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Wake-up Stroke: New Opportunities for Acute Stroke Treatment

Abstract

Purpose

This review summarizes the current science underpinning the treatment of patients with ischemic stroke who awaken with stroke symptoms. This large subset of stroke patients has historically been precluded from treatment with disability-limiting reperfusion therapies such as intravenous thrombolysis. Recent advances in neuroimaging have shifted the paradigm of treatment based upon rigid time-based criteria to treatment guided by evidence of salvageable ischemic penumbra on advanced imaging.

Recent Findings

Several recent randomized controlled trials provide evidence that imaging-guided treatment of wake-up and uncertain onset stroke patients is feasible and effective. Thrombectomy trials have demonstrated dramatic clinical benefit for this treatment modality as many as 24 h from the time patients were last known to be well. Furthermore, appropriately selected wake-up stroke patients beyond 4.5 h from last known well may also benefit from intravenous thrombolysis.

Summary

The evaluation and optimal treatment of patients with ischemic stroke is rapidly evolving, creating a moving target for stroke systems of care. Incorporating this new evidence into practice requires re-examination of how patients with stroke symptoms are evaluated and will challenge regional systems to design mechanisms to ensure rapid access to advanced imaging and treatment options.

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Fig. 1

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.

    • Mackey J, Kleindorfer D, Sucharew H, Moomaw CJ, Kissela BM, Alwell K, et al. Population-based study of wake-up strokes. Neurology. 2011;76(19):1662–7. Population-based examination of the epidemiology fo wake-up stroke.

  2. 2.

    Denny MC, Boehme AK, Dorsey AM, George AJ, Yeh AD, Albright KC, et al. Wake-up strokes are similar to known-onset morning strokes in severity and outcome. J Neurol Neurol Disord. 2014;1(1):102.

  3. 3.

    Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, et al. 2018 guidelines for the early management of patients with acute ischemic stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2018;49(3):e46–e110.

  4. 4.

    Reid JM, Dai D, Cheripelli B, Christian C, Reidy Y, Gubitz GJ, et al. Differences in wake-up and unknown onset stroke examined in a stroke registry. Int J Stroke. 2015;10(3):331–5.

  5. 5.

    Moradiya Y, Janjua N. Presentation and outcomes of “wake-up strokes” in a large randomized stroke trial: analysis of data from the International Stroke Trial. J Stroke Cerebrovasc Dis. 2013;22(8):e286–92.

  6. 6.

    Bornstein NM, Gur AY, Fainshtein P, Korczyn AD. Stroke during sleep: epidemiological and clinical features. Cerebrovasc Dis. 1999;9(6):320–2.

  7. 7.

    Fink JN, Kumar S, Horkan C, Linfante I, Selim MH, Caplan LR, et al. The stroke patient who woke up: clinical and radiological features, including diffusion and perfusion MRI. Stroke. 2002;33(4):988–93.

  8. 8.

    Nadeau JO, Fang J, Kapral MK, Silver FL, Hill MD, Registry of the Canadian Stroke N. Outcome after stroke upon awakening. Can J Neurol Sci. 2005;32(2):232–6.

  9. 9.

    Boode B, Welzen V, Franke C, van Oostenbrugge R. Estimating the number of stroke patients eligible for thrombolytic treatment if delay could be avoided. Cerebrovasc Dis. 2007;23(4):294–8.

  10. 10.

    California Acute Stroke Pilot Registry (CASPR) Investigators. Prioritizing interventions to improve rates of thrombolysis for ischemic stroke. Neurology. 2005;64(4):654–9.

  11. 11.

    Dankbaar JW, Bienfait HP, van den Berg C, Bennink E, Horsch AD, van Seeters T, et al. Wake-up stroke versus stroke with known onset time: clinical and multimodality CT imaging characteristics. Cerebrovasc Dis. 2018;45(5–6):236–44.

  12. 12.

