Therapie des akuten ischämischen Schlaganfalls

ZUSAMMENFASSUNG

Die Behandlungsmöglichkeiten des akuten ischämischen Schlaganfalls haben sich durch Weiterentwicklung bewährter und Erprobung neuer Therapieansätze in den letzten Jahren verbessert. Durch den Einsatz der erweiterten Akutbildgebung mittels multimodaler Computer- oder Magnetresonanztomografie konnte der Zugang zu Thrombolyse und Thrombektomie auch für ausgewählte Patienten mit unbekanntem oder bis zu 9 bzw. 24 h zurückliegendem Beginn der akuten Schlaganfallsymptomatik ermöglicht werden. Ergänzend zu diesen rekanalisierenden Akuttherapien zeigen adjuvante neuroprotektive und immunmodulatorische Behandlungsansätze vielversprechende Ergebnisse. Schließlich gewinnen eine verbesserte Zusammenarbeit der an der Schlaganfallversorgung beteiligten Fachdisziplinen und die Optimierung logistischer Prozesse an Bedeutung, um den zeitabhängigen Nutzen der Akuttherapie individuell zu maximieren. Der vorliegende Artikel fasst wesentliche aktuelle Studienergebnisse zur Akuttherapie des ischämischen Schlaganfalls zusammen und gibt Empfehlungen für eine evidenzbasierte Bildgebung als Grundlage effektiver Reperfusionstherapien.

ABSTRACT

Ongoing development of established as well as the discovery of new therapeutic targets in recent years have led to improvements in hyperacute ischemic stroke care. Based on advanced acute stroke imaging with either CT or MRI it is now possible to offer thrombolysis or thrombectomy to some patients who had previously been excluded from these recanalizing treatments. In addition, promising results have been obtained for neuroprotective and immunomodulatory approaches. Finally, due to the interdisciplinary nature of acute stroke care, intra-hospital process improvement has received considerable attention. In the present article, we summarise recent evidence relevant to the treatment of hyperacute ischemic stroke and derive recommendations for the evidence-based selection of advanced imaging modalities to guide decisions about effective reperfusion therapies.

Schlüsselwörter

Ischämischer Schlaganfall - Akuttherapie - Thrombolyse - Thrombektomie - Neuroprotektion - Prozessoptimierung

Key words

Ischemic stroke - reperfusion treatment - thrombolysis - thrombectomy - stroke imaging - neuroprotection - process management

• Literatur

• 1 Hacke W, Kaste M, Bluhmki E. et al Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008; 359: 1317-1329
• 2 The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group Zambello R, Trentin L. et al Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995; 333: 1581-1588
• 3 Emberson J, Lees KR, Lyden P. 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: 1929-1935
• 4 Lees KR, Emberson J, Blackwell L. et al Effects of Alteplase for Acute Stroke on the Distribution of Functional Outcomes: A Pooled Analysis of 9 Trials. Stroke 2016; 47: 2373-2379
• 5 Puig J, Shankar J, Liebeskind D. et al From “Time is Brain” to “Imaging is Brain”: A Paradigm Shift in the Management of Acute Ischemic Stroke. J Neuroimaging 2020: 3 jon.12693 Im Internet https://onlinelibrary.wiley.com/doi/abs/10.1111/jon.12693
• 6 Thomalla G, Simonsen CZ, Boutitie F. et al MRI-Guided thrombolysis for stroke with unknown time of onset. N Engl J Med 2018; 379: 611-622
• 7 Thomalla G, Cheng B, Ebinger M. et al DWI-FLAIR mismatch for the identification of patients with acute ischaemic stroke within 4·5 h of symptom onset (PRE-FLAIR): A multicentre observational study. Lancet Neurol 2011; 10: 978-986
