Journal of Stroke 2019;21(3):276-289 https://doi.org/10.5853/jos.2019.01522 Review Clinical Variables and Genetic Risk Factors Associated with the Acute Outcome of Ischemic Stroke: A Systematic Review Nuria P Torres-Aguila,a,b Caty Carrera,a,b Elena Muiño,a Natalia Cullell,c Jara Cárcel-Márquez,a Cristina Gallego-Fabrega,a,c Jonathan González-Sánchez,a,c,d Alejandro Bustamante,b Pilar Delgado,b Laura Ibañez,e Laura Heitsch,f,g Jerzy Krupinski,c,d Joan Montaner,h Joan Martí-Fàbregas,i Carlos Cruchaga,e Jin-Moo Lee,g Israel Fernandez-Cadenas,a Acute Endophenotypes Group of the International Stroke Genetics Consortium (ISGC) a Stroke Pharmacogenomics and Genetics Laboratory, Sant Pau Research Institute, Barcelona, Spain b Neurovascular Research Laboratory, Vall d’Hebron Research Institute (VHIR), Autonomous University of Barcelona, Barcelona, Spain c Stroke Pharmacogenomics and Genetics Laboratory, Mutua Terrasa Foundation of Teaching and Research, Mutua Terrassa Hospital, Terrassa, Spain d Health Care Science Department, The Manchester Metropolitan University of All Saints, Manchester, UK e Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA f Division of Emergency Medicine, Washington University School of Medicine, St. Louis, MO, USA g Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA h Department of Neurology, Virgin Rocío and Macarena Hospitals, Institute of Biomedicine of Seville (IBiS), Seville, Spain i Stroke Unit, Department of Neurology, Saint Cross and Saint Pau Hospital, Barcelona, Spain Stroke is a complex disease and one of the main causes of morbidity and mortality among the Correspondence: Israel Fernandez- Cadenas adult population. A huge variety of factors is known to influence patient outcome, including Stroke Pharmacogenomics and Genetics demographic variables, comorbidities or genetics. In this review, we expound what is known about Laboratory, Sant Pau Research Institute, C/Sant Antoni Maria Claret, 167, the influence of clinical variables and related genetic risk factors on ischemic stroke outcome, Barcelona 08025, Spain focusing on acute and subacute outcome (within 24 to 48 hours after stroke and until day 10, Tel: +34-932746000 Fax: +34-935537864 respectively), as they are the first indicators of stroke damage. We searched the PubMed data base E-mail: israelcadenas@yahoo.es for articles that investigated the interaction between clinical variables or genetic factors and acute or subacute stroke outcome. A total of 61 studies were finally included in this review. Regarding Co-correspondence: Jin-Moo Lee Department of Neurology, Washington the data collected, the variables consistently associated with acute stroke outcome are: glucose University School of Medicine, 660 S levels, blood pressure, presence of atrial fibrillation, prior statin treatment, stroke severity, type of Euclid Ave, St. Louis, MO 63110, USA Tel: +1-314-362-7382 acute treatment performed, severe neurological complications, leukocyte levels, and genetic risk Fax: +1-314-747-2244 factors. Further research and international efforts are required in this field, which should include E-mail: leejm@wustl.edu genome-wide association studies. Received: June 12, 2019 Revised: August 7, 2019 Accepted: August 28, 2019 Keywords Stroke; Outcome; Clinical variables; Genetics Copyright © 2019 Korean Stroke Society This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 276 http://j-stroke.org pISSN: 2287-6391 • eISSN: 2287-6405 Vol. 21 / No. 3 / September 2019 Introduction words used were: “ischemic stroke,” “neurological” or “neuro- logic,” “associated” or “predictor,” and “outcome.” We included Stroke is one of the main causes of morbidity and mortality articles that searched for a relationship of acute and subacute worldwide. In addition, as stroke is a main cause of disability in outcome with other clinical variables or genetic factors, and adults, there is a huge interest in improving the recovery of pa- which were written in English or Spanish. We excluded animal tients post-stroke. trials, childhood trials and articles with less than 100 patients A wide variety of factors are known to influence the out- analyzed. Using these criteria, we found 1,321 different articles come1,2 after stroke, most of which are clinical variables related by May 2019, plus six specific articles that were searched for with the disease (stroke severity, etiology, etc.), cardiovascular specific clinical variables. A total of 61 were finally included, risk factors (hypertension, heart failure, etc.) and other demo- excluding process is detailed in a flow diagram performed fol- graphic variables (age, sex, etc.). However, there are studies lowing Preferred Reporting Items for Systematic Reviews and that present contradictory results, making the relationship be- Meta-Analyses (PRISMA)14 statements (Figure 1). tween clinical variables and stroke outcome not so clear. In addition, ischemic stroke is a complex disease with a sub- Variables associated with acute outcome stantial genetic component, the heritability of which ranges from 16% to 40%.3 Several genome-wide association studies We classified the variables into three fields: (1) baseline vari- (GWAS) have found genes associated with stroke risk and have ables, (2) early outcome variables, and (3) genetic factors, been confirmed in independent studies.4-6 However, with the which summarized a total of 38, 20, and three articles, respec- exception of two recent GWAS,7,8 the studies performed to find tively (briefly detailed in Table 1). genetic variables associated with stroke outcome are candidate gene studies that have not been consistently replicated.9 Baseline variables Fast fibrinolysis or thrombectomy treatments are related We defined as baseline variables those clinical factors present with better recovery.10,11 This suggests that outcome-related at the time of stroke onset and which are non-modifiable. molecular mechanisms are taking place in the