Stroke is a complex disease and one of the main causes of morbidity and mortality among the adult population. A huge variety of factors is known to influence patient outcome, including demographic variables, comorbidities or genetics. In this review, we expound what is known about the influence of clinical variables and related genetic risk factors on ischemic stroke outcome, focusing on acute and subacute outcome (within 24 to 48 hours after stroke and until day 10, respectively), as they are the first indicators of stroke damage. We searched the PubMed data base 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 the data collected, the variables consistently associated with acute stroke outcome are: glucose levels, blood pressure, presence of atrial fibrillation, prior statin treatment, stroke severity, type of acute treatment performed, severe neurological complications, leukocyte levels, and genetic risk factors. Further research and international efforts are required in this field, which should include genome-wide association studies.
Stroke is one of the main causes of morbidity and mortality worldwide. In addition, as stroke is a main cause of disability in adults, there is a huge interest in improving the recovery of patients post-stroke.
A wide variety of factors are known to influence the outcome [
In addition, ischemic stroke is a complex disease with a substantial genetic component, the heritability of which ranges from 16% to 40% [
Fast fibrinolysis or thrombectomy treatments are related with better recovery [
In this review, we detailed what is known about the influence of clinical variables and related genetic risk factors on the acute and subacute outcome of patients after an ischemic stroke (within 24 to 48 hours after stroke and until day 10, respectively). The aim of this review is to summarize all the knowledge acquired in recent years that could be useful for clinical practice and to perform studies in the field.
We used the National Center for Biotechnology Information (NCBI) website to search in the PubMed database. The keywords used were: “ischemic stroke,” “neurological” or “neurologic,” “associated” or “predictor,” and “outcome.” We included articles that searched for a relationship of acute and subacute outcome with other clinical variables or genetic factors, and which were written in English or Spanish. We excluded animal trials, childhood trials and articles with less than 100 patients analyzed. Using these criteria, we found 1,321 different articles by May 2019, plus six specific articles that were searched for specific clinical variables. A total of 61 were finally included, excluding process is detailed in a flow diagram performed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [
We classified the variables into three fields: (1) baseline variables, (2) early outcome variables, and (3) genetic factors, which summarized a total of 38, 20, and three articles, respectively (briefly detailed in
We defined as baseline variables those clinical factors present at the time of stroke onset and which are non-modifiable. These variables include demographics, comorbidities and pharmacological treatments prior to stroke.
In the literature, age, sex and race are the demographic variables that have been most often related to the acute outcome of stroke. We found seven articles that reported association of age, sex and/or race to acute outcome.
The relation of stroke outcome with age is well established [
Another demographic factor that influences stroke outcome is sex. Stroke is a dimorphic disease, and incidence and outcome differences between genders have been reported previously [
Although the role of ethnicity in stroke outcome is not widely considered, there are several studies reporting its influence on long-term outcome. However, in reference to acute outcome, we found two studies [
Among the long list of comorbidities that can influence outcome, we included those that have been reported to be associated with stroke outcome: diabetes mellitus (DM), high blood pressure (BP), atrial fibrillation (AF), hyperlipidemia, body mass index (BMI), renal dysfunction, heart failure, prior dementia, and prior disability.
The presence of DM as well as elevated levels of glucose has been associated with worse long-term outcome and acute outcome [
We found several studies associating BP with acute neurological outcome [
AF is one of the major risk factors for stroke [
There is no clear association of hyperlipidemia comorbidity with stroke outcome, neither with acute outcome [
The BMI is associated with cardiovascular diseases, being overweight and obesity well established risk factors [
Renal dysfunction is a cardiovascular risk factor commonly found in stroke patients [
For heart failure, prior dementia or prior disability we did not find any study related with acute outcome. Nonetheless, other studies had reported the influence of these variables on longterm outcome [
Statins are prescribed for treatment of hypercholesterolemia. In stroke, statins are reported to reduce the risk of cerebrovascular events, and their role in outcome improvement have been highly studied with controversial results (several studies [
In summary, prior use of only antiplatelet drugs is not enough to influence acute stroke outcome. In contrast, treatment with statins prior to stroke could be associated with better acute outcome, but not with long-term outcome.
Early outcome variables are those that can be described during the first few hours after stroke symptoms onset, such as: leukoaraiosis, stroke severity, acute treatment performed, neurological/clinical complications, levels of blood constituents, and, in some cases, stroke etiology.
