Ophthalmic Surgery, Lasers and Imaging Retina

Clinical Science 

An Evaluation of the Relationship Between Clinically Unilateral Pseudoexfoliation Syndrome and Age-Related Macular Degeneration

Mehmet Ozgur Zengin, MD; Omer Karti, MD; Eyyup Karahan, MD; Tuncay Kusbeci, MD

Abstract

BACKGROUND AND OBJECTIVE:

To evaluate the relationship between age-related macular degeneration (AMD) and clinically unilateral pseudoexfoliation syndrome (XFS).

PATIENTS AND METHODS:

Seventy-six patients (152 eyes) with bilateral AMD and clinically unilateral XFS were included. Eyes with AMD were divided into three stages (early, intermediate, and late), based on the Beckman Initiative for Macular Research Classification Committee of fundus findings. The distribution of AMD lesions was assessed in both groups, and the subfoveal choroidal thickness (SFCT) was measured using enhanced depth imaging spectral-domain optical coherence tomography (SD-OCT).

RESULTS:

There were significantly more early and intermediate-stage AMD cases in eyes with XFS than in non-XFS fellow eyes (P < .05). In contrast, there were significantly fewer wet AMD cases in XFS eyes than in non-XFS fellow eyes (P < .05). SFCT in all AMD stages was significantly lower in eyes with XFS (P < .05).

CONCLUSION:

XFS was associated with a lower prevalence of wet AMD. Further studies are required to elucidate this association.

[Ophthalmic Surg Lasers Imaging Retina. 2018;49:12–19.]

Abstract

BACKGROUND AND OBJECTIVE:

To evaluate the relationship between age-related macular degeneration (AMD) and clinically unilateral pseudoexfoliation syndrome (XFS).

PATIENTS AND METHODS:

Seventy-six patients (152 eyes) with bilateral AMD and clinically unilateral XFS were included. Eyes with AMD were divided into three stages (early, intermediate, and late), based on the Beckman Initiative for Macular Research Classification Committee of fundus findings. The distribution of AMD lesions was assessed in both groups, and the subfoveal choroidal thickness (SFCT) was measured using enhanced depth imaging spectral-domain optical coherence tomography (SD-OCT).

RESULTS:

There were significantly more early and intermediate-stage AMD cases in eyes with XFS than in non-XFS fellow eyes (P < .05). In contrast, there were significantly fewer wet AMD cases in XFS eyes than in non-XFS fellow eyes (P < .05). SFCT in all AMD stages was significantly lower in eyes with XFS (P < .05).

CONCLUSION:

XFS was associated with a lower prevalence of wet AMD. Further studies are required to elucidate this association.

[Ophthalmic Surg Lasers Imaging Retina. 2018;49:12–19.]

Introduction

Pseudoexfoliation (PEX) syndrome (XFS) is characterized by the production and progressive accumulation of fibrillar extracellular material in many ocular tissues, including the lens capsule, zonules, iris, and anterior chamber angle.1–8 Recent studies have demonstrated that age-related macular degeneration (AMD) is associated with the presence of XFS and have emphasized that PEX and AMD share common predisposing factors with similarities in epidemiological features and pathogenesis.1,2 Similarly, in our clinical practice, we have observed that the rate of wet AMD in eyes with clinically unilateral XFS is significantly lower than in non-XFS fellow eyes. Hence, we studied a consecutive series of patients with bilateral AMD and clinically unilateral XFS syndrome. We investigated the association between AMD and XFS in clinically unilateral XFS cases. To the best of our knowledge, this association has not been investigated in patients with AMD. We also compared the subfoveal choroidal thickness (SFCT) and stage of AMD between clinically unilateral XFS eyes and non-XFS fellow eyes in patients with bilateral AMD.

Patients and Methods

Study Planning and Statement of Ethics

The study was a single-center, comparative, cross-sectional case series performed at the Department of Ophthalmology, Bozyaka Training and Research Hospital, Turkey, between April 2015 and October 2016. The study was conducted in accordance with the Tenets of the Declaration of Helsinki, with local ethical approval from the ethics committee of our hospital.

