Neuron Specific Enolase and C-reactive Protein Levels in Stroke and Its Subtypes: Correlation with Degree of Disability Aparna Pandey • Amit Kumar Shrivastava Kiran Saxena
Received: 7 December 2013 / Revised: 22 April 2014 / Accepted: 6 May 2014 Ó Springer Science+Business Media New York 2014
Abstract Stroke is an emergency which threatens life and third leading cause of death and long term disability in developed countries. The use of biomarkers in diagnosing stroke and assessing prognosis is an emerging and rapidly evolving field. The study aimed to investigate the predictive value of biochemical marker of brain damage neuronspecific enolase (NSE) and systemic inflammatory marker C-reactive protein (CRP) with respect to degree of disability at the time of admission and short term in stroke patients. We investigated 120 patients with cerebrovascular stroke who were admitted within 72 h of onset of stroke in the Department of Neurology at Sri Aurobindo Institute of Medical Sciences, Indore, India. NSE and CRP were analyzed by solid enzyme linked immunosorbent assay using analyzer and micro plate reader from Biorad 680. In all patients, the neurological status was evaluated by a standardized neurological examination and the National Institutes of Health Stroke Scale on admission and on day 7. Serum NSE and CRP concentration were found significantly increased in acute stroke cases as compared to control in present study (\0.05 and \0.001 respectively). The maximum serum NSE and CRP levels within 72 h of admission were significantly higher in patients with greater
A. Pandey Department of Biochemistry, Narshinbhai Patel Dental College and Hospital, Visnagar, India A. K. Shrivastava (&) Department of Biochemistry, Sudha Rustagi College of Dental Sciences and Research, Kheri More, Faridabad 121002, India e-mail: [email protected] K. Saxena Department of Biochemistry, Chirayu Medical College and Hospital, Bhopal, India
degree of disability at the time of admission. Both biomarkers were found significantly correlated with neurological disability and short term outcome. Our study showed that serum biomarkers NSE and CRP have high predictive value for determining severity and early neurobehavioral outcome after acute stroke. Keywords Stroke Neuron specific enolase C-reactive protein National Institutes of Health Stroke Scale
Introduction Stroke is one of the leading causes of death all over the world including India. Stroke is also a predisposing factor for epilepsy, falls and depression in developed countries [1, 2] and is a leading cause of functional impairments; with 20 % of survivors requiring institutional care after 3 months and 15–30 % being permanently disabled . Stroke is no longer a disease of the developed world: low and middle-income countries account for 85.5 % of total stroke deaths worldwide and the number of disabilityadjusted life years in these countries was approximately seven times that in high-income countries . Despite advances in research during the last decade, prevention and treatment strategies still suffer from significant limitations, and therefore new technical and analytical approaches are required. Technological advances in hunt of new blood biomarkers, during recent years, have permitted a more effective search for novel biomarkers and therapeutic targets that may allow for effective risk stratification and early diagnosis with subsequent rapid treatment. Neuron-specific enolase (NSE) is one such biochemical marker and has been the subject of many clinical and experimental studies. Previous studies [5, 6]
have focused on the release and the kinetics of NSE after acute cerebral infarction, mostly in the cerebrospinal fluid (CSF). However, daily sampling of CSF is difficult and is associated with a high risk of complications. Thus, measuring serum levels of NSE could allow frequent testing with a relatively low risk of complications. C-reactive protein (CRP) is a blood marker of inflammation and a hallmark of the acute-phase response. Its elevation bears negative prognostic implications for many conditions and it has also been shown to be a nonspecific predictor of longterm risk of cerebrovascular disease in several populations, while elevations of CRP associated with the major acutephase response following ischemic or hemorrhagic stroke are associated with death and vascular complications [7, 8]. Furthermore, CRP predicts not only incident myocardial infarction and cardiovascular death, but also the risk of ischemic stroke . The main aim of the present study was to assess and evaluate the clinical utility of NSE, and CRP and also analyze their correlation with neurological disability and short term outcome measured with the help of National Institutes of Health Stroke Scale (NIHSS).
Methods Patients A total of 200 patients with suspected stroke consecutively admitted to emergency department in which 120 patients with confirmed stroke were recruited in the stroke unit of Sri Aurobindo Institute of Medical Sciences, Indore, India. Subsequently type of stroke identified by trained neurologist on the basis of clinical examination and a computed tomography (CT) scan of the brain. A total of 88 patients were confirmed as having an ischemic stroke, 32 with a hemorrhagic stroke and 50 controls were included in the study. This study was approved by the ethics committee of hospital, and all patients or relatives gave written, informed consent. Although the level of NSE biomarker is highly specific for brain tissue, they are also expressed in other cell types under certain physiological and pathological conditions. For this reason, patients and members of the control group with clinical evidence of other neurological diseases, known malignancies, chronic inflammatory diseases, recent infection or trauma were not included. The inclusion criteria for subjects in study group were adult stroke (age [21 years) and within 72 h of admission. The exclusion criteria for subjects in study group were—CNS infection, stroke more than 72 h and peripartum stroke. Chest infection is a common complication of acute stroke, which may affect levels of CRP. Therefore, we have also excluded those patients in the present study.
