Systemic Inflammatory Marker Levels in Serous Macular Detachment Secondary to Retinal Vein Occlusion

Abstract

Purpose:

To evaluate the association of systemic inflammatory marker levels in macular edema with serous macular detachment (SMD) secondary to retinal vein occlusion (RVO).

Methods:

Patients diagnosed with RVO were categorized into two groups based on the presence or absence of SMD: Group 1 included 30 eyes with SMD, while Group 2 included 30 eyes without SMD. Levels of neutrophils, monocytes, lymphocytes, thrombocytes, and mean platelet volume (MPV) were analyzed. Systemic inflammatory markers, including neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII), were calculated and compared between the two groups.

Results:

The mean neutrophil levels were significantly higher in Group 1 (P = 0.002). The mean lymphocyte, monocytes, thrombocyte, and MPV levels did not differ significantly between groups. NLR and SII levels were significantly higher in the SMD group (P = 0.004 and P = 0.016, respectively). There was no significant difference between the groups in terms of PLR. The optimal receiver operator characteristic (ROC) cut-off value of NLR for SMD was calculated as 1.55 with 73% sensitivity and 63% specificity (area under the curve [AUC] = 0.714, 95% confidence interval [CI]: 0.584–0.845). The optimal ROC cut-off value of SII for SMD was calculated as 451.75 with 63% sensitivity and 63% specificity (AUC = 0.681, 95% CI: 0.546–0.816). In this study, branch RVO was present in 48 patients, and central RVO was present in 12 patients. Neutrophil, MPV levels, and NLR, PLR, SII ratios were similar between patients with branch and central occlusion.

Conclusion:

Neutrophil levels, NLR, and SII were found to be significantly higher in eyes with SMD secondary to RVO.

INTRODUCTION

Retinal vein occlusion (RVO) is the second most common retinal vascular disease after diabetic retinopathy.1 Macular edema (ME), seen in about 60% of cases, is the main cause of visual impairment in the majority of RVO patients.2 ME can be accompanied by cystic changes, sponge-like retinal swelling, and serous macular detachment (SMD).3 The mechanism of SMD is still not completely understood. Disruption of retinal pigment epithelium function and excessive fluid leakage from the retinal or choroidal circulation in the ischemic retina affected by RVO are believed to contribute to the development of the condition.4,5

In some studies, inflammatory factors have been reported to be associated with the pathogenesis of SMD. Higher vitreous fluid levels of vascular endothelial growth factor (VEGF), intercellular adhesion molecule-1, interleukin-6 (IL-6), and monocyte chemoattractant protein-1 have been reported in RVO patients with SMD when compared with those with only cystoid macular edema (CME).6,7

Previous studies have suggested that elevated levels of systemic inflammatory markers can be indicative of systemic inflammation and oxidative stress.8,9,10 The relationship between RVO and indicators of systemic inflammation, such as the neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR), was previously assessed in RVO, and higher levels of these indicators were reported.11,12 The association between systemic inflammation and SMD secondary to RVO is unclear. It is controversial whether SMD is specifically associated with certain serum inflammatory factors or local inflammation. Elevated levels of systemic inflammatory mediators may contribute to the development and progression of RVO, ME, and SMD.12

To the best of our knowledge, no previous studies have reported on the association between serum inflammatory marker levels and SMD in RVO. In the present study, we aimed to investigate systemic inflammatory marker levels in patients with ME with and without SMD secondary to RVO.

METHODS

Medical records of patients diagnosed with RVO who were examined in the retina department between 2016 and 2020 were retrospectively analyzed. The study conducted adhered to the tenets of the Declaration of Helsinki rules and informed consent forms were obtained from all participants. Ethics committee approval was received from the local ethics committee for conducting the study (E-71522473-050.01.04-621).

Patients with ME secondary to RVO are divided into two groups according to the presence of SMD in optical coherence tomography (OCT) images. Group 1 consisted of 30 eyes with SMD, and Group 2 consisted of 30 eyes without SMD.

