Impact of Leukoaraiosis Severity on the Association of Time to Successful Reperfusion with 90-Day Functional Outcome After Large Vessel Occlusion Stroke

  • Abdul Ghani Mikati
  • Max Mandelbaum
  • Shweta Sapnar
  • Ajit S. Puri
  • Brian Silver
  • Richard P. GoddeauJr
  • Diogo C. Haussen
  • Majaz Moonis
  • Adalia H. Jun-O’Connell
  • Nils HenningerEmail author
Original Article


The chance for a favorable outcome after mechanical thrombectomy (MT) for large vessel occlusion stroke decreases with the symptom onset-to-reperfusion time (OTR). Patients with severe leukoaraiosis are at increased risk for a poor outcome after MT. However, whether leukoaraiosis modulates to the association between OTR and 90-day functional outcome is uncertain. We retrospectively analyzed 144 consecutive patients with successful (TICI ≥ 2b/3) MT for anterior circulation large vessel occlusion within 24 h form OTR between January 2012 to November 2016. Leukoaraiosis was dichotomized to absent-to-mild (van Swieten scale score 0–2) versus moderate-to-severe (3–4) as assessed on admission head CT. Multiple linear, logistic, and ordinal regression analyses were used to determine the association between leukoaraiosis, OTR, and 90-day modified Rankin Scale (mRS) score, after adjustment for pertinent covariates. Leukoaraiosis was independently associated with the OTR on multivariable linear regression (p = 0.003). The association between OTR and 90-day outcome depended on the degree of pre-existing leukoaraiosis burden as shown by a significant leukoaraiosis-by-OTR interaction on multivariable logistic regression (OR 0.76, 95% CI 0.58–0.98, p = 0.037) and multivariable ordinal regression (OR 0.87, 95% CI 0.78–0.97, p = 0.011). Pre-existing leukoaraiosis is associated with the 90-day functional outcome after successful reperfusion and impacts the association between the OTR and 90-day mRS among patients undergoing MT. Patients with high leukoaraiosis burden need to present earlier than patients with low leukoaraiosis burden for a similar favorable outcome. Pending confirmation, these results may have important implications for optimizing patient selection for acute stroke therapies.


ASPECTS Collaterals Endovascular thrombectomy Leukoaraiosis Large vessel occlusion Small vessel disease Recanalization 


Author Contributions

AGM, MM, SS, ASP, and NH acquired the data. AGM and NH were involved in the study design and data interpretation. AGM, MM, and NH drafted the article. NH conducted statistical analyses. All authors commented on the manuscript for important intellectual content.


Dr. Henninger is supported by K08NS091499 from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Compliance with Ethical Standards

Conflicts of Interest

Dr. Henninger serves on the advisory board of Omniox, Inc. and serves as consultant to Astrocyte Pharmaceuticals, Inc. Dr. Silver receives compensation as a surveyor for the Joint Commission, for review of medicolegal malpractice cases, and for adjudication of stroke outcomes in the Women’s Health Initiative. Dr. Puri is a consultant for Stryker Neurovascular, Scientica Vascular, Cerenovus, receives research support from Stryker Neurovascular and Medtronic Neurovascular, and reports stock options in InNeuroCo. Dr. Haussen is a consultant for Stryker Neurovascular and Vesalio. All other authors declare no competing interests.

Ethical Approval

This study was reviewed and approved by our Institutional Review Board and procedures followed were in accordance with institutional guidelines and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Health Insurance Portability and Accountability Act (HIPAA) waiver of authorization was granted. We adhere to the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) guidelines (

Supplementary material

12975_2019_703_MOESM1_ESM.pdf (235 kb)
ESM 1 (PDF 234 kb)


