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INTRODUCTION

Improvement in success rates of rhegmatogenous retinal detachment (RRD) has been limited over the past decades.1 Several clinical and biochemical factors have been implicated in the visual and anatomical outcome after RRD. A better understanding of the underlying mechanisms in RRD is needed to reduce the burden of this sight-threatening condition.

S100B is a Ca+2-binding protein that is expressed in astrocytes and is involved in the regulation of several intracellular activities such as proliferation and differentiation. Several studies have shown that

S100B is a sensitive measure for determining central nervous system (CNS) injury at the molecular level before substantial changes develop. Lately, serum and cerebrospinal fluid (CSF) concentrations have been utilized as a biomarker that helps to predict the functional outcome in the acute phase of brain dam-age and neurodegenerative diseases.2–8

As being a neural tissue, retina is subject to similar mechanisms and histopathological changes with CNS. S100B has also been detected in various cells of the retina including glial cells (i.e. Müller cells) and neuronal cells of the retina.9 In this prospective study, we have investigated the relevance of S100B

Current Eye Research, 37(11), 1030–1035, 2012© 2012 Informa Healthcare USA, Inc.ISSN: 0271-3683 print/1460-2202 onlineDOI: 10.3109/02713683.2012.696769

Received 20 October 2011; revised 09 April 2012; accepted 19 May 2012

Correspondence: Ozgur Yalcinbayir, M.D., Uludag Universitesi Tip Fakultesi, Goz Hst. AD, Gorukle, 16059, Bursa, Turkey. Tel: + 90 532 774 1173. Fax: + 90 224 442 8070. E-mail: yalcinbayir@superonline.com; yalcinbayir@uludag.edu.tr

20October2011

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Original article

S100b Protein Levels in Subretinal Fluid in Rhegmatogenous Retinal Detachment

Ozgur Yalcinbayir1, Rifat Levent Buyukuysal2, Berna Akova-Budak3, and Oner Gelisken4

1Department of Ophthalmology, Uludag University School of Medicine, Bursa, Turkey, 2Department of Pharmacology, Uludag University School of Medicine, Bursa, Turkey, 3Department of Ophthalmology, Uludag University School of Medicine, Bursa, Turkey, and 4Department of Ophthalmology, Uludag University School of Medicine, Bursa, Turkey

ABSTRACT

Purpose: To investigate the relevance of the concentration of S100B in subretinal fluid (SRF) with the postop-erative anatomical and functional success and proliferative vitreoretinopathy (PVR) formation parameters in rhegmatogenous retinal detachment (RRD).

Methods: Fifty-three patients (34 male, 19 female) were included in this prospective study. Study group con-sisted of 46 patients who had scleral buckling (SB) surgery with the diagnosis of RRD. Control group consisted of six patients who had pars plana vitrectomy (PPV) for either full-thickness macular hole or subluxated intra-ocular lens. SRFs were obtained during SB surgery. Study cases were divided into three groups, corresponding to the duration of retinal detachment (DRD). Clinical characteristics including best-corrected visual acuity (BCVA), anatomical status at 6 months, the presence of postoperative PVR that resulted in recurrent detach-ment and any possible re-operations were recorded. The concentration of S100B was quantified by using an enzyme immunoassay test kit.

Results: The concentration of S100B in SRF increased significantly after RRD. And, S100B levels were evidently elevated in concordance with DRD. There was no correlation between the concentration of SRF – S100B with preoperative or postoperative BCVA. Again, S100B levels were not related to the extent of RRD or postopera-tive PVR formation.

Conclusion: Concentration of S100B in SRF is good marker of retinal stress and increases in concordance with DRD. However it would not help to predict the possible anatomical and functional success or postoperative PVR formation.

KEYWORDS: Retinal detachment, Subretinal fluid, S100B

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S100b levels in Subretinal Fluid

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concentration with the postoperative anatomical and functional success and PVR formation parameters in RRD. Accordingly we have measured the levels of S100B in SRF of cases who underwent conventional retinal detachment surgery and evaluated its use as a prognostic factor.

