Abstract
Early neurological deterioration (END) following acute ischemic stroke is a serious clinical event strongly associated with poor outcome. Regarding specifically END occurring within 24 h following stroke onset, apart from straightforward causes such as symptomatic intracranial haemorrhage and malignant edema, the cause of END remains unclear in more than a half of cases. In the latter situation, patients are often referred to as ‘progressive stroke’, a default clinical category that does not imply underlying mechanisms, precluding informed management. In this review article, we summarize the available evidence on the incidence, predictors, and associated factors of unexplained END, and discuss its underlying pathophysiology. We particularly address the hemodynamic and thrombotic mechanisms that likely play a critical role in unexplained END, and in turn highlight potential new avenues to prevent and manage this ominous event.


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Saver JL, Altman H (2012) Relationship between neurologic deficit severity and final functional outcome shifts and strengthens during first hours after onset. Stroke 43(6):1537–1541
Seners P, Turc G, Oppenheim C, Baron JC (2015) Incidence, causes and predictors of neurological deterioration occurring within 24 h following acute ischaemic stroke: a systematic review with pathophysiological implications. J Neurol Neurosurg Psychiatry 86(1):87–94
Siegler JE, Boehme AK, Albright KC, George AJ, Monlezun DJ, Beasley TM et al (2013) A proposal for the classification of etiologies of neurologic deterioration after acute ischemic stroke. J Stroke Cerebrovasc Dis 22(8):e549–e556
Jauch EC, Saver JL, Adams HP Jr, Bruno A, Connors JJ, Demaerschalk BM et al (2013) 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 44(3):870–947
Kim JM, Moon J, Ahn SW, Shin HW, Jung KH, Park KY (2016) The etiologies of early neurological deterioration after thrombolysis and risk factors of ischemia progression. J Stroke Cerebrovasc Dis 25(2):383–388
Seners P, Turc G, Tisserand M, Legrand L, Labeyrie MA, Calvet D et al (2014) Unexplained early neurological deterioration after intravenous thrombolysis: incidence, predictors, and associated factors. Stroke 45(7):2004–2009
Tisserand M, Seners P, Turc G, Legrand L, Labeyrie MA, Charron S et al (2014) Mechanisms of unexplained neurological deterioration after intravenous thrombolysis. Stroke 45(12):3527–3534
Seners P, Hurford R, Tisserand M, Turc G, Legrand L, Naggara O et al (2017) Is unexplained early neurological deterioration after intravenous thrombolysis associated with thrombus extension? Stroke 48(2):348–352
Delgado MG, Michel P, Naves M, Maeder P, Reichhart M, Wintermark M et al (2010) Early profiles of clinical evolution after intravenous thrombolysis in an unselected stroke population. J Neurol Neurosurg Psychiatry 81(3):282–285
Siegler JE, Martin-Schild S (2011) Early neurological deterioration (END) after stroke: the END depends on the definition. Int J Stroke 6(3):211–212
Josephson SA, Hills NK, Johnston SC (2006) NIH stroke scale reliability in ratings from a large sample of clinicians. Cerebrovasc Dis 22(5–6):389–395
Saver JL, Gornbein J, Starkman S (2010) Graphic reanalysis of the two NINDS-tPA trials confirms substantial treatment benefit. Stroke 41(10):2381–2390
Alexandrov AV, Felberg RA, Demchuk AM, Christou I, Burgin WS, Malkoff M et al (2000) Deterioration following spontaneous improvement: sonographic findings in patients with acutely resolving symptoms of cerebral ischemia. Stroke 31(4):915–919