• 8 Barow E, Boutitie F, Cheng B. et al Functional outcome of intravenous thrombolysis in patients with lacunar infarcts in the WAKE-UP trial. JAMA Neurol 2019; 76: 641-649
• 9 Galinovic I, Boutitie F, Fiebach JB. et al Post-hoc Analysis of Outcome of Intravenous Thrombolysis in Infarcts of Infratentorial Localization in the WAKE-UP Trial. Front Neurol 2019; 10: 983 Im Internet /pmc/articles/PMC6749039/?report=abstract
• 10 Koga M, Yamamoto H, Inoue M. et al Thrombolysis With Alteplase at 0.6 mg/kg for Stroke With Unknown Time of Onset. Stroke 2020
• 11 Ma H, Campbell BCV, Parsons MW. et al Thrombolysis Guided by Perfusion Imaging up to 9 Hours after Onset of Stroke. N Engl J Med 2019; 380: 1795-1803
• 12 Amiri H, Bluhmki E, Bendszus M. et al European Cooperative Acute Stroke Study-4: Extending the time for thrombolysis in emergency neurological deficits ECASS-4: ExTEND. Int J Stroke 2016; 11: 260-267
• 13 Davis SM, Donnan GA, Parsons MW. et al Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebo-controlled randomised trial. Lancet Neurol 2008; 7: 299-309
• 14 Campbell BCV, Ma H. et al Extending thrombolysis to 4·5–9 h and wake-up stroke using perfusion imaging: a systematic review and meta-analysis of individual patient data. Lancet 2019; 394: 139-147
• 15 Tanswell P, Modi N, Combs D. et al Pharmacokinetics and pharmacodynamics of tenecteplase in fibrinolytic therapy of acute myocardial infarction. Clin Pharmacokinet 2002; 41: 1229-1245
• 16 Schultheiss M, Härtig F, Spitzer MS. et al Intravenous thrombolysis in acute central retinal artery occlusion – A prospective interventional case series. PLoS One 2018: 13
• 17 Mac Grory B, Nackenoff A, Poli S. et al Intravenous Fibrinolysis for Central Retinal Artery Occlusion: A Cohort Study and Updated Patient-Level Meta-Analysis. Stroke 2020; 51: 2018-2025
• 18 Goyal M, Menon BK. et al Endovascular thrombectomy after large-vessel ischaemic stroke: A meta-analysis of individual patient data from five randomised trials. Lancet 2016; 387: 1723-1731 Im Internet http://www.ncbi.nlm.nih.gov/pubmed/26898852
• 19 Bracard S, Ducrocq X, Mas JL. et al Mechanical thrombectomy after intravenous alteplase versus alteplase alone after stroke (THRACE): a randomised controlled trial. Lancet Neurol 2016; 15: 1138-1147
• 20 Mocco J, Zaidat OO, Von Kummer R. et al Aspiration Thrombectomy after Intravenous Alteplase Versus Intravenous Alteplase Alone. Stroke 2016; 47: 2331-2338
• 21 Jovin TG, Chamorro A, Cobo E. et al Thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med 2015; 372: 2296-2306
• 22 Goyal M, Demchuk AM, Menon BK. et al Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med 2015; 372: 1019-1030
• 23 Evans JW, Graham BR, Pordeli P. et al Time for a time window extension: Insights from late presenters in the escape trial. Am J Neuroradiol 2018; 39: 102-106
• 24 Albers GW, Marks MP, Kemp S. et al Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. N Engl J Med 2018; 378: 708-718
• 25 Nogueira RG, Jadhav AP, Haussen DC. et al Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. N Engl J Med 2018; 378: 11-21
• 26 Jovin T, Lansberg M, Hill M. et al Thrombectomy for anterior circulation stroke beyond 6 hours from time last known well: primary results of aurora (analysis of pooled data from randomized studies of thrombectomy more than 6 hours after last known well). 4th European Stroke Organization Conference (ESOC). 2018