Patients with presence of retinal pathologies other than RVO (previous retinal artery occlusion, diabetic retinopathy, hypertensive retinopathy, and senile macular degeneration) were excluded from the study. In addition, patients with a history of prior ocular surgery, laser photocoagulation, and/or intravitreal injections were excluded. Those with known glaucoma, dry eye, previous history of malignancy, autoimmune disorders, liver and kidney dysfunction, hematological disorders, inflammatory diseases, and those currently using systemic steroids or immunomodulators were also excluded from the study.

A detailed history, physical examination, and clinical consultations were carried out and additional systemic diseases like hypertension and diabetes mellitus were evaluated. All of the patients underwent a complete ophthalmologic examination, including best-corrected visual acuity (BCVA) measured by Snellen chart, anterior segment evaluation by slit-lamp biomicroscopy, intraocular pressure measurement by noncontact tonometry, dilated fundoscopic examination using a 90-diopter lens, fundus color photography, fluorescein angiography, and spectral-domain OCT (Cirrus, Carl Zeiss Meditec Inc, Dublin, CA).

Central macular thickness (CMT) was evaluated using macular thickness scanning protocol with OCT device after pupil dilation. Standard macular imaging consisted of the macular cube (512 128) and the 5 Line Raster scanning protocols and the presence or absence of SMD was evaluated. Patients were divided into two groups according to the presence of SMD in the OCT at the time of diagnosis.

Laboratory data of RVO patients which were obtained at the time of RVO diagnosis were retrospectively analyzed from the hospital computer database. Neutrophil, lymphocyte, monocyte, platelet counts, and mean platelet volume (MPV) were obtained from peripheral venous blood samples using a Cell-DYN 3700 automated hematology analyzer (Abbott Diagnostics, Abbott Park, IL, USA). NLR was calculated by dividing the neutrophil count by the lymphocyte count and PLR by dividing the platelet count by the lymphocyte count. Systemic immune-inflammation index (SII) was calculated on the basis of platelet, neutrophil, and lymphocyte counts using the formula: Platelet × Neutrophil/Lymphocyte count.

Statistical analyses were performed using the SPSS version 21.0 statistical software package (SPSS Inc., Chicago, IL, USA). The normality of distribution of the continuous variables was determined using the Kolmogorov–Smirnov test. Differences of categorical variables between groups were analyzed using the Chi-squared test. Paired t-test was used for normally distributed data and Mann–Whitney U test was used for non-normally distributed data to compare the levels of systemic inflammation indices between groups. Receiver operator characteristic (ROC) curve analyses were performed to identify the optimal cut-off points of SII, NLR, and PLR (at which sensitivity and specificity would be maximal) for the prediction SMD. Areas under the curves (AUCs) were calculated as measures of the accuracy of the tests. P < 0.05 was considered statistically significant.

RESULTS

A total of 60 eyes were included in the study: 30 RVO patients with SMD (Group 1), 30 RVO patients with only CME (without SMD) (Group 2). The mean age was 66.4 ± 11.9 and 66.3 ± 9.5 years in groups, respectively. There were no statistically significant differences in terms of age and gender (P = 0.740, P = 0.184, respectively). In Group 1 and Group 2, 24 eyes had branch RVO (BRVO) and 6 had central RVO (CRVO).

No significant differences were found in the prevalence of systemic risk factors between the patient groups. Hypertension was the most common systemic risk factor in both groups [Table 1].

Table 1.

Demographic features and laboratory findings in the groups

	Group 1 (SMD +) (n=30)	Group 2 (SMD −) (n=30)	P
Age (years)	65.4±11.9	66.3±9.5	0.740a
Gender (male/female)	21/9	16/14	0.184c
RVO (CRVO/BRVO)	24/6	24/6	0.891c
Presence of DM, n (%)	12 (40)	14 (46.6)	0.380c
Presence of HT, n (%)	17 (56.6)	19 (63.3)	0.281c
Presence of CVD, n (%)	7 (23.3)	5 (16.6)	0.324c
Neutrophils (109/L)	4.92±1.94	3.57±1.15	0.002a
Lymphocytes (109/L)	2.31±0.75	2.41±0.81	0.842a
Monocytes (109/L)	0.46±0.23	0.49±0.21	0.487b
Platelets (109/L)	276.53±96.84	252.60±63.42	0.379a
MPV (fL)	8.46±1.11	7.96±1.37	0.055b
NLR	2.62±2.55	1.55±0.48	0.004a
PLR	148.4±163.26	114.47±43.71	0.483a
SII	866.6±1607.2	399.80±161.84	0.016a

