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The inflammatory process is involved in the development of cognitive impairment after hemorrhagic stroke. The neutrophil-lymphocyte ratio (NLR) is an indicator reflecting systemic inflammation and a reliable marker of the severity and adverse outcomes of stroke. The aim of the study was to evaluate the predic-tive value of NLR for the first time 24 hours of stroke in the development of post-stroke cognitive impairment after intracerebral hemorrhage.
neutrophil-lymphocyte ratio, inflammatory marker, inflammation, post-stroke cognitive impairment, stroke
Introduction
Post-stroke cognitive impairment (PSCI) is a serious disabling disorder due to stroke. Cognitive impairment develops in more than 30% of stroke patients, reaching the degree of dementia and leads to disability [1, 2] Currently, about 50 million people suffer from dementia, in 2030 the number of patients with dementia will reach 82 million [3].
According to experimental and clinical studies, the inflammatory process has an important role in the development of PSCI [4-7]. Several previous studies have examined the association of markers of inflammation with PSCI, but the results for certain biomarkers have been mixed. In a study by K. Narasimhalu et al. in patients after ischemic stroke, C-reactive protein (CRP), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-10 (IL-10) did not confirm the relationship with PSCI [8]. However, the results were different for CRP in the L.S. Rothenburg et al. The results showed that a high level of CRP is associated with a deterioration in cognitive functions 1 month after stroke, with respect to IL-6, no relationship was found [9]. In other studies, an association between CRP and PSCI has also been found [10, 11]. Regarding IL-1β, IL-6, IL-10, according to the results of the study by V.G. Cherkasova et al., Patients with PSCI had a high concentration of IL-1β and IL-10 in the cerebrospinal fluid and IL-6 in the blood serum, in comparison with patients with normal cognitive ability [12].
One of the inflammatory markers reflecting systemic inflammation is the neutrophil-lymphocyte ratio (NLR). Compared to the above markers, NLR is readily available with a complete blood count, which is usually done for all inpatients, without additional financial costs. Several meta-analyzes have shown that an increase in NLR is a predictor of acute ischemic and hemorrhagic strokes [13-15]. In addition, NLR is a reliable marker for predicting the severity [16] and adverse outcomes of stroke [17-19], such as infectious complications, increased hematoma volume after intracerebral hemorrhage (ICH) [20,21] and post-stroke disability [16,22,23, 24].
Based on the results of previous studies and the role of inflammation in the development of post-stroke cognitive impairment, NLR may be a prognostic marker of the occurrence of post-stroke cognitive impairment in intracerebral hemorrhage.
Purpose of the study – to evaluate the predictive value of NLR for the first time 24 hours of stroke in the development of post-stroke cognitive impairment after ICH.
Materials and methods
This retrospective case-control study included 115 patients with previous supratentorial intracerebral hemorrhage. Inclusion criteria were: age from 18 years, established diagnosis of supratentorial intracerebral hemorrhage, a complete blood count was performed on the analyzer for the first time 24 hours ICH, early recovery period. Patients with aphasia, pathology of the organs of vision and/or hearing, with acute infectious, mental illnesses and taking sedatives, glucocorticosteroid, immunosuppressive drugs or other therapy affecting the immune and cognitive status were excluded.
In order to identify pre-stroke cognitive impairments in the subjects of the study, close relatives were questioned using the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). According to the results of IQCODE, 32 patients were excluded, the results of which were more than 78 points. Cognitive status was assessed 6 months after stroke according to the American Psychiatric Association's Diagnostic and Statistical Manual using the Montreal Cognitive Assessment Scale (MoCA), Mental Status Assessment Summary (MMSE), and General Deterioration Scale (GDR). In order to exclude false results and taking into account the sensitivity of the scales, patients with mild cognitive impairment according to the results of MoCA and with mild dementia according to the MMSE were not included [25, 26]. In the categorical table of the General Impairment Scale (GDR), patients were classified into 7 stages of cognitive impairment [27]. Based on the test results, the main group included patients with a total of ≤17 MoCA points, ≤19 MMSE points, and GDR stages 2-7; in the control group - with ≥ 26 MoCA points, with ≥ 27 MMSE points and stage 1 GDR.
