Diagnostic performances of neutrophil to lymphocyte ratio and lymphocyte to monocyte ratio in acute ischemic stroke caused by cervicocranial arterial dissection

Abstract Background Inflammation plays an important role in the initiation and progression of cervicocranial arterial dissection (CCAD). New inflammatory indices derived from full cell blood count may be associated with increased risk of acute ischemic stroke (AIS) caused by CCAD. The goal of this study is to evaluate the diagnostic performances of neutrophil to lymphocyte ratio (NLR) and lymphocyte to monocyte ratio (LMR) in CCAD. Method We retrospectively analyzed 52 patients with AIS caused by CCAD from emergency room (group I), 51 patients with CCAD from emergency room or clinic(group II) and 52 controls (group III), age and sex matched. Data were collected on the admission including NLR and LMR. Results Neutrophil to lymphocyte ratio and LMR have significant differences among three groups, especially in group I vs both groups II and III (P < .001). There was a negative correlation between admission NLR and LMR. Low LMR level and high NLR level may be associated with severity of AIS caused by CCAD and significantly predict AIS in CCAD. The area under the curve of NLR and LMR were 0.77 and 0.71, respectively, on receiver operating characteristic curve analysis. The optimal cutoff values of NLR and LMR that best discriminated AIS were 2.35 (81% sensitivity and 63% specificity) and 3.67 (64% sensitivity and 77% specificity). Conclusions Neutrophil to lymphocyte ratio neutrophil to lymphocyte ratio and LMR may contribute to the diagnostic evaluation and prompt immediate therapy in patients with CCAD.


| INTRODUC TI ON
As artery detachment, artery dissection refers to the vascular disease in which blood flow enters the artery wall and causes dissection of vascular wall. 1 Cervicocranial arterial dissection (CCAD) can lead to stenosis or occlusion of the lumen has become one of the most frequent causes for ischemic stroke in the young. 1,2 Patients with CCAD are frequently complicated by coagulopathy and neurological complications, which consisted of permanent neurological dysfunction such as AIS and temporary neurological dysfunction such as headache, delirium, or a transient focal neurological deficit. 1,3 Magnetic resonance imaging (MRI) or computed tomography perfusion imaging is not always obtained for emergency cases although early diagnosis and timely treatment are essential for clinical practice. The application of carotid and cerebrovascular ultrasound increases the detection rate and the diagnostic accuracy of spontaneous CCAD. In general, we still lack a fast and effective way to identify AIS caused by CCAD and aid in risk stratification.
Inflammation plays an important role in the initiation and progression of cardio-cerebrovascular diseases. 3,4 Studies show systemic inflammatory response will push forward an immense influence on the progression and outcome of AIS and aortic dissection(AD). [5][6][7][8] Blood parameters such as neutrophils, lymphocytes, and platelets can derange and influence their respective ratios, which were found to be predictors with diagnostic accuracy in AD, AIS, and other diseases. 5,7,[9][10][11] Among them, NLR and LMR are potential inflammatory biomarkers which have recently been reported as important predictors of overall survival in patients with tumor, intracerebral hemorrhage, or acute ischemic stroke. [12][13][14][15][16] They are easily acquired blood markers through routine complete blood counts (CBC), posing little risk, or burden to the patient.
Dissection is an inflammation-related disease. AIS cause by CCAD may have different inflammatory changes compared to AIS without CCAD. The aim of this study was to evaluate alterations of NLR and LMR levels in AIS caused by CCAD, investigating the diagnostic performance of these blood markers.

| Study population
A total of 103 patients (group I and group II) with cervicocranial arterial dissection in the First Affiliated Hospital of Soochow University from April 2014 to October 2019 were included into subsequent retrospectively analysis. CCAD was initially diagnosed by cervical and cerebral vascular ultrasound or computed tomography angiography (CTA) and was further confirmed by digital subtraction angiography (DSA) or high-resolution magnetic resonance imaging (HR-MRI). AIS was confirmed by MRI. The diagnosis was made by two senior imaging doctors. Exclusion criteria were as follows: (a) Patients had infection within 2 weeks before admission, cancer, chronic inflammation, hematological diseases, morbid obesity (BMI > 32), autoimmune diseases, or treatment with immunosuppressive agents; (b) patients occurred stroke within 6 months or the modified Rankin scale (mRS)>0 before the onset; and (c) patients cannot complete a blood count within 24 hours of admission. We compared them with 52 controls (group III), age, and sex matched. Data were collected from electronic patient records, and all patients gave informed consent.