Leukoaraiosis is a radiological phenomenon which represents white matter lesions and is commonly observed in elderly people. Patients with leukoaraiosis are described as more likely to suffer ischemic stroke and it has been demonstrated that leukoaraiosis is more common and more severe in ischemic stroke patients than in healthy people [
Stroke severity is one of the variables most strongly correlated with outcome, and its association with acute outcome has been widely reported [
In one study [
By acute treatments we refer to those treatments performed to treat ischemic stroke during the acute phase, commonly thrombolysis and/or thrombectomy. We found several studies about their influence on acute outcome [
By neurological complications we mean those medical complications that may conclude with cognition deficit and could occur during the first days of hospitalization. We focused on hemorrhagic transformation (HT) and edema, due to their prevalence during acute and subacute phase.
HT is defined as an intracranial bleeding commonly detected by imaging (computed tomography or magnetic resonance imaging). In the literature, HT is commonly linked with stroke outcome and frequently more detected in IVT treated patients. Nevertheless, influence of HT on stroke outcome depends on its severity [
Cerebral edema is an accumulation of fluid in brain tissue, commonly observed in the acute phase of stroke. This neurological complication seems to have a more direct effect on stroke long-term outcome than HT [
As clinical complications, we included infections, gastrointestinal bleeding, and dysphagia. These three are the most commonly observed during the first days of hospitalization after stroke [
As there is an important inflammatory response during stroke events, the cells implicated in the immune system are likely to be associated with stroke outcome. In addition, it is reported that neutrophils are related with the blood brain barrier breakdown and their infiltration seems to be associated with higher inflammation and have a role in cerebral ischemia [
Blood platelet counts (BPC) were previously associated with ischemic stroke risk [
Red blood cell counts and hemoglobin levels could influence the reoxygenation during acute ischemic stroke and, in turn, the degree of neurological damage. Turcato et al. [
There are several reports searching for the relationship of potential candidate genes with stroke outcome, most of them performed on animal models. However, regarding acute or subacute outcome, we found very few articles that attempted to find genetic factors associated with outcome [
Among all the clinical variables that were included in this review, there are few variables strong and clearly associated with acute or subacute stroke outcome (
It is surprising that age and sex, which are used as covariate in association studies such as GWAS, had a very weak influence on acute and subacute stroke outcome. However, it has been observed that those variables had an important influence on long-term outcome. Likewise, it is interesting that BMI is clearly not associated with acute stroke outcome, in contrast with the controversy observed about the relationship of BMI with long-term outcome. Additionally, it is important to highlight the influence of initial stroke severity on acute outcome, to the extent that it has been reported as an independent predictor in different studies and commonly included as covariate for predictor scales.
Regarding genetic factors, there are several SNPs reported to be associated with neurological deterioration. However, further studies are needed to validate these data, as there is a lack of replication in most of the studies performed. Only rs20417 (located in
As limitation, we considered that there is a lack of studies with enough statistical power to detect associations and perform consistent replication analysis, and also a no-consensus definition of the acute variable studied (i.e., END) makes impossible to perform meta-analyses, an approach required in order to obtain new qualitative and quantitative findings.
In conclusion, our review provides a “state of the art” of this important field, reporting all the variables consistently associated with stroke early outcome and highlighting the lack of genetic studies. However, further research is required in this field. Analysis of acute and subacute outcome is important to understand the molecular mechanisms behind acute and long-term recovery and, finally, treat or prevent the worsening after stroke.
The authors have no financial conflicts of interest.
Alejandro Bustamante is supported by a Juan Rodes research contract from Carlos III Health Institute (JR16/00008). Israel Fernandez-Cadenas is the recipient of a research contract from the Miguel Servet Program from the Carlos III Health Institute (Instituto de Salud Carlos III) (CPII17/00021).
Flow diagram of the systematic review.
