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ORIGINAL ARTICLE
Year : 2020  |  Volume : 33  |  Issue : 3  |  Page : 1067-1071

Neutrophils-to-lymphocyte ratio in acute ischemic stroke patients


Department of Neuropsychiatry, Faculty of Medicine, Menoufia University, Shibin El-Kom, Menoufia Governorate, Egypt

Date of Submission19-Nov-2018
Date of Decision15-Dec-2018
Date of Acceptance22-Dec-2018
Date of Web Publication30-Sep-2020

Correspondence Address:
Eman S Matar
Shibin El-Kom, Menoufia Governorate
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_371_18

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  Abstract 


Objective
The aim of this study was to evaluate the neutrophils-to-lymphocyte ratio (NLR) among patients with ischemic stroke and to determine the relationship between NLR and poststroke prognosis
Background
Inflammations play a role in the pathogenesis of cerebral infarction. Cytokines and adhesion molecules regulate the increased migration of leukocytes to the brain. Neutrophils are the first type of leukocytes to infiltrate ischemic brain (30 min of cerebral ischemia), peak earlier (days 1–3), and then decrease rapidly with time. Lymphocyte recruitment into the brain is involved in the later stages of ischemic brain injury.
Patients and methods
A retrospective study was done on 60 patients with ischemic stroke and 35 age-matched and sex-matched healthy controls. NLR was assessed from the patients' blood samples.
Results
The results were collected, tabulated, and statistically analyzed by IBM personal computer and statistical package SPSS, version 2, a P value of less than 0.05 was considered statistically significant. NLR among ischemic stroke patients was significantly higher than that of the control group. The optimal cutoff value of NLR for the prediction of primary unfavorable outcome was 2.05 with a sensitivity of 90% and a specificity of 96%.
Conclusion
NLR is a nonexpensive and easy marker for predicting stroke severity on admission, which is a primary unfavorable functional outcome.

Keywords: inflammation, leukocytes, stroke


How to cite this article:
Elsheik WM, Alahmar IE, M. Ali GM, Matar ES. Neutrophils-to-lymphocyte ratio in acute ischemic stroke patients. Menoufia Med J 2020;33:1067-71

How to cite this URL:
Elsheik WM, Alahmar IE, M. Ali GM, Matar ES. Neutrophils-to-lymphocyte ratio in acute ischemic stroke patients. Menoufia Med J [serial online] 2020 [cited 2020 Oct 28];33:1067-71. Available from: http://www.mmj.eg.net/text.asp?2020/33/3/1067/296673




  Introduction Top


Inflammation plays a significant role in the pathogenesis of ischemic stroke and its mechanism is complex. Both proinflammatory and anti-inflammatory mediators are involved in the pathogenesis of ischemic stroke, an imbalance of which leads to inflammation. Inflammatory cells from both innate and acquired immune systems are involved in ischemic stroke-related inflammation, processes that are linked by the action of interleukin-17A. The neutrophil-to-lymphocyte ratio (NLR) parameter was reported to be an important measure of systemic inflammation [1].

Once activated, inflammatory cells can release a variety of cytotoxic agents including more cytokines, matrix metalloproteinases, nitric oxide and more reactive oxygen species. These substances may induce more cell damage as well as disruption of the blood–brain barrier, which potentiates brain tissue injury and contributes to secondary ischemic brain damage [2].

Neutrophils are generally the first leukocyte subtype recruited to the ischemic brain; lymphocytes were elevated in the ischemic lesion after neutrophils. Several reports have shown that inhibiting leukocyte adhesion by targeting various adhesion molecules prevent leukocytes from entering ischemic brain, resulting in reduced neurologic injury [3].

The aim of this work is to evaluate the NLR among patients with ischemic stroke and to determine the relationship between NLR and poststroke disability.


