Klinische Neurophysiologie 2002; 33(2): 88-99
DOI: 10.1055/s-2002-32780
Originalia
© Georg Thieme Verlag Stuttgart · New York

Bedeutung neuer Ultraschalltechniken für die Thrombolysetherapie des akuten Schlaganfalls

Significance of New Sonographic Techniques for the Thrombolysis Therapy of Acute StrokeD.  G.  Nabavi1 , A.  Allroggen1
  • 1Klinik und Poliklinik für Neurologie, Universitätsklinikum Münster (Direktor: Univ.-Prof. Dr. med. E. Bernd Ringelstein), Münster
Further Information

Publication History

Publication Date:
12 July 2002 (online)

Zusammenfassung

Die systemische Thrombolysetherapie beim akuten Schlaganfall führt zu einer signifikanten Verbesserung des klinischen Outcomes. Dabei werden das starre Zeitfenster und die fest definierte Medikamentendosierung der Heterogenität ischämischer Insulte kaum gerecht. Daher besteht großer Bedarf, das Thrombolysemanagement zu individualisieren und dadurch dessen Effizienz zu steigern. In dieser Übersicht werden verschiedene Ultraschall(US)techniken vorgestellt, die sowohl in diagnostischer als auch in therapeutischer Hinsicht einen signifikanten Beitrag zur Thrombolyseoptimierung leisten können. Dabei sollen sowohl bereits etablierte als auch noch in der Entwicklung befindliche Modalitäten berücksichtigt werden. Mit Einführung sog. Echokontrastverstärker wurde nicht nur die Ausbeute und Verlässlichkeit in der Akutdiagnostik intrakranieller Gefäßverschlüsse gesteigert, sondern auch eine Perfusionsmessung auf Gewebeebene (sog. US-Perfusionimaging) erst ermöglicht. Dadurch könnte die spezifische Auswahl geeigneter Thrombolysekandidaten künftig verbessert werden. Durch engmaschiges US-Monitoring während der Lysetherapie kann der Zeitpunkt der Gefäßrekanalisation am Krankenbett verfolgt und damit die Wirksamkeit der Rekanalisationstherapie nichtinvasiv bestimmt werden. Mit der US-assisistierten Thrombolyse befindet sich ein Instrument in der Entwicklung, das die frühe Rekanalisation beim akuten Gefäßverschluss beschleunigen könnte. Dadurch könnte ein modifiziertes Dosisregime ermöglicht und so das Blutungsrisiko weiter reduziert werden. Als weitere Therapieoption wird intensiv an der US-gesteuerten Freisetzung „verpackter” Pharmaka gearbeitet, wodurch eine thrombusspezifische, lokale Lysetherapie trotz systemischer Applikation in ferner Zukunft realisierbar erscheint. Diese modernen Werkzeuge der Neurosonographie besitzen ein großes Potenzial, die Thrombolysetherapie des akuten Hirninsultes künftig auf breiter Basis zu optimieren.

Abstract

Systemic thrombolysis of acute ischaemic stroke leads to significant improvement in clinical outcome. The rigid therapeutic window and the fixed medical dosage, however, are less than optimal with respect to the heterogeneity of ischaemic strokes. There is great demand for establishing more individualised treatment strategies to further increase the efficiency of thrombolytic therapy. In this review, new diagnostic and therapeutic ultrasound (US) techniques will be presented that could contribute significantly to this process. Echocontrast agents have led to improvement in the detection of vessel occlusion and have enabled brain perfusion measurements on the tissue level. Thereby the selection of candidates most suitable for recanalisation therapy could be guided. Transcranial US monitoring of time point and extent of revascularisation allows to judge the efficacy of thrombolysis which may result in individualised dose regimens. US-assisted thrombolysis has been demonstrated to potentiate purely pharmacological revascularization in various experimental settings. The delivery of encapsulated drugs via US, another exciting therapeutic tool, is currently under experimental investigation. It could provide thrombus-specific local revascularisation of occluded vessels in the distant future. Through recent progress, multimodal neurosonography has the potential to optimise thrombolytic therapy on a broad basis.