• 27 Vidale S, Longoni M, Valvassori L. et al Mechanical thrombectomy in strokes with large-vessel occlusion beyond 6 hours: A pooled analysis of randomized trials. J Clin Neurol 2018; 14: 407-412
• 28 Liu X, Dai Q, Ye R. et al Endovascular treatment versus standard medical treatment for vertebrobasilar artery occlusion (BEST): an open-label, randomised controlled trial. Lancet Neurol 2020; 19: 115-122
• 29 Yang P, Zhang Y, Zhang L. et al Endovascular thrombectomy with or without intravenous alteplase in acute stroke. N Engl J Med 2020; 382: 1981-1993
• 30 Kauw F, Heit JJ, Martin BW. et al Computed Tomography Perfusion Data for Acute Ischemic Stroke Evaluation Using Rapid Software. J Comput Assist Tomogr 2020; 44: 75-77
• 31 Gauberti M, Lapergue B, De Lizarrondo SM. et al Ischemia-reperfusion injury after endovascular thrombectomy for ischemic stroke. Stroke 2018; 49: 3071-3074
• 32 Davis SM, Lees KR, Albers GW. et al Selfotel in acute ischemic stroke: Possible neurotoxic effects of an NMDA antagonist. Stroke 2000; 31: 347-354
• 33 Aarts M, Liu Y, Liu L. et al Treatment of ischemic brain damage by perturbing NMDA receptor-PSD-95 protein interactions. Science 2002; 298: 846-850
• 34 Sun HS, Doucette TA, Liu Y. et al Effectiveness of PSD95 inhibitors in permanent and transient focal ischemia in the rat. Stroke 2008; 39: 2544-2553
• 35 Cook DJ, Teves L, Tymianski M. Treatment of stroke with a PSD-95 inhibitor in the gyrencephalic primate brain. Nature 2012; 483: 213-217
• 36 Cook DJ, Teves L, Tymianski M. A translational paradigm for the preclinical evaluation of the stroke neuroprotectant Tat-NR2B9c in gyrencephalic nonhuman primates. Sci Transl Med 2012: 4
• 37 Hill MD, Martin RH, Mikulis D. et al Safety and efficacy of NA-1 in patients with iatrogenic stroke after endovascular aneurysm repair (ENACT): A phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol 2012; 11: 942-950
• 38 Hill MD, Goyal M, Menon BK. et al Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): a multicentre, double-blind, randomised controlled trial. Lancet 2020; 395: 878-887
• 39 ClinicalTrials.gov Efficacy and Safety of Nerinetide in Participants With Acute Ischemic Stroke Undergoing Endovascular Thrombectomy Excluding Thrombolysis – Full Text View – ClinicalTrials.gov. Bethesda (MD) 2020
• 40 Chen M, Dong Y, Simard JM. Functional coupling between sulfonylurea receptor type 1 and a nonselective cation channel in reactive astrocytes from adult rat brain. J Neurosci 2003; 23: 8568-8577
• 41 Simard JM, Tsymbalyuk N, Tsymbalyuk O. et al Glibenclamide Is Superior to Decompressive Craniectomy in a Rat Model of Malignant Stroke. Stroke 2010; 41: 531-537
• 42 Wali B, Ishrat T, Atif F. et al Glibenclamide administration attenuates infarct volume, hemispheric swelling, and functional impairments following permanent focal cerebral ischemia in rats. Stroke Res Treat 2012 https://www.hindawi.com/journals/srt/2012/460909/abs/
• 43 Sheth KN, Kimberly WT, Elm JJ. et al Pilot study of intravenous glyburide in patients with a large ischemic stroke. Stroke 2014; 45: 281-283
• 44 Sheth KN, Elm JJ, Molyneaux BJ. et al Safety and efficacy of intravenous glyburide on brain swelling after large hemispheric infarction (GAMES-RP): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol 2016; 15: 1160-1169
• 45 Sheth KN, Petersen NH, Cheung K. et al Long-term outcomes in patients aged ≥ 70 years with intravenous glyburide from the Phase II GAMES-RP study of large hemispheric infarction an exploratory analysis. Stroke. Lippincott Williams and Wilkins 2018: 1457-1463
