Current Eye Research, Early Online, 1–7, 2015 ! Informa Healthcare USA, Inc. ISSN: 0271-3683 print / 1460-2202 online DOI: 10.3109/02713683.2014.1002046

RESEARCH REPORT

Evaluation of Corneal Microstructure in Pseudoexfoliation Syndrome and Glaucoma: In Vivo Scanning Laser Confocal Microscopic Study

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Nur¸sen Yu¨ksel, Esra Emre and Dilara Pirhan Department of Ophthalmology, School of Medicine, University of Kocaeli, Kocaeli, Turkey

ABSTRACT Purpose: To quantitatively evaluate corneas of patients with pseudoexfoliation syndrome (PXS) and pseudoexfoliation glaucoma (PXG) using in vivo scanning laser confocal microscopy (IVCM). Materials and Methods: The study population comprised 30 patients with PXS, 30 patients with PXG, and 30 normal control subjects. IVCM of the cornea was performed on all participants using the Rostock Cornea Module of the Heidelberg Retinal Tomograph (HRT). Mean outcome measures included density of basal epithelial cells, endothelial cells, and anterior and posterior keratocytes; and tortuosity and density of subbasal plexus nerves. Results: Mean densities of basal epithelial cells, endothelial cells, anterior and posterior keratocytes, and subbasal nerves differed significantly among the three groups. Subbasal nerve densities were significantly diminished in PXS and PXG patients (12.36 ± 2.89 and 6.8 ± 3.42 mm/mm2, respectively) compared with that of control subjects (16.13 ± 3.42 mm/mm2) (p50.05). Mean densities of anterior and posterior stromal keratocytes were significantly lower in PXS and PXG patients compared with control subjects (p50.05). Endothelial cell densities were 3073.63 ± 654.49, 2592.60 ± 276.36, and 2110.20 ± 620.53 cells/mm2 for control, PXS, and PXG groups, respectively (p50.05). The percentages of endothelial cell polymegathism and pleomorphism were higher in PXS and PXG patients compared with control subjects. Endothelial cell polymegathism and pleomorphism were more frequently associated with PXG. Conclusions: Results of this study demonstrate the existence of alterations in the (i) density of cells in the various layers of the cornea, (ii) cellular configuration of corneal endothelial cells, and (iii) density/diameter of the subbasal nerve plexus in patients with PXS, and that such alterations are common in patients with PXG. It would be beneficial to employ IVCM to assess the severity of pseudoexfoliation keratopathy (PXK). Keywords: Cornea, glaucoma, in vivo confocal microscopy, pseudoexfoliation keratopathy, pseudoexfoliation syndrome

INTRODUCTION

(POAG), pseudoexfoliation glaucoma (PXG) is more severe, carries with it a higher risk of blindness, and is associated with higher mean/maximum intraocular pressures (IOPs) at diagnosis, with a wider range of fluctuations in IOP.6 Small, white, fluffy pseudoexfoliative deposits are usually observed on the corneal endothelium, along with pigment deposition on the central corneal endothelium, in patients with PXS. The damaged corneal endothelium of PXS eyes may cause endothelial decompensation. In PXS patients, a distinct form of

Pseudoexfoliation syndrome (PXS) is an elastotic, agerelated disorder characterized by the accumulation of abnormal extracellular matrix material (EMM) in ocular tissues. While most PXS patients are asymptomatic, it is important to emphasize the association of PXS with characteristic alterations of anterior segment tissues.1–4 PXS is the most common identifiable cause of open-angle glaucoma worldwide.5 Compared to primary open angle glaucoma

Received 25 June 2014; revised 8 December 2014; accepted 17 December 2014; published online 16 January 2015 Correspondence: Nur¸sen Yu¨ksel, Department of Ophthalmology, School of Medicine, University of Kocaeli, Kocaeli, Turkey. Tel: +90 262 303 86 00. Fax: +90 262 303 75 00. E-mail: [email protected]

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corneal endotheliopathy is known to occur. This particular endotheliopathy, which can lead to early corneal endothelial decompensation, may have been previously misdiagnosed as an ‘‘atypical non guttata Fuchs’ endothelial dystrophy.’’ 7–9 In vivo confocal microscopy (IVCM) is a noninvasive imaging technique that provides high-resolution images of corneal structures in the living human eye.10,11 IVCM allows objective evaluation of changes in corneal cells and nerves. IVCM studies have revealed significant morphologic alterations in the corneas of patients with PXS.12–15 To extend such research efforts, the present study was designed to use IVCM to identify microstructural alterations of the cornea in PXS and PXG.