METHODS AND MATERIALS

Fifty-three patients (34 male, 19 female) were included in this university practice based, prospective and cross-sectional study within 19 months. Study group consisted of 46 patients who had scleral buckling (SB) surgery with the diagnosis of RRD. Control group con-sisted of six patients who had pars plana vitrectomy (PPV) for either full-thickness macular hole (n = 5) or subluxated intraocular lens (n = 1).

Cases with the diagnosis of RRD and those who were eligible for conventional SB surgery were selected for this study. Among those, cases whose subretinal fluids (SRFs) could be obtained were enrolled in the study. Patients were asked to estimate the duration of retinal detachment (DRD) definitely. DRD was defined as the time between onset of symptoms of sudden significant visual loss and surgery. Eyes with vitreous hemorrhage or any other coexistent ocular disease including high myopia (> –6 diopters) were excluded. Individuals with bleeding disorders and those who have more complicated detachments, such as giant retinal tears and patients with PVR grade C1 and higher, were not included in the study. In addition, patients who had any prior ocular surgery other than uncomplicated cataract extraction were excluded. The study was carried out with the approval of the local ethics committee and each case provided a written informed consent.

Each study participant underwent a comprehensive ophthalmologic examination, including inquiry of DRD, best-corrected visual acuity (BCVA) assesment and slit-lamp biomicroscopy. BCVA was assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart and converted to logarithm of the minimum angle of resolution (logMAR). In order to analyze our results, study cases were divided into three groups, correspond-ing to the following intervals: DRD up to 10 days (n = 13), DRD longer than 10 days and up to 30 days (n = 23), and DRD longer than 30 days (n = 10). These study subgroups were named as acute, subacute and chronic subgroups, respectively. All cases had a minimum of 6 month follow-up. The following postoperative clini-cal characteristics were recorded; BCVA, anatomical status at 6 months, the presence of postoperative PVR that resulted in recurrent detachment and any possible re-operations.

Preferably, SRF drainage was performed in eyes with relatively extensive detachments (≥3 clock hours). Again SRF was drained in highly elevated breaks and long-standing RRDs. In all cases, drainage was performed

before cryotherapy. Essentially, SRF fluid drainage was performed, using a 26-gauge needle attached to a 2-ml syringe without the plunger, as previously described.10 The needle was inserted perpendicular to the sclera, and the upsurge of fluid was seen in the transparent hub of the needle. After acquiring a minimum of 0.1 ml of SRF, the needle was withdrawn allowing spontane-ous drainage of the SRF. Sample volumes ranged from 100 µl to 1 ml. In four cases (%8.6) of the study group, due to technical straits, free-flowing SRF was aspirated from the lower fornix with a cannula. Undiluted vit-reous samples of the control group (n = 6) were col-lected during PPV, before the infusion line was opened. Vitreous was aspirated manually, via a 3 cm3 syringe. Vitreous and SRF samples were stored initially at +4°C, then moved to –80°C, as soon as possible.

Protein S100B quantification was determined by using an enzyme immunoassay test kit (BioVendor R&D LLC, Candler, NC) which was specific for the β-subunit of the S100 protein. This assay measures the β-subunit concentration in both ββ and αβ isoforms of the protein. Samples were initially diluted with distilled water (dilu-tion ratio 1/20) and 100 µl of diluted samples were used for protein S100B assay.

All statistical analyses were performed using SPSS software version–13.0 (SPSS Inc, Chicago, IL) and P values less than 0, 05 were considered statistically significant. All values have been presented in terms of mean values and standart error of mean. Kruskal Wallis and Mann Whitney U tests were used to compare the results.

RESULTS

Fifty-two eyes of 52 patients (33 male, 19 female) were enrolled in the study. Study group consisted of 46 patients (29 male, 17 female) with a mean age of 57 ± 2.1 (range: 11–79) years. Six patients (4 male, 2 female) were included in the control group, the mean age of control cases were 67.6 + 1.7 years (range: 63–73). There was no significant difference in terms of demographic informa-tion between the two groups or within the subgroups (p > 0.05). Twenty-nine eyes (%63.0) of the study group were phakic, 15 were psedophakic (%32.6) and the remaining 2 (%4.3) eyes were aphakic. No significant intraoperative complications, such as subretinal hemor-rhage or incarceration, occurred in any of the 53 eyes.

