Incidence, characteristics and outcomes in patients with embolic stroke of undetermined source: A population-based study

Published:April 12, 2019DOI:https://doi.org/10.1016/j.jns.2019.04.008

      Highlights

      • Population-based data on incidence, characteristics and outcomes of ESUS are scarce.
      • Patients in the Evros Stroke Registry were subdivided into ESUS and non-ESUS CS.
      • ESUS subtype was independently related to lower admission stroke severity.
      • ESUS subtype was not related to 1-year mortality, recurrence or functional outcome.

      Abstract

      Embolic stroke of undetermined source (ESUS) represents a subgroup of cryptogenic ischemic stroke (CS) distinguished by high probability of an underlying embolic mechanism. There are scarce population-based data regarding the incidence, characteristics and outcomes of ESUS. Consecutive patients included with first-ever ischemic stroke of undetermined cause in the previously published population-based Evros Stroke Registry were further subdivided into ESUS and non-ESUS CS. Crude and adjusted [according to the European Standard Population (ESP), WHO and Segi population] incidence rates (IR) for ESUS and non-ESUS CS were calculated. Baseline characteristics, admission stroke severity (assessed using NIHSS-score), stroke recurrence and functional outcomes [determined by modified Rankin Scale (mRS) scores], were recorded during the 1-year follow-up period. We identified 21 and 242 cases with ESUS (8% of CS) and non-ESUS CS. The crude and ESP-adjusted IR for ESUS were 17.5 (95%CI: 10–25) and 16.6 (95%CI: 10–24) per 100,000 person-years. Patients with ESUS were younger (p < .001) and had lower median admission NIHSS-scores (p < .001). Functional outcomes were more favorable in ESUS at 28, 90 and 365 days. ESUS was independently (p = .033) associated with lower admission NIHSS-scores (unstandardized linear regression coefficient: -13.34;95%CI: -23.34, −3.35) on multiple linear regression models. ESUS was not related to 1-year stroke recurrence, mortality and functional improvement on multivariable analyses. In conclusion we found that ESUS cases represented 8% of CS patients in this population-based study. Despite the fact that ESUS was independently related to lower admission stroke severity, there was no association of ESUS with long-term outcomes.