Examination Protocol and Patient Selection

All individuals included in the study were older than 50 years of age, and their demographic features were recorded. The study group consisted of newly diagnosed bilateral AMD and clinically unilateral XFS. The control group consisted of age- and sex-matched healthy subjects. All individuals underwent a comprehensive ophthalmic examination, including best-corrected visual acuity (BCVA) tests, anterior segment and posterior segment slit-lamp examination, intraocular pressure (IOP) measurement by Goldmann applanation tonometry, and a dilated fundus examination. In addition, fundus photography, fundus fluorescence angiography (FFA), and choroidal thickness (CT) measurements using the Spectralis optical coherence tomography (OCT) system (Heidelberg Engineering, Heidelberg, Germany) were performed.

Inclusion criteria for the study group were: age older than 50 years; newly diagnosed bilateral AMD and clinically unilateral XFS, where diagnosis of XFS was confirmed with slit-lamp biomicroscopy and clinically unilateral XFS was defined as the unilateral presence of detectable exfoliation material by slit-lamp examination on the anterior lens capsule or at the pupillary border after pupillary dilation, open angle in gonioscopy, IOP less than 21 mm Hg without treatment, normal optic disc appearance, and visual field test; confirmation of AMD was performed with direct and indirect fundus examination, OCT, and FFA; and no previous treatment for AMD.

Exclusion criteria for the study group were patients with PEX glaucoma or any type of glaucoma, congenital, or acquired retinal disorder, previous ocular surgery, or ocular trauma; patients with a history of any inflammatory ocular disease such as anterior or posterior uveitis; patients with any coexisting systemic disease including systemic hypertension, diabetes mellitus, and cardiovascular disease (due to the possible influence on CT), and patients with a history of any chronic drug use, including sildenafil, analgesics, antihistamines, and decongestants; any retinal disease, including diabetic retinopathy, retinal vessel occlusion, polypoidal choroidal vasculopathy (PCV), or central serous chorioretinopathy that may confound the evaluation of the retina other than AMD; patients with clinically bilateral XFS syndrome; concomitant or previous therapy to treat AMD including oral supplements of vitamins and minerals, intravitreal injections, laser photocoagulation, and photodynamic therapy; and patients not sufficiently cooperative for OCT measurements. Additionally, to reduce the effects of refractive error on OCT testing, patients with a refractive spherical diopter (D) greater than 5 D or with high cylinder diopter (> 3 D) were also excluded from the study.

We had estimated that at least 31 pairs of patients and controls would be required to achieve an 80% probability of detecting a mean between-group difference in SFCT of 33 μm with a standard deviation of 46 μm, and a standardized difference of 0.75 at a 5% significance level. The 33 μm difference in retinal nerve fiber layer thickness was considered based on the results of Turan-Vural et al.9 We initially examined 2,242 patients admitted to the retina clinic. Of these, 94 patients fulfilled the inclusion criteria of newly diagnosed bilateral AMD and clinically unilateral XFS in the present study. Eighteen of the 94 eligible patients were excluded from the study due to the exclusion criteria, including history of previous ocular surgery, chronic drug use, glaucoma, and retinal vascular diseases. In total, 152 eyes of 76 patients with a diagnosis of bilateral AMD and clinically unilateral XFS admitted to the retina clinic were included. Fifty-two age- and sex-matched healthy subjects were included in the study as a control group for CT measurements. Participants were divided into three groups for statistical analysis. Subjects with clinically unilateral XFS eyes, non-XFS fellow eyes, and controls were labeled as groups A, B, and C, respectively. Representative images of a patient with clinically unilateral XFS and bilateral AMD are shown in Figure 1.

Representative images including the anterior segment, color fundus, fundus autofluorescence, and optical coherence tomography of a patient with clinically unilateral pseudoexfoliation syndrome (XFS) and bilateral age-related macular degeneration (AMD). (A, C, E, and G) (Right eye): Eye with clinically unilateral XFS (arrow) and intermediate AMD. (B, D, F, and H) (Left eye): Non-XFS fellow eye with wet AMD.

Figure 1.

Representative images including the anterior segment, color fundus, fundus autofluorescence, and optical coherence tomography of a patient with clinically unilateral pseudoexfoliation syndrome (XFS) and bilateral age-related macular degeneration (AMD). (A, C, E, and G) (Right eye): Eye with clinically unilateral XFS (arrow) and intermediate AMD. (B, D, F, and H) (Left eye): Non-XFS fellow eye with wet AMD.

