Hostname: page-component-76c49bb84f-h2dfl Total loading time: 0 Render date: 2025-07-02T20:14:16.213Z Has data issue: false hasContentIssue false
  • English
  • Français

Pathophysiologic mechanisms, neuroimaging and treatment in wake-up stroke

Published online by Cambridge University Press:  12 September 2019

Mohamed Elfil Open the ORCID record for Mohamed Elfil [Opens in a new window] ,
Mohamed Eldokmak ,
Alireza Baratloo ,
Nada Ahmed ,
Hardik P. Amin  and
Brian B. Koo
Mohamed Elfil*
Affiliation:
Department of Neurology, Yale University, New Haven, Connecticut, USA
Mohamed Eldokmak
Affiliation:
Department of Neurology, Yale University, New Haven, Connecticut, USA
Alireza Baratloo
Affiliation:
Prehospital and Hospital Emergency Research Center, Tehran University of Medical Sciences, Tehran, Iran Department of Emergency Medicine, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
Nada Ahmed
Affiliation:
Department of Neurology, Yale University, New Haven, Connecticut, USA
Hardik P. Amin
Affiliation:
Department of Neurology, Yale University, New Haven, Connecticut, USA
Brian B. Koo
Affiliation:
Department of Neurology, Yale University, New Haven, Connecticut, USA Department of Neurology, Connecticut Veterans Affairs Healthcare Systems, Newington, Connecticut, USA
*
Mohamed Elfil, Email: Mohamed.Elfil@Yale.edu, M_elfil13@alexmed.edu.eg
Get access Rights & Permissions [Opens in a new window]

Abstract

Wake-up stroke (WUS) or ischemic stroke occurring during sleep accounts for 14%–29.6% of all ischemic strokes. Management of WUS is complicated by its narrow therapeutic time window and attributable risk factors, which can affect the safety and efficacy of administering intravenous (IV) tissue plasminogen activator (t-PA). This manuscript will review risk factors of WUS, with a focus on obstructive sleep apnea, potential mechanisms of WUS, and evaluate studies assessing safety and efficacy of IV t-PA treatment in WUS patients guided by neuroimaging to estimate time of symptom onset. The authors used PubMed (1966 to March 2018) to search for the term “Wake-Up Stroke” cross-referenced with “pathophysiology,” ‘‘pathogenesis,” “pathology,” “magnetic resonance imaging,” “obstructive sleep apnea,” or “treatment.” English language Papers were reviewed. Also reviewed were pertinent papers from the reference list of the above-matched manuscripts. Studies that focused only on acute Strokes with known-onset of symptoms were not reviewed. Literature showed several potential risk factors associated with increased risk of WUS. Although the onset of WUS is unknown, a few studies investigated the potential benefit of magnetic resonance imaging (MRI) in estimating the age of onset which encouraged conducting clinical trials assessing the efficacy of MRI-guided thrombolytic therapy in WUS.

Keywords

Wake-up strokepathophysiologyobstructive sleep apneathrombolytic therapyneuroimaging.

Information

Type
Review
Information
CNS Spectrums , Volume 25 , Issue 4 , August 2020 , pp. 460 - 467
Copyright
© Cambridge University Press 2019