Absolute Neutrophil Count (NEUT #), Absolute Lymphocyte Count (LYM #) were recorded through the Integrated Medical Information System case history data. The NLR analysis was performed as a continuous variable with a range within the normal range from 0.78 to 3.53 [28].
According to the results of computed tomography (CT) of the brain, the affected hemisphere, localization and volume of the hematoma were recorded. The volume of hematoma was measured using the ABC/2 method by means of non-contrast CT of the brain [29], the indicator of which was entered as a continuous variable. Localization of ICH was classified as lobar, medial, lateral and mixed intracerebral hematomas [30]. The degree of neurological deficit on admission was assessed using the National Institutes of Health Stroke Scale (NIHSS). Statistical processing of the results was carried out using Microsoft Excel 14.0.4760.1000 and Statistica 6.0 software. The distribution of features was assessed using the Shapiro-Wilk test. Quantitative characteristics were compared using the nonparametric Kruskal-Wallis test (H-test). Comparison of the proportions between groups was carried out using the Z-test. Correlation was assessed using Spearman's correlation coefficient. To assess the risk, the relative risk (RR) was determined. The strength of association between NLR and PSCI was assessed using odds ratio (OR). The significance level of the data was α=0.05.
The scientific research was approved by the Bioethics Committee of the NJSC "Medical University of Karaganda" (protocol №8 of 10.11.20). The study was conducted with the voluntary consent of the participants and the legal representative with the receipt of written informed consent.
Results and discussion
The groups were matched by sex and age (p> 0.05). In the main and control groups, the average age was 55.1897 and 55.193 years, the proportion of men was 46.55% (95% CI: 33.45-59.65) and 45.61% (95% CI: 32.42-58.81), respectively (Table 1).
Table 1. Characteristics of patients in the test groups
|
Indicator |
Main group n=58 |
Control group n=57 |
p- value |
|
Age, Me, (Q25; Q75) |
56.5 (49; 63) |
57 (48; 62) |
0.984 |
|
Male, % |
46.55 |
45.61 |
0.920 |
|
Left hemisphere,% |
48.28 |
57.89 |
0.301 |
|
ICH localization: |
|
|
|
|
Lobar,% |
1.72 |
12.28 |
0.026 |
|
Medial,% |
1.72 |
3.51 |
0.548 |
|
Lateral,% |
37.93 |
45.61 |
0.404 |
|
Mixed,% |
58.62 |
38.60 |
0.032 |
|
Hematoma volume (ml3), Me,(Q25; Q75) |
16.4 (9.5; 30) |
5 (3.5; 8) |
<0.001 |
|
NIHSS score (points), Me, (Q25; Q75) |
14.5 (13; 16) |
8 (5; 11) |
<0.001 |
|
Laboratory indicators: |
|||
|
The absolute number of neutrophils (x109/l), Me, (Q25; Q75) |
6.6 (4.3; 9.5) |
4.85 (3.4; 7) |
0.014 |
|
Absolute lymphocyte count (x109/l), Me, (Q25; Q75) |
1.4 (1.1;1.9) |
1.7 (1.38; 2.4) |
0.009 |
|
NLR, Me, (Q25; Q75) |
4.35 (2.59; 7.15) |
2.67 (1.76; 3.73) |
1 |
|
NLR>3,53, % |
62.07 |
33.33 |
0.002 |
|
Cognitive status assessment: |
|||
|
MoCA (points), Me, (Q25; Q75) |
15 (14; 16) |
26 (26; 27) |
<0.001 |
|
MMSE (points), Me,(Q25; Q75) |
16 (15; 17) |
28 (28; 28) |
<0.001 |
|
GDR: |
|||
|
Stage 1, % |
- |
100 |
<0.001 |
|
Stages 2-3, % |
32.76 |
- |
<0.001 |
|
Stages 4-7, % |
67.24 |
- |
<0.001 |
According to Spearman's correlation analysis, the level of cognitive impairment on the MoCA, MMSE, and GDR scales strongly positively correlated with the NIHSS score, moderately positively correlated with the volume of the hematoma, and a weak direct relationship with the localization of the hematoma was found. Consequently, cognitive dysfunction is associated with stroke severity and damage to the critical site of stroke [31,32]. In addition, MMSE and GDR had a weak positive association with ICH treatment. No correlation was found between MoCA, MMSE, GDR and age, gender, affected hemisphere (p> 0.05, Table 1).