Fundus Photograph Grading and Classification of AMD

All of the fundus photographs were recorded by the same physician (MOZ). Two retinal specialists (MOZ, OK) who were blinded to the data pertaining to the characteristics of the patients individually graded the photographs. All equivocal and wet AMD lesions were discussed between the specialists. AMD was diagnosed on the basis of the morphologic changes observed. Patients likely to have wet AMD subsequently underwent a FFA to confirm the diagnosis. AMD grading was performed by checking an area of 3,000 μm from the foveal center. In this area, the drusen size, number, and type were recorded. Hypopigmentation and hyperpigmentation of the retinal pigment epithelium (RPE) and signs of wet AMD including subretinal hemorrhage, serous or hemorrhagic RPE detachment, a subretinal neovascular membrane, and a subretinal fibrous scar were also recorded.

AMD was classified based on the 2013 consensus of the Beckman Initiative for Macular Research Classification Committee.10 All eyes were grouped into stages 1 to 3 based on this classification system after the examination of the color fundus photographs, OCT, and FFA. Stage 1, characterized by medium drusen (range: ≥ 63 μm to ≤ 125 μm) but without pigmentary abnormalities, was accepted as early AMD; stage 2, characterized by large drusen (≥ 125 μm) or with pigmentary abnormalities associated with at least medium drusen, was accepted as intermediate AMD; and stage 3, characterized by neovascular AMD, was accepted as late AMD.10

OCT Measurements by Enhanced Depth Imaging Spectral-Domain OCT

Choroidal imaging was performed using spectral-domain OCT (SD-OCT) in enhanced depth imaging (EDI) mode (Spectralis OCT; Heidelberg Engineering, Heidelberg, Germany). The EDI image was averaged for 100 scans using the automatic averaging and eye-tracking system. At the macula, we scanned the horizontal sections across the center of the fovea. The SFCT was defined as the distance between the inner surface of the sclera and the hyperreflective line corresponding to the RPE and was measured using the manual caliper function with the Heidelberg Eye Explorer software (version 1.7.0.0; Heidelberg Engineering, Heidelberg, Germany) (Figure 2). If the line was blurred, especially at the chorioscleral interface, the center of the line was traced and measured. If pigment epithelium detachment was present, Bruch's membrane was used as the inner margin of the choroid instead of the RPE line. If Bruch's membrane was not identified, the inner margin of the choroid was defined by the border between the hyporeflective sub-RPE fluid and the mesoreflective choroid tissue. All OCT measurements were performed at the same time of day, in the morning, to avoid diurnal fluctuations. For each eye, the SFCT was measured independently by two blinded clinicians (OK, MOZ), and the mean values were recorded. Each observer was masked to the other observer's measurements. The measurements were performed in a random order and masked fashion. Interobserver reproducibility of the CT measurements was assessed by measuring the intraclass correlation coefficient (ICC). To abolish bias, eyes with more than a 10 % difference in measurements between the clinicians were excluded from the study.

Subfoveal choroidal thickness (SFCT) measurement in a patient with age-related macular degeneration using enhanced depth imaging optical coherence tomography (EDI OCT). The SFCT measurements in the macular region were performed using horizontal EDI OCT scanning. SFCT was measured between the hyperreflective line corresponding to the retinal pigment epithelium and the inner surface of the sclera.

Figure 2.

Subfoveal choroidal thickness (SFCT) measurement in a patient with age-related macular degeneration using enhanced depth imaging optical coherence tomography (EDI OCT). The SFCT measurements in the macular region were performed using horizontal EDI OCT scanning. SFCT was measured between the hyperreflective line corresponding to the retinal pigment epithelium and the inner surface of the sclera.

Statistical Analyses

Statistical analyses were performed using the SPSS for Windows 17.0 software (SPSS, Chicago, IL). For each continuous variable, normality was determined by Kolmogorov-Smirnov test. Chi-squared test was used to compare categorical data, and independent sample t-test was used for the intergroup comparisons of normally distributed continuous variables. One-way analysis of variance (ANOVA) test was used to compare clinical results between the three groups. In a post-hoc analysis, the Tukey test was used to compare two groups at a time, such as XFS and non-XFS fellow eyes, XFS and healthy subjects, and non-XFS fellow eyes and healthy subjects. A P value less than .05 was considered statistically significant.

