INTRODUCTION

 

The early diagnosis of patients with ischemic stroke and its differentiation from hemorrhagic stroke is crucial in the management strategy that greatly affects the disease outcome and increases the use of the intravenous recombinant tissue-type plasminogen activator (rtPA)¹. Proper clinical assessment and neuroimaging are still the gold standard for the diagnosis of ischemic stroke and the decision of using systemic or catheter based fibrinolysis¹. Clinical and imaging interpretations require expert opinions that may be time delaying. A biomarker that aims to differentiate between hemorrhagic and ischemic stroke would be of greatest utility before brain imaging in the pre-hospital setting (e.g. during ambulance transfer to hospital).

The use of the biomarker is not intended to substitute the neuro-imaging for stroke patients. It could be used, however, in the pre-hospital setting for patient stratification to allow transfer to facilities capable of fibrinolytic therapy use in the proper time window. The diagnosis of ischemic stroke in few patients remains unclear despite the clinical evaluation and imaging¹. Biomarkers can be used in this setting to improve the accuracy of diagnosis.

The use of biomarkers for the early diagnosis of ischemic stroke is rapidly evolving. Most of the studies designed to evaluate the biomarkers of ischemic stroke targeted proteins that has a known relationship to its pathophysiology.

These proteins include markers of brain tissue damage, inflammation, endothelium dysfunction, and coagulation/thrombosis^2,3.

It is well known that inflammation plays an important role in atherogenesis and subsequently ischemic stroke. C-reactive protein (CRP) is a peripheral marker of inflammation, is also a marker of generalized atherosclerosis⁴.

Elevated plasma levels of CRP are associated with increased risks of ischemic heart disease and ischemic cerebrovascular disease⁵. Acute ischemic stroke trigger an inflammatory response that leads to increased levels of CRP. High levels of CRP may be associated with poor outcome because they reflect either an inflammatory reaction or tissue damage.

There is a need for more studies to clarify the exact role of CRP in cerebrovascular disease, and verification of its role as an early diagnostic and prognostic factor of stroke, because it is an easily measured and readily available inflammatory marker.

 

Aim of the Study

We intended in this study to evaluate the role of measuring early CRP level in differentiating ischemic stroke from hemorrhagic stroke.

 

PATIENTS AND METHODS

 

This prospective study was conducted at Intensive Care Unit, Damietta General Hospital. It included 50 patients with acute organic brain insult with symptoms duration less than 24 hours admitted in the period from May 2012 to November 2012. Their ages ranged from 45 to 75 years, with a mean age of 59.5±8.6 year old. They were 26 males (52%) and 24 females (48%). We excluded patients admitted more than 24 hours of symptoms onset and patients with previous history of recent traumatic brain injury, acute coronary syndrome, cerebrovascular events, autoimmune disease, liver cell failure, and chronic renal failure.

All patients were screened according to a strict protocol consisting of a complete medical history, a full neurological examination, standardized blood tests, 12-lead ECG and immediate CT scan of the brain.

Patients included in the study were subjected to full history taking with special emphasis on smoking index (number of cigarettes/day times number of years), hypertension defined as treatment with antihypertensive medication or documented blood pressure ≥ 140 mmHg systolic and/or ≥ 90 mmHg diastolic, Diabetes mellitus defined as treatment with antidiabetics or diagnosis of diabetes during hospital stay, and dyslipidemia.

All patients on admission were evaluated hemodynamically by vital signs assessment with special emphasis on measuring admission systolic and diastolic blood pressure (SBP and DBP) and estimating mean blood pressure (MBP) (MBP = 1/3 (SBP – DBP).

Brain CT scan was done on admission to all patients for differentiation of ischemic from hemorrhagic acute organic brain insult. According to admission CT brain, our patients were classified into two groups; Group A including patients with acute ischemic stroke and Group B involving patients with hemorrhagic stroke. Each group included 25 patients.

Neurological evaluation included assessment of stroke severity by National Institute of Health Stroke Scale (NIHSS) and stroke was categorized as mild (NIHSS 0 – 7), moderate (NIHSS 8 – 14), or severe (NIHSS > 14)^6,7.

