Prognostic Value of Neutrophil to Lymphocyte Ratio in Cerebral Venous Thrombosis Outcomes: Systematic Review

Abstract

Introduction The neutrophil-to-lymphocyte ratio (NLR) is an inflammatory marker that may be associated with the presence and degree of severity of vascular diseases and is a possible predictor of risk and mortality of cerebral venous thrombosis (CVT).

Methods Using PRISMA, the articles were evaluated based on sensitivity, specificity, cut-off, and AUC using the databases PUBMED and BVS. Inclusion criteria of articles were as follows: written in English, in cohort presentation, clinical trial, or control case with the key terms included in the abstract, title, or keywords of the selected articles.

Results A total of 700 articles were analyzed in the databases, obtained through the search string, and evaluated for the exclusion and inclusion criteria previously indicated. Four articles were included in the final analysis. The values of sensitivity (Sen) and specificity (Esp) differed among the articles analyzed, and three of the four articles showed higher specificity. Cut-off and AUC, likewise, differed in most articles, with a lower cut-off value of 2.1 and a higher value of 6.8. The AUC ranged from 0.71–0.77. The simple mean values for Sen and Esp were 62.8% and 78.7%, respectively.

Conclusion The data show that NLR can predict worse outcomes in CVT with moderate values of specificity and sensitivity (Ms Esp 78.7% / Ms Sen 62.8%).

Resumo

Introdução A razão neutrófilo-linfócito (NLR) é um marcador inflamatório que pode estar associado à presença e ao grau de gravidade de doenças vasculares e é um possível preditor de risco e mortalidade de trombose venosa cerebral (TVC).

Métodos Usando o PRISMA, os artigos foram avaliados com base na sensibilidade, especificidade, cut-off e AUC usando os bancos de dados PUBMED e BVS. Os critérios de inclusão dos artigos foram os seguintes: escritos em inglês, em apresentação de coorte, ensaio clínico ou caso controle com os termos-chave incluídos no resumo, título ou Palavras-chave dos artigos selecionados.

Resultados Um total de 700 artigos foram analisados nos bancos de dados, obtidos por meio da sequência de busca e avaliados para os critérios de exclusão e inclusão indicados anteriormente. Quatro artigos foram incluídos na análise final. Os valores de sensibilidade (Sen) e especificidade (Esp) diferiram entre os artigos analisados, e três dos quatro artigos apresentaram maior especificidade. O corte e a AUC, da mesma forma, diferiram na maioria dos artigos, com um valor de corte inferior de 2,1 e um valor superior de 6,8. A AUC variou de 0,71 a 0,77. Os valores médios simples para Sen e Esp foram 62,8% e 78,7%, respectivamente.

Conclusão Os dados mostram que a NLR é capaz de prever um pior resultado na TVC com valores moderados de especificidade e sensibilidade (Ms Esp 78,7% / Ms Sen 62,8%).

Keywords

cerebral venous thrombosis - neutrophil-lymphocyte ratio - inflammatory marker - prognosis - predictor of risk and mortality

Palavras-chave

trombose venosa cerebral - razão neutrófilo-linfócito - marcador inflamatório - prognóstico - preditor de risco e mortalidade

Introduction

Cerebral venous thrombosis (CVT) is a rare neurological condition (∼1% of cases of stroke) that is related to the aggregation of erythrocytes, fibrin, and platelets in the sinuses or dural veins of the brain and has a high degree of severity in all age groups despite being more common in young female adults.[1] [2] [3] [4] [5] [6] CVT cases are estimated at 3–12 cases per million per year.[7]

The clinical signs of this condition vary widely depending on the severity, location, and characteristics of the thrombotic process. The aggravators depend on the patient's age and complications involving the deep or cortical cerebral venous system that increase intracranial pressure, resulting in loss of consciousness.[2] Although the mechanism of CVT is not fully understood, evidence suggests that this condition is related to thrombo-inflammatory processes and risk factors, which include inflammation of the head and face, hypercoagulation, lesions in the vascular walls, and intracranial hypotension.[2] [3] [6] [8] [9] [10]

The prognosis of CVT is hindered by a variety of etiologies and clinical manifestations, with outcomes that vary from total recovery to death.[11] [12] The diagnosis of CVT is often delayed and takes ∼4–7 days after the onset of symptoms.[12] Delay in diagnosis is related to a variety of non-specific manifestations. Patients under the age of 50 years who present with headaches with atypical characteristics, focal neurological deficits, intracranial hypertension, and haemorrhagic infarction should be worked up for a possible diagnosis of CVT.[12] [13] Neuroimaging examinations are fundamental to patient prognosis and progress.[12] [13] Drug treatment for CVT includes anticoagulation, etiologic treatment, and symptomatic therapy; however, the decline in mortality from CVT cases is mainly due to better diagnosis and earlier anticoagulant treatment.[6]