Literatur

  • 1 Aaslid R, Newell D W. Transcranial Doppler. New York; Raven Press 1992
  • 2 Akiyama M, Ishibashi T, Yamada T, Furuhata H. Low-frequency ultrasound penetrates the cranium and enhances thrombolysis in vitro.  Neurosurgery. 1998;  43 828-832
  • 3 Alexandrov A V, Demchuk A M, Felberg R A. et al . High rate of complete recanalization and dramatic clinical recovery during tPA infusion when continuously monitored with 2-MHz transcranial Doppler monitoring.  Stroke. 2000;  31 610-614
  • 4 Bacon D R, Carstensen E L. Increased heating by diagnostic ultrasound due to nonlinear propagation.  J Acoust Soc Am. 1990;  88 26-34
  • 5 Baron J C, von Kummer R, Del Zoppo G J. Treatment of ischemic stroke: challenging the concept of a rigid and universal time window.  Stroke. 1995;  26 2219-2221
  • 6 Beauchamp N J, Barker P B, Wang P Y, van Zijl P C. Imaging of acute cerebral ischemia.  Radiology. 1999;  212 307-324
  • 7 Behrens S, Daffertshofer M, Spiegel D, Hennerici M. Low-frequency low-intensity ultrasound accerlerates thrombolysis through the skull.  Ultrasound Med Biol. 1999;  25 269-273
  • 8 Behrens S, Spengos K, Daffertshofer M, Schroeck H, Dempfle C, Hennerici M. Transcranial ultrasound-improved thrombolysis: diagnostic vs. therapeutic ultrasound.  Ultrasound Med Biol. 2001;  27 1683-1689
  • 9 Birnbaum Y, Luo H, Nagai T. et al . Noninvasive in vivo clot dissolution without a thrombolytic drug. Recanalization of thrombosed iliofemoral arteries by transcutaneous ultrasound combined with intravenous infusion of microbubbles.  Circulation. 1998;  97 130-134
  • 10 Burgin W S, Malkoff M, Felberg R A. et al . Transcranial Doppler ultrasound criteria for recanalization after thrombolysis for middle cerebral artery stroke.  Stroke. 2000;  31 1128-1132
  • 11 Burns P N. Harmonic imaging with ultrasound contrast agents.  Clinical Radiol. 1996;  51 50-55
  • 12 Burns P N. Overview of echo-enhanced vascular ultrasound imaging for clinical diagnosis in neurosonology.  J Neuroimaging. 1997;  7 (Suppl 1) S2-S14
  • 13 Calamante D, Thomas D L, Pell G S, Wiersma J, Turner R. Measuring cerebral blood flow using magnetic resonance imaging techniques.  J Cereb Blood Flow Metab. 1999;  19 701-735
  • 14 Christou I, Alexandrov A V, Burgin S. et al . Timing of recanalization after tissue plasminogen activator therapy determined by transcranial Doppler correlates with clinical recovery from ischemic stroke.  Stroke. 2000;  31 1812-1816
  • 15 Cintas P, Le Traon A P, Larrue V. High rate of recanalization of middle cerebral artery occlusion during 2-MHz transcranial color-coded Doppler continuous monitoring without thrombolysis.  Stroke. 2002;  33 626-628
  • 16 Demchuk A M, Burgin W S, Christou I, Felberg R A, Barber P A, Hill M D, Alexandrov A V. Thrombolysis in brain ischemia (TIBI) transcranial flow grades predict clinical severity, early recovery, and mortality in patients treated with intravenous tissue plasminogen activator.  Stroke. 2001;  32 89-93
  • 17 Devyst G, Afsar N. Is transcranial colour duplex flow imaging of use in selection of patients with acute stroke for thrombolysis?.  J Neurol Neurosurg Psychiatry. 2000;  68 794
  • 18 Droste D W, Jürgens R, Nabavi D G, Schuierer G, Weber S, Ringelstein E B. Echocontrast-enhanced ultrasound of extracranial internal carotid artery high-grade stenosis and occlusion.  Stroke. 1999;  30 2302-2306
  • 19 Droste D W, Kaps M, Nabavi D G, Ringelstein E B. Ultrasound contrast enhancing agents: principles, methods, future possibilities.  Acta Scand Neurol. 2000;  102 1-10
  • 20 Fagan S C, Morgenstern L B, Petitta A. et al . Cost-effectiveness of tissue plasminogen activator for acute ischemic stroke.  Neurology. 1998;  50 883-890