    Roveri L, La Gioia S, Ghidinelli C, Anzalone N, De Filippis C, Comi G. Wake-up stroke within 3 hours of symptom awareness: imaging and clinical features compared to standard recombinant tissue plasminogen activator treated stroke. J Stroke Cerebrovasc Dis. 2013;22(6):703–8.

  13. 13.

    Nadeau JO, Fang J, Kapral MK, Silver FL, Hill MD. Outcome after stroke upon awakening. Can J Neurol Sci. 2005;32(2):232–6.

  14. 14.

    Muller JE, Stone PH, Turi ZG, Rutherford JD, Czeisler CA, Parker C, et al. Circadian variation in the frequency of onset of acute myocardial infarction. N Engl J Med. 1985;313(21):1315–22.

  15. 15.

    Marler JR, Price TR, Clark GL, Muller JE, Robertson T, Mohr JP, et al. Morning increase in onset of ischemic stroke. Stroke. 1989;20(4):473–6.

  16. 16.

    Elliott WJ. Circadian variation in the timing of stroke onset: a meta-analysis. Stroke. 1998;29(5):992–6.

  17. 17.

    Chaturvedi S, Adams HP Jr, Woolson RF. Circadian variation in ischemic stroke subtypes. Stroke. 1999;30(9):1792–5.

  18. 18.

    Marsh EE 3rd, Biller J, Adams HP Jr, Marler JR, Hulbert JR, Love BB, et al. Circadian variation in onset of acute ischemic stroke. Arch Neurol. 1990;47(11):1178–80.

  19. 19.

    Riccio PM, Klein FR, Pagani Cassara F, Munoz Giacomelli F, Gonzalez Toledo ME, Racosta JM, et al. Newly diagnosed atrial fibrillation linked to wake-up stroke and TIA: hypothetical implications. Neurology. 2013;80(20):1834–40.

  20. 20.

    Kim TJ, Ko SB, Jeong HG, Lee JS, Kim CK, Kim Y, et al. Nocturnal desaturation in the stroke unit is associated with wake-up ischemic stroke. Stroke. 2016;47(7):1748–53.

  21. 21.

    Scheer FA, Shea SA. Human circadian system causes a morning peak in prothrombotic plasminogen activator inhibitor-1 (PAI-1) independent of the sleep/wake cycle. Blood. 2014;123(4):590–3.

  22. 22.

    Bonten TN, Snoep JD, Assendelft WJ, Zwaginga JJ, Eikenboom J, Huisman MV, et al. Time-dependent effects of aspirin on blood pressure and morning platelet reactivity: a randomized cross-over trial. Hypertension. 2015;65(4):743–50.

  23. 23.

    • Thomalla G, Cheng B, Ebinger M, Hao Q, Tourdias T, Wu O, 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(11):978–86. Observational study examing the test characteristics of DWI–FLAIR mismatch to predict stroke duration.

  24. 24.

    Silva GS, Lima FO, Camargo EC, Smith WS, Singhal AB, Greer DM, et al. Wake-up stroke: clinical and neuroimaging characteristics. Cerebrovasc Dis. 2010;29(4):336–42.

  25. 25.

    Hjort N, Butcher K, Davis SM, Kidwell CS, Koroshetz WJ, Rother J, et al. Magnetic resonance imaging criteria for thrombolysis in acute cerebral infarct. Stroke. 2005;36(2):388–97.

  26. 26.

    Huisa BN, Liebeskind DS, Raman R, Hao Q, Meyer BC, Meyer DM, et al. Diffusion-weighted imaging-fluid attenuated inversion recovery mismatch in nocturnal stroke patients with unknown time of onset. J Stroke Cerebrovasc Dis. 2013;22(7):972–7.

  27. 27.

    Campbell BC, Christensen S, Levi CR, Desmond PM, Donnan GA, Davis SM, et al. Comparison of computed tomography perfusion and magnetic resonance imaging perfusion-diffusion mismatch in ischemic stroke. Stroke. 2012;43(10):2648–53.

  28. 28.