• 46 ClinicalTrials.gov Phase 3 study to evaluate the efficacy and safety of intravenous BIIB093 (glibenclamide) for severe cerebral edema following large hemispheric infarction. NCT02864953 2019 https://clinicaltrials.gov/ct2/show/NCT02864953
• 47 Yednock TA, Cannon C, Fritz LC. et al Prevention of experimental autoimmune encephalomyelitis by antibodies against α4βl integrin. Nature 1992; 356: 63-66
• 48 Becker K, Kindrick D, Relton J. et al Antibody to the α4 integrin decreases infarct size in transient focal cerebral ischemia in rats. Stroke 2001; 32: 206-211
• 49 Langhauser F, Kraft P, Göb E. et al Blocking of α4 integrin does not protect from acute ischemic stroke in mice. Stroke 2014; 45: 1799-1806
• 50 Llovera G, Hofmann K, Roth S. et al Results of a preclinical randomized controlled multicenter trial (pRCT): Anti-CD49d treatment for acute brain ischemia. Sci Transl Med 2015: 7
• 51 Elkins J, Veltkamp R, Montaner J. et al Safety and efficacy of natalizumab in patients with acute ischaemic stroke (ACTION): a randomised, placebo-controlled, double-blind phase 2 trial. Lancet Neurol 2017; 16: 217-226
• 52 Elkind MS V, Veltkamp R, Montaner J. et al Natalizumab in acute ischemic stroke (ACTION II): a randomized, placebo-controlled trial. Neurology 2020; 10 1212/WNL.0000000000010038
• 53 Camerer E, Regard JB, Cornelissen I. et al Sphingosine-1-phosphate in the plasma compartment regulates basal and inflammation-induced vascular leak in mice. J Clin Invest 2009; 119: 1871-1879
• 54 Kraft P, Göb E, Schuhmann MK. et al FTY720 ameliorates acute ischemic stroke in mice by reducing thrombo-infammation but not by direct neuroprotection. Stroke 2013; 44: 3202-3210
• 55 Fu Y, Zhang N, Ren L. et al Impact of an immune modulator fingolimod on acute ischemic stroke. Proc Natl Acad Sci U S A 2014; 111: 18315-18320
• 56 Tian DC, Shi K, Zhu Z. et al Fingolimod enhances the efficacy of delayed alteplase administration in acute ischemic stroke by promoting anterograde reperfusion and retrograde collateral flow. Ann Neurol 2018; 84: 717-728
• 57 Zhang S, Zhou Y, Zhang R. et al Rationale and design of combination of an immune modulator Fingolimod with Alteplase bridging with Mechanical Thrombectomy in Acute Ischemic Stroke (FAMTAIS) trial. Int J Stroke 2017; 12: 906-909
• 58 Francis A, Baynosa R. Ischaemia-reperfusion injury and hyperbaric oxygen pathways: A review of cellular mechanisms. Diving Hyperb Med 2017; 47: 110-117
• 59 Chen X, Duan XS, Xu LJ. et al Interleukin-10 mediates the neuroprotection of hyperbaric oxygen therapy against traumatic brain injury in mice. Neuroscience 2014; 266: 235-243
• 60 Schäbitz WR, Schade H, Heiland S. et al Neuroprotection by hyperbaric oxygenation after experimental focal cerebral ischemia monitored by MRI. Stroke 2004; 35: 1175-1179
• 61 Bennett MH, Weibel S, Wasiak J. et al Hyperbaric oxygen therapy for acute ischaemic stroke. Cochrane Database Syst Rev 2014: 2014
• 62 ClinicalTrials.gov Penumbral Rescue by Normobaric O2 Administration in Patients With Ischemic Stroke and Target Mismatch ProFile. Bethesda (MD) 2020
• 63 ClinicalTrials.gov Hyperbaric Oxygen Brain Injury Treatment Trial – Full Text View – ClinicalTrials.gov. Bethesda (MD) 2020 https://clinicaltrials.gov/ct2/show/NCT02407028
• 64 Ren C, Gao X, Niu G. et al Delayed postconditioning protects against focal ischemic brain injury in rats. PLoS One 2008: 3