      Keywords

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      References

        • Nouh A.
        • Hussain M.
        • Mehta T.
        • Yaghi S.
        Embolic strokes of unknown source and cryptogenic stroke: implications in clinical practice.
        Front. Neurol. 2016; 7: 37
        • Tomita H.
        • Sasaki S.
        • Hagii J.
        • Metoki N.
        Covert atrial fibrillation and atrial high-rate episodes as a potential cause of embolic strokes of undetermined source: their detection and possible management strategy.
        J. Cardiol. 2018; 72: 1-9
        • Ferro J.M.
        • Massaro A.R.
        • Mas J.L.
        Aetiological diagnosis of ischaemic stroke in young adults.
        Lancet Neurol. 2010; 9: 1085-1096
        • Hart R.G.
        • Diener H.-C.
        • Coutts S.B.
        • Easton J.D.
        • Granger C.B.
        • O'Donnell M.J.
        • Cryptogenic Stroke/ESUS International Working Group
        • et al.
        Embolic strokes of undetermined source: the case for a new clinical construct.
        Lancet Neurol. 2014; 13: 429-438
        • Geisler T.
        • Mengel A.
        • Ziemann U.
        • Poli S.
        Management of Embolic Stroke of Undetermined Source (ESUS).
        Drugs. 2018; 78: 823-831
        • Perera K.S.
        • Vanassche T.
        • Bosch J.
        • Giruparajah M.
        • Swaminathan B.
        • Mattina K.R.
        • et al.
        Embolic strokes of undetermined source: prevalence and patient features in the ESUS GlobalRegistry.
        Int. J. Stroke. 2016; 11: 526-533
        • Ntaios G.
        • Papavasileiou V.
        • Milionis H.
        • Makaritsis K.
        • Manios E.
        • Spengos K.
        • et al.
        Embolic strokes of undetermined source in the Athens stroke registry: a descriptive analysis.
        Stroke. 2015; 46: 176-181
        • Gladstone D.J.
        • Spring M.
        • Dorian P.
        • Panzov V.
        • Thorpe K.E.
        • Hall J.
        • EMBRACE Investigators and Coordinators
        • et al.
        Atrial fibrillation in patients with cryptogenic stroke.
        N. Engl. J. Med. 2014; 370: 2467-2477
        • Sanna T.
        • Diener H.C.
        • Passman R.S.
        • Di Lazzaro V.
        • Bernstein R.A.
        • Morillo C.A.
        • CRYSTALAF Investigators
        • et al.
        Cryptogenic stroke and underlying atrial fibrillation.
        N. Engl. J. Med. 2014; 370: 2478-2486
        • Fonseca A.C.
        • Ferro J.M.
        Cryptogenic stroke.
        Eur. J. Neurol. 2015; 22: 618-623
        • Li L.
        • Yiin G.S.
        • Geraghty O.C.
        • Schulz U.G.
        • Kuker W.
        • Mehta Z.
        • PM Rothwell
        • Oxford Vascular Study
        Incidence, outcome, risk factors, and long-term prognosis of cryptogenic transient ischaemic attack and ischaemic stroke: a population-based study.
        Lancet Neurol. 2015; 14: 903-913
        • Tsivgoulis G.
        • Patousi A.
        • Pikilidou M.
        • Birbilis T.
        • Katsanos A.H.
        • Mantatzis M.
        • et al.
        Stroke incidence and outcomes in northeastern Greece: the Evros stroke registry.
        Stroke. 2018; 49: 288-295
        • Adams Jr., H.P.
        • Bendixen B.H.
        • Kappelle L.J.
        • Biller J.
        • Love B.B.
        • Gordon D.L.
        • 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: 35-41
        • Katsanos A.H.
        • Bhole R.
        • Frogoudaki A.
        • Giannopoulos S.
        • Goyal N.
        • Vrettou A.R.
        • et al.
        The value of transesophageal echocardiography for embolic strokes of undetermined source.
        Neurology. 2016; 87: 988-995
        • Tsivgoulis G.
        • Bogiatzi C.
        • Heliopoulos I.
        • Vadikolias K.
        • Boutati E.
        • Tsakaldimi S.
        • et al.
        Low ankle-brachial index predicts early risk of recurrent stroke in patients with acute cerebral ischemia.
        Atherosclerosis. 2012; 220: 407-412
        • Tsivgoulis G.
        • Vadikolias K.
        • Heliopoulos I.
        • Katsibari C.
        • Voumvourakis K.
        • Tsakaldimi S.
        • et al.
        Prevalence of symptomatic intracranial atherosclerosis in Caucasians: a prospective, multicenter, transcranial Doppler study.
        J. Neuroimaging. 2014; 24: 11-17
        • Safouris A.
        • Krogias C.
        • Sharma V.K.
        • Katsanos A.H.
        • Faissner S.
        • Roussopoulou A.
        • et al.
        Statin pretreatment and microembolic signals in large artery atherosclerosis.
        Arterioscler. Thromb. Vasc. Biol. 2017; 37: 1415-1422