    Boned S, Padroni M, Rubiera M, Tomasello A, Coscojuela P, Romero N, et al. Admission CT perfusion may overestimate initial infarct core: the ghost infarct core concept. J Neurointerv Surg. 2017;9(1):66–9.

  29. 29.

    Copen WA, Yoo AJ, Rost NS, Morais LT, Schaefer PW, Gonzalez RG, et al. In patients with suspected acute stroke, CT perfusion-based cerebral blood flow maps cannot substitute for DWI in measuring the ischemic core. PLoS One. 2017;12(11):e0188891.

  30. 30.

    Martins N, Aires A, Mendez B, Boned S, Rubiera M, Tomasello A, et al. Ghost infarct core and admission computed tomography perfusion: redefining the role of neuroimaging in acute ischemic stroke. Interv Neurol. 2018;7(6):513–21.

  31. 31.

    Shaker H, Khan M, Mulderink T, Koehler TJ, Scurek R, Tubergen T, et al. The role of CT perfusion in defining the clinically relevant core infarction to guide thrombectomy selection in patients with acute stroke. J Neuroimaging. 2019;29(3):331–4.

  32. 32.

    Geuskens RR, Borst J, Lucas M, Boers AM, Berkhemer OA, Roos YB, et al. Characteristics of misclassified CT perfusion ischemic core in patients with acute ischemic stroke. PLoS One. 2015;10(11):e0141571.

  33. 33.

    Austein F, Riedel C, Kerby T, Meyne J, Binder A, Lindner T, et al. Comparison of perfusion CT software to predict the final infarct volume after thrombectomy. Stroke. 2016;47(9):2311–7.

  34. 34.

    Kudo K, Christensen S, Sasaki M, Ostergaard L, Shirato H, Ogasawara K, et al. Accuracy and reliability assessment of CT and MR perfusion analysis software using a digital phantom. Radiology. 2013;267(1):201–11.

  35. 35.

    Manawadu D, Bodla S, Keep J, Jarosz J, Kalra L. An observational study of thrombolysis outcomes in wake-up ischemic stroke patients. Stroke. 2013;44(2):427–31.

  36. 36.

    Manawadu D, Bodla S, Jarosz J, Keep J, Kalra L. A case-controlled comparison of thrombolysis outcomes between wake-up and known time of onset ischemic stroke patients. Stroke. 2013;44(8):2226–31.

  37. 37.

    Bai Q, Zhao Z, Fu P, Sui H, Xie X, Chen J, et al. Clinical outcomes of fast MRI-based trombolysis in wake-up strokes compared to superacute ischemic strokes within 12 hours. Neurol Res. 2013;35(5):492–7.

  38. 38.

    Morelli N, Rota E, Immovilli P, Cosottini M, Giorgi-Pierfranceschi M, Magnacavallo A, et al. Computed tomography perfusion-based thrombolysis in wake-up stroke. Intern Emerg Med. 2015;10(8):977–84.

  39. 39.

    Dorado L, Ahmed N, Thomalla G, Lozano M, Malojcic B, Wani M, et al. Intravenous thrombolysis in unknown-onset stroke: results from the safe implementation of treatment in stroke-international stroke thrombolysis registry. Stroke. 2017;48(3):720–5.

  40. 40.

    Hu YZ, Xu ZQ, Lu XY, Chen J. Efficacy and safety of thrombolysis for stroke of unknown onset time: a meta-analysis. J Thromb Thrombolysis. 2014;38(4):528–39.

  41. 41.

    •• Thomalla G, Simonsen CZ, Boutitie F, Andersen G, Berthezene Y, Cheng B, et al. MRI-guided thrombolysis for stroke with unknown time of onset. N Engl J Med. 2018;379(7):611–22. Phase 3 trial of thrombolysis among wake-up strokes selected by MRI DWI-FLAIR

  42. 42.