  Patients and Methods Top


An informed consent was taken from each person in the study. A retrospective study was conducted on 60 patients (n = 60) who were admitted to the Neurology Department, Menoufia University from May 2016 till May 2018 and a control group (n = 35) of normal individuals matched for age and sex who were selected from Menoufia University Hospital workers and patients' relatives. The protocol was approved by the ethical committee of the Menoufia medical school and an informed written consent was obtained from the participants.

  1. The inclusion criteria include:


    1. Patients with acute ischemic stroke (AIS) (within 48 h from the onset)
    2. Patients with first time ischemic stroke
    3. Patients above 45 years old: as autoimmune diseases are more prevalent in those younger than 45 years old which cause systemic inflammations and increase the NLR


  2. Exclusion criteria include those:


    1. Patients with severe debilitating diseases
    2. Patients with a history of recent infection, trauma, and/or recent surgical operations (during the last few days up to 1 week before ischemic stroke onset).


  1. General examination was done to exclude any cause of acute systemic inflammation (as baseline core body temperature and/or a region of local tenderness, hotness, and swelling)
  2. National Institute of Health Stroke Scale (NIHSS) was conducted for each patient on hospital admission to assess stroke severity and modified Rankin scale (MRS) was conducted for each patient 3 months after the onset of ischemic stroke to measure the degree of disability/dependence
  3. In addition to routine laboratory investigations, NLR was assessed using Beckman Coulter LH 750 hematology analyzers (Beckman Coulter, Miami, Florida, USA) within 24 h from the stroke onset
  4. Also erythrocytes sedimentation rate was done for every person to exclude autoimmune diseases that can raise the NLR.


Imaging

ECG

ECG was done using ATM-300 cardio 3-channel ECG (New Delhi, Delhi, China) for each individual to screen for the presence or absence of atrial fibrillation and hypertension-induced ECG changes as risk factors for ischemic stroke.

Transthoracic echocardiography

Two-dimensional echocardiography was performed using Vivid-9-General Electric Healthcare (GE-Vingmed, Horten, Norway) equipped with Harmonic 5 MHz variable frequency phased array transducer (NY, USA) to search for valvular vegetations, intramural thrombus, or wall motion hypokinesia as risk factors for the development of ischemic stroke.

Duplex ultrasonography of carotid arteries and veretebrobasilar system was done using Hitachi ultrasonography (gray and colored scales) to assess the degree of carotid artery stenosis and atheromatous plaques (soft or calcified).

Computed tomography of the brain

It was done using Toshiba Alexion (CanonMedical, Tokyo, Japan), 16-channel computed tomography (WDC, USA), initially on admission and after 48 h as a follow-up for each patient. Imagings were reported by a radiologist at the Radiology Department, Menoufia University Hospital.

Statistical methods

A retrospective study was conducted on 60 patients (n = 60) and a control group (n = 35) of normal individuals matched for age and sex. Data were collected, tabulated, and statistically analyzed by statistical package SPSS, version 22 (IBM Corp., Armonk, New York, USA, 2013). χ2 was used to study the association between two qualitative variables. A P value of less than 0.05 was considered statistically significant.


  Results Top


The study population included a total of 95 participants, 60 patients with ischemic stroke (mean age ± SD, 59.23 ± 5.74 years) and 35 healthy individuals without ischemic stroke (mean age ± SD, 57.86 ± 3.83 years); 53.3% of the patients were men and 46.7% were women, while in the control group, 51.4% were men and 48.6% were women.

The mean ± SD value of NLR among ischemic stroke patients (2.20 ± 1.44) was significantly higher than that of the control group (1.43 ± 0.29) (P = 0.001) [Table 1].
Table 1: Comparison between acute ischemic stroke patients and controls regarding neutrophils-to-lymphocyte ratio

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On binary logistic regression analysis for relevant risk factors, NLR of at least 2 was a significant risk factor in AIS patients.