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Article purchase

Temporarily unavailable

References

Fink, JN, Kumar, S, Horkan, C, et al.The stroke patient who woke up: clinical and radiological features, including diffusion and perfusion MRI. Stroke. 2002;33(4):988–993.Google Scholar
Mackey, J, Kleindorfer, D, Sucharew, H, et al.Population-based study of wake-up strokes. Neurology 2011;76(19):1662–1667.Google Scholar
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):232–236.Google Scholar
Silva, GS, Lima, FO, Camargo, EC, et al.Wake-up stroke: clinical and neuroimaging characteristics. Cerebrovasc Dis. 2010;29(4):336–342.Google Scholar
Tsai, JP, Albers, GW. Wake-Up Stroke: Current Understanding. Top Magn Reson Imaging. 2017;26(3):97–102.Google Scholar
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–e292.Google Scholar
Elliott, WJ. Circadian variation in the timing of stroke onset: a meta-analysis . Stroke. 1998;29(5):992–996.Google Scholar
Somers, VK, Dyken, ME, Mark, AL, Abboud, FM. Sympathetic-nerve activity during sleep in normal subjects. New Eng J. Med. 1993;328(5):303–307.Google Scholar
Andrews, NP, Gralnick, HR, Merryman, P, Vail, M, Quyyumi, AA. Mechanisms underlying the morning increase in platelet aggregation: a flow cytometry study. J Am Coll Cardiol. 1996;28(7):1789–1795.Google Scholar
Kario, K, Yano, Y, Matsuo, T, Hoshide, S, Asada, Y, Shimada, K. Morning blood pressure surge, morning platelet aggregation, and silent cerebral infarction in older Japanese hypertensive patients. J Hypertens. 2011;29(12):2433–2439.Google Scholar
Redon, J.The normal circadian pattern of blood pressure: implications for treatment. Int J Clin Pract Suppl. 2004(145):3–8.Google Scholar
Wouters, A, Lemmens, R, Dupont, P, Thijs, V. Wake-up stroke and stroke of unknown onset: a critical review. Front Neurol. 2014;5:153.Google Scholar
Goto, S, Sakai, H, Goto, M, et al.Enhanced shear-induced platelet aggregation in acute myocardial infarction. Circulation. 1999;99(5):608–613.Google Scholar
Ikeda, Y, Handa, M, Kawano, K, et al.The role of von Willebrand factor and fibrinogen in platelet aggregation under varying shear stress. J Clin Invest. 1991;87(4):1234–1240.Google Scholar
Riccio, PM, Klein, FR, Pagani Cassara, F, et al.Newly diagnosed atrial fibrillation linked to wake-up stroke and TIA: hypothetical implications. Neurology. 2013;80(20):1834–1840.Google Scholar
Kim, YJ, Kim, BJ, Kwon, SU, Kim, JS, Kang, DW. Unclear-onset stroke: Daytime-unwitnessed stroke vs. wake-up stroke. Int J Stroke. 2016;11(2):212–220.Google Scholar
Redline, S, Yenokyan, G, Gottlieb, DJ, et al.Obstructive sleep apnea-hypopnea and incident stroke: the sleep heart health study. Am J Resp Critical Care Med. 2010;182(2):269–277.Google Scholar
Koo, BB, Bravata, DM, Tobias, LA, et al.Observational study of obstructive sleep apnea in wake-up stroke: the SLEEP TIGHT Study. Cerebrovasc Dis. 2016;41(5-6):233–241.Google Scholar
Hsieh, SW, Lai, CL, Liu, CK, Hsieh, CF, Hsu, CY. Obstructive sleep apnea linked to wake-up strokes. J Neurol. 2012;259(7):1433–1439.Google Scholar
Zirak, P, Gregori-Pla , C, Blanco, I, et al. Characterization of the microvascular cerebral blood flow response to obstructive apneic events during night sleep. Neurophotonics. 2018;5(4):1–11.Google Scholar
Bradley, TD, Floras, JS. Obstructive sleep apnoea and its cardiovascular consequences. Lancet. 2009;373(9657):82–93.Google Scholar
Kim, TJ, Ko, SB, Jeong, HG, et al.Nocturnal Desaturation in the Stroke Unit Is Associated With Wake-Up Ischemic Stroke. Stroke. 2016;47(7):1748–1753.Google Scholar
Tanimoto , A, Mehndiratta, P, Koo, BB. Characteristics of wake-up stroke. J Stroke Cerebrovasc Dis 2014;23(6):1296-1299.Google Scholar
Bezerra, DC, Sharrett, AR, Matsushita, K, et al.Risk factors for lacune subtypes in the Atherosclerosis Risk in Communities (ARIC) Study. Neurology. 2011;78(2):102–108.Google Scholar
Ozdemir , O, Beletsky, V, Hachinski, V, Spence, JD. Cerebrovascular events on awakening, patent foramen ovale and obstructive sleep apnea syndrome. J Neurol Sci. 2008;268(1-2):193–194.Google Scholar