Data Collection Included patients were subjected to the following protocol; patient co-morbidities were collected from clinical records using the detailed history, criteria according to WHO reference range. Detailed neurological examination was carried out by using the NIHSS and CT scan within 12 h of admission in order to define the size and location of the ischemic or hemorrhagic lesion. The venous blood samples were drawn within 72 h from the onset of symptoms blood was allowed to clot at room temperature, and serum was obtained immediately by centrifugation at 3,500 rpm for 10 min. Serum was aliquoted into plastic tubes and stored at -27 °C until assayed. Serum levels of NSE and CRP were measured with commercially available quantitative ‘‘sandwich’’ enzyme-linked immunosorbent assay kits obtained from R&D Systems. The values were greater than 2 mg/L consider as cut-off point for pathological levels of CRP. The severity of stroke was scored on admission and 7th day of admission by the neurologist, using the NIHSS. The NIHSS score consists of 11 items and a total score of 42 points. Score of 0 = no stroke, 1–4 = minor stroke, 5–20 = moderate stroke, 21–42 = severe stroke. Early neurological worsening was diagnosed as an increase in NIHSS by two or more points (or stroke related death) between admission and day 7  and who remained stable or improved in the same period were classified as no worsening. Statistical Analysis Demographic, clinical and laboratory frequency variables were calculated. Statistical analyses were performed with SPSS for windows, version 17. Continuous variables were tested for normal distribution using the Kolmogorov– Smirnov test. Biomarkers value expressed as mean ± SD. Statistical significance for intergroup difference was assessed by student t test or ANOVA test for continuous variables. To study the correlation between quantitative variables, Pearson test was used. A probability value p \ 0.05 was considered statistically significant.
Results The demographic and clinical data are shown in Table 1. There were 120 patients diagnosed with stroke according to NIHSS and CT scan out of 200 patients evaluated at emergency department and 50 controls were evaluated. Of these, 27 % patients had brain hemorrhage on the computed tomography scan performed in emergency department, 73 % patients had ischemic stroke. In the study
Neurochem Res Table 1 Clinical and demographic characteristics of the stroke patients and controls
Table 3 Biomarkers and disability score in ischemic and hemorrhagic stroke
Ischemic stroke patients (n = 88)
Hemorrhagic stroke patient (n = 32)
17.95 ± 4.54
29.08 ± 5.99
Ischemic stroke patients (n = 88)
Hemorrhagic stroke patients (n = 32)
Controls (n = 50)
Age (years) \50
56 (64 %)
23 (72 %)
30 (60 %)
23 (26 %)
10 (31 %)
14 (28 %)
40 (45 %)
2 (6 %)
34 (68 %)
21 (24 %)
7 (22 %)
13 (26 %)
11 (13 %)
4 (13 %)
8 (16 %)
2.90 ± 1.7
5.6 ± 1.1
13.48 ± 7.1
21.63 ± 1.74
NIHSS at 7th day of admission
12.30 ± 7.81
25.58 ± 3.3
Values are in mean ± SD, *** extremely significant, * significant
Values are in mean ± SD, NS not significant, p [ 0.05
Table 2 Serum NSE and CRP concentrations in the stroke patients and control Variables
CRP (mg/L) NIHSS at the time of admission
Stroke patients (n = 120)
Control (n = 50)
22.6 ± 7.7
7.48 ± 1.51
4.11 ± 0.9
0.88 ± 0.49
Values are in mean ± SD, *** extremely significant, * significant
group percentage of males (68 %) was more as compared to females (32 %). Incidence of hypertension (66 %), atrial fibrillation (35 %), diabetes mellitus (28 %) was more in the stroke patients as compared to other risk factors. Table 2 shows the levels of biomarkers NSE and CRP in stroke patients and healthy control. Concentration of NSE was significantly higher in stroke patients as compared to control group (22.6 ± 7.7 vs. 7.48 ± 1.51 ng/mL, p \ 0.05). In addition CRP significantly increased in stroke patients than control group (4.11 ± 0.9 vs. 0.88 ± 0.49 mg/L, p \ 0.001). Table 3 indicates result of comparison of biomarkers and neurological deficit between ischemic and hemorrhagic stroke subtypes. Levels of localized brain biomarker NSE were significantly increased in hemorrhagic stroke as compared to ischemic stroke (29.08 ± 5.99 vs. 17.95 ± 4.54 ng/mL, p \ 0.001). Moreover data showed concentrations of systemic inflammatory marker CRP were higher in hemorrhagic stroke as compared to ischemic stroke (5.6 ± 1.1 vs. 2.9 ± 1.7 mg/L) with statistically significant p value (p \ 0.001). The mean baseline NIHSS scores at the time of admission (21.63 ± 1.74 vs. 13.48 ± 7.1, p \ 0.05)
and 7th day of admission (25.58 ± 3.3 vs. 12.3 ± 7.81, p \ 0.05) were higher in patients with hemorrhagic stroke than in those with ischemic stroke. We found highly significant positive correlation between NIHSS and each of CRP (Fig. 1a), and NSE (Fig. 1b) (p \ 0.01) (r = 0.951, r = 0.939 respectively) at the time of admission. The graph demonstrates that patients with an adverse neurological disability had a significant higher release of both the markers. The association between release of biomarkers and neurological disability followed the same pattern in patients with ischemic and hemorrhagic stroke subtypes. Short term outcome (assessed by NIHSS) at 7th day of admission was significantly correlated with serum concentrations of both biomarkers NSE and CRP. Again the positive correlations were found between NIHSS score at 7th day of admission and CRP (r = 0.912, p \ 0.01, Fig. 2a), and NSE (r = 0.945, p \ 0.01, Fig. 2b). We also estimated biomarkers levels and neurological deficit in mild, moderate and severe groups categorized on the basis of NIHSS scores. Severe group showed increased concentration of NSE (33.1 ± 1.5) as compared to mild and moderate groups (15.5 ± 5.4 and 23.8 ± 7.4 ng/mL respectively) (p \ 0.001). We found same patterns in the case of CRP. CRP levels were high in severe group (4.94 ± 1.1) as compared to mild and moderate groups (0.99 ± 1.1 and 3.15 ± 2.1 mg/L respectively) (p \ 0.001). On other hand neurological deficit at the time of admission (p \ 0.05) and 7th day of admission (p \ 0.01) were also significantly higher in severe group as compared to mild and moderate groups.