An NLR of at least 2 was significantly more prevalent among patients with diabetes mellitus (DM), hypercholesterolemia, and those with no history of carotid artery stenosis. NLR of at least 2 was not significant in relation to smoking, hypertension, hyperuricemia and combined risk factors, carotid artery stenosis and atrial fibrillation [Figure 1].
Figure 1: Risk factors of acute ischemic stroke in patients as regards NLR (<2 and ≥2) relatively. AF, atrial fibrillation; CAS, carotid artery stenosis; DM, diabetes mellitus; NLR, neutrophils-to-lymphocyte ratio.

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The majority of AIS patients 61.7% had moderate-to-severe ischemic stroke on admission on NIHSS (≥6) [Table 2].
Table 2: National Institute of Health Stroke Scale on admission in relation to risk factors and neutrophils-to-lymphocyte ratio in acute ischemic stroke patients

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On MRS done 3 months later from stroke onset, about half of the AIS patients had moderate-to-severe disability (MRS ≥3). MRS of at least 3 was significantly more prevalent among patients with DM, hypercholesterolemia, and NLR of at least 2 [Figure 2].
Figure 2: Mod.RS after 3 months from stroke onset. AF, atrial fibrillation; CAS, carotid artery stenosis; DM, diabetes mellitus; EFT, epicardial fat thickness; HTN, hypertension; Mod.RS, modified Rankin scale; NLR, neutrophils-to-lymphocyte ratio.

Click here to view


The optimal cutoff value of NLR for the prediction of primary unfavorable outcome was 2.05 with a sensitivity of 90% and a specificity of 96% (area under the curve: 0.991, 95% confidence interval: 0.063–0.390) [Table 3].
Table 3: Sensitivity, specificity, cutoff points, and area under the curve of neutrophils-to-lymphocyte ratio for the prediction of modified Rankin scale (≥3) after 3 months from stroke onset in acute ischemic stroke patients

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  Discussion Top


Inflammatory response is important in ischemic stroke and elevated white blood cell count is associated with worse outcome in patients with AIS. It has been suggested that inflammatory cells exacerbate the damage by attacking the penumbra area in addition to the core area of infarction. Neutrophils are recruited rapidly in cerebral vessels within hours [1].

Neutrophils infiltrated in the ischemic brain may lead to the release of inflammatory mediators such as cytokines, thus damaging the tissues. Lymphocytes accumulate in the ischemic brain 3–6 days after stroke, which is later than neutrophils . Lymphocytes could cause the release of proinflammatory cytokines and cytotoxic substances which cause more damage to the ischemic brain tissue and in turn more stroke severity and poor stroke outcome, but the exact mechanisms on how NLR affect the prognosis of ischemic stroke are not yet approved [2].

A retrospective study was conducted on 60 patients with AIS and a control group of 35 healthy individuals matched for age and sex. The majority of AIS patients (61.7%) had moderate-to-severe stroke (NIHSS ≥6) on admission. An NIHSS of at least 6 in those who had moderate-to-severe AIS was significantly more prevalent among patients with DM (P = 0.001), hypercholesterolemia (P = 0.008) and NLR of at least 2 (P = 0.001), and that came in agreement with Saver and Altman [3].

An NLR of at least 2 was significantly more prevalent among patients with DM (P = 0.001) and hypercholesterolemia (P = 0.01), whereas an NLR of at least 2 was not significant in relation to smoking, hypertension, BMI, carotid artery stenosis, atrial fibrillation, hyperuricemia, and combined risk factors more than 2 and that came in agreement with Akıl and colleagues [4],[5].

There was a strong correlation between the NLR and the NIHSS score; the results indicate that a higher NLR is associated with stroke severity on admission and that came in agreement with Tokgoz and colleagues [2],[5],[6],[7].

On MRS done 3 months from AIS onset, NLR was associated with unfavorable outcomes (MRS ≥3), which means that NLR is a predictor of poststroke disability and that came in agreement with [6],[7],[8],[9].

However, another study has shown that higher total white blood cell and neutrophil counts were associated with more severe stroke at admission. In contrast, lower lymphocyte counts were associated with a lesser improvement during the first week after admission and with poor functional outcome at 3 months [10].