Seven days following the onset of stroke, we evaluated the outcome of patients using two different scores including modified Rankin Scale (mRS) ^8-10 and Barthel ADL index (BI)¹¹. Poor outcome was defined to have mRS score > 2 or BI < 95.

Blood samples were withdrawn on admission for routine laboratory tests and for CRP level assay. Three ml of venous blood were taken through a venipuncture and sent codded by the patient's number to the lab. The lab was blinded to the samples.

 

Statistical Methods

Data were prospectively collected and coded prior to analysis using the professional statistical Package for Social Science (SPSS version 16)

-        The description of data was in the form of mean (±) SD for quantitative data, and frequency and proportion for qualitative data.

-        Student-t Test (t): was used for comparison between two groups as regards normally distributed (parametric) quantitative data.

-        Chi-Square Test (x²): was used for comparison between two groups as regards qualitative data.

-        Spearman correlation coefficient test (r): was used to test a positive or negative relationship between two variables.

-        Results were considered significant if P ≤ 0.05 and highly significant if ≤ 0.01.

-        A receiver operating characteristic (ROC) analysis was performed to define a cut-off value of serum CRP for the identification of patients with ischemic stroke and the associated specificity and sensitivity levels.

 

RESULTS

 

Baseline Characteristics & Demographics:

Fifty patients were enrolled in our study with mean age of 59.5±8.6 years. Forty two percent of our patients had age of 61-70 year old. Age group 51-70 year old constituted 72% of whole patients enrolled in our study, while patients younger than 50 year old constituted 26% of all patients and patients older than 70 year old constituted only 2% of all patients (Figure 1).

The study included 26 males (52%), 24 females (48%). There was significant difference in gender distribution in terms of age groups with more male involvement in younger age groups and more female contribution in older age groups (P-value 0.025) (Figure 1). Thirteen of our patients (26%) were smokers with smoking index 328±122 while 37 patients (74%) were non-smokers.

The mean arterial pressure of our patient population was 132.1±26.4 mmHg with systolic blood pressure of 181±37 mmHg and diastolic blood pressure of 108±22 mmHg. Eighteen of our patients (36%) were dyslipidemic and the remaining 32 patients (64%) were non-dyslipidemic. The serum cholesterol level of our patients was 227.2±54.5 mg/L (Table 1).

Severity of stroke assessed by NIHSS revealed a mean score of 13±14 with 15 patients (30%) stratified as severe (NIHSS > 14), 5 patients (10 %) as moderate (NIHSS 8 – 14), and 30 patients (60 %) as mild stroke (NIHSS 0 – 7)  (Table 2 and Figure 2).

Outecome assessed 7 days after admission by mRS revealed poor outcome (mRS > 2) in 22 patients (44 %) and favorable outcome (mRS < 2) in 28 patients (56%). The mean mRS for the whole population was 2.7±2.2 (Table 2 and Figure 3).

Evaluation of the outecome however by BI revealed poor outcome (BI < 95) in 32 patients (64 %) with mean BI for the whole population of 60.7±41 (Table 2 and Figure 3).

There was strong positive correlation between disease severity assessed by NIHSS and outcome assessed by mRS (r = 0.9, P<0.001) and strong negative correlation with the outcome assessed by BI (r = -0.96, P<0.001) (Figure 4).

 

Comparison between Ischemic Stroke and Hemorrhagic Stroke:

We classified our patients according to the results of CT brain done on admission into two 25 patients groups; Group A included patients with ischemic stroke and Group B included patients with hemorrhagic stroke. Both groups were comparable with no significant difference including age, gender, presence of diabetes, and presence of dyslipidemia (Table 3).

Despite the tendency toward more severe presentation in hemorrhagic stroke [NIHSS > 14 in 10 patients (40%), NIHSS 8 – 14 in 4 patients (16%), and NIHSS < 7 in 11 patients (44%)] compared to 5 (20%), 1 (4%), and 19 (76%) patients in ischemic stroke respectively, this difference did not reach the statistical significance (P=0.06) (Figure 5). The mean NIHSS was 10.2±13 in ischemic stroke compared to 15.8±15.3 in hemorrhagic stroke (P=0.2).