MATERIALS AND METHODS Patients A total of 90 patients from the Department of Ophthalmology, School of Medicine, University of Kocaeli, Kocaeli, Turkey, participated in this prospective study, conducted between April 2013 and April 2014. 30 PXS patients (n = 30 eyes), 30 PXG patients (n = 30 eyes), and 30 age-matched control subjects (n = 30 eyes) were included. The study adhered to the tenets of the Declaration of Helsinki and was approved by the Ethical Committee of Kocaeli University Medical Faculty. Signed informed consent was obtained from each participant after a detailed description of the procedure. All participants received a complete ophthalmological examination, including measurement of refractive error, biomicroscopy of the anterior segment, measurement of IOP by applanation tonometry, measurement of central corneal thickness (CCT) by ultrasonic pachymetry (UP) (average of three readings), gonioscopy, and fundoscopic examination with a Goldmann three-mirror contact lens following pupil dilation. Visual field examinations were performed using program 30-2 of the Humphrey visual field analyzer (HFA II, ZeissHumprey Instruments, London, UK). All participants were further evaluated by Spectralis spectraldomain optical coherence tomography (SD-OCT) (Heidelberg Engineering, Heidelberg, Germany) to determine retinal nerve fiber layer (RNFL) thickness. Maps of RNFL thickness changes were automatically generated by the SD-OCT and exported to a computer. Inclusion criteria for control subjects, all of whom were recruited during routine screening visits, were no history of any ocular diseases (apart from refractive error), IOPs 521 mm Hg, normal optic nerve heads, normal visual fields, and no family history of glaucoma.

PXG in PXS eyes was defined according to the following criteria: highest recorded IOP 422 mm Hg, open anterior chamber angle by gonioscopy, and optic nerve damage (e.g. focal notching or diffuse thinning of the neuroretinal rim, visible nerve fiber layer defects, asymmetry of the vertical cup-to-disk ratio of 40.2 between eyes, peripapillary atrophy, and optic disk hemorrhages) by fundus examination, concurrent glaucomatous visual field damage, and decreased RNFL thickness by OCT. Only one eye of each study participant in any study group was selected for statistical analysis. For patients with unilateral PXS or PXG, only the clinically involved eye was included in data evaluation. In patients with bilateral PXS, the one eye was chosen at random. In bilaterally affected PXG patients, the eye with more advanced lesions was evaluated. In control group subjects, the one eye was chosen at random. Exclusion criteria for study participation included the following: active ocular infection or inflammation, use of ocular medications (except artificial tears), previous ocular surgery, history of ocular trauma, progressive retinal disease, history of any allergic hypersensitivity, use of contact lenses, and any corneal disease. Also excluded were PXS patients with suspicious eyes, e.g. pre-perimetric glaucoma, or ocular hypertension.

Confocal Microscopy IVCM of the cornea was performed using the Rostock Cornea Module of the Heidelberg Retina Tomograph (HRT) (Heidelberg Engineering GmbH, Heidelberg, Germany). A 60  water-immersion objective lens (Olympus, Hamburg, Germany) and a 670-nm diode laser (class-1 laser light source) allowed a scanning area of 384  384 mm2, with lateral and vertical resolutions of 1 mm and magnifications of up to 800X. Before examination, one drop of 0.5% proparacaine hydrochloride (Alcaine; Alcon, Couvreur, Belgium) topical anesthetic was applied to the lower conjunctival sac. Each participant was required to place his/her chin on a chin-plate and to fixate on a small light. After application of the topical anesthetic, a sterile lucent methylcellulose gel-containing receptacle (tomacup) was placed in front of the camera lens in such a way as to make contact with the center of the cornea. After adjusting placement of the receptacle and camera focus, the camera lens was advanced to the endothelium, beginning at the superficial epithelium, in order to obtain images of each layer. Images were recorded at points along the Z-axis in single-scan mode to obtain a minimum of 200 images/scan. Scans were repeated twice for each eye. All images were collected for future selection. Current Eye Research