On binary logistic regression analysis for relevant risk factors in acute ischemic stroke patients, NLR was a significant risk factor in acute ischemic stroke patients after adjustment of hypercholesterolemia and carotid artery stenosis and that came in agreement with Tokgoz et al. [11].

The NLR was a highly valid prognostic marker in predicting poststroke disability (MRS ≥3), after 3 months from stroke onset. The optimal cutoff value of NLR for the prediction of primary unfavorable outcome was 2.05 with a sensitivity of 90% and a specificity of 96% (area under the curve: 0.991, 95% confidence interval: 0.063–0.390) and that came in agreement with Xue and colleagues [5],[8].

The explanations for the differences between the results of this study and others are:

  1. The relatively small size of the study groups
  2. The study design was retrospective and the data were collected from one hospital, both of which might cause a selection bias
  3. A higher relative proportion of patients with large artery atherosclerosis was enrolled than patients with cardioembolism.


The NLR should be routinely used as a prognostic marker in patients with acute ischemic stroke. The NLR should be assessed in different subtypes of ischemic strokes. Anti-inflammatory and immune-modulating therapies in acute ischemic stroke should be studied.


  Conclusion Top


NLR is a simple, nonexpensive, and easy marker for predicting stroke severity on admission, which is a primary unfavorable functional outcome.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Iadecola C, Anrather J. The immunology of stroke: from mechanisms to translation. Nat Med 2011; 17:796–808.  Back to cited text no. 1
    
2.
Tokgoz S, Kayrak M, Akpinar Z, Seyithanoglu A, Guney F, Yuruten B, et al. Neutrophil lymphocyte ratio as a predictor of stroke. J Stroke Cerebrovasc Dis 2013; 22:1169–1174.  Back to cited text no. 2
    
3.
Saver JL, Altman H. Relationship between neurologic deficit severity and final functional outcome shifts and strengthens during first hours after onset. Stroke 2012; 43:1537.  Back to cited text no. 3
    
4.
Akıl E, Akıl MA, Varol S, Ozdemir HH, Yucel Y, Arslan D, et al. Echocardiographic epicardial fat thickness and neutrophil to lymphocyte ratio are novel inflammatory predictors of cerebral ischemic stroke. J Stroke Cerebrovasc Dis 2014; 23:2328–2334.  Back to cited text no. 4
    
5.
Xue J, Huang W, Chen X, Li Q, Yu T, Shao B, et al. Neutrophil-to-lymphocyte ratio is a prognostic marker in acute ischemic stroke. J Stroke Cerebrovasc Dis 2017; 26:650–657.  Back to cited text no. 5
    
6.
Altintas O, Tasal A. The relationship of platelet-to-lymphocyte ratio with clinical outcome and final infarct core in acute ischemic stroke patients who have undergone endovascular therapy. Neurol Res 2016; 38:759–765.  Back to cited text no. 6
    
7.
Brooks SD, Spears C. Admission neutrophil-lymphocyte ratio predicts 90 day outcome after endovascular stroke therapy. J Neurointerv Surg 2014; 6:578–583.  Back to cited text no. 7
    
8.
Altun I, Akin F, Biteker M. The role of epicardial fat thickness and neutrophil-to-lymphocyte ratio are needed to be studied in real-world stroke patients. J Stroke Cerebrovasc Dis 2015; 24:1100.  Back to cited text no. 8
    
9.
Nardi K, Milia P. Admission leukocytosis in acute cerebral ischemia: influence on early outcome. J Stroke Cerebrovasc Dis 2012; 21:819–824.  Back to cited text no. 9
    
10.
Kim J, Song TJ. Different prognostic value of white blood cell subtypes in patients with acute cerebral infarction. Atherosclerosis 2012; 222:464–467.  Back to cited text no. 10
    
11.
Tokgoz S, Kayrak M, Akpinar Z, Seyithano A. Neutrophil lymphocyte ratio as a predictor of stroke. J Stroke Cerebrovasc Dis 2013; 22:1169–1174.  Back to cited text no. 11
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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