Following, the receiver operating characteristic analysis (ROC) was employed to compare the predictive abilities of relevant inflammatory predictors for island sign in patients with HE. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the curve (AUC) of NLR for predicting island sign were 76.74%, 79.66%, 40.70%, 94.90%, and 0.817, respectively, the best predictive cut-off value was 14.53 (Fig. 2). The ROC curves and the areas under the curves (AUCs) of laboratory parameters for predicting island sign are also determined in our study, and results elucidated that NLR harbored the best predictive ability for island sign by comparing with other laboratory values (Fig. 2).
Based on the results, we concluded that elevated NLR could independently predict island sign but not HE. Moreover, increasing of both WBC and ANC are associated with the existence of island sign, while lower ANC could independently predict the existence of island sign. Over all the predicative parameters, NLR showed the best predictive ability for island sign. Taken together, we systematically demonstrated that NLR was associated with the outcome of patients with ICH with HE, and might be used as a valuable predictive marker for HE and the existence of island sign.
Accumulating evidences indicated that HE triggered inflammation accelerates brain injury after ICH in patients.[8,9,13,14] Although the relationship between leukocyte and prognosis in patients with ICH was well documented,[15,16] but the link between early HE and subsets of leucocytes was still controversial.[9,8,17,18] In our study, after strictly excluded the confounders, we could not find that WBC, ANC, and NLR act as biomarker in early HE, except an elevation of them were observed. However, WBC, ANC, and ALC were detected to have the strong predictive ability in island sign, which represented an efficient neuroimaging predictor for early hematoma enlargement. As one of the latest neuroradiologic features, island sign may reflect the active bleeding and is supposed to depict multifocal small bleeding hematomas around the main hematoma. Due to this indirect evidence, we expect that all those biomarkers mentioned above exist potential predicting values of early HE in patients with ICH. However, the exact underlying mechanisms of the links between blood routine variables and HE remain elusive and need to further investigate.
The NLR represents a combined index that reflects systemic immune status. As a novel inflammatory marker, it was recently identified to independently predict the progression and outcome of many diseases in human patients.[19–22] Accumulating results from several studies reported that NLR was associated with hematoma size, 30-day mortality, 90-day mortality, and poor outcome in patients with IHC. However, whether NLR could be also used for predicting HE in patients with ICH remains unknown. Here, we revealed that NLR was associated with island sign and showed the best predictive value of this neuroradiologic feature by comparing with other laboratory parameters. But the irrelevance of NLR with hematoma growth in patients with ICH was also observed. The possible reasons of this phenomenon were as follow: firstly, elevating NLR could induce neurotoxicity thus activated the matrix metalloproteinases, which triggered the basal membrane components degradation, BBB breakdown, and brain edema and active bleeding. Secondly, inflammatory cascades were activated by thrombin during HE and resulted the elevation of WBC count, C-reactive protein, and interleukin-6, which further promotes HE.[27,28] At last, cellular immune response was reported to damage coagulation function and microvascular integrity via inducing C-reactive protein (CRP) activation, which is a relatively chronic process.[13,29] Therefore, it is expected that systemic increasing of neutrophil correlated with participates the pathologic progression of active bleeding and contributes to secondary brain injury and poor clinical outcome of patients with ICH with ICH. But further researches need to be conducted to clarify the underlying details in patients with ICH.
There are still some limits in this study. Firstly, all our conclusions were obtained from retrospective study with relative small sample size. A significant proportion of patients were excluded due to unavailable imaging information or missing laboratory parameter from admission blood work which may lead to potential selection bias. Following, we involved a relatively small group of patients with subtentorial ICH, which might not represent the patients with brainstem hemorrhage and cerebellar hemorrhage. Thirdly, as the largest hospital in west of China, we always took the patients with worse clinical condition, which might also bias our results. Finally, ABC/2 method is less accurate than modern planimetric techniques to evaluate hematoma volume.
We demonstrated that NLR was an efficient marker to predict island sign in patients with ICH. Other than that significantly increasing of both WBC and ANC, as well as decreasing of ALC were correlated with HE in patients with ICH. Overall, our findings suggested that systemic cellular immunologic responses may be involved in the pathologic process of active bleeding.
Fan Zhang, Yang M, and Chuanyuan Tao conceived and coordinated the study, designed, performed and analyzed the experiments, wrote the paper. Chuanyuan Tao, Juan Qian, Sen Lin, Yuelong Wang and Fan Zhang carried out the data collection and data analysis. Chao You and Mu Yang revised the paper. All authors reviewed the results and approved the final version of the manuscript.
Conception and design: Zhang F, Yang M, Tao C.
Acquisition of data: Tao C, Zheng J, Qian J, Zhang F.
Analysis and interpretation of data: Zhang F, Yang M, Wang Y, Qian J, Zheng J, Lin S.
Drafting the article: Zhang F, Yang M, Qian J and Tao C.
Supervision: You C.
Review & editing: All the authors.
Data curation: Fan Zhang, Juan Qian, Yuelong Wang, Chao You.
Formal analysis: Fan Zhang, Sen Lin.
Investigation: Fan Zhang, Chuanyuan Tao.
Methodology: Fan Zhang, Juan Qian, Chuanyuan Tao, Yuelong Wang, Sen Lin, Chao You, Mu Yang.
Project administration: Fan Zhang, Sen Lin, Mu Yang.
Software: Yuelong Wang.
Supervision: Chao You, Mu Yang.
Writing – original draft: Fan Zhang, Chuanyuan Tao, Chao You.
Writing – review & editing: Juan Qian, Mu Yang.
. Qureshi AI, Mendelow AD, Hanley DF. Intracerebral haemorrhage. Lancet 2009;373:1632–44.