Results

The study group consisted of 152 eyes of 76 patients (39 males). The mean age was 68.4 years ± 9.7 years (range: 50 years to 86 years). The mean refractive error was −1.22 D ± 1.13 D (range: −3.25 D to +1.75 D) in group A and −1.41 D ± 1.26 D (range: −3.50 to +2.0 D) in group B. The mean axial length was 23.14 mm ± 1.65 mm (range: 22 mm to 25 mm) in group A and 23.52 mm ± 1.71 mm (range: 22 mm to 25 mm) in group B. The control group (group C) included 52 eyes of 52 healthy subjects (27 males). The mean age was 67.6 years ± 10.2 years (range: 50 years to 78 years). The mean refractive error was −1.63 D ± 1.32 D (range: −3.50 D to + 1.0 D). The mean axial length was 23.61 mm ± 1.70 mm (range: 22 mm to 25 mm). There were no differences between the groups regarding the refractive error and axial length (P = .312 and P = .260, respectively). The mean BCVA (logMAR) was 0.32 ± 0.23 in XFS eyes (group A), 1.12 ± 0.52 in non-XFS fellow eyes (group B), and 0.12 ± 0.12 in controls (group C). The mean BCVA in groups A and C was significantly better than that in group B (P < .001). The demographic and clinical information for each group are summarized in Table 1.

Characteristics of Patients With AMD With and Without XFS

Table 1:

Characteristics of Patients With AMD With and Without XFS

In the 76 eyes with XFS, early, intermediate, and advanced AMD were noted in 19 (25.0 %), 48 (63.1%), and nine eyes (11.9%), respectively. In the 76 fellow eyes with non-XFS, the corresponding values were six (7.9%), 11 (14.4%), and 59 eyes (77.7%), respectively. There were significantly more advanced AMD cases in non-XFS eyes than in XFS fellow eyes, but significantly more early and intermediate-stage AMD cases in eyes with XFS than in non-XFS fellow eyes (P < .05). The detailed distribution of these cases according to AMD stage is given in Table 2. When we evaluated groups A and B together as one group, which was divided into two different age groups between early and advanced AMD, the mean age of patients with early and advanced AMD was 68.6 years ± 8.9 years and 68.4 years ± 7.4 years, respectively. There was not a significant difference between the two AMD stages in terms of age (P = .243).

Statistical Analysis of Differences in Subfoveal Choroidal Thickness Between AMD Stages

Table 2:

Statistical Analysis of Differences in Subfoveal Choroidal Thickness Between AMD Stages

The mean SFCT was 193.32 μm ± 35.9 μm in group A, 246.38 μm ± 32.1 μm in group B, and 274.21 μm ± 38.2 μm in group C and was significantly lower in XFS eyes (P = .001). In group A, the mean SFCT was 204.3 μm ± 30.9 μm in eyes with early AMD, 181.4 μm ± 32.4 μm in eyes with intermediate AMD, and 233.7 μm ± 27.8 μm in eyes with advanced AMD. In group B, the values were 242.5 μm ± 32.2 μm, 206.3 μm ± 34.1 μm, and 254.2 μm ± 25.9 μm, respectively. The differences between groups were statistically significant (P = .001), even after adjusting for spherical equivalence and sex distribution. Subgroups analyses indicated that SFCT in all stages of AMD was significantly lower in group A than in group B (P = .016, P = .026, and P = .032, respectively) (Table 2). In our study, the interobserver ICCs for the SFCT measurements were 0.921.

Discussion

The present study demonstrated two important findings. First, SFCT in all AMD stages was found to be significantly lower in eyes with XFS. Second, an inverse association was found between XFS and wet AMD.

Evaluation of CT Changes in Patients With XFS and AMD

XFS seems to widely affect vascular structures. The increase in flow resistance in eyes with XFS is an interesting feature. Vascular changes in XFS are associated with obstruction and the loss of small vessels, neovascularization, increased permeability, and an elevated resistive index of the ophthalmic artery. These changes are probably the result of accumulation of pseudoexfoliative material in the vessel walls. Repo et al.11 showed that increased resistance in the ophthalmic artery was due to the presence of PEX in patients with at least one transient ischemic attack. Similarly, Mitchell et al.12 demonstrated widespread elastosis in the walls of vessels and an increase in vascular risk factors in subjects with XFS. Although XFS is usually unilateral when first detected,13,14 electron microscopic observations have almost invariably revealed exfoliation fibers in the conjunctiva of clinically uninvolved fellow eyes.15 Furthermore, postmortem examinations on subjects with clinically unilateral XFS using monoclonal antibody for the pseudoexfoliative material have demonstrated that clinically affected eyes have significant immunoreactions while clinically unaffected fellow eyes also have a mild immunoreaction of the iris vessels.16 These studies support the presence of pseudoexfoliative material in unaffected fellow eyes, however, why this asymmetry occurs remains unknown.