Shaikh, ZF, Jaye, J, Ward, N, et al.Patent foramen ovale in severe obstructive sleep apnea: clinical features and effects of closure. Chest. 2013;143(1):56–63.Google Scholar
Beelke, M, Angeli, S, Del Sette, M, et al.Obstructive sleep apnea can be provocative for right-to-left shunting through a patent foramen ovale. Sleep. 2002;25(8):856–862.Google Scholar
Ciccone, A, Proserpio, P, Roccatagliata, DV, Nichelatti, M, Gigli, GL, Parati, G, et al.Wake-up stroke and TIA due to paradoxical embolism during long obstructive sleep apnoeas: a cross-sectional study. Thorax. 2013;68(1):97–104.Google Scholar
Jauch, EC, Saver, JL, Adams, HP Jr., et al.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. 2013;44(3):870–947.Google Scholar
Odland, A, Saervoll, P, Advani, R, Kurz, MW, Kurz, KD. Are the current MRI criteria using the DWI-FLAIR mismatch concept for selection of patients with wake-up stroke to thrombolysis excluding too many patients? Scand J Trauma Resusc Emerg Med. 2015;23:22.Google Scholar
Serena, J, Davalos, A, Segura, T, Mostacero, E, Castillo, J. Stroke on awakening: looking for a more rational management. Cerebrovasc Dis. 2003;16(2):128–133.Google Scholar
European Stroke Organisation Executive Committee (ESOW). Guidelines for management of ischaemic stroke and transient ischaemic attack 2008. Cerebrovasc Dis. 2008;25(5):457–507.Google Scholar
Adams, HP Jr., Adams, RJ, Brott, T, et al.Guidelines for the early management of patients with ischemic stroke: a scientific statement from the Stroke Council of the American Stroke Association. Stroke. 2003;34(4):1056–1083.Google Scholar
Tomura, N, Uemura, K, Inugami, A, Fujita, H, Higano, S, Shishido, F. Early CT finding in cerebral infarction: obscuration of the lentiform nucleus. Radiology. 1988;168(2):463–467.Google Scholar
Alegiani, AC, MacLean, S, Braass, H, et al. Dynamics of water diffusion changes in different tissue compartments from acute to chronic stroke—a serial diffusion tensor imaging study. Front Neurol. 2019;10:158.Google Scholar
del Zoppo, GJ, von Kummer, R, Hamann, GF. Ischaemic damage of brain microvessels: inherent risks for thrombolytic treatment in stroke. J Neurol Neurosurg Psychiatry. 1998;65(1):1–9.Google Scholar
Huisa, BN, Raman, R, Ernstrom, K, et al.Alberta stroke program early CT score (ASPECTS) in patients with wake-up stroke. J Stroke Cerebrovasc Dis. 2010;19(6):475–479.Google Scholar
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):703–708.Google Scholar
Rubin, MN, Barrett, KM. What to do With Wake-Up Stroke. Neurohospitalist. 2015;5(3):161–172.Google Scholar
Todo, K, Moriwaki, H, Saito, K, Tanaka, M, Oe, H, Naritomi, H. Early CT findings in unknown-onset and wake-up strokes. Cerebrovasc Dis. 2006;21(5-6):367–371.Google Scholar
Khandelwal, N.CT perfusion in acute stroke. Indian J Radiol Imaging. 2008;18(4):281–286.Google Scholar
Tomandl, BF, Klotz, E, Handschu, R, et al.Comprehensive imaging of ischemic stroke with multisection CT. Radiographics. 2003;23(3):565–592.Google Scholar
Srinivasan, A, Goyal, M, Al Azri, F, Lum, C. State-of-the-art imaging of acute stroke. Radiographics. 2006;26 Suppl 1:S75–S95.Google Scholar
Wintermark, M, Flanders, AE, Velthuis, B, 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(4):979–985.Google Scholar
Campbell, BCV, Christensen, S, Levi, CR, et al.Cerebral blood flow is the optimal CT perfusion parameter for assessing infarct core. Stroke. 2011;42(12):3435–3440.Google Scholar
Ma, H, Campbell, BCV, Parsons, MW, et al.Thrombolysis guided by perfusion imaging up to 9 hours after onset of stroke. New Eng J Med. 2019;380(19):1795–1803.Google Scholar
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):483–490.Google Scholar
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(4):299–309.Google Scholar
Campbell, BCV, Ma, H, Ringleb, PA, 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(10193):139–147.Google Scholar
Tenecteplase in Wake-up Ischaemic Stroke Trial. https://ClinicalTrials.gov/show/NCT03181360.Google Scholar
Tsikouris, JP, Tsikouris, AP. A review of available fibrin-specific thrombolytic agents used in acute myocardial infarction. Pharmacotherapy. 2001;21(2):207–217.Google Scholar