Average follow-up was 7.5 ± 0.06 months (6 months to 14 months) for the study group and 6.7 ± 0.3 months (6 months to 11 months) for the control group. For all study eyes, mean DRD was 44.6 days (range: 5 days to 18 months). Mean preoperative BCVA for the study group and the control group were 2.05 ± 0.2 and 2.22 ± 0.5 logMAR units respectively. Mean postoperative BCVA significantly improved to 1.04 ± 0.1 logMAR units in the study group (p < 0.001) and 0.88 ± 0.1 logMAR units in the control group (p < 0.05).

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Mean value of S100B protein was 2655 ± 29.6 pg/ml in the study group whereas it was 141.1 ± 26 pg/ml in the control group. There was a statistically significant difference between the two groups (p < 0.001). Evaluation of the subgroups demonstrated that, S100B levels tend to rise as the DRD gets longer. (Table 1). Among all subgroups, concentration of S100B was the highest in the chronic sub-group. Mann Whitney U test revealed that there was statistically significant difference only between the acute (DRD: 1–10 days) and the chronic (DRD ≥ 30 days) sub-groups (p < 0.01). Our results suggest that S100B levels were not affected by preoperative BCVA or postoperative BCVA (p > 0.05).

Primary anatomical success rate was 76.0 % at the 6th month follow-up. Mean concentrations of S100B were 2983 ± 38.9 pg/ml and 2726.6 ± 60,5 pg/ml pg/ml in the primary anatomical success group and re-operation groups, respectively. There was no statistically signifi-cant difference between the two groups (Table 1). No correlation existed between the anatomical success of the re-operation group and the levels of S100b. Statistical analysis revealed that the concentration of S100B in SRF had no relevance with the extent of detachment (p > 0.05). Readings of S100B were similar in cases who had macula-on and macula-off RRDs. Again, the method of obtaining SRF did not influence the levels of S100B (Table 1).

DISCUSSION

In the last decade, S100 protein family members have drawn widespread attention in various disciplines of medicine. The S100 family is a group of cytosolic pro-teins that contains EF-hand calcium-binding domains and actually consists of more than 20 members

including S100A1 and S100B.11 In the literature, research regarding S100 proteins have a wide range, however the exact role of S100 proteins is not completely understood.

S100B is one of the most studied S100 proteins; espe-cially its role in connection with CNS has been investi-gated in detail. Several studies have shown that S100B is a reliable marker of blood–brain barrier permeability and CNS injury.12,13 Serum levels of S100B, measured beyond 24 h after acute ischemic stroke onset, have demonstrated significant correlation with brain dam-age.2–4,14 Currently serum levels of S100B is being used to select patients with minor head injury who do not need further neuroradiological evaluation. Several stud-ies have compared CT scans with serum levels of S100B and have concluded that values below certain levels are associated with low risk of prominent neuroradiological changes or significant clinical sequelae.15 The significant elevations of S100B in CSF and in serum, in conjunction with or without NSE, have also been used to predict neurological prognosis after resuscitation in cardiac arrest.16,17 Recently, Ide et al. have suggested that early increase in levels of CSF S100B after carbon monoxide poisoning may be used as a predictor of a possible persistent vegetative state.18 Sen et al. summarized the above outlined situation in their current report. The authors have underlined the diagnostic value of serum and CSF concentrations of S100B as a screening tool and progression parameter for CNS injury and compared it with the role of C-reactive protein (CRP) as a marker of systemic inflammation.8

S100B concentration in cerebrospinal fluid (CSF) or serum can also be considered as a suitable surrogate marker for the diagnostic or prognostic assessment of a variety of diseases. Recently Jung et al. have reported that S100B concentrations in CSF seems promising to discriminate bacterial from viral meningitis.19 Again,

TABLE 1 Mean concentration of S100B and standard error of mean in different groups of the study.Description Mean concentration of S100B (pg/ml)Control group (n = 6) 141.1 + 26.3Study group (n = 46) 2655.0 + 29.6†

