Current Eye Research, 2015; 40(5): 470–475 ! Informa Healthcare USA, Inc. ISSN: 0271-3683 print / 1460-2202 online DOI: 10.3109/02713683.2014.930157
ORIGINAL ARTICLE
Corneal Biomechanical Comparison of Pseudoexfoliation Syndrome, Pseudoexfoliative Glaucoma and Healthy Subjects Serpil Yazgan1, Ugur Celik2, Ne¸se Alago¨z3 and Mehmet Ta¸s4 1
Ophthalmology Department, Zonguldak Karaelmas University, Zonguldak, Turkey, 2Gaziosmanpasa Taksim Training and Research Hospital, Istanbul, Turkey, 3Beyoglu Eye Training and Research Hospital, Istanbul, Turkey, and 4Ophthalmology Department, Malatya State Hospital, Istanbul, Turkey
ABSTRACT Purpose: To evaluate the differences in corneal biomechanical properties between healthy subjects and patients with pseudoexfoliation syndrome (PEX) and pseudoexfoliative glaucoma (PEXG) using the ocular response analyzer (ORA). Materials and methods: One hundred eighteen eyes of 45 healthy, 43 PEX and 30 PEXG eyes were included in to the study. Corneal biomechanical parameters measurements were obtained using ORA. The main parameters assessed were corneal hysteresis (CH), corneal resistance factor (CRF), Goldmann-correlated pressure measurement (IOPg) and corneal compensated intraocular pressure (IOPcc). Ultrasound pachymetry was used for measurement of central corneal thickness (CCT). Results: In healthy subjects, PEX and PEXG eyes’ mean CH values were 10.3 ± 1.4, 8.2 ± 1.4 and 6.8 ± 1.7 mmHg, respectively. The difference in mean CH between the PEXG and other two groups were statistically significant (p50.001). Mean CRF values were 10.3 ± 0.7, 7.9 ± 1.6 and 7.9 ± 1.9 mmHg, in healthy subjects PEX and PEXG, respectively. The difference in mean CRF between the PEX and PEXG was not statistically significant (p = 0.630), however the mean CRF was significantly higher in healthy subjects, compared to other two groups. Mean CCT were 546.3 ± 28, 525.5 ± 35 and 509 ± 36 l, in healthy subjects, PEX and PEXG, respectively. The differences on CCT were also significant among the three groups (p50.001). Conclusion: In this study, the corneal biomechanical features of subjects with PEX were found to be changed as compared to healthy controls. In these patients; CH, CRF and CCT were decreased which was more obvious in patients with PEXG in comparison to PEX patients. Keywords: Corneal biomechanics, glaucoma, ocular response analyzer, pseudoexfoliation syndrome, pseudoexfoliative glaucoma
INTRODUCTION
The pathological changes also occur in the ophthalmic arterial and venous vessels and also around the lamina cribrosa in the eye.1–5 Pseudoexfoliation syndrome is the most common identifiable cause of glaucoma.2 Accumulation of white material on the anterior lens surface is the most constant diagnostic feature of PEX. The classic pattern consists of three different zones that become visible when the pupil is fully dilated. PEX material can also be identified significantly at the pupillary border. Pigment loss of the iris epithelium in the
Pseudoexfoliation syndrome (PEX) is an age-related systemic disease characterized by the synthesis and accumulation of an abnormal fibrillar extracellular material throughout the anterior segment of the eye. PEX is recognized by the ophthalmologist during a routine biomicroscopic examination. This disease involves dysregulation of elastin synthesis and formation of irregular elastic fiber aggregates, with a concomitant significant reduction of collagen fibers.