    •• Ma H, Campbell BCV, Parsons MW, Churilov L, Levi CR, Hsu C, et al. Thrombolysis guided by perfusion imaging up to 9 hours after onset of stroke. N Engl J Med. 2019;380(19):1795–803. Phase 3 trial of thrombolysis among wake-up strokes selected by MRI DWI-FLAIR

  43. 43.

    Ringleb P, Bendszus M, Bluhmki E, Donnan G, Eschenfelder C, Fatar M, et al. Extending the time window for intravenous thrombolysis in acute ischemic stroke using magnetic resonance imaging-based patient selection. Int J Stroke. 2019;14(5):483–90.

  44. 44.

    Masatoshi Koga, Haruko Yamamoto, Manabu Inoue, Koko Asakura, Junya Aoki, Takao Kanzawa, et al. MRI-guided thrombolysis with alteplase at 0.6mg/kg for stroke with unknown time of onset: THAWS randomized controlled trial. European Stroke Conference Late Breaking Abstracts. European Stroke Journal. 2019;4(suppl):779–89.

  45. 45.

    •• Campbell BCV, Ma H, Ringleb PA, Parsons MW, Churilov L, Bendszus M, 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 (London, England). 2019;394(10193):139–47. Meta-analysis of EPITHET, EXTEND, and ECASS-4

  46. 46.

    Straka M, Albers GW, Bammer R. Real-time diffusion-perfusion mismatch analysis in acute stroke. J Magn Reson Imaging. 2010;32(5):1024–37.

  47. 47.

    Koga M, Toyoda K, Kimura K, Yamamoto H, Sasaki M, Hamasaki T, et al. THrombolysis for acute wake-up and unclear-onset strokes with alteplase at 0·6 mg/kg (THAWS) trial. Int J Stroke. 2014;9(8):1117–24.

  48. 48.

    Ebinger M, Iwanaga T, Prosser JF, De Silva DA, Christensen S, Collins M, et al. Clinical-diffusion mismatch and benefit from thrombolysis 3 to 6 hours after acute stroke. Stroke. 2009;40(7):2572–4.

  49. 49.

    Goyal M, Menon BK, van Zwam WH, Dippel DW, Mitchell PJ, Demchuk AM, et al. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet. 2016;387(10029):1723–31.

  50. 50.

    •• Nogueira RG, Jadhav AP, Haussen DC, Bonafe A, Budzik RF, Bhuva P, et al. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. N Engl J Med. 2018;378(1):11–21. DAWN trial - demonstrated efficacy of thrombectomy beyond 6 hours in patients selected with MRI or CTP

  51. 51.

    •• Albers GW, Marks MP, Kemp S, Christensen S, Tsai JP, Ortega-Gutierrez S, et al. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. N Engl J Med. 2018;378(8):708–18. DEFUSE 3 trial - demonstrated efficacy of thrombectomy beyond 6 hours in patients selected with MRI or CTP

  52. 52.

    Jadhav AP, Aghaebrahim A, Jankowitz BT, Haussen DC, Budzik RF, Bonafe A, et al. Benefit of endovascular thrombectomy by mode of onset: secondary analysis of the DAWN trial. Stroke. 2019;50(11):3141–6.

  53. 53.

    Skolarus LE, Meurer WJ, Shanmugasundaram K, Adelman EE, Scott PA, Burke JF. Marked regional variation in acute stroke treatment among Medicare beneficiaries. Stroke. 2015;46(7):1890–6.

  54. 54.

    Asaithambi G, Tong X, George MG, Tsai AW, Peacock JM, Luepker RV, et al. Acute stroke reperfusion therapy trends in the expanded treatment window era. J Stroke Cerebrovasc Dis. 2014;23(9):2316–21.

  55. 55.

    Garcia Ruiz R, Silva Fernandez J, Garcia Ruiz RM, Recio Bermejo M, Arias Arias A, Del Saz Saucedo P, et al. Response to symptoms and prehospital delay in stroke patients. is it time to reconsider stroke awareness campaigns? J Stroke Cerebrovasc Dis. 2018;27(3):625–32.