Dunn, CJ, Goa, KL. Tenecteplase: a review of its pharmacology and therapeutic efficacy in patients with acute myocardial infarction. Am J Cardiovasc Drugs. 2001;1(1):51–66.Google Scholar
Vymazal, J, Rulseh, AM, Keller, J, Janouskova, L. Comparison of CT and MR imaging in ischemic stroke. Insights Imaging. 2012;3(6):619–627.Google Scholar
von Kummer, R, Nolte, PN, Schnittger, H, Thron, A, Ringelstein, EB. Detectability of cerebral hemisphere ischaemic infarcts by CT within 6 h of stroke. Neuroradiology. 1996;38(1):31–33.Google Scholar
Chalela, JA, Kidwell, CS, Nentwich, LM, et al.Magnetic resonance imaging and computed tomography in emergency assessment of patients with suspected acute stroke: a prospective comparison. Lancet. 2007;369(9558):293–298.Google Scholar
Fiebach, JB, Schellinger, PD, Gass, A, et al.Stroke magnetic resonance imaging is accurate in hyperacute intracerebral hemorrhage: a multicenter study on the validity of stroke imaging. Stroke. 2004;35(2):502–506.Google Scholar
Schellinger, PD, Thomalla, G, Fiehler, J, et al.MRI-based and CT-based thrombolytic therapy in acute stroke within and beyond established time windows: an analysis of 1210 patients. Stroke. 2007;38(10):2640–2645.Google Scholar
Albers, GW, Thijs, VN, Wechsler, L, et al.Magnetic resonance imaging profiles predict clinical response to early reperfusion: the diffusion and perfusion imaging evaluation for understanding stroke evolution (DEFUSE) study. Ann Neurol. 2006;60(5):508–517.Google Scholar
Thomalla, G, Gerloff, C. Treatment concepts for wake-up stroke and stroke with unknown time of symptom onset. Stroke. 2015;46(9):2707–2713.Google Scholar
Thomalla, G, Schwark, C, Sobesky, J, et al.Outcome and symptomatic bleeding complications of intravenous thrombolysis within 6 hours in MRI-selected stroke patients: comparison of a German multicenter study with the pooled data of ATLANTIS, ECASS, and NINDS tPA trials. Stroke. 2006;37(3):852–858.Google Scholar
Kurz, MW, Advani, R, Behzadi, GN, Eldoen, G, Farbu, E, Kurz, KD. Wake-up stroke-Amendable for thrombolysis-like stroke with known onset time? Acta Neurol Scand. 2017;136(1):4–10.Google Scholar
Bang, OY. Multimodal MRI for ischemic stroke: from acute therapy to preventive strategies. J Clin Neurol. 2009;5(3):107–119.Google Scholar
Kim, BJ, Kang, HG, Kim, HJ, et al.Magnetic resonance imaging in acute ischemic stroke treatment. J Stroke. 2014;16(3):131–145.Google Scholar
Tatlisumak, T, Strbian, D, Abo Ramadan, U, Li, F. The role of diffusion- and perfusion-weighted magnetic resonance imaging in drug development for ischemic stroke: from laboratory to clinics. Curr Vasc Pharmacol. 2004;2(4):343–355.Google Scholar
Neumann-Haefelin , T, Wittsack, H-J , Wenserski, F, et al.Diffusion- and Perfusion-Weighted MRI. Stroke. 1999;30(8):1591–1597.Google Scholar
Jovin, TG, Saver, JL, Ribo, M, et al.Diffusion-weighted imaging or computerized tomography perfusion assessment with clinical mismatch in the triage of wake up and late presenting strokes undergoing neurointervention with Trevo (DAWN) trial methods. Int J Stroke. 2017;12(6):641–652.Google Scholar
Lansberg, MG, Straka, M, Kemp, S, et al.MRI profile and response to endovascular reperfusion after stroke (DEFUSE 2): a prospective cohort study. Lancet Neurol. 2012;11(10):860–867.Google Scholar
Heiss, WD, Sobesky, J. Comparison of PET and DW/PW-MRI in acute ischemic stroke. Keio J Med. 2008;57(3):125–131.Google Scholar
Iosif, C, Oppenheim, C, Trystram, D, Domigo, V, Meder, JF. MR imaging-based decision in thrombolytic therapy for stroke on awakening: report of 2 cases. AJNR Am J Neuroradiol. 2008;29(7):1314–1316.Google Scholar
Breuer, L, Schellinger, PD, Huttner, HB, et al.Feasibility and safety of magnetic resonance imaging-based thrombolysis in patients with stroke on awakening: initial single-centre experience. Int J Stroke. 2010;5(2):68–73.Google Scholar
Cho, AH, Sohn, SI, Han, MK, et al.Safety and efficacy of MRI-based thrombolysis in unclear-onset stroke. A preliminary report. Cerebrovasc Dis. 2008;25(6):572–579.Google Scholar