first 24 to 48 These variables include demographics, comorbidities and phar- hours, the period defined as the acute phase of stroke. Acute macological treatments prior to stroke. outcome is defined as the outcome during the acute phase, and it is the first indicator of the impact of stroke on patient health. Acute outcome commonly reports the neurological sta- tus of the patient, usually measured by the National Institute 1,321 Records identified 6 Additional records Identification throught PubMed identified throught of Health Stroke Scale (NIHSS). This scale is a systematic as- database searching specific searching sessment tool that provides a quantitative measure of neuro- logical deficit, evaluating different neurological aspects (con- 1,327 Records after duplicates removed sciousness, language, neglect, etc.), and can be used to predict long term outcome.12,13 Consequently, acute outcome is associ- 382 Records excluded by filters: Screening 1,327 Records screened - Not in English or Spanish ated with long-term outcome. - No-human studies In this review, we detailed what is known about the influ- ence of clinical variables and related genetic risk factors on the 452 Articles excluded: acute and subacute outcome of patients after an ischemic - Childhood or infant studies 945 Abstracts assesed - Reviews and case-reports stroke (within 24 to 48 hours after stroke and until day 10, re- for eligibility - Studies with <100 participants Eligibility spectively). The aim of this review is to summarize all the - No ischemic stroke studies knowledge acquired in recent years that could be useful for 432 Full-text articles excluded: clinical practice and to perform studies in the field. 493 Full-text articles - No acute outcome studied assesed for eligibility - No relevant variable studied Methods Included 61 Studies included We used the National Center for Biotechnology Information (NCBI) website to search in the PubMed database. The key- Figure 1. Flow diagram of the systematic review. https://doi.org/10.5853/jos.2019.01522 http://j-stroke.org 277 Torres-Aguila et al. What Impacts Acute Ischemic Stroke Outcome? Table 1. Detailed summary of each article included in this review Study Outcome studied (definition) Cohort size (n) Variable studied Influence Adams et al. 7-day and 3-mo outcome (measured by Barthel Index and 1,281 Stroke severity Association (1999)12 the Glasgow Outcome Scale) Kugler et al. Early recovery at 24 hr and 1 wk (Barthel Index) 2,219 Age Week influence (only at 1 wk) (2003)16 Siegler et al. END (increase in NIHSS score of ≥2 points within 24 hr) 366 Age Independent association (2013)18 Sex No association Stroke severity Independent association Yeo et al. ENI (reduction of ≥10 points on NIHSS score, or score of 4 or 263 Age Non-independent association (2013)19 less, at 2 hr); CNI (reduction in NIHSS score of ≥8 points Sex Female gender associated with CNI between 2 and 24 hr, or an NIHSS score of ≤4 at 24 hr) Stroke severity Independent predictor of CNI Naess et al. 7-day NIHSS, neurological worsening, mortality 1,867 Age >80 yr associated with worse outcome (2014)20 Boehm et al. END (increase of ≥2 points on NIHSS score during first 24 hr 4,925 Age Covariate (2014)21 after hospitalization) Sex Non-independent association Ethnicity Non-independent association Geng et al. END (increase of ≥2 points on NIHSS score during 1st wk 1,064 Age No association (2017)22 after stroke) Sex No association Diabetes mellitus Association with END Hyperlipidemia LDL and total cholesterol were associ- ated with END, but not triglycerides Body mass index No association with END Hassaballa et 7-day and 3-mo outcome (measured by Glasgow Outcome 1,093 Ethnicity No association al. (2001)25 Scale) Machumpu- ENR (improvement at least 50% on NIHSS score within 24 161 Diabetes mellitus Association (hyperglycemia patients rath et al. hr) were less likely to have ENR) (2011)26 Roquer et al. END (increase of ≥4 points on NIHSS score during first 72 hr Diabetes mellitus Association with END (2014)27 after stroke) Tang et al. Favorable neurological outcome (decrease of ≥4 points on 419 Diabetes mellitus Predictor of unfavorable outcome (2016)28 NIHSS score or score of 0 at 24 hr, decrease of ≥8 points on NIHSS score or an score of 0 at 7 days; good functional outcome (mRS 0–1) at 3 mo Yi et al. END (increase of ≥2 points on NIHSS score within 10 days 426 Diabetes mellitus Association with END (2016)29 after admission) Hui et al. END (increase of ≥2 points on NIHSS score within 5 days af- 336 Diabetes mellitus Association with END (2018)30 ter stroke) Forlivesi et al. No neurological improvement (NIHSS score at 24 hr ≥NIHSS 200 Diabetes mellitus Association with END (2018)31 score at baseline) Vlcek et al. 5-day outcome (Rankin Scale score >2 was defined as poor 372 Blood pressure Independent association with poor (2003)32 outcome) outcome (high diastolic BP) Castillo et al. END (diminution on Canadian Stroke Scale of ≥1 points 304 Blood pressure Extreme values of BP were associated (2004)33 within first 48 hr); neurological outcome and mortality at with poor outcome 3 mo Pezzini et al. END (increase of ≥4 points on NIHSS score at 48 hr); 90-day 264 Blood pressure Association, but dependent on stroke (2011)34 functional status (measured by mRS) etiology Geeganage et Death or neurological deterioration at 10 days 1,479 Blood pressure Association (high systolic BP) al. (2011)35 Kvistad et al. CNR (no ischemic stroke symptoms at 24 hr); favorable 749 Blood pressure No association (2013)36 short-term outcome (7-day mRS score of 0–1) Chung et al. END within 72 hr (increase of NIHSS score of ≥2 points) 1,116 Blood pressure Independent association with END (2015)37 (high systolic BP) 278 http://j-stroke.org https://doi.org/10.5853/jos.2019.01522 Vol. 21 / No. 3 / September 2019 Table 1. Continued Study Outcome studied (definition) Cohort size (n) Variable studied Influence Gill et al. Early