Detailed summary of each article included in this review
Study | Outcome studied (definition) | Cohort size (n) | Variable studied | Influence |
---|---|---|---|---|
Adams et al. (1999) [ |
7-day and 3-mo outcome (measured by Barthel Index and the Glasgow Outcome Scale) | 1,281 | Stroke severity | Association |
Kugler et al. (2003) [ |
Early recovery at 24 hr and 1 wk (Barthel Index) | 2,219 | Age | Week influence (only at 1 wk) |
Siegler et al. (2013) [ |
END (increase in NIHSS score of ≥2 points within 24 hr) | 366 | Age | Independent association |
Sex | No association | |||
Stroke severity | Independent association | |||
Yeo et al. (2013) [ |
ENI (reduction of ≥10 points on NIHSS score, or score of 4 or less, at 2 hr); CNI (reduction in NIHSS score of ≥8 points between 2 and 24 hr, or an NIHSS score of ≤4 at 24 hr) | 263 | Age | Non-independent association |
Sex | Female gender associated with CNI | |||
Stroke severity | Independent predictor of CNI | |||
Naess et al. (2014) [ |
7-day NIHSS, neurological worsening, mortality | 1,867 | Age | >80 yr associated with worse outcome |
Boehm et al. (2014) [ |
END (increase of ≥2 points on NIHSS score during first 24 hr after hospitalization) | 4,925 | Age | Covariate |
Sex | Non-independent association | |||
Ethnicity | Non-independent association | |||
Geng et al. (2017) [ |
END (increase of ≥2 points on NIHSS score during 1st wk after stroke) | 1,064 | Age | No association |
Sex | No association | |||
Diabetes mellitus | Association with END | |||
Hyperlipidemia | LDL and total cholesterol were associated with END, but not triglycerides | |||
Body mass index | No association with END | |||
Hassaballa et al. (2001) [ |
7-day and 3-mo outcome (measured by Glasgow Outcome Scale) | 1,093 | Ethnicity | No association |
Machumpu-rath et al. (2011) [ |
ENR (improvement at least 50% on NIHSS score within 24 hr) | 161 | Diabetes mellitus | Association (hyperglycemia patients were less likely to have ENR) |
Roquer et al. (2014) [ |
END (increase of ≥4 points on NIHSS score during first 72 hr after stroke) | Diabetes mellitus | Association with END | |
Tang et al. (2016) [ |
Favorable neurological outcome (decrease of ≥4 points on 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 | 419 | Diabetes mellitus | Predictor of unfavorable outcome |
Yi et al. (2016) [ |
END (increase of ≥2 points on NIHSS score within 10 days after admission) | 426 | Diabetes mellitus | Association with END |
Hui et al. (2018) [ |
END (increase of ≥2 points on NIHSS score within 5 days after stroke) | 336 | Diabetes mellitus | Association with END |
Forlivesi et al. (2018) [ |
No neurological improvement (NIHSS score at 24 hr ≥NIHSS score at baseline) | 200 | Diabetes mellitus | Association with END |
Vlcek et al. (2003) [ |
5-day outcome (Rankin Scale score >2 was defined as poor outcome) | 372 | Blood pressure | Independent association with poor outcome (high diastolic BP) |
Castillo et al. (2004) [ |
END (diminution on Canadian Stroke Scale of ≥1 points within first 48 hr); neurological outcome and mortality at 3 mo | 304 | Blood pressure | Extreme values of BP were associated with poor outcome |
Pezzini et al. (2011) [ |
END (increase of ≥4 points on NIHSS score at 48 hr); 90-day functional status (measured by mRS) | 264 | Blood pressure | Association, but dependent on stroke etiology |
Geeganage et al. (2011) [ |
Death or neurological deterioration at 10 days | 1,479 | Blood pressure | Association (high systolic BP) |
Kvistad et al. (2013) [ |
CNR (no ischemic stroke symptoms at 24 hr); favorable short-term outcome (7-day mRS score of 0-1) | 749 | Blood pressure | No association |
Chung et al. (2015) [ |
END within 72 hr (increase of NIHSS score of ≥2 points) | 1,116 | Blood pressure | Independent association with END (high systolic BP) |
Gill et al. (2016) [ |
Early neurological outcome (improvement of NIHSS score at 24 hr) | 327 | Blood pressure | Independent association with ENR (low diastolic BP) |
Kellert et al. (2017) [ |
ENI (improvement of ≥20% on NIHSS score, or improvement of ≥8 points on NIHSS score); long-term functional outcome (mRS at 90 days) | 28,976 | Blood pressure | No association |