Received 11 January 2014; revised 4 May 2014; accepted 24 May 2014; published online 20 June 2014 Correspondence: Ugur Celik, MD, Merkezefendi Mah, Mevlana Cad, Sedeftepe Evleri, Blok: 96 No: 26, Zeytinburnu, Istanbul, Turkey. Tel: +90 535 965 17 40. E-mail: [email protected]
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Corneal Biomechanics of Pseudoexfoliation region near the iris sphincter and pigment deposition on anterior chamber structures are other two important findings of PEX.2 Abnormally accumulated fibers in pseudoexfoliative glaucoma (PEXG) are claimed to disrupt the normal drainage of aqueous humor and cause intraocular pressure elevation.6 PEXG has a more serious clinical progress and worse prognosis compared to primary open angle glaucoma (POAG).2,7 Almost all the structures of anterior segment of the eye are affected in PEX. Typical exfoliative fibers have been demonstrated via electron microscopy (EM) in the corneal endothelium.8,9 Corneal endotheliopathy seen in PEX includes changes in endothelial cell density and morphologic alterations.9,10 Beside these EM findings Zheng et al.11 demonstrated the significant changes on the density of corneal basal epithelial cells, stromal keratocytes and the endothelium in PEX by using in vivo confocal microscopy. Both the endothelial and cellular structural changes of the corneal layers accompanied with changes in the extracellular matrix might affect the corneal biomechanics.12,13 Inferring from these previously reported findings, we postulated that corneal biomechanical properties in eyes with PEX might be different from those of normal subjects. Ocular response analyzer (ORA) successfully reveals the biomechanical properties of the cornea. With this device, parameters reflecting the biomechanical properties of the cornea such as corneal hysteresis (CH), corneal resistance factor (CRF), Goldmann correlated intraocular pressure measurement (IOPg) and corneal compensated intraocular pressure (IOPcc) measurements can be evaluated. CRF reflecting the elastic properties of the cornea is partially independent of intraocular pressure but it has a strong relationship between central corneal thickness (CCT). CH reflecting the viscous properties of the cornea shows the changes in the organization of collagen lamellae and it is independent of CCT. CH and CRF are good indicators to comprehend the biomechanical properties of the cornea.14–17 In this study, we aimed to investigate how corneal biomechanical properties vary in patients with PEX and PEXG in comparison to healthy subjects by using ORA.
PATIENTS AND METHODS This observational, cross-sectional study was performed at Malatya State Hospital, Department of Ophthalmology in Malatya, Turkey between January 2013 and September 2013. The study population included healthy subjects as the control group, and previously diagnosed PEX and PEXG patients. Hospital’s ethics committee approved the study. An informed consent was obtained from each patient. The !
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patients having any accompanying ocular disease or previous history of any surgical intervention, dense cataract, ±4.00 D or higher spherical refractive error, 3.00 D or higher cylindrical refractive error and subjects being on corticosteroid treatment either systemically or topically were excluded from the study. The patients with chronic renal disease, hepatic disease, rheumatologic disease and diabetes were also excluded. Patients with PEX and PEXG were consecutively selected and included in the study. The diagnosis of glaucoma was based on evaluation of IOP, CCT, optic disk examination, visual field testing and evaluation of peripapillary retinal nerve fibers. PEX was defined as the presence of pseudoexfoliative material accumulation on the anterior lens capsule or at the pupillary border, pupillary ruff defects and transillumination defects of the pupillary ruff and iris sphincter. PEXG was defined as the presence of above-mentioned PEX findings with associated findings of glaucoma.7 The existence of pseudoexfoliative material was reassured after full mydriasis. All participants in the control and PEX groups had maximum IOP measured 522 mmHg and normal appearing optic disc (cup-to-disc ratios of 0.50 or less w/o vertical cupping, no cup-to-disc asymmetry, absence of any disc hemorrhage). Patients with IOP 422 mmHg and/or suspicious optic disc appearance further underwent Humphrey perimetry. All patients underwent a complete ocular examination including auto-refractometric measurement with Topcon KR 8000 auto refractor keratometer (Topcon Medical Systems, Inc), uncorrected and best-corrected visual acuities with Snellen charts, slit-lamp biomicroscopic examination, fundus examination, IOP measurement by Goldmann applanation tonometry (GAT), and detailed anterior and posterior segment evaluation. Gonioscopy with Goldmann three-mirror lens was conducted at the end of the visit. Ocular response analyzer measurements were performed prior to any contact procedures and pupillary dilatation to minimize the probable effects of applanation and dilatation on the corneal biomechanical properties. To reduce the effects of corneal diurnal variation, all examinations were performed between 09:00 and 12:00. No eye drops were used before ORA measurements. The average of the two pressure values in ORA (Pressure 1, Pressure 2) provides the IOPg reading. ORA also determines a second IOP value called IOPcc. CH, CRF, IOPcc, IOPg were measured and obtained consecutively, and only the best quality readings according to the best Waveform Score (WS) were selected for the analysis of ORA readings. All ORA readings had WS of 44.0. Central corneal thickness was measured after all non-contact measurements were completed by the help of ORA-attached handheld ultrasonic
472 S. Yazgan et al. pachymeter after instillation of one drop of topical proparacaine HCl 0.5% (Alcaine; Alcon Laboratories, UK). The instrument took three measurements from central cornea and the thinnest corneal thickness measurement was recorded.