Acute sub-group (DRD: < 10 days (n = 13)) 2065.0 + 334.3†

Subacute sub-group (DRD: 11 – 30 days (n = 23)) 2681.3 + 246.0†, a

Chronic sub-group (DRD: > 31 days (n = 10)) 3362,6 + 250,0†, b Anatomical success (n = 35) 2983 + 31.1†

Anatomical failure (n = 11) 2726.6 + 99.0 †, c

Macula on RRD (n = 11) 2658.1 + 112.1 †

Macula off RRD (n= 35) 2625.3 + 14.9†, d

SRF obtained with needle drainage (n = 42) 2655 + 32.4†

SRF obtained with fornix aspiration (n = 4) 2065 + 301.3†, e

† Statistically significantly different than the control group (p < 0.001).aNo statistically significant difference between the acute sub-group (DRD: < 10 days) and the subacute sub-group (DRD: 11–30 days)

(p > 0.05).bStatistically significant difference between the acute sub-group (DRD: < 10 days) and the chronic sub-group (DRD: > 30 days)

(p < 0.01).cNo statistically significant difference between the anatomical success subgroup and the anatomical failure sub-group (p > 0.05).dNo statistically significant difference between those who have macula on RRD and those who have macula off RRD (p > 0.05).eNo statistically significant difference between the two methods of obtaining SRF (p > 0.05).

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serum levels of S100B have been proposed as a suitable biomarker for the relapse of neuromyelitis optica.20 Since the 1980s it has been known that patients with multiple sclerosis have higher levels of S100b concentrations in CSF and serum.21 At the present, these parameters are considered as a convenient tool for monitoring immunosuppressive therapy in those cases.22 On the other hand, recently published results of Falcone et al. suggest that serum levels of S100B could be used as an adjunctive biomarker to assess suicidal risk in patients with mood disorders or schizophrenia.23 Furthermore, higher levels of S100B have been detected in serum or CSF of patients who were suffering from Alzheimer disease or Down syndrome and it has been shown that S100B is also released from malignancies including schwannoma, melanoma and neuroblastoma.14,24

For a long time, S100B has been thought as a glial marker protein in the nervous system. Previously Müller cells were considered among extracerebral sources of S100B and believed to be the only source within the eye.25,26 However, emerging data showed that S100B is present in several layers of the retina. S100B has been demonstrated in the outer limiting membrane, outer nuclear layer, outer plexiform layer and in neuro-nal cells of inner nuclear layer, ganglion cell layer, and the inner limiting membrane of the retina. On the other hand, S100A1 has been found to display a more limited distribution, S100A1 is found mostly in the outer seg-ment of photoreceptors.9

In the current study, our results showed that the con-centration of S100B in SRF, increases significantly after RRD. In addition, S100B levels are explicitly elevated in concordance with DRD. Among all study participants, chronic cases (DRD longer than 30 days) have had the highest readings of S100B. Statistical significance was present between the acute (DRD: 1–10 days) and the chronic (DRD ≥ 30 days) sub-groups. We could not find any correlation between the concentration of SRF- S100B with preoperative or postoperative BCVA. S100B levels were not related to the extent of RRD or the postopera-tive anatomical and functional success. Statistical analy-sis showed that S100B could not indicate an upcoming postoperative PVR formation.

A review of the literature shows that only a few pub-lications exist regarding the SRF levels of S100 proteins. The study of Cochran et al. is related to detection and quantification of S100 protein in ocular melanomas. The authors have found various amounts of S100 protein in SRF and high levels of S100 protein were associated mainly with hypomelanotic tumours.27 The other publication is a work by Quintyn et al. and has focused on assessing the cellular damage after RRD.28 In the latter publication, authors quantified SRF levels of neuron-specific enolase (NSE) and S100 protein in order to assess neuronal suffering in RRD. Twelve cases were included in the study. The results of the study showed that both S100 and NSE increased after RRD. No correlation was found between S100 concentration

and the duration or extent of RRD. The authors have concluded that these two parameters, when assessed in SRF, express cellular damage and are good markers of retinal stress. Our results are parallel to the findings of Quintyn et al. However, we suppose that the results of Quintyn et al. are reflecting the combined function and the levels of various proteins in S100 family.