Corneal Confocal Microscopy in Pseudoexfoliation

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Image Analyses Confocal images of the central cornea were obtained from all participants and the three best images (wellfocused, taken of the same layer, and with good contrast) of each layer (subbasal epithelium, subbasal nerve plexus, anterior stroma, posterior stroma, and endothelium) were selected for analyses. The subbasal epithelium was identified as the layer just above Bowman’s membrane; anterior stroma, as the first layer immediately posterior to Bowman’s layer; and posterior stroma, as the layer immediately anterior to Descemet’s membrane. All images were subsequently analyzed by the same specialist (NY), who was masked to diagnosis.

Cell Density Analyses Using both manual cell marking (450 cells) and automatic calculations (The Heyex 3.0.2 software, Heidelberg Engineering, Heidelberg, Germany), cells within specific standard-dimension regions of interest (ROIs) in each corneal layer were counted. Cells that were incompletely contained within a ROI were not counted. Results are expressed as cell/mm2. The average of three images was used for all analyses.

Subbasal Nerve Plexus Density The density of subbasal nerves was calculated using the entire length of the nerve that was visible within a single frame. Density measurements were performed using Image J software (http://rsb.info.nih.gov/ij/ download.html) to facilitate quantification of elongated image structures. The total lengths of subbasal nerves were measured in pixel units and converted to m or mm units by the software. The number of subbasal nerves was defined as the total number of long nerve fiber bundles observed within a single frame.16,17 Nerve fiber tortuosity was graded from 0 to 4, according to the tortuosity grading scale of OliveiraSoto and Efron:17Grade 0, nearly straight; Grade 1, slightly tortuous; Grade 2, moderately tortuous, with numerous changes in the direction of the fiber; Grade 3, very tortuous; and Grade 4, extremely tortuous.

Statistical Analyses Results are expressed as mean ± SD. Using version 13 SPSS for Windows (SPSS Inc., Chicago, IL), statistical analyses of continuous data were done using analysis of variance (ANOVA), Tukey’s test for multiple comparisons, and the Mann–Whitney U-test. Categorical data were analyzed using Pearson’s !

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2-test. A p-value of50.05 was considered statistically significant.

RESULTS Demographics all participants are shown in Table 1. No significant differences with respect to mean age and gender were found between the three groups. Mean CCTs were significantly thinner in the PXS group than in the PXG and control groups (543.9 ± 14.4, 560.5 ± 20.16, and 558.3 ± 14.4 mm, respectively). Mean IOPs were significantly higher in the PXG group than in the PXS and control groups. Mean basal epithelial cell densities (cells/mm2) were significantly lower in both the PXS and PXG groups than in the control group (p50.05), but there was no difference between the two pseudoexfoliation groups. Anterior and posterior keratocyte densities differed significantly among the three groups (p50.05). Mean anterior and posterior stromal keratocyte densities were significantly lower in the PXS and PXG groups than in the control group. Comparison of PXS and PXG groups revealed significantly decreased anterior and posterior stromal keratocyte densities in PXG patients (p50.05) (Table 2). Endothelial cell densities for the control, PXS, and PXG groups were 3073.63 ± 654.49, 2592.60 ± 276.36, and 2110.20 ± 620.53 cells/mm2, respectively. Mean endothelial cell densities were significantly lower in the PXS and PXG groups compared with the control group (p50.05). The PXG group had significantly lower mean endothelial cell densities compared with the PXS group (p50.05). There were higher percentages of endothelial cell polymegathism and pleomorphism in the PXS and PXG groups compared with those of the control group (41.9 ± 9.10, 47.96 ± 11.85, and 35.10 ± 7.6%, respectively) (p50.05). There were higher degrees of pleomorphism in PXS and PXG patients compared with control group subjects (52.23 ± 9.82, 58.53 ± 11.88, and 44.3 ± 9.72%, respectively) (p50.05). Overall, endothelial cell polymegathism and pleomorphism in PXS were more frequently associated with glaucoma (p50.05) (Figure 1). Overall, 37% of PXS eyes and 45% of PXG eyes displayed deposits of hyperreflective material in the endothelium. Densities of subbasal nerves were significantly lower in the PXS and PXG groups compared with the control group (12.36 ± 2.89, 6.8 ± 3.42, and 16.13 ± 3.42 mm/mm2, respectively) (p50.05). The number of nerves was also significantly lower in the PXS and PXG groups than in the control group (30.13 ± 7.49),18.46 ± 6.91, and 38.62 ± 7.12/mm2, respectively (p50.05) (Figure 2). Compared with PXS patients, PXG patients exhibited significantly lower densities and numbers of subbasal nerves.