  • 21 Federlein J, Postert T, Meves S, Weber S, Przuntek H, Büttner T. Ultrasound evaluation of pathological brain perfusion in acute stroke using second harmonic imaging.  J Neurol Neurosurg Psychiatry. 2000;  69 616-622
  • 22 Fisher P D, Narayanan K, Liang M D. The use of high-frequency ultrasound for the dissection of small-diameter blood vessels and nerves.  Ann Plast Surg. 1992;  28 326-230
  • 23 Francis C W, Blinc A, Lee S, Cox C. Ultrasound accelerated transport of recombinant tissue plasminogen activator into clots.  Ultrasound Med Biol. 1995;  21 419-424
  • 24 Frinking P J, Bouakaz A, de Jong N, Ten Cate F J, Keating S. Effect of ultrasound on the release of microencapsulated drugs.  Ultrasonics. 1998;  36 709-712
  • 25 Furlan A J, Kanoti G. When is thrombolysis justified in patients with acute ischemic stroke? A bioethical perspective.  Stroke. 1997;  28 214-218
  • 26 Gahn G, Gerber J, Hallmeyer S, Hahn G, Ackerman R H, Reichmann H, von Kummer R. Contrast-enhanced transcranial color-coded duplex sonography in stroke patients with limited bone windows.  Am J Neuroradiol. 2000;  21 509-514
  • 27 Gerriets T, Seidel G, Fiss I, Modrau B, Kaps M. Contrast-enhanced transcranial color-coded duplex sonography. Efficiency and validity.  Neurology. 1999;  52 1133-1137
  • 28 Gerriets T, Postert T, Goertler M, Stolz E, Eclacheztki F, Sliwka U, Seidel G, Weber S, Kaps M. DIAS I: duplex-sonographic assessment of the cerebrovascular status in acute stroke: a useful tool for future stroke trials.  Stroke. 2000;  31 2342-2345
  • 29 Goertler M, Kross R, Baeumer M. et al . Diagnostic impact and prognostic relevance of early contrast-enhanced transcranial color-coded duplex sonography in acute stroke.  Stroke. 1998;  29 955-962
  • 30 Harpaz D, Chen X, Francis C W. et al . Ultrasound enhancement of thrombolysis and reperfusion in vitro.  J Am Coll Cardiol. 1993;  21 1507-1511
  • 31 Hiser W, Porter T, Li S. et al . Inhibition of carotid artery neointimal formation following balloon injury using ultrasound-targeted deposition of antisense to C-MYC protooncogene bound to intravenously delivered perfluorocarbon microbubbles (Abstract).  J Am Soc Echocardiography. 1998;  11 498
  • 32 Huber P, Debus J, Jenne J. et al . Therapeutic ultrasound in tumor therapy: principles, applications, and new developments.  Radiologie. 1996;  36 64-71
  • 33 Itoh T, Matsumoto M, Uchimoto R. et al . Perfusion imaging of the brain by B-mode ultrasonography. An experimental study in rabbits.  Stroke. 1995;  26 2353-2357
  • 34 Jayaweera A R, Edwards N, Glasheen W P, Villanueva F S, Abbot R D, Kaul S. In vivo myocardial kinetics of air-filled albumin microbubbles during myocardial contrast echocardiography. Comparison with radiolabelled red blood cells.  Circ Res. 1994;  74 1157-1165
  • 35 Kaps M, Damian M S, Teschendorf U, Dorndorf W. Transcranial Doppler ultrasound findings in middle cerebral artery occlusion.  Stroke. 1990;  21 532-537
  • 36 Kaps M. Extra- und intrakranielle Farbduplex-Sonographie. Berlin, Heidelberg; Springer-Verlag 1994
  • 37 Kaps M, Seidel G, Gerriets T. Transcranial duplex monitoring discloses hemorrhagic complication following rt-PA thrombolysis.  Acta Neurol Scand. 1996;  93 61-63
  • 38 Kornowski R, Meltzer R S, Chernine A, Vered Z, Battler A. Does external ultrasound accelerate thrombolysis? Results from a rabbit model.  Circulation. 1994;  89 339-344
  • 39 Kudo S. Thrombolysis with ultrasound effect.  Tokyo Med J. 1989;  104 1005-1012
  • 40 Lanza G M, Wallace K D, Scott M J. et al . A novel site-targeted ultrasonic contrast agent with broad biomedical application.  Circulation. 1997;  95 3334-3340