neurological outcome (improvement of NIHSS score at 327 Blood pressure Independent association with ENR (low (2016)38 24 hr) diastolic BP) Kellert et al. ENI (improvement of ≥20% on NIHSS score, or improvement 28,976 Blood pressure No association (2017)39 of ≥8 points on NIHSS score); long-term functional out- come (mRS at 90 days) Kang et al. END (worsening by 2 points on NIHSS score) at 1, 2 and 3 2,545 Blood pressure Independent association (systolic BP) (2017)40 days Keezer et al. Poor outcome at 10 days (Rankin Scale score >3) 364 Blood pressure Independent association with poor (2008)41 outcome (high and low BP values) Sare et al. Neurological impairment (high 7-day NIHSS score than 1,722 Blood pressure Association with neurological impair- (2009)42 median NIHSS score); 90-day functional outcome ment and poor outcome (high systol- (measured by mRS) ic BP) Zhang et al. END (increase in NIHSS score ≥4 or increase in Ia of NIHSS 278 Blood pressure Independent association (high systolic (2018)43 ≥1 within 72 hr after recanalization treatment) BP) Stroke etiology Independent association in intrave- nous treated patients (large artery occlusion) Sanák et al. 24 hr and 7-day NIHSS score; 7-day mortality 157 Atrial fibrillation Association with 7-day mortality (2010)45 Yaghi et al. ENR (decrease of ≥8 points in NIHSS score, or score of 0–1 306 Atrial fibrillation Significantly more present on non-ENR (2016)46 at 24 hr) group; independent negative associa- tion with ENR Restrepo et al. 7-day NIHSS score 142 Hyperlipidemia Association with hyperlipidemia history (2009)47 Choi et al. END (increase in NIHSS score of ≥4 at 24 hr) or ENR (reduc- 736 Hyperlipidemia Extreme triglyceride levels associated (2012)48 tion of NIHSS score of ≥4) within a week after stroke with poor outcome onset Branscheidt et ENR (improve >40% on NIHSS score at 24 hr); good 896 Body mass index No association al. (2016)51 outcome (mRS 0–1), favorable outcome (mRS 0–2) and mortality at 3 mo Power et al. NIHSS score at baseline and 24 hr 229 Renal dysfunction Association (2013)53 Lo et al. NIHSS improvement at 24 hr post-thrombolysis; 3-mo 199 Renal dysfunction No association (2015)54 functional independence; 30-day mortality Yu et al. 10-day functional outcome (mRS) 339 Prior statin treatment Association (2009)56 Prior antithrombotic No association treatment Ní Chróinín et 7- and 28-day functional outcome (mRS); 7-, 28-, 90-day, 448 Prior statin treatment Associated with good outcome al. (2011)58 and 1-yr mortality Tsivgoulis et al. ECR (reduction of ≥10 points NIHSS score at 24 hr); good 1,660 Prior statin treatment Association with ECR (2015)59 functional outcome (mRS 0–1) and mortality at 3 mo Yi et al. Neurological deterioration (increase of 2 points of NIHSS 1,124 Prior statin treatment Concomitant use of antiplatelet and (2017)60 during 10 days after admission) statins was associated with a favor- able outcome Prior antithrombotic Concomitant use of antiplatelet and treatment statins was associated with a favor- able outcome Cappellari et Neurological improvement (reduction of ≥4 points in NIHSS 250 Prior statin treatment Prior and continued use of statins after al. (2011)61 score between 24 and 72 hr) stroke was associated with worse outcome McAlpine et al. ENR (diminution on NIHSS score during first 24 hr after 158 Leukoaraiosis No association (2014)63 stroke) https://doi.org/10.5853/jos.2019.01522 http://j-stroke.org 279 Torres-Aguila et al. What Impacts Acute Ischemic Stroke Outcome? Table 1. Continued Study Outcome studied (definition) Cohort size (n) Variable studied Influence Saposnik et al. 7-, 30-day, and 1-yr mortality; neurological deterioration 3,631 Stroke severity Independent association (2008)64 (measured by Canadian Neurological Scale, worsening neurological deficit or deterioration in the level of consciousness) Kim et al. Early dramatic recovery (reduction of ≥8 points in NIHSS 102 Stroke severity Independent association (2017)65 score or NIHSS score of 0–1 at 24 hr) Schmitz et al. ENR (NIHSS score improvement of ≥4 points at 24 hr) 557 Stroke etiology Cardioembolic stroke patients more (2017)66 likely to have ENR Forlivesi et al. Neurological improvement (NIHSS score improvement of ≥4 122 Stroke etiology Large artery strokes had lower odds ra- (2017)67 points or NIHSS score of 0) at 7 days tio than cardioembolic strokes Ciccone et al. Neurologic deficit (NIHSS score ≥6) at 7 days; functional 362 Acute treatment No association (2013)68 outcome (mRS) and mortality at 90 days Saver et al. NIHSS score changes at 27 hr; 3-mo functional outcome 196 Acute treatment Mechanical thrombectomy after IVT (2015)69 (mRS) treatment had higher NIHSS score decrease Jovin et al. ENR (decrease of 4 points in NIHSS at 24 hr); functional 206 Acute treatment Mechanical thrombectomy had better (2015)70 (Barthel Index) and neurological (NIHSS score) outcome at outcome 90 days Fiorelli et al. END (increase of NIHSS score of ≥4 at 24 hr post-stroke 609 Hemorrhagic Independent association (server HT) (1999)71 onset); 3-mo disability (mRS score ≥1) and 3-mo death transformation Kablau et al. ENR (decrease of >4 on NIHSS score) and END (increase of 122 Hemorrhagic No association with END; non-severe (2011)72 >4 on NIHSS score) at 5 days transformation HT more common on ENR Dharmasaroja ENR (NIHSS of 0 to 4 at 24 hr) 203 Hemorrhagic Inversely association with ENR et al. (2011)73 transformation Gill et al. Reduction in NIHSS score after 24 hr 339 Hemorrhagic Inversely associated (server HT) (2016)74 transformation Boehme et al. END (NIHSS score increase of ≥2 at 24 hr) 334 Infections Non-independent association (2013)77 Nardi et al. NIHSS score at baseline and at 72 hr; functional outcome 811 Leukocyte counts Independent association (2012)80 (mRS) at discharge Kumar et al. Neurological deterioration (NIHSS score increase of ≥2 292 Leukocyte counts Association (2013)81 within 24 hr) Tian et al. ENI (decrease