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TABLE 1. Demographics of study participants.

Age (years) (mean ± SD) Female Male CCT (mm) Intraocular pressure (mmHg) (mean ± SD)

Control subjects (n = 30) No. (%)

PSX patients (n = 30) No. (%)

PSG patients (n = 30) No. (%)

64.1 ± 6.4 14 (46) 16 (54) 558.3 ± 14.4 15.42 ± 1.45

65.8 ± 7.4 15 (50) 15 (50) 543.9 ± 14.4* 18.42 ± 1.69

66.5 ± 6.8 13 (43) 17 (57) 560.5 ± 20.16 28.12 ± 7.02*

*NS yNS yNS p50.05 p50.05

ANOVA, analysis of variance; CCT, central corneal thickness; IOP, intraocular pressure; PXS, pseudoexfoliation syndrome; PXG, pseduexfoliation glaucoma. *p values based on ANOVA. yp values based on Pearson’s 2 test.

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TABLE 2. In vivo confocal microscopy findings.

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Basal epithelial cell density, cells/mm Anterior stromal keratocyte density, cells/mm2 Posterior stromal keratocyte density, cells/mm2 Endothelial cell density(cells/mm2) Polymegathism,rate (%) Pleomorphism,rate (%) Subbasal nerve density (mm/mm2) Number of subbasal nerves (No/mm2) Tortuosity of subbasal nerves

Normal

PXS

PXG

p*

p**

p***

5798 ± 610 351.03 ± 46.29 277.03 ± 34.45 3073.63 ± 654.49 35.10% ± 7.6% 44.3% ± 9.72% 16.13 ± 3.42 38.62 ± 7.12 1.8 ± 0.8

4969 ± 542 309.73 ± 52.14 240.06 ± 42.4 2592.60 ± 276.36 41.9% ± 9.10% 52.23% ± 9.82% 12.36 ± 2.89 30.13 ± 7.49 2.5 ± 1.4

4736 ± 327 274.86 ± 42.28 200.78 ± 52.30 2110.20 ± 620.53 47. 96% ± 11.85% 58.53% ± 11.88% 6.8 ± 3.42 18.46 ± 6.91 3.4 ± 0.8

0.01 0.001 0.01 0.003 0.03 0.02 0.00 0.001 0.03

0.01 0.001 0.001 0.001 0.00 0.00 0.00 0.00 0.00

0.3 0.01 0.03 0.003 0.02 0.04 0.00 0.00 0.001

PXS, pseudoexfoliation syndrome; PXG, pseudoexfoliation glaucoma; Comparisons: *pseudoexfoliation syndrome and control group, ** pseudoexfoliation glaucoma and control group, *** pseudoexfoliation syndrome and pseudoxfoliation glaucoma (Analysis of variance, Tukey test for multiple comparisons).

FIGURE 1. Endothelial layers of control (a), pseudoexfoliation syndrome (b) and pseudoexfoliation glaucoma (c) eyes.

IVCM analyses of subbasal nerves are presented in Table 2. Among PXG patients, 70.4% had subbasal nerve tortuosity  Grade 3. In general, the degrees of tortuosity in PXS and PXG patients were significantly greater than those of control group subjects (p50.05).