Several studies have investigated ocular blood flow in eyes with XFS and non-XFS fellow eyes and control eyes. Ocakoglu et al.17 showed that mean blood flow was significantly lower in both eyes with clinically unilateral XFS and non-XFS fellow eyes than in control eyes. The differences in ocular blood flow between eyes with XFS and non-XFS fellow eyes were not statistically significant. They also found that non-XFS fellow eyes also had lower blood flow values than control eyes. Similarly, Dayanir et al.18 demonstrated that the mean ophthalmic artery blood flow measurements of clinically unilateral eyes with XFS were lower than unaffected fellow eyes; however, the difference was not statistically significant. They also found that XFS subjects had a lower mean CT than controls. However, these results did not reach any statistical significance. Turan et al.9 suggested that XFS was associated with an overall thinning of the subfoveal choroid, similar to Eroglu et al.,19 who observed that subjects with clinically unilateral XFS have significantly thinner choroids than unaffected fellow eyes and healthy controls. We found similar findings. Hence, in cases with clinically unilateral XFS, CT decline not only in eyes with XFS but also in non-XFS fellow eyes, but the reduction is more prominent in XFS eyes.

Previous studies that have investigated the CT in AMD have reported inconsistent findings. Some studies have reported a decreased CT,20,21 whereas others have indicated no difference in CT in either nonexudative or neovascular AMD.22–25 The question of whether choroidal thinning occurs in AMD remains a subject of significant debate. A major confounding factor is age, because AMD progression increases in prevalence with advancing age at the same time that the choroid undergoes natural age-related thinning. The choroid is known to undergo both structural and functional changes with age. In a previous study that used a Doppler technique, foveolar choroidal blood flow in healthy eyes significantly decreased with age.26 A more recent study that used SD-OCT reported that SFCT decreased by approximately 1.56 μm each year.27

Therefore, any attempt to address CT in different types of AMD requires careful adjustment for this parameter.27 Kim et al.28 examined 37 eyes with nonexudative AMD, 24 eyes with neovascular AMD, and 29 control eyes. The mean SFCT was 187 μm ± 64 μm in nonexudative AMD compared to 242 μm ± 66 μm in the control group. Lee et al.29 found that the CT decreases in the later stages of nonexudative AMD. We examined 152 eyes with AMD, stratified using the Beckman Initiative for Macular Research classification of fundus findings, and found choroidal thinning in the intermediate stages of nonexudative AMD.

Jonas et al.30 examined 204 eyes with intermediate and neovascular AMD and similarly found no difference in SFCT from both types compared to 228 control eyes after matching for age, refractive error, and axial length.

On the other hand, in a recent study by Kim et al.,28 the mean SFCT was 185 mm ± 69 mm in 24 eyes with exudative AMD. Rahman et al.31 also reported that SFCT did not differ significantly among 15 eyes affected by neovascular AMD. Our data are in good agreement with these previous studies. We found that the SFCT decreased in the intermediate stages of nonexudative AMD. In addition, we also observed that the SFCT was unchanged in neovascular AMD.

Evaluation of Relationship Between AMD and XFS

In our study, the rate of nonexudative AMD was 90.3% in eyes with clinically unilateral XFS and 17.8% in non-XFS fellow eyes. The differences between eyes with XFS and non-XFS fellow eyes were statistically significant. However, XFS was associated with a lower prevalence of wet AMD. We observed an inverse association between XFS and wet AMD.