NIHSS score of ≥4 points or complete recovery 240 Leukocyte counts Independent association (2018)82 after 24 hr of intravenous treatment) Furlan et al. 7-, 30-, and 90-day mortality rate 9,230 Blood platelet counts Non-independent association for 7-day (2016)84 mortality rate; associated with 30- and 90-day mortality Turcato et al. Lack of neurological improvement at 7 days (no NIHSS score 316 Red blood cell counts Association with worse outcome (2017)85 of 0, nor NIHSS score ≤4 from baseline) Pinho et al. NIHSS score at baseline and NIHSS score changes at 24 hr 602 Red blood cell counts No association (2018)86 Furlan et al. 7-, 30-, and 90-day mortality rate 9,230 Red blood cell counts High hemoglobin associated with high (2016)87 7-day mortality Yi et al. 10-day END (NIHSS score increase of ≥2 points) 396 Genetic factors CYP polymorphism associated with (2017)88 CYP plasma metabolites levels in END patients Yi et al. 10-day END (NIHSS score increase of ≥2 points) 297 Genetic factors 3 SNPs independent risk predictors for (2017)89 END Yi et al. 10-day END (NIHSS score increase of ≥2 points) 850 Genetic factors High-risk interactive genotypes were (2017)90 associated with END END, early neurological deterioration; NIHSS, National Institute of Health Stroke Scale; ENI, early neurological improvement; CNI, continuous neurological im- provement; LDL, low density lipoprotein; ENR, early neurological recovery; mRS, modified Rankin Scale; BP, blood pressure; CNR, complete neurological recov- ery; ECR, early clinical recovery; HT, hemorrhagic transformation; CYP, cytochrome P450. 280 http://j-stroke.org https://doi.org/10.5853/jos.2019.01522 Vol. 21 / No. 3 / September 2019 Demographics with 1,064 patients, sex was not associated with END at 1 week. In the literature, age, sex and race are the demographic vari- So, it seems that the influence of sex on acute outcome might ables that have been most often related to the acute outcome be dependent on other variables. of stroke. We found seven articles that reported association of Although the role of ethnicity in stroke outcome is not wide- age, sex and/or race to acute outcome. ly considered, there are several studies reporting its influence The relation of stroke outcome with age is well established.15 on long-term outcome. However, in reference to acute out- Some prior studies reported advancing age as a major negative come, we found two studies21,25 that fulfilled our inclusion cri- factor in morbidity, mortality, and long-term stroke outcome. teria for this review (others did not reach sample size). In both Regarding acute outcome, there are also several studies report- studies, authors found no significant differences in acute out- ing its association with age.16-21 Kugler et al.16 analyzed a co- come between Afro-American patients and Caucasian patients. hort of 2,219 patients to study the association between age and early recovery after ischemic stroke. The authors studied Comorbidities the functional status with the Barthel Index score at 24 hours Among the long list of comorbidities that can influence out- after admission, at 1 week and at discharge. Linear multiple re- come, we included those that have been reported to be associ- gression showed significant independent negative influence of ated with stroke outcome: diabetes mellitus (DM), high blood age on functional status at 1 week and at discharge, although pressure (BP), atrial fibrillation (AF), hyperlipidemia, body mass this influence was weak. Other authors20 analyzed age as a di- index (BMI), renal dysfunction, heart failure, prior dementia, chotomic variable, dividing the cohort used into ≥80 or <80 and prior disability. years old (592 and 1,275 patients were included in each group, The presence of DM as well as elevated levels of glucose has respectively). They found that elder patients presented higher been associated with worse long-term outcome and acute out- NIHSS score (at baseline and 7-day) and, at day 7, more neuro- come.22,26-31 The largest study27 that reported an association of logical worsening and mortality. However, linear regression DM with acute outcome included 1,088 patients. In this study, analysis showed that a higher 7-day NIHSS score was associ- DM was associated with END (defined as an increase of ≥4 on ated with a higher NIHSS score on admission and neurological NIHSS score during the first 72 hours after stroke). These studies worsening, but not with age ≥80. In contrast, in one study22 indicate that DM or high levels of glucose on admission are as- with 1,064 patients that searched for variables associated with sociated with worse outcome in the acute and subacute phase. early neurological deterioration (END; defined as an increase of We found several studies associating BP with acute neuro- ≥2 in NIHSS score during the first week after stroke), the au- logical outcome.32-43 In one study with 1,116 patients included thors did not find significant differences in age between END (210 with END), the authors37 analyzed the relationship among and non-END patients. So, it seems that only older ages might different measures of BP and END presented within 72 hours be associated with worse acute and subacute outcome, al- after stroke onset. Authors analyzed mean, maximum and min- though the association of age with long-term outcome is imum systolic and diastolic BP as well as the difference be- much clearer. tween maximum and minimum, the standard derivation and Another demographic factor that influences stroke outcome is the coefficient of variation. The statistical analyses showed sex. Stroke is a dimorphic disease, and incidence and outcome that all parameters, except diastolic BP mean, were indepen- differences between genders have been reported previously.23,24 dently associated with END. Moreover, other authors38 also However, due to the difference in lifespan between men and found a relationship between systolic BP and early