^aPaired t-test, ^bMann–Whitney U-test, ^cChi-square test. Significant P values are given in bold. RVO: Retinal vein occlusion, CRVO: Central RVO, BRVO: Branch RVO, DM: Diabetes mellitus, HT: Hypertension, CVD: Cardiovascular disease, SMD: Serous macular detachment, MPV: Mean platelet volume, NLR: Neutrophil-lymphocyte ratio, PLR: Platelet-lymphocyte ratio, SII: Systemic immune inflammation index

The BCVA was 0.21 ± 0.17 in Group 1 and 0.17 ± 0.17 in Group 2 (P = 0.308). The mean intraocular pressure was 16.1 ± 2.8 in Group 1, and 16.1 ± 3.8 mmHg in Group 2 (P > 0.05) [Table 1]. The CMT thicknesses were 651.94 ± 110.45 in Group 1 and 513.62 ± 98.56 in Group 2 (P = 0.02). The CMT thickness was significantly higher in the SMD group.

The laboratory data of groups are shown in Table 1. The mean neutrophil count was significantly higher in Group 1 (P = 0.002). Mean lymphocyte, monocytes, thrombocyte levels, MPV, and PLR did not differ significantly between groups (P = 0.842, P = 0.487, P = 0.379, P = 0.055, and P = 0.483, respectively).

The mean NLR value was 2.62 ± 2.55 in Group 1 and 1.55 ± 0.48 in Group 2 (P = 0.004). The mean SII value was 866.06 ± 1607.26 in Group 1 and 399.80 ± 161.84 in Group 2 and it was significantly higher in Group 1 (P = 0.016).

The optimal ROC cut-off value of NLR for SMD was calculated as 1.55 with 73% sensitivity and 63% specificity (AUC: 0.714, 95% confidence interval [CI]: 0.584–0.845). The optimal ROC cut-off value of SII for SMD was calculated as 451.75 with 63% sensitivity and 63% specificity (AUC: 0.681,95% CI: 0.546–0.816) [Figure 1].

Figure 1.

Receiver operator characteristic curve of neutrophil-lymphocyte ratio and systemic immune inflammation index for the prediction of serous macular detachment. ROC: Receiver operator characteristic

Of the 60 patients included in this study, BRVO was present in 48 patients, and CRVO was present in 12 patients. Neutrophil, MPV levels, and NLR, PLR, SII ratios were similar between patients with branch and central occlusion (P = 0.456, P = 0.731, P = 0.540, P = 0.217, and P = 0.439, respectively).

DISCUSSION

The results of our study showed that neutrophil levels, NLR and SII were significantly higher in RVO patients with SMD. Conversely, other measured systemic inflammatory marker levels were similar in eyes with and without SMD.

In RVO, systemic risk factors include hypertension, diabetes, thrombophilia, and atherosclerotic risk factors such as dyslipidemia, cardiovascular disease, and obesity.13,14,15 Atherosclerosis and thrombosis are known to increase the risk of RVO, and these conditions are closely linked to underlying inflammation.13,16 In the literature, there are many studies on various systemic and ophthalmic diseases, with different results. Systemic inflammatory markers have been used as an indicator of inflammation in many systemic diseases including diabetes, cardiovascular disease, cancers and ocular diseases including dry eye, primary open-angle glaucoma, senile macular degeneration, and retinal vascular occlusions.8,9,17,18,19,20,21,22,23 Conflicting results may be due to the role and level of inflammation in these various diseases. These markers become more prominent in diseases such as uveitis, dry eye, and glaucoma, where inflammation plays a significant role. In literature, an association between increased systemic inflammatory marker levels and retinal vascular diseases such as RVO, retinal artery occlusion, and diabetic retinopathy was reported.18,19,20 Chronic local and systemic inflammation which leads to endothelial dysfunction, leukocyte extravasation, thrombosis, and development of atherosclerotic plaque might be implicated in the mechanisms underlying the development of RVO.16,24