DISCUSSION This study demonstrates that PXS potentially affects all layers of the cornea. Compared with control subjects, densities of basal epithelial cells, stromal cells, endothelial cells, and subbasal nerves were decreased, and the degree of tortuosity increased, in

PXS patients. In addition, there were greater variations in the corneas of PXG eyes compared with PXS eyes. Pseudoexfoliation keratopathy (PXK) may potentiate some of the known complications of PXS. PXK develops as a consequence of specific changes in corneal microstructures. PXS is progressive, with the amount of pseudoexfoliative material correlating clinically and histologically in affected eyes.18–20 Alterations in corneal microstructures in PXS, along with the fact that these alterations are manifested more profoundly in PXG, suggest a correlation between the specific alteration and the stage of disease progression. Consequently, we hypothesized Current Eye Research

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Corneal Confocal Microscopy in Pseudoexfoliation

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FIGURE 2. Subbasal nerve plexus of control (a), pseudoexfoliation syndrome (b), and pseudoexfoliation glaucoma (c, d) eyes.

that corneal confocal imaging would be helpful not only in elucidating the progression of PXS, but also in assessing the severity of PXK and, perhaps, predicting the course of PXG progression. Two previous studies used confocal microscopy to study the density of keratocytes in eyes (affected and contralateral) of patients with unilateral PXS.14,21 Both studies reported corneal cell densities to be lower in PXS eyes compared with normal eyes, and that the contralateral eye of persons with unilateral PXS shared similar morphological changes with the affected eye. Unfortunately, these studies did not include a PXG group. Our study demonstrated significant decreases in the density of corneal cells in PXS eyes, and that such decreases are more prominent in PXG eyes. Pseudoexfoliative material in PXS stroma were delineated by transmission electron microscopy (TEM).17 The presence of such fibrillar material in the anterior stroma could account for the decreased number of keratocytes in PXS eyes. Keratocytes play active roles in maintaining corneal transparency and structural stromal stability by regulating the size of collagen fibrils as well as the amount of proteoglycans in the extracellular matrix.22 Thus, such changes could very well alter the viscosity and elasticity of the corneal matrix. Recently, Yenerel et al.23 reported that corneal hysteresis and corneal resistance factors were significantly lower in PXS eyes compared with !

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normal eyes. Ayala 24 found that corneal hysteresis in PXG was significantly lower than in POAG. To add to previous studies,19,25,26 our study showed endothelial cell density to be decreased, pleomorphism and polymegathism of cells to be increased, and pseudoexfoliative materials to be precipitated in endothelial cells of PXS eyes. Furthermore, our study indicated that there is greater cell loss and more morphological abnormalities of corneal endothelial cells in PXG eyes compared with PXS. Wali et al.27 reported a more pronounced endothelial cell deterioration in PXG eyes compared with glaucoma-only eyes. Zimmermann et al.28 measured corneal endothelial cell density using endothelial cell mirror microscopy and found decreased endothelial cell density to be associated with more advanced stages of PXS, whether or not glaucoma was present. Zimmermann et al. also reported that the influence of the pseudoexfoliation process was greater than that of IOP. The corneal endothelium of PXS patients may be affected by cataract surgery. Hayashi et al.29 reported that damage to the corneal endothelium and a greater increase in CCT were more pronounced after cataract surgery in PXS eyes versus eyes with no PXS. Maintenance of corneal thickness depends on an intact barrier function and a healthy endothelium, but reports regarding CCT in eyes with PXS and PXG are controversial.30–32 We found that mean CCTs were