neurological women, age is an important factor to take into consideration outcome (END) in a cohort of 327 ischemic stroke patients. when sex influence is analyzed in stroke outcome.18,19,21,22 Specifically, authors found that a reduction in systolic BP 24 Boehme et al.21 performed a study to analyze the influence of hours after thrombolysis was independently associated with sex and ethnicity on outcomes in which they included a total of improvement in NIHSS score at 24 hours after thrombolysis. All 4,925 patients, (27.6% women, 26.9% Afro-Americans). The those findings suggest that BP (both diastolic and systolic) is outcomes of interest were admission NIHSS, END (defined as in- influencing outcome, with high systolic BP and diminution of crease of ≥2 points in NIHSS score within the first 24 hours after diastolic BP being associated with worse outcome. hospitalization) and functional outcome. Authors found differ- AF is one of the major risk factors for stroke44 and its impact ences in admission NIHSS and functional outcome depending on on outcome has been widely studied, although mostly with sex, although after adjusting by age and glucose on admission, reference to long-term outcome. Regarding acute outcome, the association was no longer significant. In addition, in a study22 one study45 analyzed a cohort of 157 patients treated with in- https://doi.org/10.5853/jos.2019.01522 http://j-stroke.org 281 Torres-Aguila et al. What Impacts Acute Ischemic Stroke Outcome? travenous thrombolysis (IVT). No association of AF with NIHSS in a cohort of 229 ischemic stroke patients treated with IVT. was found at 24 hours or 7 days, and, even AF was significantly The authors found that patients with eGFR <60 mL/min had associated with 3-month modified Rankin Scale (mRS) and higher NIHSS scores at baseline and at 24 hours. On the other 7-day mortality, this association was no longer significant in hand, another study,54 with 199 patients recruited, did not find the multivariable regression analysis. On the other hand, in a any significant difference in NIHSS improvement at 24 hours more recent study,46 authors searched for factors associated post-thrombolysis, functional independence at 3 months, nor with early neurological recovery (ENR; defined as a decrease of 30-day mortality between patients with or without renal dys- ≥8 points in NIHSS score or a score of 0 to 1 at 24 hours) in a function. As a consequence, it is not clear if renal dysfunction cohort of 306 patients treated with IVT. In this case, AF was could be associated with worse acute outcome. Further re- significantly more present in the non-ENR group; this was also search is needed to clarify these controversial results. associated with 90-day mortality and 90-day disability. For heart failure, prior dementia or prior disability we did not There is no clear association of hyperlipidemia comorbidity find any study related with acute outcome. Nonetheless, other with stroke outcome, neither with acute outcome.22,47,48 In one studies had reported the influence of these variables on long- study,47 the authors briefly reported an association between term outcome.1,55 history of hyperlipidemia and 7-day NIHSS score in their co- hort of 142 patients. Alternatively, other authors48 analyzed the Pharmacological treatments prior to stroke relationship between triglycerides (TG) and END (increase in Statins are prescribed for treatment of hypercholesterolemia. NIHSS score of ≥4 at 24 hours, or ENR, reduction of NIHSS In stroke, statins are reported to reduce the risk of cerebrovas- score of ≥4) within a week after stroke onset. Authors include cular events, and their role in outcome improvement have been a total of 736 patients in their study. Statistical analysis highly studied with controversial results (several studies47,56-60 showed that TG levels had a non-linear J-shape association found that statins improved outcome, although another study61 with END and inverse J-shape association with ENR. Those re- did not find this association). Besides, antithrombotic drugs are sults suggested that hypoTG and hyperTG were a risk factor for used to prevent stroke recurrence and several studies have also poor early outcome after ischemic stroke. In contrast, other analyzed the influence of prior antithrombotic treatments on study22 found that total cholesterol and low density lipoprotein acute outcome.56,60 In the most recent study,60 the authors used levels were associated with END (defined as an increase of ≥2 a cohort of 1,124 patients to examine the association of statins on NIHSS score in the first week after stroke) in a cohort of and antiplatelet pretreatments with neurological deterioration 1,064 patients, but not TG. Consequently, it seems that lipid after stroke (defined as an increase of 2 points on NIHSS dur- content may have an influence on acute outcome, but further ing 10 days after admission). They found that only concomitant research is needed to establish a definitive conclusion. use of antiplatelet and statins was associated with a favorable The BMI is associated with cardiovascular diseases, being outcome. Moreover, another study56 with a cohort of 339 pa- overweight and obesity well established risk factors.49 Never- tients observed that statins pretreatment was associated with theless, its influence on stroke outcome has been controversial good outcome (mRS score of 0 to 3) at 10 days, as well as the due to the “obesity paradox.”50 A recent study51 included 896 concomitant use of antihypertensive, antiplatelet and statins patients treated with IVT to determine the association of BMI drugs, but not with the use of antiplatelet drugs alone. Fur- with 3-month stroke outcome and, as secondary outcome, ENR thermore, Tsivgoulis et al.59 found that use of statins prior to at 24 hours (defined as an improvement of >40% on NIHSS stroke was independently related with early clinical neurologi- score). In all cases, BMI was not