Neutrophils and lymphocytes promote an activation in acute or chronic inflammation. NLR, which is an indicator of the balance of the neutrophils and the lymphocytes, provides information on both inflammatory conditions and the stress response.9 In many studies, it has been shown that NLR is elevated with diabetes, and correlates with the severity of the disease.17,18,25 Farah et al. concluded that NLR could be a predictor of acute venous thromboembolism.10 In a meta-analysis of 8 studies, Liu et al. reported that the NLR and PLR were significantly elevated in patients with RVO compared with controls.12 Different results have been previously reported due to variations in study design and characteristics of the patient groups. Şahin et al. demonstrated an association between higher NLR and PLR values with the development of RVO. However, in contrast, Turkseven Kumral et al. reported no significant difference in NLR and MPV between the RVO and control groups.20,26

Despite the unclear pathophysiology of SMD, several studies have indicated potential associations between inflammation and the occurrence of SMD.6,7 Noma et al. reported that increased VEGF and IL-6 are involved in the pathogenesis of SMD associated with CRVO.6 Park et al. concluded that aqueous humor VEGF levels were higher in patients with SMD compared to patients without SMD.27 Although the association between aqueous and vitreous proinflammatory factors and SMD secondary to RVO has been reported previously, the impact of systemic inflammation on SMD has not been investigated thus far.7,27 Elevated levels of systemic inflammatory mediators may participate in the development and progression of RVO, ME, and SMD. Microvascular changes secondary to RVO lead to tissue ischemia, increased permeability, breakdown of the blood-retinal barrier, and edema.6 The breakdown of the blood-retinal barrier could facilitate extracapillary leakage of serum proteins and their passage from the bloodstream into the vitreous fluid, thereby enabling the serum to have an effect on intravitreal protein levels.6 The present study results showed that neutrophils (an indicator of inflammation), NLR, and SII levels were significantly higher in RVO patients with SMD. Our results may be related to the breakdown of the blood–retinal barrier, which is driven by the inflammation and oxidative stress in RVO especially in patients with SMD.

SII which is composed of the combination of three peripheral inflammatory cells, could better reflect the local immune response and systemic inflammation status than other inflammatory parameters.8,28 It has been evaluated in various ocular diseases such as primary open-angle glaucoma, dry eye, retinal vascular occlusion, and diabetic retinopathy, and it has been reported that the SII was significantly higher in these patient groups.12,21 Similarly, in our study, the SII was significantly higher in RVO patients with SMD.

MPV which reflects the states of platelets is associated with inflammation. Platelets with a higher MPV are known to exhibit increased metabolic activity, which may be associated with an elevated thrombotic potential. There is a positive correlation between increased MPV levels and occlusive diseases such as stroke and myocardial infarction.29 Şahin et al. reported higher MPV levels in RVO patients.26 Conversely, some studies have not shown any relationship between MPV and RVO.20,30,31 In concordance with the results of Ornek et al.’s. study, MPV values were similar between the groups in our study.

There were some limitations in the current study. First, due to the retrospective nature of the study, some serum inflammatory markers such as C-reactive protein could not be evaluated. Other inflammatory markers may reveal additional information about inflammatory status. Second, the study did not evaluate local inflammatory factors, which would have enabled the analysis of the correlation between systemic and local inflammatory factors. These results could have provided insights into whether local or systemic inflammatory factors play a more predominant role in the development of SMD in RVO. Third, the current study consisted of patients with diabetes and hypertension which may affect the inflammatory status; however, our study groups had similar proportion of patients with hypertension and diabetes. Studies focused on patients without any other systemic risk factors would be more appropriate for definite conclusions. Further clinical studies with a greater number of cases are needed to better understand the association between systemic inflammation and SMD in RVO patients.

In conclusion, neutrophil, NLR, and SII levels were elevated in RVO patients with SMD. To our knowledge, this is the first study evaluating serum inflammation markers in RVO patients with and without SMD, and our results demonstrate that increased systemic inflammatory mediators might be associated with a higher incidence of SMD. However, to better understand the relationship between systemic inflammatory markers and the prediction and prognosis of RVO, further studies are needed in patients without any other general risk factors.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.