        • Tsivgoulis G.
        • Katsanos A.H.
        • Sharma V.K.
        • Krogias C.
        • Mikulik R.
        • Vadikolias K.
        • et al.
        Statin pretreatment is associated with better outcomes in large artery atherosclerotic stroke.
        Neurology. 2016; 86: 1103-1111
        • Saver J.L.
        • Gornbein J.
        Treatment effects for which shift or binary analyses are advantageous in acute stroke trials.
        Neurology. 2009; 72: 1310-1315
        • Lewis J.R.
        • Sauro J.
        When 100% really Isn't 100%: improving the accuracy of small-sample estimates of completion rates.
        J Usabil. Stud. 2006; 1: 136-150
        • Firth D.
        Bias reduction of maximum likelihood estimates.
        Biometrika. 1993; 80: 27-38
        • Hart R.G.
        • Catanese L.
        • Perera K.S.
        • Ntaios G.
        • Connolly S.J.
        Embolic stroke of undetermined source: a systematic review and clinical update.
        Stroke. 2017; 48: 867-872
        • Ferro J.M.
        Ischaemic stroke of undetermined cause.
        Lancet Neurol. 2015; 14: 871-872
        • Gordon D.L.
        • Bendixen B.H.
        • Adams Jr., H.P.
        • Clarke W.
        • Kappelle L.J.
        • Woolson R.F.
        Interphysician agreement in the diagnosis of subtypes of acute ischemic stroke: implications for clinical trials. The TOAST Investigators.
        Neurology. 1993; 43: 1021-1027
        • Arauz A.
        • Morelos E.
        • Colín J.
        • Roldán J.
        • Barboza M.A.
        Comparison of functional outcome and stroke recurrence in patients with Embolic Stroke of Undetermined Source (ESUS) vs. Cardioembolic Stroke Patients.
        PLoS One. 2016; 11e0166091
        • Hart R.G.
        • Sharma M.
        • Mundl H.
        • Kasner S.E.
        • Bangdiwala S.I.
        • Berkowitz S.D.
        • NAVIGATE ESUS Investigators
        • et al.
        Rivaroxaban for stroke prevention after embolic stroke of undetermined source.
        N. Engl. J. Med. 2018; 378: 2191-2201
        • Hart R.G.
        Cardiogenic embolism to the brain.
        Lancet. 1992; 339: 589-594
        • Ntaios G.
        • Papavasileiou V.
        • Lip G.Y.
        • Milionis H.
        • Makaritsis K.
        • Vemmou A.
        • et al.
        Embolic stroke of undetermined source and detection of atrial fibrillation on follow-up: how much causality is there?.
        J. Stroke Cerebrovasc. Dis. 2016; 25: 2975-2980
        • Maier I.L.
        • Schregel K.
        • Karch A.
        • Weber-Krueger M.
        • Mikolajczyk R.T.
        • Stahrenberg R.
        • et al.
        Association between embolic stroke patterns, ESUS etiology, and new diagnosis of atrial fibrillation: a secondary data analysis of the find-AF trial.
        Stroke Res. Treat. 2017; 20171391843
        • Muruet W.
        • Flach C.
        • Rudd A.
        • Wolfe C.
        • Douiri A.
        Embolic strokes of undetermined source in the South London Stroke Register: a population based cohort study.
        Eur. Stroke J. 2018; 3: 24
        • Ntaios G.
        • Papavasileiou V.
        • Milionis H.
        • Makaritsis K.
        • Vemmou A.
        • Koroboki E.
        • et al.
        Embolic strokes of undetermined source in the Athens stroke registry: an outcome analysis.
        Stroke. 2015; 46: 2087-2093
        • Marini C.
        • De Santis F.
        • Sacco S.
        • Russo T.
        • Olivieri L.
        • Totaro R.
        • Carolei A.
        Contribution of atrial fibrillation to incidence and outcome of ischemic stroke: results from a population-based study.
        Stroke. 2005; 36: 1115-1119
        • Saxena R.
        • Lewis S.
        • Berge E.
        • Sandercock P.A.
        • Koudstaal P.J.
        Risk of early death and recurrent stroke and effect of heparin in 3169 patients with acute ischemic stroke and atrial fibrillation in the International Stroke Trial.
        Stroke. 2001; 32: 2333-2337
        • Vemmos K.N.
        • Bots M.L.
        • Tsibouris P.K.
        • Zis V.P.
        • Grobbee D.E.
        • Stranjalis G.S.
        • Stamatelopoulos S.
        Stroke incidence and case fatality in southern Greece: the Arcadia stroke registry.
        Stroke. 1999; 30: 363-370
        • Kolominsky-Rabas P.L.
        • Weber M.
        • Gefeller O.
        • Neundoerfer B.
        • Heuschmann P.U.
        Epidemiology of ischemic stroke subtypes according to TOAST criteria: incidence, recurrence, and long-term survival in ischemic stroke subtypes: a population-based study.
        Stroke. 2001; 32: 2735-2740