  • 41 Lassen N A, Perl W. Tracer kinetic methods in medical physiology. New York; Raven Press 1979
  • 42 Lauer C G, Burge R, Tang D V, Bass B G, Gomez E R, Alving B M. Effect of ultrasound on tissue-type plasminogen activator-induced thrombolysis.  Circulation. 1992;  86 1257-1264
  • 43 Levkovits J, Plow E F, Topol E J. Platelet glycoprotein IIb/IIIa receptors in cardiovascular medicine.  N Engl J Med. 1995;  332 1553-1559
  • 44 Ley-Pozo J A, Ringelstein E B, Willmes K. Noninvasive detection of occlusive disease of the carotid siphon and middle cerebral artery.  Ann Neurol. 1990;  28 640-647
  • 45 Lindner J R, Song J, Xu F, Klibanov A L, Singbartl K, Ley K, Kaul S. Noninvasive ultrasound imaging of inflammation using microbubbles targeted to activated leukocytes.  Circulation. 2000;  102 2745-2750
  • 46 Lindner J R, Kaul S. Delivery of drugs with ultrasound.  Echocardiography. 2001;  18 329-337
  • 47 Luo H, Nishioka T, Fishbein M C, Cerek B, Forrester J S, Kim C J, Berglund H, Siegel R J. Transcutaneous ultrasound augments lysis of arterial thrombi in vivo.  Circulation. 1996;  94 775-778
  • 48 Lynn J G, Zwemer R L, Chick A J. et al . A new method for the generation and use of focused ultrasound in experimental biology.  J Gen Physiol. 1942;  26 179-193
  • 49 Maurer M, Mullges W, Becker G. Diagnosis of MCA-occlusion and monitoring of systemic thrombolytic therapy with contrast enhanced transcranial duplex sonography.  J Neuroimaging. 1999;  9 99-101
  • 50 Meairs S, Daffertshofer M, Neff W, Eschenfelder C, Hennerici M. Pulse-inversion contrast harmonic imaging: ultrasonographic assessment of cerebral perfusion.  Lancet. 2000;  35 550-551
  • 51 Meier P, Zierler K L. On the theory of the indicator-dilution method for measurement of blood flow and volume.  J Appl Physiol. 1954;  6 731-744
  • 52 Meyer K, Metzler V, Seidel G, Toth D, Aach T. Human cerebral perfusion analysis with ultrasound contrast agent constant infusion - a pilot study on healthy volunteers using transcranial grey-scale harmonic imaging technique (Abstract). Rotterdam; 6th European Symposium on Ultrasound Contrast Imaging 2001
  • 53 Molina C A, Montaner J, Abilleira S. et al . Time course of tissue plasminogen activator-induced recanalization in acute cardioembolic stroke. A case-control study.  Stroke. 2001;  32 2821-2827
  • 54 Nabavi D G, Droste D W, Kemeny V, Schulte-Altedorneburg G, Weber S, Ringelstein E B. Potential and limitations of echocontrast-enhanced ultrasonography in acute stroke patients.  Stroke. 1998a;  29 949-954
  • 55 Nabavi D G, Droste D W, Schulte-Altedorneburg G, Kemeny V, Panzica M, Weber S, Ringelstein E B. Klinische Bedeutung der Echokontrastverstärkung in der neurovaskulären Diagnostik. Erfahrungsbericht nach einjähriger offener Anwendungsstudie.  Fortschr Neurol Psychiat. 1998b;  66 466-473
  • 56 Nabavi D G, Cenic A, Craen R A, Gelb A W, Bennett J D, Kozak R, Lee T Y. CT assessment of cerebral perfusion: experimental validation and initial clinical experience.  Radiology. 1999;  213 141-149
  • 57 Nabavi D G, Lüdemann P. Thrombolysetherapie beim ischämischen Schlaganfall.  Psycho. 2000;  26 624-628
  • 58 Pohl C, Tiemann K, Schlosser T, Becher H. Stimulated acoustic emission detected by transcranial color Doppler ultrasound. A contrast-specific phenomenon useful for the detection of cerebral tissue perfusion.  Stroke. 2000;  31 1661-1666
  • 59 Porter T R, Iversen P L, Li S. et al . Interaction of diagnostic ultrasound with synthetic oligonucleotid-labeled perfluorocarbon-exposed sonicated dextrose albumin microbubbles.  J Ultrasound Med. 1996;  15 577-584
  • 60 Porter T R, Xie F. Therapeutic ultrasound for gene delivery.  Echocardiography. 2001;  18 349-353