associated with any studied cal recovery in their cohort of 1,660 patients, although it was outcome, even after adjusting for potential confounding fac- not related with good 3-month outcome. tors. Moreover, these findings were observed in another study22 In summary, prior use of only antiplatelet drugs is not with 1,064 patients, where no association was found between enough to influence acute stroke outcome. In contrast, treat- BMI and 1-week END. In conclusion, it seems that BMI had no ment with statins prior to stroke could be associated with bet- impact on acute outcome. ter acute outcome, but not with long-term outcome. Renal dysfunction is a cardiovascular risk factor commonly found in stroke patients,52 it is defined as estimated glomerular Early outcome variables filtration rate (eGFR) <60 mL/min. We found two studies that Early outcome variables are those that can be described during analyzed the role of eGFR with acute outcome.53,54 On one the first few hours after stroke symptoms onset, such as: leu- hand, one study53 analyzed the association of renal dysfunction koaraiosis, stroke severity, acute treatment performed, neuro- 282 http://j-stroke.org https://doi.org/10.5853/jos.2019.01522 Vol. 21 / No. 3 / September 2019 logical/clinical complications, levels of blood constituents, and, Acute treatments in some cases, stroke etiology. By acute treatments we refer to those treatments performed to treat ischemic stroke during the acute phase, commonly Leukoaraiosis thrombolysis and/or thrombectomy. We found several studies Leukoaraiosis is a radiological phenomenon which represents about their influence on acute outcome.68-70 In one study,69 au- white matter lesions and is commonly observed in elderly people. thors tested the efficacy of mechanical thrombectomy after IVT Patients with leukoaraiosis are described as more likely to suffer compared to the use of IVT alone. A total of 196 patients un- ischemic stroke and it has been demonstrated that leukoaraiosis derwent randomization, with 98 patients in each group; there is more common and more severe in ischemic stroke patients were no significant differences in demographic or clinical char- than in healthy people.62 However, little is known about the role acteristics between groups. The primary outcome of the study of leukoaraiosis on acute stroke outcome, and most of the stud- was functional outcome at 3 months, and secondary outcome ies have been performed with small cohorts. In the largest was NIHSS changes at 27 hours. They found that combined study63 that we found, the authors analyzed the association of treatment had a significantly better outcome at 3 months and leukoaraiosis with ENR (defined as diminution on NIHSS score a higher decrease in NIHSS score, with a better neurological during the first 24 hours after stroke) in 158 patients and did not status at 27 hours. Moreover, another study70 found similar re- find any association. However, larger studies are warranted to sults in a cohort of 206 patients divided into two groups: med- clarify the role of leukoaraiosis in acute outcome. ical therapy (control group; including IVT when eligible) and medical therapy combined with endovascular therapy by Soli- Stroke severity taire stent retriever (thrombectomy group). They found that the Stroke severity is one of the variables most strongly correlated thrombectomy group presented a higher rate of ENR (defined with outcome, and its association with acute outcome has as a decrease of 4 points in NIHSS at 24 hours) as well as bet- been widely reported.12,17-19,64,65 In the largest study,64 a cohort ter 90-day functional and neurological outcome (by Barthel of 3,631 ischemic stroke patients was analyzed to describe the Index score and NIHSS score respectively). In conclusion, me- influence of clinical variables on 7-, 30-day, and 1-year mor- chanical thrombectomy (after IVT or not) is associated with a tality. The authors found that stroke severity (measured by Ca- better acute and long-term outcome. nadian Neurological Scale) was independently associated with mortality at all three time points, as well as neurological dete- Neurological complications rioration during hospitalization. Stroke severity therefore seems By neurological complications we mean those medical compli- to be more highly related with acute outcome than other fac- cations that may conclude with cognition deficit and could oc- tors, as its association is always reported as an independent cur during the first days of hospitalization. We focused on association after multivariable regression analysis. hemorrhagic transformation (HT) and edema, due to their prevalence during acute and subacute phase. Stroke etiology HT is defined as an intracranial bleeding commonly detected In one study,66 authors observed that cardioembolic (CE) stroke by imaging (computed tomography or magnetic resonance im- patients were more likely to have ENR (NIHSS score improve- aging). In the literature, HT is commonly linked with stroke ment of ≥4 points at 24 hours) than large vessel disease (LVD) outcome and frequently more detected in IVT treated patients. etiology in their cohort of 557 ischemic stroke patients; no dif- Nevertheless, influence of HT on stroke outcome depends on ferences were found between LVD and the other Trial of Org its severity.71-74 Fiorelli et al.71 analyzed the influence of HT on 10172 in Acute Stroke Treatment (TOAST) categories. Moreover, ischemic stroke outcome: END (increase of NIHSS score of ≥4 another study67 found similar results in their cohort of 122 at 24 hours post-stroke onset), 3-month disability (Rankin ischemic stroke patients when analyzing 7-day neurological score ≥1) and 3-month death. Authors used a cohort of 609 improvement depending on stroke subtype. So, it seems that patients treated with IVT or placebo, and used the European LVD is associated with worse acute outcome in terms of recov- Cooperative Acute Stroke