AbstractBackground Immunity plays key roles in pathophysiology

Abstract:

Background: Immunity plays key roles in pathophysiology of intracerebral hemorrhage (ICH).

Aim: The aim of the study was to determine whether the peripheral leukocyte count and neutrophil-to-lymphocyte ratio (NLR) predicted neurological deterioration (ND) after ICH. Patients and methods: We identified consecutive patients with ICH who had blood sampling performed within 24 hours from symptom’s onset. Total white blood cells (WBC), absolute neutrophil count (ANC) and absolute lymphocyte count (ALC) were retrieved, and the NLR computed as the ratio of the ANC to ALC values.

The study endpoint was the occurrence of neurological deterioration (ND) within 7 days after ICH. One hundred ninety-two subjects were enrolled, whose 54 (28.1%) presented ND.

Results: At multivariate analysis, the WBC, ANC , ALC and NLR were independently associated with ND. The NLR resulted the best discriminating variable for the occurrence of the adverse outcome.

Conclusion: The NLR predicted ND after acute ICH and can aid in the risk stratification of patients..

Keywords: cerebrovascular disease, intra-cerebral hemorrhage, lymphocyte, neutrophil, neutrophil-to-lymphocyte ratio

Introduction

Spontaneous intracerebral haemorrhage (ICH) represents approximately 10% to 15% of all strokes and affects over 1 million people per year worldwide.

It is characterized by high rates of mortality and residual disability among survivors, and currently no therapeutic strategies have demonstrated definitive benefit [1]. Neurological deterioration (ND) is common after ICH and it is associated with increased length of in-hospital stay, poor functional recovery and death [2]; notwithstanding, reliable and easy-to-use predictors allowing the early identification of unstable at-risk patients are not well established.

Immune reaction is a major feature of ICH pathology and influences its course; the response to cerebral hematoma is not bounded to the brain and results in systemic effects, and inflammatory markers on admission, such as fever, elevated leukocyte count, interleukin-6 and C-reactive protein are associated with worse prognosis [3–5].

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The neutrophil-to-lymphocyte ratio (NLR), an easily available synthesis of the inflammatory levels and enhanced immune pathways, is associated to 3-month recovery in ICH patients [6, 7], but its link with short term outcome is unknown. The aim of this study was to evaluate the relationship between the total and differential leukocyte counts and the NLR at admission with the occurrence of ND during the initial week after ICH onset.

Patients and methods

Our study included forty patients diagnosed with sICH, with mean age 58.125±11.37 years ranging from 30 to 83 years with median of age 60 years. Males were 31 (77.5%) and 9 (22.5%) were females. The overall mortality was 7 patients (17.5%).

Inclusion criteria:

1. Patient’s age : Above 18 years old.

2. Patients with first ever spontaneous intracerebral haemorrhage diagnosed with (CT) scan of the brain.

3. Admission within the first 24 hours of onset to stroke and intensive care units of Neurology Department in Zagazig University Hospitals.

Exclusion criteria :

1- Patients presenting with isolated intraventricular hemorrhage as the majority of these cases are associated with an underlying microvascular causes [8] ,

2- hemorrhage secondary to brain tumor, dural venous sinus thrombosis or ruptured arteriovenous malformation or aneurysm,

3- patients on anticoagulants,

4- patients receiving immunomodulatory treatment (e.g. corticosteroids, azathioprine, methotrexate, other cytostatic and biologicals agents as monoclonal antibodies) as theses agents alter the immune system and immunity plays key roles in pathophysiology of intracerebral hemorrhage ,

5- patients with head injury and surgery within 4 weeks preceding the event,

6- patients with pre-existing infections like tuberculosis and hemorrhagic diseases or blood malignancies.

7- patients with severe degree of hepatic or renal disease.

Patients were subjected to the following:

• A written informed consent was obtained and signed by the patient himself or the patient’s first degree relatives when the patient’s consciousness is impaired.

• Full history was taken, stressing on vascular risk factors including hypertension, diabetes mellitus, dyslipidemia, smoking, use of anticoagulants and previous stroke.

• General and neurological examination with assessment of neurological function on admission using Glasgow Coma Score (GCS) and classifying our patients into three categories; those with score of 3-7, 8-13 and more than 13 [9] and using the National institutes of Health Stroke Scale (N.I.H.S.S.), an 11-item neurologic examination stroke scale that provides a quantitative measure of stroke-related neurologic deficit. The maximum possible score is 42, with the minimum score being a 0, each of score items given between a 0 and 4. The severity of the stroke can be categorized according to the points of the score into: No stroke symptoms (0), minor (1-4), moderate (5-15), moderate to severe (16-20) and severe (21- 42). Its items include

1a. Level of Consciousness, 1b. Level of Consciousness Questions, 1c. Level of Consciousness Commands, 2. Best Gaze, 3. Visual fields, 4. Facial Palsy, 5. Motor Arm, 6. Motor Leg, 7. Limb Ataxia, 8. Sensory, 9. Best Language, 10. Dysarthria and 11. Extinction and Inattention [10]

• The body temperature on admission was recorded orally or rectally and our patients were classified accordingly into hypothermia < 36.5 ?, normothermia 36.5-37.4 ?, subfebrile 37.5- 38.4 ? and febrile >38.5 ? [11].