. Qureshi AI, Tuhrim S, Broderick JP, et al. Spontaneous intracerebral hemorrhage. N Engl J Med 2001;344:1450–60.
. Aronowski J, Zhao X. Molecular pathophysiology of cerebral hemorrhage: secondary brain injury. Stroke 2011;42:1781–6.
. Brouwers HB, Chang Y, Falcone GJ, et al. Predicting hematoma expansion
after primary intracerebral hemorrhage. JAMA Neurol 2014;71:158–64.
. Chan S, Conell C, Veerina KT, et al. Prediction of intracerebral haemorrhage expansion with clinical, laboratory, pharmacologic, and noncontrast radiographic variables. Int J Stroke 2015;10:1057–61.
. Chen S, Zhao B, Wang W, et al. Predictors of hematoma expansion
predictors after intracerebral hemorrhage. Oncotarget 2017;8:89348–63.
. Yu Z, Zheng J, Ali H, et al. Significance of satellite sign and spot sign in predicting hematoma expansion
in spontaneous intracerebral hemorrhage. Clin Neurol Neurosurg 2017;162:67–71.
. Lattanzi S, Cagnetti C, Provinciali L, et al. Neutrophil-to-lymphocyte ratio predicts the outcome of acute intracerebral hemorrhage. Stroke 2016;47:1654–7.
. Silva Y, Leira R, Tejada J, et al. Molecular signatures of vascular injury are associated with early growth of intracerebral hemorrhage. Stroke 2005;36:86–91.
. Kothari RU, Brott T, Broderick JP, et al. The ABCs of measuring intracerebral hemorrhage volumes. Stroke 1996;27:1304–5.
. Davis SM, Broderick J, Hennerici M, et al. Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage. Neurology 2006;66:1175–81.
. Li Q, Liu QJ, Yang WS, et al. Island sign
: an imaging predictor for early hematoma expansion
and poor outcome in patients with intracerebral hemorrhage. Stroke 2017;48:3019–25.
. Kuhlmann CR, Librizzi L, Closhen D, et al. Mechanisms of C-reactive protein-induced blood-brain barrier disruption. Stroke 2009;40:1458–66.
. Lee KR, Colon GP, Betz AL, et al. Edema from intracerebral hemorrhage: the role of thrombin. J Neurosurg 1996;84:91–6.
. Leira R, Davalos A, Silva Y, et al. Early neurologic deterioration in intracerebral hemorrhage: predictors and associated factors. Neurology 2004;63:461–7.
. Sun W, Peacock A, Becker J, et al. Correlation of leukocytosis with early neurological deterioration following supratentorial intracerebral hemorrhage. J Clin Neurosci 2012;19:1096–100.
. Suzuki S, Kelley RE, Dandapani BK, et al. Acute leukocyte and temperature response in hypertensive intracerebral hemorrhage. Stroke 1995;26:1020–3.
. Morotti A, Phuah CL, Anderson CD, et al. Leukocyte count and intracerebral hemorrhage expansion. Stroke 2016;47:1473–8.
. Crumley AB, McMillan DC, McKernan M, et al. Evaluation of an inflammation
-based prognostic score in patients with inoperable gastro-oesophageal cancer. Br J Cancer 2006;94:637–41.
. Xue P, Kanai M, Mori Y, et al. Neutrophil-to-lymphocyte ratio for predicting palliative chemotherapy outcomes in advanced pancreatic cancer patients. Cancer Med 2014;3:406–15.
. Tokgoz S, Keskin S, Kayrak M, et al. Is neutrophil/lymphocyte ratio predict to short-term mortality in acute cerebral infarct independently from infarct volume? J Stroke Cerebrovasc Dis 2014;23:2163–8.
. Brooks SD, Spears C, Cummings C, et al. Admission neutrophil-lymphocyte ratio predicts 90 day outcome after endovascular stroke therapy. J Neurointerv Surg 2014;6:578–83.
. Giede-Jeppe A, Bobinger T, Gerner ST, et al. Neutrophil-to-lymphocyte ratio is an independent predictor for in-hospital mortality in spontaneous intracerebral hemorrhage. Cerebrovasc Dis 2017;44:26–34.
. Wang F, Hu S, Ding Y, et al. Neutrophil-to-lymphocyte ratio and 30-day mortality in patients with acute intracerebral hemorrhage. J Stroke Cerebrovasc Dis 2016;25:182–7.
. Tao C, Wang J, Hu X, et al. Clinical value of neutrophil to lymphocyte
and platelet to lymphocyte ratio after aneurysmal subarachnoid hemorrhage. Neurocrit Care 2017;26:393–401.
. Nguyen HX, O’Barr TJ, Anderson AJ. Polymorphonuclear leukocytes promote neurotoxicity through release of matrix metalloproteinases, reactive oxygen species, and TNF-alpha. J Neurochem 2007;102:900–12.
. Mayer SA, Lignelli A, Fink ME, et al. Perilesional blood flow and edema formation in acute intracerebral hemorrhage: a SPECT study. Stroke 1998;29:1791–8.
. Xi G, Wagner KR, Keep RF, et al. Role of blood clot formation on early edema development after experimental intracerebral hemorrhage. Stroke 1998;29:2580–6.
. Roberts CJ, Birkenmeier TM, McQuillan JJ, et al. Transforming growth factor beta stimulates the expression of fibronectin and of both subunits of the human fibronectin receptor by cultured human lung fibroblasts. J Biol Chem 1988;263:4586–92.
Keywords:Copyright © 2018 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
hematoma expansion; inflammation; intracranial hemorrhage; island sign; neutrophil to lymphocyte