Study I (ECASS I) protocol for HT ery compared with CE stroke etiology. However, both studies classification (hemorrhagic infarct 1 or 2 [HI-1, H1-2]; paren- were performed on patients undergoing thrombolysis, so fur- chymal hematoma 1 or 2 [PH-1, PH-2]). They found that PH-2 ther research is needed to clarify the role of stroke etiology in subtype entailed higher risk of END and 3-month death, inde- acute stroke outcome. pendently of age and extent of initial ischemic damage, in pla- cebo and IVT patients. On the other hand, in the most recent https://doi.org/10.5853/jos.2019.01522 http://j-stroke.org 283 Torres-Aguila et al. What Impacts Acute Ischemic Stroke Outcome? study74 authors used a cohort of 339 stroke patients to analyze ies analyzing the relation of leukocytes (including neutrophils the influence of HT on stroke outcome at 24 hours after and lymphocytes) with acute stroke outcome.80-82 In Nardi et thrombolysis measured by NIHSS. In this case, authors found al.,80 authors aimed to establish whether admission leukocyte that PH-2 subtype of HT was associated with worse neurologi- count affects early stroke outcome. A total of 811 ischemic cal outcome. The authors concluded that mild to moderate HT stroke patients were included in the study. NIHSS score was should not be considered a complication and might be related measured at baseline and after 72 hours, as well as mRS at dis- with successful treatment and vascular recanalization. In sum- charge, and leukocytes counts were measured within 12 hours mary, we may conclude that severe HT (i.e., PH-1, PH-2) is as- post-stroke onset. Authors found that higher leukocytes counts sociated with worse acute outcome. were independently associated with high NIHSS scores at base- Cerebral edema is an accumulation of fluid in brain tissue, line and 72 hours, and with poor functional outcome at dis- commonly observed in the acute phase of stroke. This neuro- charge. So, it seems that leukocyte counts have an impact on logical complication seems to have a more direct effect on subacute outcome independently of age or NIHSS at baseline. stroke long-term outcome than HT.75 However, we found no Blood platelet counts (BPC) were previously associated with references in the literature to its influence on acute or sub- ischemic stroke risk,83 although their influence on outcome is acute outcome. poorly described. The study by Furlan et al.84 described the as- sociation of abnormal BPC with outcome. They analyzed the Other clinical complications mortality rate in a cohort of 9,230 patients at 7, 30, and 90 As clinical complications, we included infections, gastrointesti- days post-stroke. In a univariate analysis, all variables were as- nal bleeding, and dysphagia. These three are the most com- sociated with BPC, but after adjustment by principal confound- monly observed during the first days of hospitalization after ers, only 30- and 90-day mortality remains significant. So, it stroke.76 However, in reference to acute or subacute outcome, seems that abnormal BPC (such as thrombocytopenia or we only found information about infections. In Boehme et al.,77 thrombocytosis) is associated with long term outcome but not the authors analyzed the influence of infections on acute out- with acute outcome. However, further studies are needed to come of ischemic stroke patients for the first time, with END confirm these findings. being the primary outcome (NIHSS score increase of ≥2 at 24 Red blood cell counts and hemoglobin levels could influence hours). They used a cohort of 334 patients, of which 77 had an the reoxygenation during acute ischemic stroke and, in turn, infection, and classified the infections as present on admission the degree of neurological damage. Turcato et al.85 analyzed (POA; infection diagnosed within the first 24 hours) and hospi- the influence of red blood cell distribution width (RDW) on tal-acquired infections (HAIs; infection diagnosed after 24 stroke outcome in a cohort of 316 ischemic stroke patients. hours). Authors found that both POA and HAIs were associated Authors analyzed the association of RDW with lack of neuro- with END, but after adjustment by age, NIHSS at baseline, glu- logical improvement at 7 days (no NIHSS score of 0, nor NIHSS cose on admission and IVT treatment, only HAIs remained sig- score ≤4 from baseline). They found that patients with RDW nificant. Thus, as END was defined at 24 hours, and HAIs were ≥14.5% showed a significantly lower decrease in NIHSS score posterior to 24 hours, we cannot conclude that infections af- at 24 hours and 7 days from baseline compared to patients fect acute outcome. And, as POA were not independently asso- with RDW <14.5%. A more recent study,86 which included 602 ciated with END, it seems that the influence of prior infections patients, found that RDW was not associated with NIHSS nor on acute outcome is much lower than the influence of other NIHSS changes at 24 hours. Nevertheless, RDW was associated variables, such as stroke severity or acute treatment. with 1-year survival and better 3-month functional outcome in older patients (≥75 years). On the other hand, Furlan et al.87 Blood constituents analyzed the influence of blood hemoglobin concentration As there is an important inflammatory response during stroke (HGB) on stroke severity and outcome after ischemic stroke in events, the cells implicated in the immune system are likely to a large cohort of 9,230 ischemic stroke patients. They found be associated with stroke outcome. In addition, it is reported that high HGB, but not low HGB, was an independent predictor that neutrophils are related with the blood brain barrier break- of increased 7-day mortality compared to normal HGB. In sum- down and their infiltration seems to be associated with higher mary, it seems that high oxygen availability in acute phase of inflammation and have a role in cerebral ischemia,78 and higher stroke is associated with worse