Outcome evaluation by both mRS and BI revealed non-significant difference between hemorrhagic and ischemic strokes. Poor outcome as evaluated by mRS was present in 8 patients (32 %) of ischemic stroke group compared to 14 patients (56 %) of hemorrhagic stroke group (P=0.07) and poor outcome as evaluated by BI was present in 15 patients (60%) of ischemic stroke group compared to 17 patients (68 %) of hemorrhagic stroke group (P=0.4) (Figure 6).

SBP, DBP, and MBP were significantly higher in patients with hemorrhagic stroke than in those with ischemic stroke. SBP and DBP were 154±20 mmHg and 92±11 mmHg in ischemic stroke compared to 208±30 mmHg and 123±19 mmHg respectively in hemorrhagic stroke (P<0.001 for both). MBP was 113±14 mmHg in ischemic stroke compared to 151±22 mmHg in hemorrhagic stroke (P<0.001) (Figure 7).

CRP was significantly higher in ischemic stroke than in hemorrhagic stroke. CRP was 9±5.5 mg/L in ischemic stroke compared to 6.2±3.8 mg/L in hemorrhagic stroke (P=0.039) (Figure 8).

Despite the significant difference of serum CRP between ischemic and hemorrhagic strokes, we detected a serum level of 5.8 mg/L to have a sensitivity of only 64% and a specificity of only 60% to identify ischemic stroke (Figure 9).

 

 

 

Figure 1.               Age groups involved in the study, divided in 10 years intervals

with their corresponding frequency in both genders.

Table 1. General characteristics in study population.

 

	Mean ± SD
Age (Year)	59.5 ± 8.6
Smoking index	85.2 ± 157.2
Systolic Blood Pressure (mmHg)	181 ± 37
Diastolic Blood Pressure (mmHg)	108 ± 22
Mean Blood Pressure (mmHg)	132.1 ± 26.4
Random Blood Sugar (mg %)	237.1 ± 104.3
Serum Cholesterol	227.2 ± 54.5
CRP (mg/L)	7.6 ± 4.9

 

Table 2. Severity and outcome scoring in study population.

 

	Mean ± SD
NIHSS score	13.0 ± 14.4
modified Rankin score	2.7 ± 2.2
Barthel ADL index	60.7 ± 41

 

 

 

 

Figure 2. Presentation Severity according to NIHSS.

 

 

 

Figure 3. Outcome according to mRS and BI.

 

 

Figure 4.               Correlation between NIHSS and modified Rankin score and Barthel ADL index.

 

 

Table 3. Demographic data in both groups.

 

		Ischemic stroke	Hemorrhagic stroke	P-value
Age (Year old)		58.7 ± 9.3	60.3 ± 8	0.5
Gender	Male [N (%)]	13 (52 %)	13 (52 %)	1
	Female [N (%)]	12 (48 %)	12 (48 %)
Diabetes Mellitus [N (%)]		18 (72 %)	18 (72 %)	1
Dyslipidemia [N (%)]		9 (36 %)	9 (36 %)	1

 

 

 

 

Figure 5.               Disease severity in both groups.

 

 

Figure 6.               Poor Outcome in both groups.

 

 

 

Figure 7.               SBP, MBP, and DBP in both groups.

 

 

 

Figure 8.               CRP of both groups.

 

 

 

Figure 9.               Cut-off CRP to identify patients with ischemic stroke using ROC analysis.

 

 

DISCUSSION

 

Cerebrovascular stroke is a common medical and socioeconomic problem worldwide¹². Stroke is the third most common cause of death and the first leading cause of disability in developed and developing countries¹². It could be hemorrhagic or ischemic stroke. Both types can cause different degrees of disabilities. Management of both types as well as expecting disease severity and outcome are different.

C-reactive protein is a glycoprotein produced by the liver, which is normally absent from the blood. The presence of acute inflammation with tissue destruction within the body stimulates its production¹³.

We intended in this study to evaluate the use of CRP as an early marker for differentiation between hemorrhagic and ischemic stroke.