Ebinger, M, Scheitz, JF, Kufner, A, Endres, M, Fiebach, JB, Nolte, CH. MRI-based intravenous thrombolysis in stroke patients with unknown time of symptom onset. Eur J Neurol. 2012;19(2):348–350.Google Scholar
Kang, DW, Sohn, SI, Hong, KS, et al.Reperfusion therapy in unclear-onset stroke based on MRI evaluation (RESTORE): a prospective multicenter study. Stroke. 2012;43(12):3278–3283.Google Scholar
Aoki, J, Kimura, K, Iguchi, Y, Shibazaki, K, Sakai, K, Iwanaga, T. FLAIR can estimate the onset time in acute ischemic stroke patients. J Neurol Sci. 2010;293(1-2):39–44.Google Scholar
Emeriau, S, Serre, I, Toubas, O, Pombourcq, F, Oppenheim, C, Pierot, L. Can diffusion-weighted imaging-fluid-attenuated inversion recovery mismatch (positive diffusion-weighted imaging/negative fluid-attenuated inversion recovery) at 3 Tesla identify patients with stroke at <4.5 hours? Stroke. 2013;44(6):1647–1651.Google Scholar
Thomalla, G, Rossbach, P, Rosenkranz, M, et al.Negative fluid-attenuated inversion recovery imaging identifies acute ischemic stroke at 3 hours or less. Ann Neurol. 2009;65(6):724–732.Google Scholar
Petkova, M, Rodrigo, S, Lamy, C, et al.MR imaging helps predict time from symptom onset in patients with acute stroke: implications for patients with unknown onset time. Radiology. 2010;257(3):782–792.Google Scholar
Aoki, J, Kimura, K, Iguchi, Y, et al.Intravenous thrombolysis based on diffusion-weighted imaging and fluid-attenuated inversion recovery mismatch in acute stroke patients with unknown onset time. Cerebrovasc Dis. 2011;31(5):435–441.Google Scholar
Bai, Q, Zhao, Z, Fu, P, 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):492–497.Google Scholar
Mourand, I, Milhaud, D, Arquizan, C, et al.Favorable Bridging Therapy Based on DWI-FLAIR Mismatch in Patients with Unclear-Onset Stroke. AJNR Am J Neuroradiol. 2016;37(1):88–93.Google Scholar
Schwamm, LH, Wu, O, Song, SS, et al.Intravenous thrombolysis in unwitnessed stroke onset: MR WITNESS trial results. Ann Neurol. 2018;83(5):980–993.Google Scholar
Thomalla, G, Simonsen, CZ, Boutitie, F, et al.MRI-guided thrombolysis for stroke with unknown time of onset. N Engl J Med. 2018;379(7):611– 622.Google Scholar
Koga, M, Toyoda, K, Kimura, K, 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):1117–1124.Google Scholar
Koga, M, Yamamoto, H, Inoue, M, Asakura, K, Aoki, J, Kanzawa, T, et al.MRI-guided thrombolysis with alteplase at 0.6mg/kg for stroke with unknown time of onset: THAWS randomized controlled trial. Paper presented at 5th European Stroke Organisation Conference; 2019; Milan, Italy.Google Scholar
Johnson, K, Johnson, D. Frequency of sleep apnea in stroke and TIA patients: a meta-analysis . J Clin Sleep Med. 2010;6(2):131–137.Google Scholar
Iranzo, A, Santamaria, J, Berenguer, J, Sanchez, M, Chamorro, A. Prevalence and clinical importance of sleep apnea in the first night after cerebral infarction. Neurology. 2002;58:911–916.Google Scholar
Good, D, Henkle, J, Gelber, D, Welsh, J, Verhulst, S. Sleep-disordered breathing and poor functional outcome after stroke. Stroke. 1996;27:252–259.Google Scholar
Aaronson, JA, van Bennekom, CA, Hofman, WF, et al.Obstructive sleep apnea is related to impaired cognitive and functional status after stroke. Sleep. 2015;38(9):1431–1437.Google Scholar
Aaronson, JA, Hofman, WF, van Bennekom, CA, et al.Effects of continuous positive airway pressure on cognitive and functional outcome of stroke patients with obstructive sleep apnea: a randomized controlled trial. J Clin Sleep Med. 2016;12(4):533–541.Google Scholar
Bravata, DM, Sico, J, Vaz Fragoso, CA, et al.Diagnosing and treating sleep apnea in patients with acute cerebrovascular disease. J Am Heart Assoc. 2018;7(16):e008841.Google Scholar
McEvoy, RD, Antic, NA, Heeley, E, et al.CPAP for prevention of cardiovascular events in obstructive sleep apnea. N Engl J Med. 2016;375(10): 919– 931.Google Scholar
Siarnik, P, Kollar, B, Carnicka, Z, et al.Association of sleep disordered breathing with wake-up acute ischemic stroke: a full polysomnographic study. J Clin Sleep Med. 2016;12(4):549–554.Google Scholar