In the main group, the NLR ranged from 1.2378-19.2, in 62.07% (95% CI: 49.33-74.81) the NLR was more than 3.53. In the control group, NLR was in the range of 0.2881-21, NLR over 3.53 was found in 33.33% (95% CI: 20.85-45.82). When comparing the proportions using the Z-test, it was revealed that in the acute period of ICH, more patients had cognitive dysfunction with an NLR level> 3.53, in comparison with the control (p = 0.002) (Table 1).
Spearman's correlation analysis revealed that NLR had a weak direct relationship with the NIHSS score at admission, localization, hematoma volume (p <0.05, Table 2). There was no statistically significant correlation between NLR and the affected hemisphere (p> 0.05, Table 2). According to Jie Qin et al. NLR was moderately positively correlated with hematoma volume assessed by NIHSS, but was not associated with ICH localization [33]. These results indicate that neutrophils and lymphocytes associated with stroke severity are involved in brain tissue damage in ICH.
Table 2. Spearman's correlation analysis between NLR and stroke severity
|
Indicator |
Spearman |
t(N-2) |
p-level |
|
Affected hemisphere |
-0.16638 |
-1.7937 |
0.075537 |
|
Localization of hematoma |
0.26214 |
2.8875 |
0.004654 |
|
Hematoma volume |
0.28928 |
3.2125 |
0.001715 |
|
NIHSS score |
0.25251 |
2.7741 |
0.006478 |
As a result of the risk assessment, an increase in NLR> 3.53 increases the incidence of PSCI by 1.78 times (RR-1.785, 95% CI: 1.216-2.621). An increase in NLR> 3.53 for the first time 24 hours of stroke is associated with a high chance of developing post-stroke cognitive dysfunction at 6 months after ICH (OR - 3.273, 95% CI: 1.524-7.030). This is due to the fact that in acute ICH, intraparenchymal blood and local aseptic necrosis trigger inflammation [34]. Through the highly permeable blood-brain barrier, neutrophils infiltrate the hematoma area from 30 minutes to several hours, reaching a peak of 1–3 days [35]. Unlike neutrophils, T-lymphocytes are recruited later, approximately 3-4 days after hemorrhagic stroke [36]. Despite the fact that neutrophils are involved in recovery, they also have a damaging effect [37,38]. Localized brain damage leads to neuronal death and loss of synapses, contributing to the development of cognitive dysfunction [39].
There are several limitations to this study. First, the study was retrospective with a limited number of samples, which led to hematomas varying in volume and location. Second, due to the complex nature of ICH, it was not possible to exclude possible factors influencing the patient's baseline cognitive level. Nevertheless, our results will serve to improve the prediction of post-stroke cognitive impairment in patients with intracerebral hemorrhage for early cognitive rehabilitation.
Conclusion. Based on the results obtained, an increase in NLR> 3.53 for the first time 24 hours ICH is associated with the development of post-stroke cognitive impairment at 6 months after stroke. Thus, NLR can be used as a marker for the first time 24 hours of spontaneous intracerebral hemorrhage for early prediction of the development of post-stroke cognitive impairment.
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