Statistical Methods Statistical analyses were performed with SPSS 18.0 software (SPSS Inc., Chicago, IL). Distribution of data was determined by Shapiro–Wilks test. Continuous variables were expressed as mean ± SD and categorical variables as frequency and percent. Depending on the data distributions ANOVA or Kruskal–Wallis test was used to determine the differences among the three groups. p Value of 50.05 were considered statistically significant for all tests.
RESULTS In the study, 118 eyes of 118 patients were evaluated. In control group, 45 eyes of 45 subjects; in PEX group 43 eyes (in 29 subjects with bilateral PEX one eye was randomly selected; in 14 subjects with unilateral PEX, the eye involved was selected for the study) and in PEXG group 30 eyes (in 18 subjects with bilateral PEX one eye was randomly selected; in 12 subjects with unilateral PEX, the eye involved was selected for the study) were evaluated. (Table 1)
TABLE 1 Demographics of the groups. Control
PEX
PEXG
p Value
Gender, n (%) 0.141 Male 26 (57.8%) 27 (62.8%) 17 (56.7%) Female 19 (42.2%) 16 (37.2%) 13 (43.3%) Age (year, 67.83 ± 6.75 74.12 ± 7.60 73.50 ± 5.36 0.076 mean ± SD) 0.02 ± 1,9 0.03 ± 1,7 0.08 ± 1,7 0.117 Refractive error (SE,D)a SE, spherical equalent; D, diopter; SD, standard deviation.
The mean age was 67.83 ± 6.75 for Group 1 (range 55–85 years), 74.12 ± 7.60 for Group 2 (range 56–85 years) and 73.50 ± 5.36 for Group 3 (range 60–80 years). There was not any statistical difference in age and gender distribution among the three groups (p = 0.076, p = 0.141, Table 1). No statistical difference was determined among the mean spherical equivalent values of the groups (p = 0.117, Table 1). In PEXG group, three subjects were newly diagnosed and were not using any medication. Five subjects have been on topical monoteraphy (prostaglandin analogue). Of the remaining 22 subjects, 7 subjects were using a prostaglandin-timolol combination drug therapy as topical treatment, 10 subjects topical carbonic anhydrase inhibitor-timolol combination and 5 subjects a prostaglandin analogue-topical carbonic anhydrase inhibitor-timolol combination treatment. The comparison of results of the three groups were shown in Table 2 for ORA parameters. In CH values, there was a significant difference among the three groups (p50.001). CH was significantly lower in patients with PEXG compared with both PEX syndrome and normal subjects. (Table 2) The average CH value was 1.9 mmHg lower in PEX group compared to control group, whereas in PEXG group CH value was 3.2 lower than that of the control group. For CRF values, there was also a significant difference among the three groups (p50.001). CRF values were highest in the control group and lowest in PEXG group. Although there was not statistically significant difference between PEX and PEXG group (p = 0.630), the comparison between the control and PEX group and, the control and PEXG group demonstrated statistically significant difference (P150.001, P250.001; respectively). Mean CRF values were 2.3 mmHg lower in PEX group and 2.5 mmHg lower in PEXG group compared to control group. With regard to CCT values, the differences of the three groups were also statistically significant. Mean CCT value was highest in control group and lowest in PEXG group. Dual group comparisons showed higher CCT values in control group compared to both PEX and PEXG group (P150.001, P250.001, respectively).