• 65 Weir P, Maguire R, O’Sullivan SE. et al A meta-analysis of remote ischaemic conditioning in experimental stroke. J Cereb Blood Flow Metab 2020: 0271678X2092407
• 66 England TJ, Hedstrom A, O’Sullivan SE. et al Remote Ischemic Conditioning After Stroke Trial 2: A Phase IIb Randomized Controlled Trial in Hyperacute Stroke. J Am Heart Assoc 2019; 8: e013572
• 67 Hougaard KD, Hjort N, Zeidler D. et al Remote ischemic perconditioning as an adjunct therapy to thrombolysis in patients with acute ischemic stroke: A randomized trial. Stroke 2014; 45: 159-167
• 68 Pico F, Lapergue B, Ferrigno M. et al Effect of In-Hospital Remote Ischemic Perconditioning on Brain Infarction Growth and Clinical Outcomes in Patients with Acute Ischemic Stroke: The RESCUE BRAIN Randomized Clinical Trial. JAMA Neurol 2020: 77
• 69 ClinicalTrials.gov Clinical Trial on Remote Ischemic Conditioning in Acute Ischemic Stroke Within 9 Hours of Onset in Patients Ineligible to Recanalization Therapies. Bethesda (MD) 2020 https://clinicaltrials.gov/ct2/show/NCT04400981
• 70 ClinicalTrials.gov Remote Ischemic Conditioning for Acute Moderate Ischemic Stroke. Bethesda (MD) 2018 https://clinicaltrials.gov/ct2/show/NCT03740971
• 71 ClinicalTrials.gov Thrombolysis and RIPC in acute ischemic stroke (TRIPCAIS). Bethesda (MD) 2018 https://clinicaltrials.gov/ct2/show/NCT03218293
• 72 ClinicalTrials.gov Neuroprotective Effect of Remote Ischemic Conditioning in Ischemic Stroke Treated With Mechanical Thrombectomy. Bethesda (MD) 2019 https://clinicaltrials.gov/ct2/show/NCT03915782
• 73 ClinicalTrials.gov Remote ischemic conditioning in patients with acute stroke (RESIST). Bethesda (MD) 2018 https://clinicaltrials.gov/ct2/show/NCT03481777
• 74 ClinicalTrials.gov Effect of Remote Ischemic Conditioning on Vascular Health in Stroke Patients. Bethesda (MD) 2018 https://clinicaltrials.gov/ct2/show/NCT03635177
• 75 Diansan S, Shifen Z, Zhen G. et al Resection of the nerves bundle from the sphenopalatine ganglia tend to increase the infarction volume following middle cerebral artery occlusion. Neurol Sci 2010; 31: 431-435
• 76 Levi H, Schoknecht K, Prager O. et al Stimulation of the sphenopalatine Ganglion induces reperfusion and blood-brain barrier protection in the Photothrombotic stroke model. PLoS One 2012: 7
• 77 Bar-Shir A, Shemesh N, Nossin-Manor R. et al Late stimulation of the sphenopalatine-ganglion in ischemic rats: Improvement in N-acetyl-aspartate levels and diffusion weighted imaging characteristics as seen by MR. J Magn Reson Imaging 2010; 31: 1355-1363
• 78 Henninger N, Fisher M. Stimulating circle of Willis nerve fibers preserves the diffusion-perfusion mismatch in experimental stroke. Stroke 2007; 38: 2779-2786
• 79 Bornstein NM, Saver JL, Diener HC. et al Sphenopalatine Ganglion Stimulation to Augment Cerebral Blood Flow: A Randomized, Sham-Controlled Trial. Stroke 2019; 50: 2108-2117
• 80 Bornstein NM, Saver JL, Diener HC. et al An injectable implant to stimulate the sphenopalatine ganglion for treatment of acute ischaemic stroke up to 24 h from onset (ImpACT-24B): an international, randomised, double-blind, sham-controlled, pivotal trial. Lancet 2019; 394: 219-229
• 81 Janssen PM, Venema E, DIppel DiWJ. Effect of workflow improvements in endovascular stroke treatment: A systematic review and meta-analysis. Stroke 2019; 50: 665-674
• 82 Nabavi DG, Koennecke HC, Ossenbrink M. et al Certification criteria for stroke units in Germany: Update 2018. Nervenarzt 2019; 90: 335-342