Grotta JC, Welch KM, Fagan SC, Lu M, Frankel MR, Brott T et al (2001) Clinical deterioration following improvement in the NINDS rt-PA Stroke Trial. Stroke 32(3):661–668
Heldner MR, Jung S, Zubler C, Mordasini P, Weck A, Mono ML et al (2015) Outcome of patients with occlusions of the internal carotid artery or the main stem of the middle cerebral artery with NIHSS score of less than 5: comparison between thrombolysed and non-thrombolysed patients. J Neurol Neurosurg Psychiatry 86(7):755–760
Haussen DC, Bouslama M, Grossberg JA, Anderson A, Belagage S, Frankel M et al (2016) Too good to intervene? Thrombectomy for large vessel occlusion strokes with minimal symptoms: an intention-to-treat analysis. J Neurointerv Surg. doi:10.1136/neurintsurg-2016-012633
Rajajee V, Kidwell C, Starkman S, Ovbiagele B, Alger JR, Villablanca P et al (2006) Early MRI and outcomes of untreated patients with mild or improving ischemic stroke. Neurology 67(6):980–984
Kim JT, Park MS, Chang J, Lee JS, Choi KH, Cho KH (2013) Proximal arterial occlusion in acute ischemic stroke with low NIHSS scores should not be considered as mild stroke. PLoS One 8(8):e70996
Salam KA, Ummer K, Pradeep Kumar VG, Noone ML (2014) Intravenous thrombolysis for acute ischemic stroke in the 3- to 4.5-h window–the Malabar experience. Int J Stroke 9(4):426–428
Simonsen CZ, Schmitz ML, Madsen MH, Mikkelsen IK, Chandra RV, Leslie-Mazwi T et al (2016) Early neurological deterioration after thrombolysis: clinical and imaging predictors. Int J Stroke 11(7):776–782
Goyal M, Menon BK, van Zwam WH, Dippel DW, Mitchell PJ, Demchuk AM et al (2016) Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet 387(10029):1723–1731
Sarraj A, Sangha N, Hussain MS, Wisco D, Vora N, Elijovich L et al (2016) Endovascular therapy for acute ischemic stroke with occlusion of the middle cerebral artery M2 segment. JAMA Neurol 73(11):1291–1296
Yu AY, Hill MD, Coutts SB (2015) Should minor stroke patients be thrombolyzed? A focused review and future directions. Int J Stroke 10(3):292–297
Hacke W, Schwab S, Horn M, Spranger M, De Georgia M, von Kummer R (1996) ‘Malignant’ middle cerebral artery territory infarction: clinical course and prognostic signs. Arch Neurol 53(4):309–315
Awadh M, MacDougall N, Santosh C, Teasdale E, Baird T, Muir KW (2010) Early recurrent ischemic stroke complicating intravenous thrombolysis for stroke: incidence and association with atrial fibrillation. Stroke 41(9):1990–1995
Georgiadis D, Engelter S, Tettenborn B, Hungerbuhler H, Luethy R, Muller F et al (2006) Early recurrent ischemic stroke in stroke patients undergoing intravenous thrombolysis. Circulation 114(3):237–241
Heiss WD (2016) Malignant MCA infarction: pathophysiology and imaging for early diagnosis and management decisions. Cerebrovasc Dis 41(1–2):1–7
Jickling GC, Liu D, Stamova B, Ander BP, Zhan X, Lu A et al (2014) Hemorrhagic transformation after ischemic stroke in animals and humans. J Cereb Blood Flow Metab 34(2):185–199
Whiteley WN, Slot KB, Fernandes P, Sandercock P, Wardlaw J (2012) Risk factors for intracranial hemorrhage in acute ischemic stroke patients treated with recombinant tissue plasminogen activator: a systematic review and meta-analysis of 55 studies. Stroke 43(11):2904–2909
Derex L, Nighoghossian N (2008) Intracerebral haemorrhage after thrombolysis for acute ischaemic stroke: an update. J Neurol Neurosurg Psychiatry 79(10):1093–1099