| Clinical information collection
We collected all study population's data, including demographic, medical histories, and clinical characteristics. Hypertension was determined by the previous use of antihypertensive medication, a systolic blood pressure ≥140 mm Hg, or a diastolic blood pressure ≥90 mm Hg. Diabetes was defined as previous use of hypoglycemic drugs, fasting blood glucose ≥7.0 mmol/L or postprandial blood glucose ≥11.1 mmol/L. Blood count analysis was carried out by autoanalyzer (Japan, Sysmex XS-500i). The serum biochemical parameters were assayed by automatic biochemical analyzer (America, Siemens ADVIA 1800). Laboratory technicians were blind to the clinical characteristics or medical histories of the study population. The National Institutes of Health Stroke Scale (NIHSS) was used to assess the severity of stroke at admission and discharge.

| Statistical analyses
Continuous variables were checked for the normal distribution as-

| RE SULT
The demographic and clinical characteristics of study population are showed in Table 1. There was no difference in age or gender among three groups. As expected, patients in groups I and II were more often with histories of smoking, diabetes, stroke or TIA and hyperlipidemia compared to controls. But there was no significant difference in history of hypertension or drinking among three groups.
Though systolic and diastolic blood pressure on admission were similar in all three groups, headache was more often in CCAD population than controls, and without difference between group I and group II of note.
The NLR level was positively correlated with the NIHSS score on admission (r = −.47, P < .001), and the LMR level was negatively correlated with the NIHSS score on admission (r = −.41, P < .001), respectively. And there was a negative correlation between admission NLR and LMR (r = −.51, P < .001) (Figure 1). High NLR and low LMR levels may be associated with severity of AIS caused by CCAD.
We found that NLR is significantly higher in AIS by CCAD compared to both CCAD without AIS and controls (P < .001, Figure 2), with no significant difference between the last two groups (  Figure 3). For LMR, which is significantly lower in AIS by CCAD compared to both CCAD without AIS and controls (P < .001, Figure 2), with no difference between the last two groups (

| D ISCUSS I ON
We have shown, for the first time, NLR and LMR have significant differences in AIS by CCAD compared to CCAD without ischemic stroke and controls. These objective and fast biomarkers may improve our diagnostic accuracy for AIS caused by CCAD.
Inflammation plays a significant role in both pathogenesis of CCAD and stroke. [17][18][19] Leucocytosis occurs as part of the acute inflammatory process. [22][23][24][25] In previous studies, high neutrophil counts have been associated with adverse prognosis in AD and AIS, whereas high lymphocyte counts have been associated with protective effects in cerebrovascular patients. 6,14,26 And among patients with AD and AIS, it has been shown that an increased NLR is a predictor of in-hospital mortality and prognosis. 6,27 Though our data analysis, the NLR level was positively correlated with severity of stroke on admission. NLR was significantly higher in AIS by CCAD compared to both CCAD without AIS and controls, as were the leukocyte and the neutrophils. Our best cutoff value of NLR with a high degree of sensitivity but fairly low specificity was 2.35. Therefore, NLR is a novel parameter which may indicate inflammation and carry some diagnostic performances in CCAD. Meanwhile, lymphocytes were highest in CCAD without AIS.
This may due to the regulatory function of some specific lymphocyte subsets in inflammation-inducing neuroprotection, 26 which need further exploration on modulating immune response to treat CCAD.
Similarly, LMR has been reported to be associated with adverse prognosis in multiple malignancies and cardio-cerebrovascular disease. 12,13,28-30 Low LMR signifies low lymphocyte count and high monocyte count. As another important immunoregulator different from lymphocyte, monocyte is involved into secondary injury following acute ischemic events. 31 It is considered to differentiate into 3 major subtypes and classical monocyte, for instance, can promote vascular injury and neuronal death after AD and AIS by expressing pro-inflammatory cytokines. 31,32 In previous retrospective analysis, higher proportion of monocyte after stroke was an independent predictor of 3-month poor outcome. 12  Our data should be interpreted with some caution due to limitations of the study. These include retrospective bias inherent to the study design and a small sample size. The association with race and metabolic diseases such as diabetes or nonalcoholic fatty liver disease have not been analyzed. And this study only analyzed the blood samples collected for the first time after admission. Further research need analysis the dynamic changes of this biomarkers during the course of CCAD.

| CON CLUS ION
This study suggests that NLR and LMR on admission as inflammatory biomarkers which might be useful in the diagnosis of AIS by CCAD.
These reliable and easy-to-use predictors could contribute to clinical treatment strategy design in patients with CCAD. And further exploration on modulating immune response to treat CCAD are needed in the future.