  1. 1.
    Bracard S, Ducrocq X, Mas JL, Soudant M, Oppenheim C, Moulin T, et al. Mechanical thrombectomy after intravenous alteplase versus alteplase alone after stroke (THRACE): a randomised controlled trial. Lancet Neurol. 2016;15(11):1138–47. Scholar
  2. 2.
    Jovin TG, Chamorro A, Cobo E, de Miquel MA, Molina CA, Rovira A, et al. Thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med. 2015;372(24):2296–306. Scholar
  3. 3.
    Saver JL, Goyal M, Bonafe A, Diener HC, Levy EI, Pereira VM, et al. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med. 2015;372(24):2285–95. Scholar
  4. 4.
    Goyal M, Demchuk AM, Menon BK, Eesa M, Rempel JL, Thornton J, et al. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med. 2015;372(11):1019–30. Scholar
  5. 5.
    Berkhemer OA, Fransen PS, Beumer D, van den Berg LA, Lingsma HF, Yoo AJ, et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med. 2015;372(1):11–20. Scholar
  6. 6.
    Campbell BC, Mitchell PJ, Kleinig TJ, Dewey HM, Churilov L, Yassi N, et al. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med. 2015;372(11):1009–18. Scholar
  7. 7.
    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. Google Scholar
  8. 8.
    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. Scholar
  9. 9.
    Saver JL, Goyal M, van der Lugt A, Menon BK, Majoie CB, Dippel DW, et al. Time to treatment with endovascular thrombectomy and outcomes from ischemic stroke: a meta-analysis. JAMA. 2016;316(12):1279–88. Scholar
  10. 10.
    Jovin TG, Saver JL, Ribo M, Pereira V, Furlan A, Bonafe A, 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):641–52. Scholar
  11. 11.
    Saposnik G, Strbian D. Enlightenment and challenges offered by DAWN trial (DWI or CTP assessment with clinical mismatch in the triage of wake up and late presenting strokes undergoing neurointervention with Trevo). Stroke. 2018;49(2):498–500. Google Scholar
  12. 12.
    Liebeskind DS, Jahan R, Nogueira RG, Zaidat OO, Saver JL, Investigators S. Impact of collaterals on successful revascularization in Solitaire FR with the intention for thrombectomy. Stroke. 2014;45(7):2036–40. Google Scholar
  13. 13.
    Albers GW, Lansberg MG, Kemp S, Tsai JP, Lavori P, Christensen S, et al. A multicenter randomized controlled trial of endovascular therapy following imaging evaluation for ischemic stroke (DEFUSE 3). Int J Stroke. 2017;12(8):896–905. Google Scholar
  14. 14.
    Rocha M, Jovin TG. Fast versus slow progressors of infarct growth in large vessel occlusion stroke: clinical and research implications. Stroke. 2017;48(9):2621–7. Google Scholar
  15. 15.
    Meretoja A, Keshtkaran M, Tatlisumak T, Donnan GA, Churilov L. Endovascular therapy for ischemic stroke: save a minute-save a week. Neurology. 2017;88(22):2123–7. Scholar
  16. 16.
    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. Scholar
  17. 17.
    Gilberti N, Gamba M, Premi E, Costa A, Vergani V, Delrio I, et al. Leukoaraiosis is a predictor of futile recanalization in acute ischemic stroke. J Neurol. 2017;264(3):448–52. Scholar
  18. 18.
    Guo Y, Zi W, Wan Y, Zhang S, Sun B, Shang X, et al. Leukoaraiosis severity and outcomes after mechanical thrombectomy with stent-retriever devices in acute ischemic stroke. J Neurointerv Surg. 2018;11:137–40. Scholar
  19. 19.
    Kongbunkiat K, Wilson D, Kasemsap N, Tiamkao S, Jichi F, Palumbo V, et al. Leukoaraiosis, intracerebral hemorrhage, and functional outcome after acute stroke thrombolysis. Neurology. 2017;88(7):638–45. Scholar
  20. 20.
    Zhang J, Puri AS, Khan MA, Goddeau RP Jr, Henninger N. Leukoaraiosis predicts a poor 90-day outcome after endovascular stroke therapy. AJNR Am J Neuroradiol. 2014;35(11):2070–5. Scholar
  21. 21.
    Henninger N, Lin E, Baker SP, Wakhloo AK, Takhtani D, Moonis M. Leukoaraiosis predicts poor 90-day outcome after acute large cerebral artery occlusion. Cerebrovasc Dis. 2012;33(6):525–31. Scholar
  22. 22.
    Henninger N, Lin E, Haussen DC, Lehman LL, Takhtani D, Selim M, et al. Leukoaraiosis and sex predict the hyperacute ischemic core volume. Stroke. 2013;44(1):61–7. Google Scholar
  23. 23.
    Ay H, Arsava EM, Rosand J, Furie KL, Singhal AB, Schaefer PW, et al. Severity of leukoaraiosis and susceptibility to infarct growth in acute stroke. Stroke. 2008;39(5):1409–13. Google Scholar
  24. 24.
    Henninger N, Khan MA, Zhang J, Moonis M, Goddeau RP Jr. Leukoaraiosis predicts cortical infarct volume after distal middle cerebral artery occlusion. Stroke. 2014;45(3):689–95. Google Scholar
  25. 25.
    Patti J, Helenius J, Puri AS, Henninger N. White matter hyperintensity-adjusted critical infarct thresholds to predict a favorable 90-day outcome. Stroke. 2016;47(10):2526–33. Google Scholar
  26. 26.
    Rabinstein AA, Albers GW, Brinjikji W, Koch S. Factors that may contribute to poor outcome despite good reperfusion after acute endovascular stroke therapy. Int J Stroke. 2018;14(1):23–31. 1747493018799979. Scholar
  27. 27.