Del Bene A, Palumbo V, Lamassa M, Saia V, Piccardi B, Inzitari D (2012) Progressive lacunar stroke: review of mechanisms, prognostic features, and putative treatments. Int J Stroke 7(4):321–329
Muir KW, Buchan A, von Kummer R, Rother J, Baron JC (2006) Imaging of acute stroke. Lancet Neurol 5(9):755–768
Alawneh JA, Moustafa RR, Baron JC (2009) Hemodynamic factors and perfusion abnormalities in early neurological deterioration. Stroke 40(6):e443–e450
Alawneh JA, Jones PS, Mikkelsen IK, Cho TH, Siemonsen S, Mouridsen K et al (2011) Infarction of ‘non-core-non-penumbral’ tissue after stroke: multivariate modelling of clinical impact. Brain 134(Pt 6):1765–1776
Bang OY, Kim GM, Chung CS, Kim SJ, Kim KH, Jeon P et al (2010) Differential pathophysiological mechanisms of stroke evolution between new lesions and lesion growth: perfusion-weighted imaging study. Cerebrovasc Dis 29(4):328–335
Usnich T, Albach FN, Brunecker P, Fiebach JB, Nolte CH (2012) Incidence of new diffusion-weighted imaging lesions outside the area of initial hypoperfusion within 1 week after acute ischemic stroke. Stroke 43(10):2654–2658
Parsons MW, Barber PA, Desmond PM, Baird TA, Darby DG, Byrnes G et al (2002) Acute hyperglycemia adversely affects stroke outcome: a magnetic resonance imaging and spectroscopy study. Ann Neurol 52(1):20–28
McCormick M, Hadley D, McLean JR, Macfarlane JA, Condon B, Muir KW (2010) Randomized, controlled trial of insulin for acute poststroke hyperglycemia. Ann Neurol 67(5):570–578
Rosso C, Corvol JC, Pires C, Crozier S, Attal Y, Jacqueminet S et al (2012) Intensive versus subcutaneous insulin in patients with hyperacute stroke: results from the randomized INSULINFARCT trial. Stroke 43(9):2343–2349
Lemkes BA, Hermanides J, Devries JH, Holleman F, Meijers JC, Hoekstra JB (2010) Hyperglycemia: a prothrombotic factor? J Thromb Haemost 8(8):1663–1669
Ribo M, Molina C, Montaner J, Rubiera M, Delgado-Mederos R, Arenillas JF et al (2005) Acute hyperglycemia state is associated with lower tPA-induced recanalization rates in stroke patients. Stroke 36(8):1705–1709
Serena J, Rodriguez-Yanez M, Castellanos M (2006) Deterioration in acute ischemic stroke as the target for neuroprotection. Cerebrovasc Dis 21(Suppl 2):80–88
Bai J, Lyden PD (2015) Revisiting cerebral postischemic reperfusion injury: new insights in understanding reperfusion failure, hemorrhage, and edema. Int J Stroke 10(2):143–152
Pan J, Konstas AA, Bateman B, Ortolano GA, Pile-Spellman J (2007) Reperfusion injury following cerebral ischemia: pathophysiology, MR imaging, and potential therapies. Neuroradiology 49(2):93–102
Molina CA (2010) Futile recanalization in mechanical embolectomy trials: a call to improve selection of patients for revascularization. Stroke 41(5):842–843
Nacu A, Bringeland GH, Khanevski A, Thomassen L, Waje-Andreassen U, Naess H (2016) Early neurological worsening in acute ischaemic stroke patients. Acta Neurol Scand 133(1):25–29
Lansberg MG, Straka M, Kemp S, Mlynash M, Wechsler LR, Jovin TG et al (2012) MRI profile and response to endovascular reperfusion after stroke (DEFUSE 2): a prospective cohort study. Lancet Neurol 11(10):860–867
Zhu G, Michel P, Aghaebrahim A, Patrie JT, Xin W, Eskandari A et al (2013) Prediction of recanalization trumps prediction of tissue fate: the penumbra: a dual-edged sword. Stroke 44(4):1014–1019