We used the NIHSS for evaluating the stoke severity. The NIHSS was developed and subsequently validated as a tool for assessing the initial stroke severity^6,7. It has subsequently been shown to be predictive of a variety of stroke functional outcomes^{7,14-16. In our study, there was strong positive correlation between NIHSS and outcome assessed by mRS and strong negative correlation with the outcome assessed by BI. Many other studies showed that the NIHSS has a strong predictive value for the stroke outcome.}

Fonarow et al, 2012 found that NIHSS is a very strong discriminator of mortality risk and that it has a near-linear relationship between first recorded NIHSS and higher 30-day mortality risk. This study also demonstrated that with categorization of NIHSS into three or four groups, acute ischemic stroke patients can be readily identified as being at low, medium, or high risk for 30-day mortality¹⁷.

Stroke severity as indexed by NIHSS has also been shown to be predictive of mortality after acute ischemic stroke in many other researches^15,16,18-21. One study of 360 ischemic stroke patients admitted to a single hospital identified admission stroke severity as measured by NIHSS score as the strongest predictor of 3-month mortality¹⁹.

Severe presentation was recorded in 40% of the patients in hemorrhagic stroke and in 20% in ischemic stroke.

The mean NIHSS was 10.2±13 in ischemic stroke compared to 15.8±15.3 in hemorrhagic stroke. There was no difference between both groups in outcome evaluated by both mRS and BI. Poor outcome as evaluated by mRS was present 32% of ischemic stroke compared to 56% of hemorrhagic stroke and poor outcome evaluated by BI was present in 60% of ischemic stroke compared to 68% of hemorrhagic stroke group.

We found in our study that the serum CRP level was significantly higher in ischemic stroke compared to hemorrhagic stroke and accordingly it could be used as adjunctive method for the differentiation between both types.

However despite this finding, we could not achieve a cut-off value with high sensitivity and specificity for the diagnosis of ischemic stoke. The best sensitivity and specificity to identify ischemic stroke were only 64% and 60% respectively and was for a serum level of 5.8 mg/L.

Our results were in agreement with the results of other researchers (22-24). This could be explained by the crucial role played by the inflammatory process in the pathogenesis of ischemic stroke while theoretically it has no role in the hemorrhagic stroke. Atherothrombosis of the cerebral vessels is considered a disorder of inflammation and acute phase reactant proteins produced in a first few hours (13). In the study of Eikelboom et al (23), the serum CRP was assessed within 7 days of the symptoms however Terruzzi et al (24) assessed it within 6 hours of the onset. In our work, we assessed the serum CRP level immediately on admission. Ridker et al concluded that the rise of serum CRP occurs within 6 hours of inflammation. This could explain the difficulty of using the CRP for the early pre-hospital identification of ischemic stroke¹³.

Contrary to these findings, other investigators concluded that the use of CRP is of less value as an indicator for predicting ischemic stroke^25,26. Serum CRP level was found to be significantly correlated with the stroke severity and outcome irrespective on the type of the stroke. It was positively correlated with NIHSS, with mRS, and negatively correlated with BI.

Important diagnostic questions in the management of acute ischemic stroke can be summarized to include, does this patient have a stroke; especially if brain imaging is normal?, does this patient have an ischemic stroke?, and is this patient is a candidate for fibrinolytic therapy?

The use of CRP in our study did not give a solution for these questions, and accordingly we could not identify the serum CRP as an ideal marker for early diagnosis of ischemic stroke.

 

Conclusions

We concluded that serum CRP could differentiate ischemic from hemorrhagic stroke as an adjunct to clinical and neuroimaging results. We could not however recommend its use for decision making in context of indication for fibrinolytics therapy.

The use of serum CRP or other biomarkers that can identify patients with ischemic stroke at an early stage is enthusiastic and need a greater wider scale studies.

 

Acknowledgement

We would like to thank the ICU team of Damietta General Hospital for their support and efforts in data collection of this work. I would like also to gratefully and sincerely thank Dr. Hosam Salah, Lecturer of Neurology, Cairo University for his guidance, understanding and his support with reading and editing of this work.

 

[Disclosure: Authors report no conflict of interest]

 

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