, A.V. Sonothrombolysis in Ischemic Stroke. Curr Treat Options Neurol 15, 91–103 (2013). https://doi.org/10.1007/s11940-012-0214-5

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