Laboratory investigations:

• Complete blood count with special attention to the total leukocytic count (patient was considered to heve leuckocytosis when WBCs are higher than 11000 [12]), absolute neutrophil count (ANC), absolute lymphocyte count (ALC).

• Neutrophil-to-lymphocytes ratio (NLR) (by dividing ANC by ALC) with cutoff value calculated in our study to be >9.1 .

• Blood glucose level and its correlation with the patient’s history if he was a known diabetic or not, to identify patients with admission stress hyperglycemia.

• Liver and kidney functions as both systems dysfunction alter the coagulation cascade and change the characteristics of brain hematomas regarding its volume and site.

• Acute phase reactants specially CRP and erythrocyte sedimentation rate (ESR).

Radiological investigations :

• Chest digital X-ray on admission to evaluate lung and cardiac condition basically.

• Computerized Tomography: Using GE ProSpeed Dual Slice F II CT with MX135 Tube. It relies on x-ray transmission through brain but differs from conventional radiography in that it has more sensitive x-ray detection system, its images consists of slices and the data are manipulated by a computer. It consists of x-ray tube and detectors that rotate around the patient’s head. The source and detector rotate over a small angle (roughly 1°) and a new measurement is taken then the scanner repeats this process until a rotation of 180° has been reached then all thousands of measurements for reconstructing one slice have been done. The range of densities recorded is increased about 10 times than in conventional radiography. The operator selects the level and thickness to be imaged (that usually 5mm thickness). The image, then, is made up of tiny spots (pixels) of varying shades of grey, as is a black-and-white television picture. [13]

CT brain was done ,for all patients, on admission with stress on identification of site of hematoma right or left hemispheric, supra or infratentorial; size of hematoma which is measured by the formula (Equation A x B x C ? 0.5) where A and B indicate the largest perpendicular diameters through the hyperdense area on the CT scan, and C indicates the thickness of the ICH (the number of slices containing hemorrhage), presence of surrounding edema, intraventricular extension [14].

Follow up:

All patients were followed up to detect early neurological deterioration defined as a 4 point or greater increase in the NIHSS score or 2 point or greater decrease in the GCS or death from the time of admission to 7 days post-hemorrhage [15] .

Statistical analyses:

The data were coded and entered using the statistical package SPSS.The data were summarized using mean and SD and median and IQ range for quantitative data, and number and percentage for qualitative data. Student’s t-test was used to assess statistical differences between the two groups of quantitative data. Nonparametric Mann–Whitney (MW) and Kruskal–Wallis (KW)tests were used for quantitative variables, which were not normally distributed. . P values less than or equal to 0.05 were considered statistically significant.

Results

We included in this prospective cohort study 40 adult patients with first ever acute intracerebral hemorrhage (31 males and 9 females with age ranged from 30 to 83 years).The mean age was 58.125±11.37. We found statistically significant positive correlation between high values of NLR and early neurological deterioration.

Discussion :

Spontaneous intracerebral hemorrhage (sICH) has been described to be the most fatal form of stroke accounting for nearly 10-15% of all strokes worldwide. The rate of mortality and disability after sICH reflects the pressing need to improve current therapy. Accurate identification of its outcome predictors may help ideal beginning time for immediate intervention and management. Earlier studies have investigated significant associations between clinical, laboratory and radiographic factors on one hand and outcomes in patients with sICH on the other hand [16].

Our study included forty patients diagnosed with sICH, with mean age 58.125±11.37 years ranging from 30 to 83 years with median of age 60 years. Males were 31 (77.5%) and 9 (22.5%) were females. The overall mortality was 7 patients (17.5%).

Within 72 hours after ICH, if WBC count in the peripheral blood was greater than 11,000/mL?, there was a relatively high likelihood of END [17]. In the current study, we found that WBCs count ranged from 3300 to 27500 with median 10000.0 per microliter, the elevated WBCs count was statistically significant related to END (P=0.001). This was correlated with the results of [18] who found that admission leukocytosis is significantly related to poor outcome and END (P= 0.014) in patients with sICH. This is also matching with the results of [19] who found that the elevated WBCs count was statistically significant related to overall mortality (P= 0.010). Admission leukocytosis was associated with END within the first 3 days of admission. Contrary to our results, [20] found 53 patients out of 128 patients with admission leukocytosis with no significant relation to poor outcome (P= 0.9). Also [21], studied 139 patients with ICH, and they found that about 69 patients (53.5%) have leukocytosis on admission, and that admission leukocytosis has no significant relation to mortality (P=