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significantly thinner in PXS, but not in PXG, eyes. Such a reduction in CCT may be explained by the decreased densities of corneal cells. Despite significant decreases in the density of corneal cells in PXS and PXG, advanced alterations in the corneal endothelium can affect stromal hydration, thereby resulting in increased CCT. Furthermore, a concommitantly elevated IOP may also contribute to greater CCTs in PXG. Ozcura et al.31 found that CCT was less in eyes with PXS than in those without, although there was no difference in CCT between eyes with PXG and normal eyes. Hence, it would be useful to use confocal microscopy to assess the relationship between severity of endotheliopathy and corneal thickness changes in PXS and PXG eyes. Future studies should also concentrate on the association between IVCM findings and corneal thickness in eyes with pseudoexfoliation. In this study, we demonstrated that the densities of subbasal corneal nerves are diminished and the nerves more tortuous in corneas with PXS than in healthy control corneas. Furthermore, these changes are more pronounced in patients with PXG than in those with PXS. We speculate that impaired signaling mechanisms between the corneal endothelium and corneal nerves play roles in the pathogenesis of endothelial cell loss. Moreover, we suggest that alterations in corneal subbasal nerves play roles in the etiopathogenesis of PXK and that a correlation exists between the marked reduction of subbasal plexus nerve fibers and severity of pseudoexfoliation. Nerve fibers are important for corneal tropism and for maintaining a healthy ocular surface. Detorakis et al.33 found a decrease in central corneal mechanical sensitivity in eyes with PXS. Zheng et al.14 reported that a reduced number of subbasal nerves was correlated with corneal hypoesthesia. Other studies have shown tear film instability to be associated with pseudoexfoliation.34–36 A diminished nerve density may help to explain reduced corneal sensitivity and tear secretion in patients with PXS. Previous confocal microscopy studies reported that there were decreased numbers of nerve fibers and increased tortuosity in topically treated glaucoma patients compared with control subjects.16 For this reason, we did not include such patients in our study. The limitations of our in vivo confocal study include small central scanning area, absence of peripheral corneal innervation analysis, (iii) limited number of corneal images for data analysis, and (iv) variety of definitions of morphological parameters. In conclusion, we show that the alterations observed by IVCM in PXS patients potentially affect all layers of the cornea, are more severe in PXS patients, and that PXK may be depictive of progressive corneal damage. IVCM is a useful tool for detecting corneal differences, including varying corneal endothelium lesions and stromal abnormalities,

in PXS. Further studies are needed to devise a new PXS grading scheme for determining the severity of corneal involvement.

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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27. Wali UK, Bialasiewicz AA, Rizvi SG, Al-Belushi H. In vivo morphometry of corneal endothelial cells in pseudoexfoliation keratopathy with glaucoma and cataract. Ophthalmic Res 2009;41:175–179. 28. Zimmermann N, Wu¨nscher M, Schlo¨tzer-Schrehardt U, Erb C. Corneal endothelial cell density and its correlation with the severity of pseudoexfoliation. Klin Monbl Augenheilkd 2014;231:158–163. 29. Hayashi K, Manabe S, Yoshimura K, Kondo H. Corneal endothelial damage after cataract surgery in eyes with pseudoexfoliation syndrome. J Cataract Refract Surg 2013; 39:881–887. 30. Puska P, Vasara K, Harju M, Seta¨la¨ K. Corneal thickness and corneal endothelium in normotensive subjects with unilateral exfoliation syndrome. Graefes Arch Clin Exp Ophthalmol 2000;238:659–663. 31. Ozcura F, Aydin S, Dayanir V. Central corneal thickness and corneal curvature in pseudoexfoliation syndrome with and without glaucoma. J Glaucoma 2011;20:410–413. 32. Kitsos G, Gartzios C, Asproudis I, Bagli E. Central corneal thickness in subjects with glaucoma and in normal individuals (with or without pseudoexfoliation syndrome). Clin Ophthalmol 2009;3:537–42. 33. Detorakis ET, Koukoula S, Chrisohoou F, Konstas AG, Kozobolis VP. Central corneal mechanical sensitivity in pseudoexfoliation syndrome. Cornea. 2005;24:688–691. 34. Kozobolis VP, Christodoulakis EV, Naoumidi II, Siganos CS, Detorakis ET, Pallikaris LG. Study of conjunctival goblet cell morphology and tear film stability in pseudoexfoliation syndrome. Graefes Arch Clin Exp Ophthalmol. 2004;242:478–483. 35. Kozobolis VP, Detorakis ET, Tsopakis GM, Pallikaris IG. Evaluation of tear secretion and tear film stability in pseudoexfoliation syndrome. Acta Ophthalmol Scand 1999;77:406–409. ¨ ncel BA, Pinarci E, Akova YA. Tear osmolarity in 36. O unilateral pseudoexfoliation syndrome. Clin Exp Optom 2012;95:506–509.

Evaluation of Corneal Microstructure in Pseudoexfoliation Syndrome and Glaucoma: In Vivo Scanning Laser Confocal Microscopic Study.

To quantitatively evaluate corneas of patients with pseudoexfoliation syndrome (PXS) and pseudoexfoliation glaucoma (PXG) using in vivo scanning laser...
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