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/thrombosis2,3.
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 severity6,7. It has subsequently been shown to be
predictive of a variety of stroke functional outcomes7,14-16. 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 researches15,16,18-21. 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 stroke25,26. 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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الملخص
العربى
تقييم
استخدام البروتين التفاعلي س كعلامة حيوية محتملة للتفرقة بين جلطات ونزيف المخ
التشخيص المبكر لمرضى السكتة الدماغية والتفرقة
بين نزيف المخ وجلطاته يعتبر ذو أهمية كبيرة لتمييز المرضى الذين يمكن إعطاؤهم
مذيبات الجلطات مبكراً. تهدف هذه الدراسة الي تقييم استخدام البروتين التفاعلي س
في مرضى السكتة الدماغية للتفرقة المبكرة بين جلطات المخ ونزيف المخ.
تم إجراء هذا البحث على 50 مريضاً أصيبوا بأعراض السكتة
الدماغية للمرة الأولى في حياتهم. تم سحب عينات لتحديد البروتين التفاعلي س فور
دخول المريض للمستشفى وتم عمل أشعة مقطعية لتحديد ما إذا كانت السكتة الدماغية
نتيجة جلطة أو نزيف بالمخ. تم تقييم درجة شدة السكتة الدماغية عن طريق مقياس
المعهد الوطني للسكتة الدماغية وبعد سبعة أيام تم تقييم الحالة الإكلينيكية للمريض
ودرجة العجز عن طريق مقياس رانكن المعدل ومقياس بارثل أدل.
مجموعتا الدراسة كانتا متجانستين مع عدم وجود
فروق دالة إحصائية فى الخصائص الديموجرافية والإكلينيكية للمرضى. كانت نسبة
البروتين التفاعلي س فى الدم أعلى فى مرضى الجلطة الدماغية عنها فى مرضى نزيف
المخ. نسبة البروتين التفاعلي س أكثر من 5,8 مج/لتر فى مرضى السكتة الدماغية يمكن
أن تعنى ان هذه السكتة الدماغية نتيجة جلطة بالمخ ولكن بنسبة حساسية 64% ونسبة خصوصية
60% فقط.
خلصت الدراسة إلى أنه على الرغم من أن ارتفاع نسبة البروتين
التفاعلي س يكون أعلى فى مرضى الجلطة عنه فى نزيف المخ , إلا أن نسبة حساسيته
وخصوصيته غير كبيرة بالصورة الكافية.