  • 61 Postert T, Federlein J, Pzruntek H, Büttner T. Insufficient and absent acoustic temporal bone window: potential and limitations of transcranial contrast-enhanced color-coded sonography and contrast-enhanced power-based sonography.  Ultrasound Med Biol. 1997;  23 857-862
  • 62 Postert T, Braun B, Federlein J, Przuntek H, Köster O, Büttner T. Diagnosis and monitoring of middle cerebral artery occlusion with contrast-enhanced transcranial color-coded real-time sonography in patients with inadequate acoustic bone windows.  Ultrsound Med Biol. 1998a;  24 333-340
  • 63 Postert T, Muhs A, Meves S, Federlein J, Przuntek H, Büttner T. Transient response harmonic imaging. An ultrasound technique related to brain perfusion.  Stroke. 1998b;  29 1901-1907
  • 64 Price R J, Skyba D M, Kaul S. et al . Delivery of colloidal particles and red blood cells to tissue through microvessel ruptures created by targeted microbubble destruction with ultrasound.  Circulation. 1998;  98 1264-1267
  • 65 Riesz P, Kondo T. Free radical formation induced by ultrasound and its biological implications.  Free Radic Biol med. 1992;  13 247-270
  • 66 Rim S J, Leong-Poi H, Lindner J R. et al . Quantification of cerebral perfusion with „real-time” contrast-enhanced ultrasound.  Circulation. 2001;  104 2582-2587
  • 67 Ringelstein E B, Kahlscheuer B, Niggemeyer E, Otis S. Transcranial doppler sonography: Anatomical landmarks and normal velocity values.  Ultrasound Med Biol. 1990;  16 745-761
  • 68 Ringelstein E B, Biniek R, Weiller C, Ammeling B, Nolte P N, Thron A. Type and extent of hemispheric brain infarctions and clinical outcome in early and delayed middle cerebral artery recanalization.  Neurology. 1992;  42 289-298
  • 69 Rosenschein U, Furman V, Kerner E, Fabian I, Bernheim J, Eshel Y. Ultrasound imaging-guided noninvasive ultrasound-thrombolysis: preclinical results.  Circulation. 2000;  102 238-245
  • 70 Schartl M, Fritzsch T, Miszalok V. Quantification of myocardial perfusion by contrast echocardiography.  Can J Cardiol. 1986;  Suppl A 25A-31A
  • 71 Schlief R. Echo enhancement: agents and techniques-basic principles.  Adv Echo Agents. 1994;  4 5-19
  • 72 Sehgal C M, Leveen R F, Shlansky-Goldberg R DE. Ultrasound-assisted thrombolysis.  Invest Radiol. 1993;  28 939-943
  • 73 Seidel G, Algermissen C, Christoph A, Claassen L, Vidal-Langwasser M, Katzer T. Harmonic imaging of the human brain: visualization of brain perfusion with ultrasound.  Stroke. 2000a;  31 151-154
  • 74 Seidel G, Algermissen C, Christoph A. et al . Visualization of human brain perfusion with harmonic grey scale and Power Doppler technology: an animal pilot study.  Stroke. 2000b;  31 1728-1734
  • 75 Seidel G, Meyer K. Harmonic imaging. A new method of ultrasound imaging of brain perfusion.  Nervenarzt. 2001;  72 600-609
  • 76 Siddiqi F, Blinc A, Braaten J, Francis C W. Ultrasound increases flow through fibrin gels.  Thromb Haemost. 1995;  73 495-498
  • 77 Siddiqi F, Odrljin T M, Fay P J, Cox C, Francis C W. Binding of tissue-plasminogen activator to fibrin: effect of ultrasound.  Blood. 1998;  91 2019-2025
  • 78 Siegel R J, Atar S, Fishbein M C. et al . Noninvasive, transthoracic, low-frequency ultrasound augments thrombolysis in a canine model of acute myocardial infarction.  Circulation. 2000;  101 2026-2029
  • 79 Skyba D M, Price R J, Linka A Z. et al . Direct in vivo visualization of intravascular destruction of microbubbles by ultrasound and its local effects on tissue.  Circulation. 1998;  98 290-293
  • 80 Spengos K, Behrens S, Daffertshofer M, Dempfle C E, Hennerici M. Acceleration of thrombolysis with ultrasound through the cranium in a flow model.  Ultrasound Med Biol. 2000;  26 889-895