TABLE 2 Measurements and comparisons of the groups.
CHa (mmHg) CRFb (mmHg) CCTc (mm) IOPccd (mmHg) IOPge (mmHg) GATf (mmHg)
Control (group 1)
PEX (group 2)
PEXG (group 3)
Pair 1*
Pair 2*
Pair 3*
p Value**
10.3 ± 1.5 10.3 ± 1.7 546.3 ± 28 15.9 ± 2.8 15.4 ± 3.2 15.2 ± 3.15
8.2 ± 1.4 7.9 ± 1.6 525.5 ± 35 16.5 ± 2.7 13.3 ± 3.1 13.4 ± 3.10
6.8 ± 1.7 7.9 ± 1.9 509 ± 36 20.2 ± 4.2 15.9 ± 4.2 15.7 ± 4.02
50.001 50.001 50.001 0.33 50.001 50.001
50.001 50.001 50.001 50.001 0.632 0.232
50.001 0.630 0.016 50.001 50.001 50.001
50.001 50.001 50.001 50.001 50.001 50.001
Pair 1, Group 1 and Group 2 comparison; Pair 2, Group 1 and Group 3 comparison; Pair 3, Group 2 and Group 3 comparison. p*, all groups comparison (one-way ANOVA test); **Bonferroni adjusted Mann–Whitney U test or Tukey test. a Corneal hysteresis, bcorneal resistance factor, ccentral corneal thickness, dcornea compensated intra ocular pressure, eGoldmann correlated intra ocular pressure, fintraocular pressure Goldmann applanation tonometry. Current Eye Research
Corneal Biomechanics of Pseudoexfoliation The difference between PEX and PEXG groups was statistically significant as well (p = 0.016). Mean IOPcc values were 0.4 mmHg higher in PEX group and 5.2 mmHg higher in PEXG group compared to control group. Mean IOPg values were 2.1 mmHg lower in PEX group, and 0.5 mmHg higher in PEXG group compared to control group. Mean GAT values were 1.8 mmHg lower in PEX group but 0.5 mmHg higher in PEXG group compared to control group (Table 2).
DISCUSSION Corneal hysteresis is a corneal biomechanical marker measured by ORA device. CH gives an idea about the viscosity of the cornea, thus it reflects the changes in the corneal stromal collagen organization. The ability to measure this effect is the key to the understanding of biomechanical properties of the cornea and their influence on IOP measurement process.7,15–18 CH is not affected by the CCT.7,15–18 On the other hand, CRF is providing information about the elasticity of the cornea and it is strongly linked to CCT.7,16–18 Approximately 5% of pseudoexfoliation syndrome has been known to develop progressive glaucoma in 5 years, and this rate is increasing to 15% within 10 years.19,20 In spite of the technological improvements, it is still unknown how it produces a glaucomatous damage. In vivo, confocal microscopic studies indicated that in subjects with one eye showing clinical proves of pseudoexfoliation, PEX material may be found without any clinical findings in the follow eyes as well.11,21 Currently, it is known that, pseudoexfoliation syndrome is not only an ophthalmologic problem but is a multifactorial systemic disease.2 In different studies, a significant relationship between cardiovascular disease, cardiovascular mortality and PEX has also been reported.22–24 While assessing the clinical findings of our study thoroughly, CH values were highest in the control group whereas they were lowest in PEXG group and this difference was statistically significant. Also, the comparison of CH values between PEX and PEXG group showed that CH values were significantly lower in PEXG group. Similarly, CRF values in control group were highest and in PEXG were lowest. In PEX group, CRF values were slightly higher than PEXG group but the difference was not significant. Considering the CCT, the values were highest in the control group and lowest in PEXG group. The dual comparison for PEXG and PEX groups showed CCT values being significantly higher in PEX group. According to analysis of the results of these three measurements, the decrease of CCT parallels with the decrease of CH and CRF in pseudoexfoliation syndrome. !