The mechanisms underlying the protective effects of XFS on wet AMD are currently unclear. One possible explanation is that ocular blood flow may be more impaired in eyes with XFS, which can be related to a thinner choroid. Therefore, this may impair choroidal neovascular membrane formation. Another explanation may be changes in connective tissue and sclera rigidity in eyes with XFS. Previous studies have shown that increased ocular scleral rigidity may be a significant risk factor for the development of AMD.32 According to Friedman et al.,33 increasing ocular rigidity could lead to a decrease in the compliance of the sclera and the choroidal vessels. As the sclera becomes increasingly rigid and noncompliant, the filling of the vortex veins is decreased whereas the resistance of the choroidal vessels is increased, which may cause a defect in the Bruch's membrane in the macular area, with the final outcome of choroidal neovascularization (mechanical theory). Another possible pathophysiologic process by which increasing ocular rigidity, which impairs the transfer of nutrients and oxygen, contributes to the development of choroidal neovascularization is the induced hypoxia (ischemic theory) that is caused by decreased choroidal perfusion, which affects the normal function of retinal pigment epithelium. This hypoxia could lead to the secretion of molecular angiogenic factors such as vascular endothelial growth factor (VEGF) with the final outcome of choroidal neovascularization.31,32 Previous studies have demonstrated that XFS may be associated with changes in ocular rigidity. The exact mechanism by which PEX may affect ocular biomechanical behavior cannot be determined based on this study. The possible presence of pseudoexfoliative material at the vascular walls of ophthalmic vessels supplying the uveal circulation as previously reported could affect their elasticity and thus the choroidal contribution to ocular rigidity.34–36 Alternatively, potential changes in the sclera might also offer an explanation for changes in ocular rigidity. In addition, pseudoexfoliative material has also been detected in orbital tissues, such as orbital connective tissue, extraocular muscles, and vortex veins, implying that vascular compliance or the elastic modulus of these tissues could be altered in association with PEX.37,38 Reduced ocular rigidity may inhibit the formation of these pathophysiological events, which may underline the protective effects of XFS on wet AMD. Further studies are needed to elucidate the possible association between XFS and wet AMD. If this association is further supported by additional studies, it seems logical to develop treatment modalities that alter ocular rigidity.

There were several limitations to this study. First, the number of enrolled patients was small, giving limited statistical power to detect small differences in CT between patients with AMD with clinically unilateral XFS. Second, the measurement of CT was performed only in the subfoveal region. Measurements performed around the optic disc and from nasal and temporal aspects of the fovea might have provided more accurate results. Third, the calculation of average CT in the macular region was performed manually due to the lack of automatic software. Objective, automated measurements would yield more convincing results and conclusions.

In conclusion, we investigated the association between AMD and XFS syndrome. We observed an inverse association between XFS and wet AMD. The small sample used in this study weakened our statistical results, and thus further studies are needed to elucidate the precise mechanism of this relationship. However, our results justify the feasibility of a much larger study investigating the association between AMD and patients with XFS.

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Characteristics of Patients With AMD With and Without XFS

Group A (XFS Eyes)Group B (Non-XFS Eyes)Group C (Control Eyes)P Value
Age (Years)68.4 ± 9.7 (50–86)68.4 ± 9.7 (50–86)67.6 ± 10.2 (50–78).256
Gender (Male / Female)39/3739/3727/25.946
BCVA0.32 ± 0.231.12 ± 0.520.12 ± 0.12< .001
Refractive Error (Diopters)−1.22 ± 1.13 (−3.25 to +1.75)−1.41 ± 1.26 (−3.50 to +2.0)−1.63 ± 1.32 (−3.50 to +1.0).312
Axial Length (mm)23.14 ± 1.65 (22 to 25)23.52 ± 1.71 (22 to 25)23.61 ± 1.70 (22 to 25).260
SFCT (μm)193.32 ± 35.9246.38 ± 32.1274.21 ± 38.2.001

Statistical Analysis of Differences in Subfoveal Choroidal Thickness Between AMD Stages

Early AMDIntermediate AMDAdvanced AMD (Exudative)P Value
XFS eyes (Group A)19489
  SFCT (μm) Mean ± SD204.3 ± 30.9181.4 ± 32.4233.7 ± 27.8.001
Non-XFS Fellow Eyes (Group B)61159
  SFCT (μm) Mean ± SD242.5 ± 32.2206.3 ± 34.1254.2 ± 25.9.001
P ValueP1 = .016P2 = .026P3 = .032
Authors

From Bozyaka Training and Research Hospital, Department of Ophthalmology, Izmir, Turkey (MOZ, OK, TK); and Van Training and Research Hospital, Van, Turkey (EK).

The authors report no relevant financial disclosures.

Address correspondence to Omer Karti, MD, Saim cikrikci cad. No:59, Bozyaka/ İzmir, Turkey; email: kartiomer@gmail.com.

Received: March 09, 2017
Accepted: August 02, 2017

10.3928/23258160-20171215-02

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