• 83 Scott PA, Meurer WJ. et al A multilevel intervention to increase community hospital use of alteplase for acute stroke (INSTINCT): A cluster-randomised controlled trial. Lancet Neurol 2013; 12: 139-148
• 84 Dirks M, Niessen LW, Van Wijngaarden JDH. et al Promoting thrombolysis in acute ischemic stroke. Stroke 2011; 42: 1325-1330
• 85 Haesebaert J, Nighoghossian N, Mercier C. et al Improving access to thrombolysis and inhospital management times in ischemic stroke a stepped-wedge randomized trial. Stroke 2018; 49: 405-411
• 86 Ajmi SC, Advani R, Fjetland L. et al Reducing door-to-needle times in stroke thrombolysis to 13 min through protocol revision and simulation training: A quality improvement project in a Norwegian stroke centre. BMJ Qual Saf 2019; 28: 939-948
• 87 Meretoja A, Strbian D, Mustanoja S. et al Reducing in-hospital delay to 20 minutes in stroke thrombolysis. Neurology 2012; 79: 306-313
• 88 Dickson RL, Sumathipala D, Reeves J. Stop Stroke© Acute Care Coordination Medical Application: A Brief Report on Postimplementation Performance at a Primary Stroke Center. J Stroke Cerebrovasc Dis 2016; 25: 1275-1279
• 89 Matsumoto S, Koyama H, Nakahara I. et al A visual task management application for acute ischemic stroke care. Front Neurol 2019: 10
• 90 Klingner C, Günther A, Brodoehl S. et al Talk About Thrombolysis. Regular Case-Based Discussions of Stroke Thrombolysis Improve Door-to-Needle Time by 20 %. J Stroke Cerebrovasc Dis 2019; 28: 876-881
• 91 Mehta T, Strauss S, Beland D. et al Stroke Simulation Improves Acute Stroke Management: A Systems-Based Practice Experience. J Grad Med Educ 2018; 10: 57-62
• 92 Bohmann FO, Kurka N, du Mesnil de Rochemont R. et al Simulation-Based Training of the Rapid Evaluation and Management of Acute Stroke (STREAM) – A Prospective Single-Arm Multicenter Trial. Front Neurol 2019; 10
• 93 Braksick SA, Kashani K, Hocker S. Neurology Education for Critical Care Fellows Using High-Fidelity Simulation. Neurocrit Care 2017; 26: 96-102
• 94 Tahtali D, Bohmann F, Rostek P. et al Crew-Ressource-Management und Simulatortraining in der akuten Schlaganfalltherapie. Nervenarzt 2016; 87: 1322-1331
• 95 Kassardjian CD, Willems JD, Skrabka K. et al In-Patient Code Stroke: A Quality Improvement Strategy to Overcome Knowledge-to-Action Gaps in Response Time. Stroke 2017; 48: 2176-2183
• 96 Krogias C, Bartig D, Kitzrow M. et al Availability of mechanical thrombectomy for acute stroke: Analysis of the health care reality in Germany. Nervenarzt 2017; 88: 1177-1185
• 97 Menon BK, Xu H, Cox M. et al Components and Trends in Door to Treatment Times for Endovascular Therapy in Get With The Guidelines-Stroke Hospitals. Circulation 2019; 139: 169-179
• 98 Psychogios MN, Behme D, Schregel K. et al One-stop management of acute stroke patients minimizing door-to-reperfusion times. Stroke 2017; 48: 3152-3155
• 99 Schönenberger S, Uhlmann L, Hacke W. et al Effect of conscious sedation vs general anesthesia on early neurological improvement among patients with ischemic stroke undergoing endovascular thrombectomy: A randomized clinical trial. JAMA 2016; 316: 1986-1996
• 100 Hendén PL, Rentzos A. et al General Anesthesia Versus Conscious Sedation for Endovascular Treatment of Acute Ischemic Stroke: The AnStroke Trial (Anesthesia during Stroke). Stroke 2017; 48: 1601-1607
• 101 Thomalla, et al Acute imaging for evidence-based treatment of ischemic stroke. Current Opinion in Neurology 2019; 32: 521-529