    Shi ZS, Loh Y, Liebeskind DS, Saver JL, Gonzalez NR, Tateshima S, et al. Leukoaraiosis predicts parenchymal hematoma after mechanical thrombectomy in acute ischemic stroke. Stroke. 2012;43(7):1806–11. Scholar
  28. 28.
    Atchaneeyasakul K, Leslie-Mazwi T, Donahue K, Giese AK, Rost NS. White matter hyperintensity volume and outcome of mechanical thrombectomy with stentriever in acute ischemic stroke. Stroke. 2017;48(10):2892–4. Google Scholar
  29. 29.
    Yoo AJ, Andersson T. Thrombectomy in acute ischemic stroke: challenges to procedural success. J Stroke. 2017;19(2):121–30. Scholar
  30. 30.
    Snelling BM, Sur S, Shah SS, Chen S, Menaker SA, McCarthy DJ, et al. Unfavorable vascular anatomy is associated with increased revascularization time and worse outcome in anterior circulation thrombectomy. World Neurosurg. 2018;120:e976–e83. Scholar
  31. 31.
    Powers WJ, Derdeyn CP, Biller J, Coffey CS, Hoh BL, Jauch EC, et al. 2015 American Heart Association/American Stroke Association focused update of the 2013 guidelines for the early management of patients with acute ischemic stroke regarding endovascular treatment: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2015;46(10):3020–35. Scholar
  32. 32.
    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. Scholar
  33. 33.
    Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993;24(1):35–41.Google Scholar
  34. 34.
    Bruno A, Akinwuntan AE, Lin C, Close B, Davis K, Baute V, et al. Simplified modified Rankin scale questionnaire: reproducibility over the telephone and validation with quality of life. Stroke. 2011;42(8):2276–9. Google Scholar
  35. 35.
    Wardlaw JM, Smith EE, Biessels GJ, Cordonnier C, Fazekas F, Frayne R, et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol. 2013;12(8):822–38. Scholar
  36. 36.
    van Swieten JC, Hijdra A, Koudstaal PJ, van Gijn J. Grading white matter lesions on CT and MRI: a simple scale. J Neurol Neurosurg Psychiatry. 1990;53(12):1080–3.Google Scholar
  37. 37.
    Gurol ME, Irizarry MC, Smith EE, Raju S, Diaz-Arrastia R, Bottiglieri T, et al. Plasma beta-amyloid and white matter lesions in AD, MCI, and cerebral amyloid angiopathy. Neurology. 2006;66(1):23–9. Scholar
  38. 38.
    Higashida RT, Furlan AJ, Roberts H, Tomsick T, Connors B, Barr J, et al. Trial design and reporting standards for intra-arterial cerebral thrombolysis for acute ischemic stroke. Stroke. 2003;34(8):e109–37. Google Scholar
  39. 39.
    Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics. 1977;33(1):159–74.Google Scholar
  40. 40.
    Barber PA, Demchuk AM, Zhang J, Buchan AM. Validity and reliability of a quantitative computed tomography score in predicting outcome of hyperacute stroke before thrombolytic therapy. ASPECTS Study Group Alberta Stroke Programme Early CT Score. Lancet. 2000;355(9216):1670–4.Google Scholar
  41. 41.
    Khan M, Baird GL, Goddeau RP Jr, Silver B, Henninger N. Alberta Stroke Program Early CT Score infarct location predicts outcome following M2 occlusion. Front Neurol. 2017;8:98. Scholar
  42. 42.
    Bruno A, Switzer JA. Letter by Bruno and Switzer regarding article, “Prestroke modified Rankin Stroke Scale has moderate interobserver reliability and validity in an acute stroke setting”. Stroke. 2013;44(5):e43. Google Scholar
  43. 43.
    van Straaten EC, Fazekas F, Rostrup E, Scheltens P, Schmidt R, Pantoni L, et al. Impact of white matter hyperintensities scoring method on correlations with clinical data: the LADIS study. Stroke. 2006;37(3):836–40. Google Scholar
  44. 44.
    Kim GM, Park KY, Avery R, Helenius J, Rost N, Rosand J, et al. Extensive leukoaraiosis is associated with high early risk of recurrence after ischemic stroke. Stroke. 2014;45(2):479–85. Scholar
  45. 45.
    Valdes Hernandez Mdel C, Morris Z, Dickie DA, Royle NA, Munoz Maniega S, Aribisala BS, et al. Close correlation between quantitative and qualitative assessments of white matter lesions. Neuroepidemiology. 2013;40(1):13–22. Scholar
  46. 46.
    Raza SA, Barreira CM, Rodrigues GM, Frankel MR, Haussen DC, Nogueira RG, Rangaraju S (2018) Prognostic importance of CT ASPECTS and CT perfusion measures of infarction in anterior emergent large vessel occlusions. J Neurointervent Surg. doi:, neurintsurg-2018-014461.

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Abdul Ghani Mikati
    • 1
  • Max Mandelbaum
    • 1
  • Shweta Sapnar
    • 1
  • Ajit S. Puri
    • 2
    • 3
  • Brian Silver
    • 1
  • Richard P. GoddeauJr
    • 1
  • Diogo C. Haussen
    • 4
  • Majaz Moonis
    • 1
  • Adalia H. Jun-O’Connell
    • 1
  • Nils Henninger
    • 1
    • 5
    Email author
  1. 1.Department of NeurologyUniversity of Massachusetts Medical SchoolNorth WorcesterUSA
  2. 2.Department of RadiologyUniversity of Massachusetts Medical SchoolWorcesterUSA
  3. 3.Department of NeurosurgeryUniversity of Massachusetts Medical SchoolWorcesterUSA
  4. 4.Department of NeurologyEmory University/Marcus Stroke and Neuroscience Center-Grady Memorial HospitalAtlantaUSA
  5. 5.Department of PsychiatryUniversity of Massachusetts Medical SchoolWorcesterUSA

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