Kang et al. (2017) [ |
END (worsening by 2 points on NIHSS score) at 1,2 and 3 days | 2,545 | Blood pressure | Independent association (systolic BP) |
Keezer et al. (2008) [ |
Poor outcome at 10 days (Rankin Scale score >3) | 364 | Blood pressure | Independent association with poor outcome (high and low BP values) |
Sare et al. (2009) [ |
Neurological impairment (high 7-day NIHSS score than median NIHSS score); 90-day functional outcome (measured by mRS) | 1,722 | Blood pressure | Association with neurological impairment and poor outcome (high systolic BP) |
Zhang et al. (2018) [ |
END (increase in NIHSS score ≥4 or increase in Ia of NIHSS ≥1 within 72 hr after recanalization treatment) | 278 | Blood pressure | Independent association (high systolic BP) |
Stroke etiology | Independent association in intravenous treated patients (large artery occlusion) | |||
Sanák et al. (2010) [ |
24 hr and 7-day NIHSS score; 7-day mortality | 157 | Atrial fibrillation | Association with 7-day mortality |
Yaghi et al. (2016) [ |
ENR (decrease of ≥8 points in NIHSS score, or score of 0–1 at 24 hr) | 306 | Atrial fibrillation | Significantly more present on non-ENR group; independent negative association with ENR |
Restrepo et al. (2009) [ |
7-day NIHSS score | 142 | Hyperlipidemia | Association with hyperlipidemia history |
Choi et al. (2012) [ |
END (increase in NIHSS score of ≥4 at 24 hr) or ENR (reduction of NIHSS score of ≥4) within a week after stroke onset | 736 | Hyperlipidemia | Extreme triglyceride levels associated with poor outcome |
Branscheidt et al. (2016) [ |
ENR (improve >40% on NIHSS score at 24 hr); good outcome (mRS 0–1), favorable outcome (mRS 0–2) and mortality at 3 mo | 896 | Body mass index | No association |
Power et al. (2013) [ |
NIHSS score at baseline and 24 hr | 229 | Renal dysfunction | Association |
Lo et al. (2015) [ |
NIHSS improvement at 24 hr post-thrombolysis; 3-mo functional independence; 30-day mortality | 199 | Renal dysfunction | No association |
Yu et al. (2009) [ |
10-day functional outcome (mRS) | 339 | Prior statin treatment | Association |
Prior antithrombotic treatment | No association | |||
Ní Chróinín et al. (2011) [ |
7- and 28-day functional outcome (mRS); 7-, 28-, 90-day, and 1-yr mortality | 448 | Prior statin treatment | Associated with good outcome |
Tsivgoulis et al. (2015) [ |
ECR (reduction of ≥10 points NIHSS score at 24 hr); good functional outcome (mRS 0–1) and mortality at 3 mo | 1,660 | Prior statin treatment | Association with ECR |
Yi et al. (2017) [ |
Neurological deterioration (increase of 2 points of NIHSS during 10 days after admission) | 1,124 | Prior statin treatment | Concomitant use of antiplatelet and statins was associated with a favorable outcome |
Prior antithrombotic treatment | Concomitant use of antiplatelet and statins was associated with a favorable outcome | |||
Cappellari et al. (2011) [ |
Neurological improvement (reduction of ≥4 points in NIHSS score between 24 and 72 hr) | 250 | Prior statin treatment | Prior and continued use of statins after stroke was associated with worse outcome |
McAlpine et al. (2014) [ |
ENR (diminution on NIHSS score during first 24 hr after stroke) | 158 | Leukoaraiosis | No association |
Saposnik et al. (2008) [ |
7-, 30-day, and 1-yr mortality; neurological deterioration (measured by Canadian Neurological Scale, worsening neurological deficit or deterioration in the level of consciousness) | 3,631 | Stroke severity | Independent association |
Kim et al. (2017) [ |
Early dramatic recovery (reduction of ≥8 points in NIHSS score or NIHSS score of 0–1 at 24 hr) | 102 | Stroke severity | Independent association |
Schmitz et al. (2017) [ |
ENR (NIHSS score improvement of ≥4 points at 24 hr) | 557 | Stroke etiology | Cardioembolic stroke patients more likely to have ENR |
Forlivesi et al. (2017) [ |
Neurological improvement (NIHSS score improvement of ≥4 points or NIHSS score of 0) at 7 days | 122 | Stroke etiology | Large artery strokes had lower odds ratio than cardioembolic strokes |
Ciccone et al. (2013) [ |
Neurologic deficit (NIHSS score ≥6) at 7 days; functional outcome (mRS) and mortality at 90 days | 362 | Acute treatment | No association |