The neutrophil-to-lymphocyte ratio (NLR) is a prognostic inflammatory marker with a high value that may be associated with the presence and higher degree of severity of vascular diseases, classifying it as a risk and mortality predictor of cardiovascular diseases.[3] [14] [15] The ease and low cost of performing the blood count is another advantage in the use of NLR as a prognostic predictor of thrombo-inflammatory diseases, cardiac events, ischemic stroke, neoplasms, sepsis, and infectious pathologies.[3] [16] [17] [18] [19] [20] [21] [22] [23] The NLR integrates information from the innate (nonspecific) and adaptive (specific) compartments of the immune system, categorizing a reliable measure of the body's inflammatory load.[18] Poredoš et al. also indicate a faster NLR in demonstrating the evolution of these diseases.[22]

The NLR was recently postulated as a thrombo-inflammatory marker with a high potential for predicting adverse outcomes and mortality in cases of cerebrovascular diseases, such as CVT.[24] [25] [26] Increased NLR is associated with worsening cases of thrombosis and inflammation as well as an indicator of progressing destructive inflammation.[3] [6] NLR is also seen as a more stable and viable marker than isolated changes in neutrophil or lymphocyte levels.[6] The combination of the NLR with other markers, such as the platelet-to-lymphocyte ratio (PLR), increases the accuracy in the study of clinical pictures of cerebral venous thrombosis.[27] [28] [29] [30]

This study aims to evaluate the prognosis accuracy of higher NLR in patients with CVTBiblioteca virtual.

Methodology

Search for Articles

To conduct this study, following PRISMA guidelines articles and data were collected from the PUBMED and Biblioteca Virtual em Saúde (BVS) platforms using the search string (“Neutrophil to Lymphocyte Ratio” OR “Neutrophil-lymphocyte ratio” OR “Neutrophil/lymphocyte ratio” OR “NLR” OR “Inflammation index” OR “Inflammatory markers” OR “Inflammation mediators” OR “inflammatory Status” OR “inflammation prognostic”) AND (“cerebral venous thrombosis” OR “venous thrombosis” OR “venous sinus thrombosis” OR “deep cerebral venous thrombosis” OR “deep venous thrombosis” OR “intracranial thrombosis” OR “CVT” OR “VTE” OR ” Cerebral sinus venous thrombosis” OR “Cerebral venous and sinus thrombosis” OR “sagittal sinus thrombosis” OR “dural sinus thrombosis” OR “intracranial venous thrombosis” OR “CSVT” deep cerebral venous thrombosis. On the platforms, the filters selected for the search were clinical trials, cohort, and case-control studies between 2010 and 2021. Subsequently, the articles obtained from this search and any relevant references cited in the articles were reviewed by two independent and blinded reviewers, the senior author reviewed discrepancies between them.

Inclusion and Exclusion Criteria

Inclusion and exclusion criteria are shown in [Table 1].

Table 1 Inclusion and Exclusion criteria of articles presents on the study

Inclusion	Exclusion
1. Article must be written in English	1. Incomplete texts
2. Article must be in cohort presentation, clinical trial, or control case	2. Inadequate follow-up of the patients
3. Key terms must be included in abstract and/or title and/or keywords of the selected articles	3. Not expressing results for the research question
4. Adequate analysis score in the NewCastle Ottawa Score	4. Articles that do not show data on sensitivity, specificity, area under the curve, or cut-off value that involve NLR in the context of CVT

Quality Assessment

The selected articles were evaluated using the presence or absence of sensitivity, specificity, cut-off, AUC, and time. Articles that did not have values for these variables were excluded at this stage. Bibliographic citations of the included studies were checked by applying crossed references to find another suitable article.

Articles were submitted for analysis using the Newcastle Ottawa Scale (NOS), a tool developed to assess the quality of nonrandomized studies available at http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. The NOS uses three perspectives to judge the study: the selection of study groups, comparability of the groups, and ascertainment of the exposure or outcome of interest for case-control or cohort studies, respectively. The analysis of the articles presented in this study is shown in [Table 2].