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Our clinical findings were confirmed by the study held by Zheng et al.11 They showed the pathological changes in PEX by using in vivo confocal microscopy. In the related study, a control group, a unilateral PEX group and the contralateral eye of those patients were evaluated and all the layers of cornea were screened by confocal microscopy. According to results of this study; the density of basal epithelial cells, stromal keratocytes and endothelial cells were found to be significantly decreased in PEX group and in their contralateral eye. Thus, the decrease in CCT was thought to be related to the apoptosis of keratocytes. Albeit the results of study held by Cankaya and Yenerel et al. showed no difference in CCT values of PEX and PEXG groups; various clinical studies indicated that CCT were thinner in eyes with PEX and PEXG.8,11,25–27 Similar to our study results, Yenerel et al.26 found that the CH and CRF were significantly lower in eyes with PEX, while Cankaya et al. and Ayala et al. found only CH being lower in pseudoexfoliative eyes.25,26,28 The altered biomechanical properties in PEX are supported by the confocal microscopic studies demonstrating the stromal changes and extracellular material deposition in eyes with PEX.23,29 In present study, when IOP values were evaluated; GAT and IOPg results were similar. There was not a significant difference for GAT and IOPg values between control group and PEXG, whereas GAT and IOPg values were significantly lower in PEX group. Furthermore, IOPcc values were statistically higher in PEXG group however there was not statistical difference between control group and PEX group in respect to IOPcc values. These findings suggest that, GAT and IOPg values, known as being effected by CCT and by corneal biomechanical features, are inadequate for a reliable IOP measurement. On the other hand, IOPcc values, known as not being affected by corneal features, provide real and reliable IOP measurement for three groups. Thus, paralleling with the decrease of CCT values in pseudoexfoliative eyes, IOP measurements seem to be either normal or lower than the real values when GAT is used for IOP measurement. As a matter of fact, a case series presented by Rao et al.30 indicated that five pseudoexfoliative eyes of three patients had advanced glaucomatous damage, thin cornea but normal intraocular pressure (523 mmHg) when the pressure measurements are done using GAT. The association between corneal biomechanical changes and glaucoma was studied previously. In a prospective longitudinal study, Medeiros et al. reported that the CH measurements were significantly associated with risk of glaucoma progression. Eyes with lower CH had faster rates of visual field loss than those with higher CH and this study also supported the role of CH as an important factor to be considered in the assessment of the risk of progression in patients
474 S. Yazgan et al. with glaucoma. Daniel et al. also reported that CH was closely related to visual field changes rather than to structural markers of glaucoma damage as measured by optical coherent topography (OCT). The results of the present study indicates that the change in biomechanical features of cornea starts before the pathophysiological glaucomatous process develops in patients with PEX. It has been known that, even if the IOP values were within normal range, the glaucomatous process might still develop.2,6 These results may suggest that, in PEX, the phenomenon may not only be related to the increase in IOP but also to the structural changes that affect the entire globe; and thus the optic nerve damage becomes even more pronounced with the damage to optic nerve vessels. It is known that CRF and CH values are affected by age. With the effect of ageing, the bonds between the corneal collagen fibers are increasing in number and thus the cornea becomes more rigid and strong in structure. However, this hardening reduces the visco-elastic response of the cornea. Kida et al.31 examined the effect of ageing on the corneal biomechanical properties and diurnal variation of biomechanical properties. The results of this study showed that, CH and CRF values decrease with age and show diurnal variations. In our study, the mean age of all three groups were found to be similar (p40.05), by which the effect of age were excluded. ORA measurements were performed between the hours 09:00–12.00 in the morning to exclude the diurnal changes. Evaluation of the visual field and retinal nerve fiber thickness besides the ORA findings could resulted in valuable data on PEX and PEXG, however it has been the limitation of our study. In addition, the small number of PEXG eyes receiving different antiglaucomatous medication limited the assessment and comparison of biomechanical parameters of those groups. The early detection of PEX/PEXG with ORA findings needs long term prospective studies involving larger patient cohorts. In conclusion, in the present study, corneal biomechanical features of subjects with PEX were found to be changed as compared to healthy controls. In these patients; CH, CRF and CCT were found to be lower which was more obvious in patients with PEXG in comparison to PEX patients.