  • 81 Steffen W, Fishbein M C, Luo H, Tabak S W, Carbonne M, Maurer G, Siegel R J. High intensity, low frequency catheter-delivered ultrasound dissolution of occlusive coronary artery thrombi: an in vitro and in vivo study.  J Am Coll Cardiol. 1994;  24 1571-1579
  • 82 Suchkova V N, Baggs R B, Francis C W. Effect of 40-kHz ultrasound on acute thrombotic ischemia in a rabbit femoral artery thrombosis model: enhancement of thrombolysis and improvement of capillary muiscle perfusion.  Circulation. 2000;  101 2296-2301
  • 83 Tachibana K, Tachibana S. Albumin microbubble echo-contrast material as an enhancer for ultrasound accelerated thrombolysis.  Circulation. 1995;  92 1148-1150
  • 84 Tachibana K, Tachibana S. The use of ultrasound for drug delivery.  Echocardiography. 2001;  18 323-328
  • 85 Teupe C, Richter S, Fisslthaler B. et al . Vascular gene transfer of phosphomimetic endothelial nitric oxide sythetase (S1177D) using ultrasound-enhanced destruction of plasmid-loaded microbubbles improves vasoreactivity.  Circulation. 2002;  105 1104-1111
  • 86 Tiemann K, Veltmann C, Ghanem A, Lohmeier S, Bruce M. et al . The impact of power on the destruction of echocontrast agents and on the origin of tissue harmonic signals using power pulse-inversion imaging.  Ultrasound Med Biol. 2001;  27 1525-1533
  • 87 The NINDS rt-PA Stroke Study Group . Tissue plasminogen activator for acute ischemic stroke.  N Engl J Med. 1995;  333 1581-1587
  • 88 The TIMI study group . The thrombolysis in myocardial infarction (TIMI) trial: phase I findings.  N Engl J Med. 1985;  312 932-936
  • 89 Unger E C, McCreery T P, Sweitzer R H. et al . In vitro studies of a new thrombus-specific ultrasound contrast agent.  Am J Cardiol. 1998;  81 58G-61G
  • 90 Unger E C, Hersh E, Vannan M, McCreery T. Gene delivery using ultrasound contrast agents.  Echocardiography. 2001;  18 355-361
  • 91 Valtot F, Kopel J, Haut J. Therapeutic ultrasound for the treatment of glaucoma.  Bull Soc Belge Ophthalmol. 1992;  24 181-186
  • 92 Villanueva F S, Jankowski R J, Klibanov S. et al . Microbubbles targeted to intracellular adhesion molecule-1 bind to activated coronary endothelial cells.  Circulation. 1998;  98 1-5
  • 93 von Reutern G M. Für die „Neurosonology in Acute Ischemic Stroke” Studie.  Zwischenbericht im Internet unter: http://www.nsrg.org.tw/doc/NAIS-report.pdf
  • 94 Walker K W, Pantley G A, Sahn D J. Ultrasound mediated destruction of contrast agents. Effect of ultrasound intensity, exposure, and frequency.  Invest Radiol. 1997;  32 728-732
  • 95 Wei K, Skyba D, Firschke C, Lindner J R, Jayaweera A R, Kaul S. Interaction between microbubbles and ultrasound: in vitro and in vivo observations.  J Am Coll Cardiol. 1997;  29 1081-1088
  • 96 Wei K, Jayaweera A R, Firoozan S, Linka A, Skyba D, Kaul S. Quantification of myocardial blood flow with ultrasound-induced destruction of microbubbles administered as a constant venous infusion.  Circulation. 1998;  97 473-483
  • 97 Wiesmann M, Seidel G. Ultrasound perfusion imaging of the human brain.  Stroke. 2000;  31 2421-2425
  • 98 Williams A R. Ultrasound: biological effects and potential hazards. New York; Academic Press 1983: 231
  • 99 Wu Y, Unger E C, McCreery T P. et al . Binding and lysis of blood clots using MRX-408.  Invest Radiol. 1998;  33 880-885
  • 100 Zivin J A. Factors determining the therapeutic window for stroke.  Neurology. 1998;  50 599-603
  • 101 Zivin J A. Thrombolytic stroke therapy: past, present, and future.  Neurology. 1999;  53 14-19

Priv.-Doz. Dr. med. Darius G. Nabavi

Klinik und Poliklinik für Neurologie · Westfälische Wilhelms-Universität

Albert-Schweitzer-Straße 33

48129 Münster

Email: nabavi@uni-muenster.de

    >