  56. 56.

    Springer MV, Labovitz DL, Hochheiser EC. Race-ethnic disparities in hospital arrival time after ischemic stroke. Ethn Dis. 2017;27(2):125–32.

  57. 57.

    Gardener H, Pepe PE, Rundek T, Wang K, Dong C, Ciliberti M, et al. Need to prioritize education of the public regarding stroke symptoms and faster activation of the 9-1-1 system: findings from the Florida-Puerto Rico CReSD stroke registry. Prehosp Emerg Care. 2019;23(4):439–46.

  58. 58.

    Tong D, Reeves MJ, Hernandez AF, Zhao X, Olson DM, Fonarow GC, et al. Times from symptom onset to hospital arrival in the get with the guidelines–stroke program 2002 to 2009. Stroke. 2012;43(7):1912–7.

  59. 59.

    • Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2019;50(12):e344–418. Most recent acute stroke care guidelines.

  60. 60.

    Prabhakar AM, Gottumukkala RV, Hemingway J, Hughes DR, Patel SS, Duszak R Jr. Increasing utilization of emergency department neuroimaging in Medicare beneficiaries from 1994 to 2015. Am J Emerg Med. 2018;36(4):680–3.

  61. 61.

    Ginde AA, Foianini A, Renner DM, Valley M, Camargo JCA. Availability and quality of computed tomography and magnetic resonance imaging equipment in U.S. emergency departments. Acad Emerg Med. 2008;15(8):780–3.

  62. 62.

    Fonarow GC, Zhao X, Smith EE, Saver JL, Reeves MJ, Bhatt DL, et al. Door-to-needle times for tissue plasminogen activator administration and clinical outcomes in acute ischemic stroke before and after a quality improvement initiative. JAMA. 2014;311(16):1632–40.

  63. 63.

    Madhok DY, Keenan KJ, Cole SB, Martin C, Hemphill JC 3rd. Prehospital and emergency department-focused mission protocol improves thrombolysis metrics for suspected acute stroke patients. J Stroke Cerebrovasc Dis. 2019;28(12):104423.

  64. 64.

    Sanossian N, Fu KA, Liebeskind DS, Starkman S, Hamilton S, Villablanca JP, et al. Utilization of emergent neuroimaging for thrombolysis-eligible stroke patients. J Neuroimaging. 2017;27(1):59–64.

  65. 65.

    Burgos AM, Saver JL. Evidence that tenecteplase is noninferior to alteplase for acute ischemic stroke. Stroke. 2019;50(8):2156–62.

  66. 66.

    Campbell BCV, Mitchell PJ, Churilov L, Yassi N, Kleinig TJ, Dowling RJ, et al. Tenecteplase versus alteplase before thrombectomy for ischemic stroke. N Engl J Med. 2018;378(17):1573–82.

  67. 67.

    • Jadhav AP, Desai SM, Kenmuir CL, Rocha M, Starr MT, Molyneaux BJ, et al. Eligibility for endovascular trial enrollment in the 6- to 24-hour time window: analysis of a single comprehensive stroke center. stroke. 2018;49(4):1015–7. Examination of eligibility for enrollment in DAWN and DEFUSE 3.

  68. 68.

    Smith EE, Kent DM, Bulsara KR, Leung LY, Lichtman JH, Reeves MJ, et al. Accuracy of prediction instruments for diagnosing large vessel occlusion in individuals with suspected stroke: a systematic review for the 2018 guidelines for the early management of patients with acute ischemic stroke. Stroke. 2018;49(3):e111–e22.

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Correspondence to J. Adam Oostema.

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Oostema, J.A., Kahn, M.A. Wake-up Stroke: New Opportunities for Acute Stroke Treatment. Curr Emerg Hosp Med Rep (2020). https://doi.org/10.1007/s40138-020-00205-6

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Keywords

  • Ischemic stroke
  • Wake-up stroke
  • Thrombolysis
  • Mechanical thrombectomy
  • MRI
  • CT perfusion