acute and subacute outcome, neutrophil counts before thrombolysis have been associated although more research is needed. with worse 3-month outcomes.79 However, there are few stud- 284 http://j-stroke.org https://doi.org/10.5853/jos.2019.01522 Vol. 21 / No. 3 / September 2019 Genetic factors Table 2. Reviewed variables classified depending on its association with stroke outcome There are several reports searching for the relationship of po- tential candidate genes with stroke outcome, most of them Stroke outcome Early outcome (acute and Baseline variable Genetic factor performed on animal models. However, regarding acute or sub- variable sub-acute) acute outcome, we found very few articles that attempted to Associated Glucose levels or Stroke severity rs20417 (located find genetic factors associated with outcome.88-90 The genes of diabetes melli- Type of acute treat- in COX-2 gene) tus ment performed interest in those studies were: cytochrome P450 (CYP), cyclo- Blood pressure Sever neurological oxygenase-2 (COX-2), prostaglandin I2 synthase (PTGIS), Atrial fibrillation complications thromboxane A synthase 1 (TBXAS1), purinergic receptor P2Y1 Prior statin (PH-2) treatment Leukocyte levels (P2RY1), and integrin subunit beta 3 (ITGB3, or GPIIa). In those Might associat- Hyperlipidemia Leukoaraiosis Candidate genes: studies, authors found different single nucleotide polymor- ed Renal dysfunc- Stroke etiology CYP phisms (SNPs) independently associated with END at 10 days tion Prior infections PTGIS after stroke (defined as a NIHSS score increase of ≥2). However, Blood platelet TBXAS1 counts P2RY1 no replication was performed in those studies. Only the SNP of Red blood cells or ITGB3 COX-2, rs20417,was independently associated to END in two hemoglobin levels different studies.89,90 So, it seems that genetic factors could Unknown Heart failure Cerebral edema Prior dementia Gastrointestinal have an influence on END, although further in-depth research Prior disability bleeding is needed in this area. Additionally, in reference to long-term Dysphagia stroke outcome, two GWAS (Genetic contribution to functional No associated Age Outcome and Disability after Stroke [GODS]7 and Genetics of Sex Ethnicity Ischemic Stroke functional outCOME [GISCOME]8 studies, with Body mass index 1,791 and 6,165 participants, respectively) have been recently PH-2, parenchymal hematoma 2; COX-2, cyclooxygenase-2; CYP, cyto- published with remarkable results. One study7 had found a lo- chrome P450; PTGIS, prostaglandin I2 synthase; TBXAS1, thromboxane A cus located within a candidate gene, confirmed by an external synthase 1; P2RY1, purinergic receptor P2Y1; ITGB3, integrin subunit beta 3. replication. These studies are beginning to clarify the influence of genetics on patient recovery, which can help us to under- with long-term outcome. Additionally, it is important to high- stand all the mechanisms involved. light the influence of initial stroke severity on acute outcome, to the extent that it has been reported as an independent pre- Conclusions dictor in different studies and commonly included as covariate for predictor scales. Among all the clinical variables that were included in this re- Regarding genetic factors, there are several SNPs reported to view, there are few variables strong and clearly associated with be associated with neurological deterioration. However, further acute or subacute stroke outcome (Table 2). These are: glucose studies are needed to validate these data, as there is a lack of levels or DM, BP, presence of AF, prior statin treatment, stroke replication in most of the studies performed. Only rs20417 (lo- severity, type of acute treatment performed, sever neurological cated in COX-2 gene) was reported to be associated with END complications (PH-2), and leukocytes levels. These clinical vari- in two different studies.89,90 Alternatively, genetic factors have ables can easily be collected, so might be useful for prognosis been found to be associated with long-term outcome,7,8 pro- of acute outcome. Other clinical variables that might be asso- viding evidence of the utility of GWAS for exploring the genes ciated include hyperlipidemia, renal dysfunction, BPCs, and red associated with stroke outcome. Genetic analyses in this field blood cells (or hemoglobin) levels. For these variables, further may be useful to understand the molecular mechanisms behind research is required to establish a clear association. the acute stroke outcome, and are required as no GWAS are It is surprising that age and sex, which are used as covariate currently reported. in association studies such as GWAS, had a very weak influ- As limitation, we considered that there is a lack of studies ence on acute and subacute stroke outcome. However, it has with enough statistical power to detect associations and per- been observed that those variables had an important influence form consistent replication analysis, and also a no-consensus on long-term outcome. Likewise, it is interesting that BMI is definition of the acute variable studied (i.e., END) makes im- clearly not associated with acute stroke outcome, in contrast possible to perform meta-analyses, an approach required in or- with the controversy observed about the relationship of BMI der to obtain new qualitative and quantitative findings. https://doi.org/10.5853/jos.2019.01522 http://j-stroke.org 285 Torres-Aguila et al. What Impacts Acute Ischemic Stroke Outcome? In conclusion, our review provides a “state of the art” of this variants are associated with worse ischemic stroke function- important field, reporting all the variables consistently associated al outcome. Circ Res 2019;124:114-120. with stroke early outcome and highlighting the lack of genetic 8. Söderholm M, Pedersen A, Lorentzen E, Stanne TM, Bevan S, studies. However, further research is required in this field. Analy- Olsson M, et al. 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