Discussion Demographical data of our study clearly depicts that the maximum number of stroke patients were in\50 years age group. Indian studies have shown that about 10–15 % of strokes occur in people below the age of 50 years  and
Fig. 1 Correlation between a CRP and NIHSS score at the time of admission, and b NSE and NIHSS score at the time of admission in stroke patients
Fig. 2 Correlation between a CRP and NIHSS score at 7th day of admission, and b NSE and NIHSS score at 7th day of admission in stroke patients
nearly one-fifth of patients with first ever strokes admitted to hospitals are aged \50 years . Higher proportions of younger individuals are affected in India compared to developed countries. In the study group percentage of males (68 %) was more as compared to females (32 %). Men are more likely to have a stroke than women . This may be due to differences in risk factors such as smoking and drinking which are more prevalent among men in India compared with women . Despite advances in the field of neurological imaging, there are inherent limitations in the techniques such as their time-consuming nature, the individual variation in the analyses of radiological images and the availability and
cost of the equipment . Many hope that novel protein or genomic blood biomarkers might improve stroke diagnosis, make better predictions of stroke outcome, identify better drug candidates, or target treatments for stroke to those patients most likely to benefit. The present study deals with the role of brain biomarker NSE and systemic inflammatory marker CRP as a parameter for estimation of parenchymal damage and early neurological worsening. The mean serum NSE, in patients with cerebrovascular stroke was found to be significantly higher (p \ 0.034) than in controls. There are several reports indicating increased concentration of NSE in stroke patients as compared to control group [16–18]. Moreover Brea et al.
 reported elevated level of NSE in hemorrhagic stroke patients. Increased NSE serum levels correspond to the cytoplasm loss of NSE in neurons and are detectable before irreversible neuronal damage takes place. This result suggests that the analysis of serum NSE during the acute phase of stroke is valuable for evaluating the neurological deficit of cerebral infarction patients. In the present study, when NSE levels were compared in different sub types of stroke, the level of NSE was more in hemorrhagic stroke than ischemic stroke. Dwi Lily and Endang Retnowati  also compared mean value of NSE in different stroke subtype and reported that serum NSE levels in acute stroke patients after onset can be used to estimate the extent of brain damage (lesion volume), but it cannot be used to differentiate the type of stroke. Klaus et al.  concluded that stroke in patients with hemorrhagic stroke is more severe than strokes in patients with infarcts. The relative frequency of hemorrhagic stroke is increasing, with increasing stroke severity, being 2 % in very mild strokes and 30 % in the very severe strokes. NSE potentially used as a marker for destructive processes in the central nervous system because serum NSE levels correspond to the ischemia-induced cytoplasmic loss of NSE in neurons. The reason for high NSE concentration in patients with hemorrhage stroke could be possible because strokes are generally more severe in patients with hemorrhagic stroke, and level of NSE is directly proportional to severity of stroke. In present study, the initial serum NSE level was significantly higher in patients in the severe as compared to moderate and mild disability groups. A previous report by Bharosay et al.  showed that patients with NIHSS score 21–42 had higher initial NSE serum levels than patients with NIHSS score 5–20 or 0–4. High concentration of NSE in blood in the patients with severe NIHSS score are the consequence of massive neuronal and blood brain barrier damage, which allows NSE to pass from CSF to the peripheral blood. However, in the mild and moderate stroke patients groups, there is less neuronal damage and so concentration of NSE are proportionally lower than in severe stroke NIHSS score. In the current study initial increased level of NSE positively correlated with the severity of neurological deficit (NIHSS score at admission) and short term neurological outcome (NIHSS score at 7th day after admission). Fassbender et al.  and Missler et al.  suggested that the initial NSE level well correlated with degree of neurological deficit and short term out come. NSE is good biochemical marker of functional outcome in patients with acute cerebral infarction. This suggests that although the exact lesion size was not measured precisely in present study, the initial NSE level well correlated with degree of neurological deficit and short term out come.