Liebeskind DS, Kim D, Starkman S, Changizi K, Ohanian AG, Jahan R et al (2010) Collateral failure? Late mechanical thrombectomy after failed intravenous thrombolysis. J Neuroimaging 20(1):78–82
Campbell BC, Christensen S, Tress BM, Churilov L, Desmond PM, Parsons MW et al (2013) Failure of collateral blood flow is associated with infarct growth in ischemic stroke. J Cereb Blood Flow Metab 33(8):1168–1172
Beard DJ, McLeod DD, Logan CL, Murtha LA, Imtiaz MS, van Helden DF et al (2015) Intracranial pressure elevation reduces flow through collateral vessels and the penetrating arterioles they supply. A possible explanation for ‘collateral failure’ and infarct expansion after ischemic stroke. J Cereb Blood Flow Metab 35(5):861–872
Murtha LA, McLeod DD, McCann SK, Pepperall D, Chung S, Levi CR et al (2014) Short-duration hypothermia after ischemic stroke prevents delayed intracranial pressure rise. Int J Stroke 9(5):553–559
Beard DJ, Murtha LA, McLeod DD, Spratt NJ (2016) Intracranial Pressure and Collateral Blood Flow. Stroke 47(6):1695–1700
Naggara O, Raymond J, Domingo Ayllon M, Al-Shareef F, Touze E, Chenoufi M et al (2013) T2* “susceptibility vessel sign” demonstrates clot location and length in acute ischemic stroke. PLoS ONE 8(10):e76727
Assouline E, Benziane K, Reizine D, Guichard JP, Pico F, Merland JJ et al (2005) Intra-arterial thrombus visualized on T2* gradient echo imaging in acute ischemic stroke. Cerebrovasc Dis 20(1):6–11
Shinohara Y, Kinoshita T, Kinoshita F (2012) Changes in susceptibility signs on serial T2*-weighted single-shot echo-planar gradient-echo images in acute embolic infarction: comparison with recanalization status on 3D time-of-flight magnetic resonance angiography. Neuroradiology 54(5):427–434
Irino T, Watanabe M, Nishide M, Gotoh M, Tsuchiya T (1983) Angiographical analysis of acute cerebral infarction followed by “cascade”-like deterioration of minor neurological deficits. What is progressing stroke? Stroke 14(3):363–368
Qazi EM, Sohn SI, Mishra S, Almekhlafi MA, Eesa M, d’Esterre CD et al (2015) Thrombus Characteristics Are Related to Collaterals and Angioarchitecture in Acute Stroke. Can J Neurol Sci 42(6):381–388
Vanacker P, Cordier M, Janbieh J, Federau C, Michel P (2014) Floating arterial thrombus related stroke treated by intravenous thrombolysis. Cerebrovasc Dis 38(2):117–120
Kim JT, Heo SH, Yoon W, Choi KH, Park MS, Saver JL et al (2016) Clinical outcomes of patients with acute minor stroke receiving rescue IA therapy following early neurological deterioration. J Neurointerv Surg 8(5):461–465
Bang OY, Goyal M, Liebeskind DS (2015) Collateral circulation in ischemic stroke: assessment tools and therapeutic strategies. Stroke 46(11):3302–3309
Zinkstok SM, Beenen LF, Majoie CB, Marquering HA, de Haan RJ, Roos YB (2014) Early deterioration after thrombolysis plus aspirin in acute stroke: a post hoc analysis of the Antiplatelet Therapy in Combination with Recombinant t-PA Thrombolysis in Ischemic Stroke trial. Stroke 45(10):3080–3082
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Pierre Seners is funded by la Fondation pour la Recherche Médicale (FDM 41382).
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Seners, P., Baron, JC. Revisiting ‘progressive stroke’: incidence, predictors, pathophysiology, and management of unexplained early neurological deterioration following acute ischemic stroke. J Neurol 265, 216–225 (2018). https://doi.org/10.1007/s00415-017-8490-3
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DOI: https://doi.org/10.1007/s00415-017-8490-3