Saver et al. (2015) [ |
NIHSS score changes at 27 hr; 3-mo functional outcome (mRS) | 196 | Acute treatment | Mechanical thrombectomy after IVT treatment had higher NIHSS score decrease |
Jovin et al. (2015) [ |
ENR (decrease of 4 points in NIHSS at 24 hr); functional (Barthel Index) and neurological (NIHSS score) outcome at 90 days | 206 | Acute treatment | Mechanical thrombectomy had better outcome |
Fiorelli et al. (1999) [ |
END (increase of NIHSS score of ≥4 at 24 hr post-stroke onset); 3-mo disability (mRS score ≥1) and 3-mo death | 609 | Hemorrhagic transformation | Independent association (server HT) |
Kablau et al. (2011) [ |
ENR (decrease of >4 on NIHSS score) and END (increase of >4 on NIHSS score) at 5 days | 122 | Hemorrhagic transformation | No association with END; non-severe HT more common on ENR |
Dharmasaroja et al. (2011) [ |
ENR (NIHSS of 0 to 4 at 24 hr) | 203 | Hemorrhagic transformation | Inversely association with ENR |
Gill et al. (2016) [ |
Reduction in NIHSS score after 24 hr | 339 | Hemorrhagic transformation | Inversely associated (server HT) |
Boehme et al. (2013) [ |
END (NIHSS score increase of ≥2 at 24 hr) | 334 | Infections | Non-independent association |
Nardi et al. (2012) [ |
NIHSS score at baseline and at 72 hr; functional outcome (mRS) at discharge | 811 | Leukocyte counts | Independent association |
Kumar et al. (2013) [ |
Neurological deterioration (NIHSS score increase of ≥2 within 24 hr) | 292 | Leukocyte counts | Association |
Tian et al. (2018) [ |
ENI (decrease NIHSS score of ≥4 points or complete recovery after 24 hr of intravenous treatment) | 240 | Leukocyte counts | Independent association |
Furlan et al. (2016) [ |
7-, 30-, and 90-day mortality rate | 9,230 | Blood platelet counts | Non-independent association for 7-day mortality rate; associated with 30- and 90-day mortality |
Turcato et al. (2017) [ |
Lack of neurological improvement at 7 days (no NIHSS score of 0, nor NIHSS score ≤4 from baseline) | 316 | Red blood cell counts | Association with worse outcome |
Pinho et al. (2018) [ |
NIHSS score at baseline and NIHSS score changes at 24 hr | 602 | Red blood cell counts | No association |
Furlan et al. (2016) [ |
7-, 30-, and 90-day mortality rate | 9,230 | Red blood cell counts | High hemoglobin associated with high 7-day mortality |
Yi et al. (2017) [ |
10-day END (NIHSS score increase of ≥2 points) | 396 | Genetic factors | CYP polymorphism associated with CYP plasma metabolites levels in END patients |
Yi et al. (2017) [ |
10-day END (NIHSS score increase of ≥2 points) | 297 | Genetic factors | 3 SNPs independent risk predictors for END |
Yi et al. (2017) [ |
10-day END (NIHSS score increase of ≥2 points) | 850 | Genetic factors | High-risk interactive genotypes were associated with END |
END, early neurological deterioration; NIHSS, National Institute of Health Stroke Scale; ENI, early neurological improvement; CNI, continuous neurological improvement; LDL, low density lipoprotein; ENR, early neurological recovery; mRS, modified Rankin Scale; BP, blood pressure; CNR, complete neurological recovery; ECR, early clinical recovery; HT, hemorrhagic transformation; CYP, cytochrome P450.
Reviewed variables classified depending on its association with stroke outcome
Stroke outcome (acute and sub-acute) | Baseline variable | Early outcome variable | Genetic factor |
---|---|---|---|
Associated | Glucose levels or diabetes mellitus | Stroke severity | rs20417 (located in |
Blood pressure | Type of acute treatment performed | ||
Atrial fibrillation | Sever neurological complications (PH-2) | ||
Prior statin treatment | Leukocyte levels | ||
Might associated | Hyperlipidemia | Leukoaraiosis | Candidate genes: |
Renal dysfunction | Stroke etiology | ||
Prior infections | |||
Blood platelet counts | |||
Red blood cells or hemoglobin levels | |||
Unknown | Heart failure | Cerebral edema | |
Prior dementia | Gastrointestinal bleeding | ||
Prior disability | Dysphagia | ||
No associated | Age | ||
Sex | |||
Ethnicity | |||
Body mass index |
PH-2, parenchymal hematoma 2; COX-2, cyclooxygenase-2;