The mean value of inflammatory marker CRP in total stroke was higher as compared to control groups. Bharosay et al. , Di Napoli et al. [26, 27] and Eikelboom et al.  also reported that the level of CRP, a peripheral marker of inflammation, has consistently been observed to be related to the risk of cerebrovascular and cardiovascular events, and it is consistently elevated in the circulation of patients after acute stroke. When CRP levels were compared in different subtypes of stroke, the mean CRP level was more in hemorrhagic than ischemic stroke. Mishra et al.  also found significantly increased levels of CRP in hemorrhagic stroke patients although these results are different from those of Wakugawa et al.  in the Hisayama study in which they observed no clear association between CRP levels and hemorrhagic stroke occurrence. Present data suggested that inflammation plays a crucial role in the development of brain injury after hemorrhage. CRP is an acute phase protein produced by the liver. It is normally absent in the blood. The presence of acute inflammation with tissue destruction within the body stimulates its production, allowing the inflammation to be confirmed. In the present study, the initial serum CRP level was significantly higher in patients of severe disability group than in the mild and moderate disability groups. Elkind et al.  observed that higher the CRP level, more is the chance stroke severity and of mortality. Kumar et al.  suggested that the relationship between CRP and post stroke mortality may in part reflect inflammation-induced endothelial cell dysfunction and platelet activation. The present study concluded that CRP level was markedly elevated in patients with severe disability stroke patients, which tends to cause larger infarcts and greater disability, and they were significantly lower in patients of mild and moderate stroke patients, which causes small infarcts. In present data CRP positively correlated with the severity of neurological deficit (NIHSS score at admission) and short term neurological outcome (NIHSS score at 7th day after admission). Ladenvall et al.  and Audebert et al.  reported positive correlation between stroke severity and level of CRP. Association between high CRP and a high stroke severity remain unexplained. There is a distinct possibility that elevated CRP is a direct response to the extent of cerebral tissue injury. But as an inflammatory marker, it is also possible that high CRP is associated with underlying processes that cause a more severe stroke. There are only few Indian studies, which estimated levels of NSE and CRP in stroke patients [18, 22, 25, 29, 32]. Some studies have focused on NSE and overlooked CRP or vice versa, and most studies have not correlated them with NIHSS score [22, 25]. Therefore, our study is the first Indian study, to the best of our knowledge, which estimated levels of NSE along with CRP in the stroke patients (both ischemic and hemorrhagic) and correlated
them with NIHSS score as a strategy to predict disease severity and outcome in stroke.
Stroke is associated with diverse immune responses. The high incidence of mortality and disability in stroke patients is likely to be a result of inflammation and an impaired immune function. Therefore, present study investigated biomarker and inflammatory markers in stroke patients within 72 h of onset of acute stroke. Our results show the association of brain biomarkers NSE and inflammatory marker CRP with neurological deficit suggesting the contribution of parenchymal damage and inflammation as a prognostic indicator for the development of clinical complications following cerebral acute events. In reality, there is a substantial interest in the use of biomarkers to identify subjects at higher risk for the development of complications following thrombolysis therapy. The present study examines the level of biomarker in between hemorrhagic and ischemic stroke, in particular, to the hypothesis that different plasma levels of biomarkers assessed at baseline in subjects could be predictive for both diagnosis and clinical outcome. We highlight the importance of differentiation of pathological levels of serum biomarkers to improve not only clinical decision making but also post acute clinical outcome. It is essential to increase the number of informative markers and to assess their relative contributions to diagnosis, prediction of stroke severity and outcome, and stratification of patients for stroke therapy in a practical and cost-effective manner.
13. 14. 15.
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