Table 2 NewCastle Ottawa Scale (NOS) scores of the articles in this study

Study analyzed	Score on NewCastle Ottawa Scale (NOS)
Aguiar, D	8
Li, Shen	9
Wang, L	9
Akboga, Y	8

Results

A total of 385 articles were identified in the research, of which 189 were on the PUBMED platform, while 196 were on the BVS network. Of the articles found, 125 were removed as duplicates, and one article, analyzed in its entirety, was likewise removed because it did not contain relevant information for the review. Four of these articles were included using the inclusion criteria described in the methodology. The articles were given a score from the Newcastle-Ottawa Scale (NOS) of 8 for the titles of AGUIAR and AKBOGA and 9 for the articles by Wang and Li, which were considered satisfactory for the analysis of the exposed data ([Table 2]). The article selection process is described in the flowchart recommended by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses platform (PRISMA flowchart).

PRISMA Flowchart

The selected articles were dated from 2016 to 2020, with an analysis period ranging from 33 months[3] to 71 months.[29] The data found in the included articles are listed in [Table 3].

Table 3 Sensitivity Values (SEN), Specificity (ESP), Area under the curve (AUC), Cut off, Number (N), and Period

Author	Year	N	Period	NLR Cut-off	NRL Sen	NRL Esp	AUC
Aguiar, D	2020	62	48 months	5.1	67%	79%	0.71
Li, Shen	2020	270	71 months	6.8	56.5%	83.3%	0.74
Wang, L	2018	95	36 months	4.2	61.5%	86.6%	0.77
Akboga, Y	2016	277	33 months	2.1	66.3%	66%	0.73

Discussion

Cerebral venous thrombosis is related to more severe cases with late diagnosis, and the evolution of the patients has not been fully elucidated. The NLR can be especially important in this scenario to provide information on the patient's inflammatory condition, which helps in the prognosis of patients.

The main results of the analyzed studies show that Aguiar et al. reported an association between higher baseline levels of NLR and worse functional prognosis at the 90^th day in patients with CVT. AKBOGA, which was published in the Journal of the Neurological Sciences, presents similar values of sensitivity and specificity of the NLR and had the lowest cut-off and AUC than those of the other studies. WANG showed an evident difference between specificity and sensitivity among the selected articles. Their paper reported the highest specificity, a cut-off of 4.2, and the highest AUC. Li had the lowest sensitivity, the second highest specificity value, and the highest cut-off. Their AUC was similar to that of the other papers. Finally, AGUIAR presented the highest sensitivity and specificity in the mean values, a cut-off of 5.1, and the lowest AUC. The simple averages of the sensitivity and specificity values were 62.8% and 78.7%, respectively.

Wang et al. revealed that the group with NLR that was higher than the cut-off showed poorer outcomes when compared with patients with good outcomes. The analysis found that the baseline NLR was significantly associated with a high risk of poor outcomes at discharge, suggesting that baseline inflammation could influence and predict the short-term outcomes of CVT and that higher NLRs were significantly and independently related to the presence of CVT.

All articles analyzed showed that the NLR is strongly associated with CVT. Improved results of inflammation biomarkers in gender groups were reported in one of the four studies but were not cited in the others. An important result was the improved effect of NLR on mortality when compared with independent counts of neutrophils or lymphocytes.

Wang L had some significant limitations. As a retrospective study, some data were missing, and the evaluation of the outcome at a fixed time point could not be evaluated. In addition, some patients were lost to follow-up for various reasons; the number of studied inflammatory factors and the study population were too small to obtain an acceptable conclusion. Furthermore, the underlying mechanism of inflammation acting on CVT cannot be precisely explained by this type of clinical study, necessitating further exploration of this aspect. Akboga, Y was a single-center study, and local PLR and NLR values were used for analysis rather than temporal trends.

The analyzed articles provided new data that show the relationship between higher admission NLR and worse prognosis in CVT, which shows that NLR can be useful for the prognosis of CVT when compared with the count of neutrophils and lymphocytes alone.

Our results can be used in clinical practice not alone, but with other factors and the clinicians can make decisions regarding more aggressive therapies or more frequents imagiologic or laboratory follow us for example for ICU discharges, patients with CVT and higher admissions values of NLR should be considered as a risk group for worse outcome (functional outcome).

Conclusion

NLR can predict with moderate accuracy prognosis in patients with CVT, it's a safe, and low-cost tool that can be helpful in clinical practice.

Conflict of Interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Acknowledgments

None.

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Publication History

Received: 20 September 2023

Accepted: 21 October 2024

Article published online:
27 March 2025