The precise role and the mechanisms of S100B in the retina is not known yet. Recent studies have dem-onstrated that both S100B and S100A1 are associated with disc membrane-bound guanylate cyclase activ-ity and play a role in the mechanism of phototrans-duction.9 Current evidence shows that S100B exerts functional roles by acting as an intracellular regulator and an extracellular signal. Intracellularly S100B acts as a stimulator of proliferation and migration and an inhibitor of apoptosis and differentiation.29 On the other hand, extracellular S100B has a dual concentra-tion dependent effect via interaction with the recep-tor for advenced glycation end products (RAGE) in neuronal cells. Accordingly, S100B stimulates neuronal growth and survival in lower concentrations, however, in higher concentrations it shows an opposite effect and may induce neuronal apoptosis. RAGE is a mul-tiligand receptor that has been associated with both neuroprotection and neurodegeneration and inflam-matory response.30 Ligands of cellular RAGE have also been detected in the vitreous cavity31; suggesting that similar mechanisms may apply to the retina.

In this study, we suppose that the elevated levels of S100B in SRF is a result of the ischemic insult that affects the outer neural retina. Inherently, separation of neural retina and pigment epithelium leads to the lack of nutrient and oxygen supply in the outer retina and thus causes an ischemic insult. In support of the above-mentioned conclusion, we observed that S100B levels tend to rise as the DRD gets longer. Namely, levels of SRF S100B in the chronic subgroup were significantly different from those in the acute subgroup (p < 0.01). This observation may point out that prolonged ischemia in case of retinal detachment causes prominent increase in S100B levels. However, we do not know whether the levels of S100B are elevated as a consequence of isch-emia or as a response to ischemia. It is still unknown whether elevated levels of S100B exert a protective effect against ischemia or enhances degeneration dur-ing ischemia.

To the best of our knowledge, no study has, as yet, focused particularly on the concentration of S100B in SRF and its relevance with the postoperative features of RRD. The results presented in this study are in concordance with the notion that S100B is a damage-associated molecular pattern factor. As previously outlined, S100B is released in case of a tissue injury and may participate in inflammation and tissue repair or the pathophysiology of chronic inflammation, depending on its local concentration.29–32 Our results do not suggest whether or not S100B may participate in

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the pathophysiology of RRD or PVR. However, severe forms of PVR cases were not included in this study and eventually, it was not possible to compare S100B protein levels between severe and mild forms of PVR in RRD. There are some limitations in our study; the small number of subjects and the relatively short follow-up can be listed. On the other hand, some modifications in the setting of our study might have been picked at the first place to eliminate some drawbacks. Actually, the origin of SRF is derived from liquefied vitreous, herewith questions may be raised about the accuracy of a comparison between SRF and vitreous. Although this approach is widely accepted, concentrations of S100B might have been assessed in samples of serum together with SRF and vitreous in order to avoid such concerns. Furthermore, it might have been useful to study SRF levels of S100B together with NSE which is a biomarker that reflects neuronal suffering, and see whether they contribute better in predicting anatomical and functional outcome.

Yet, pathophysiologic and prognostic factors about RRD still remains insufficiently enlightened. Everyday new prognostic markers, such as SRF levels of low transforming growth factor-β 2, are being identified as predictors of postoperative PVR formation and func-tional outcome.33 Our results demonstrate that S100B values of SRF would not help to predict the possible anatomical and functional success. It is likely that SRF levels of S100B is far from being a prognostic marker of postoperative PVR formation.

In our opinion, S100B is an open area for research in the field of ophthalmology and medicine. Still several studies are ongoing on developing inhibitors of S100 proteins.34 Novel studies can be done regarding the value of S100B and S100A1 in retinal diseases. It would be interesting to see whether the degree of ischemic insult and blood barrier distruption may be determined in retinal vascular diseases like retinal vein occlusion and diabetic retinopathy. Ocular fluid assessments could be of value in the research efforts.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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