DECLARATION OF INTEREST This study was not supported by any of the company. None of the authors has financial or proprietary interests in any material or method mentioned. These data have not been previously published.
REFERENCES 1. Thorleifsson G, Magnusson KP, Sulem P, Walters GB, Gudbjartsson H, Stefansson H, et al. Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma. Science 2007;317:1397–1400. 2. Schlotzer-Schrehardt U, Naumann GO. Ocular and systemic pseudoexfoliation syndrome. Am J Ophthalmol 2006;141:921–937. 3. Schlotzer-Schrehardt UM, Koca MR, Naumann GO, Volkholz H. Pseudoexfoliation syndrome. Ocular manifestation of a systemic disorder? Arch Ophthalmol 1992; 110:1752–1756. 4. Streeten BW, Li ZY, Wallace RN, Eagle Jr RC, Keshgegian AA. Pseudoexfoliative fibrillopathy in visceral organs of a patient with pseudoexfoliation syndrome. Arch Ophthalmol 1992;110:1757–1762. 5. Schlotzer-Schrehardt U, Kuchle M, Hofmann-Rummelt C, Kaiser A, Kirchner T. Latent TGF-beta 1 binding protein (LTBP-1); a new marker for intra-and extraocular PEX deposits. Klin Monbl Augenheilkd 2000;216:412–419. 6. Bhat S. Pseudoexfoliation syndrome: an identifiable cause of open angle glaucoma. KJO 2010;22:330–335. 7. Ritch R, Schlo¨tzer-Schrehardt U. Exfoliation syndrome. Surv Ophthalmol 2001;45:265–315. 8. Schlo¨tzer-Schrehardt U, Ku¨chle M, Do¨rfler S, Naumann GOH. Corneal endothelial involvement in pseudoexfoliation syndrome. Arch Ophthalmol 1993;111:666–674. 9. Miyake K, Matsuda M, Inaba M. Corneal endothelial changes in pseudoexfoliation syndrome. Am J Ophthalmol 1989;108:49–52. 10. Brooks AM, Grant G, Robertson IF, Gillies WE. Progressive corneal endothelial cell changes in anterior segment disease. Aust NZ J Ophthalmol 1987;15:71–78. 11. Zheng X, Inoue Y, Shiraishi A, Hara Y, Goto T, Ohashi Y. In vivo confocal microscopic and histological findings of unknown bullous keratopathy probably associated with pseudoexfoliation syndrome. BMC Ophthalmol. 2012;12:17. 12. Hjortdal JO, Jensen PK. Extensibility of the normohydrated human cornea. Acta Ophthalmol Scand 1995;73: 12–17. 13. de Voogd S, Ikram MK, Wolfs RC, Jansonius NM, Witteman JCM, Hofman A, de Jong FH. Is diabetes mellitus a risk factor for open-angle glaucoma? Ophthalmology 2006;113:1827–1831. 14. Sullivan-Mee M, Billingsley SC, Patel AD, Halverson KD, Alldredge BR, Qualls C. Ocular response analyzer in subjects with and without glaucoma. Optom Vis Sci 2008; 85:463–470. 15. Chihara E. Assessment of true intraocular pressure: the gap between theory and practical data. Surv Ophthalmol 2008;53:203–218. 16. Kotecha A. What biomechanical properties of the cornea are relevant for the clinician? Surv Ophthalmol 2007;52: 109–114. 17. Kotecha A, Elsheikh A, Roberts CR, Zhu H, GarwayHeath DF. Corneal thickness- and age-related biomechanical properties of the cornea measured with the ocular response analyzer. Invest Ophthalmol Vis Sci 2006;47: 5337–5347. 18. Luce DA. Determining in vivo biomechanical properties of the cornea with an ocular response analyzer. J Cataract Refract Surg 2005;31:156–162. 19. Henry JC, Krupin T, Schmitt M, Lauffer J, Miller E, Ewing MQ et al. Long-term: follow up of pseudoexfolialion and the development of elevated intraocular pressure. Ophthalmology 1997;94:545–550. Current Eye Research
Corneal Biomechanics of Pseudoexfoliation 20. Konstm ACP. Glaucoma in eyes with exfoliation syndrome. 3rd International Glaucoma Syposium – ICS. Prague, Czech Republic, March 21–25, 2001. 21. Martone G, Casprini F, Traversi C, Lepri F, Pichierri P, Caporossi A. Pseudoexfoliation syndrome: in vivo confocal microscopy analysis. Clin Exp Ophthalmol 2007;35: 582–585. 22. French DD, Margo CE, Harman LE. Ocular pseudoexfoliation and cardiovascular disease : a national cross-section comparison study. N Am J Med Sci 2012;4:468–473. 23. Demir N, Ulus T, Yucel OE, Kumral ET, Singar E, Tanboga HI. Assessment of myocardial ischaemia using tissue Doppler imaging in pseudoexfoliation syndrome. Eye (Lond) 2011;25:1177–1180. 24. Shrum KR, Hattenhauer MG, Hodge D. Cardiovascular and cerebrovascular mortality associated with ocular pseudoexfoliation. Am J Ophthalmol 2000;129:83–86. ¨ zcelik D, Demirdogen E, 25. Cankaya AB, Anayol A, O Yilmazbas P. Ocular response analyzer to assess corneal biomechanical properties in exfoliation syndrome and exfoliative glaucoma. Graefes Arch Clin Exp Ophthalmol 2012;250:255–260.
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26. Yenerel NM, Gorgun E, Kucumen RB, Oral D, Dinc UA, Ciftci F. Corneal biomechanical properties of patients with pseudoexfoliation syndrome. Cornea 2011; 30:983–986. 27. Inoue K, Okugawa K, Oshika T, Amano S. Morphological study of corneal endothelium and corneal thickness in pseudoexfoliation syndrome. Jpn J Ophthalmol 2003;47: 235–239. 28. Ayala M. Corneal hysteresis in normal subjects and in patients with primary open-angle glaucoma and pseudoexfoliation glaucoma. Ophthalmic Res 2011;46: 187–191. 29. Sbeity Z, Palmiero PM, Tello C, et al. Non-contact in vivo confocal scanning laser microscopy in exfoliation syndrome, exfoliation syndrome suspect and normal eyes. Acta Ophthalmol 2011;89:241–247. 30. Rao A. Normotensive pseudoexfoliation glaucoma: a new phenotype? Semin Ophthalmol 2012;27:48–51. 31. Kida T, Liu JH, Weinreb RN. Effects of aging on corneal biomechanical properties and their impact on 24-hour measurement of intraocular pressure. Am J Ophthalmol 2008;146:567–572.
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ORIGINAL ARTICLE
Corneal Biomechanical Comparison of Pseudoexfoliation Syndrome, Pseudoexfoliative Glaucoma and Healthy Subjects Serpil Yazgan1, Ugur Celik2, Ne¸se Alago¨z3 and Mehmet Ta¸s4 1
Ophthalmology Department, Zonguldak Karaelmas University, Zonguldak, Turkey, 2Gaziosmanpasa Taksim Training and Research Hospital, Istanbul, Turkey, 3Beyoglu Eye Training and Research Hospital, Istanbul, Turkey, and 4Ophthalmology Department, Malatya State Hospital, Istanbul, Turkey
ABSTRACT Purpose: To evaluate the differences in corneal biomechanical properties between healthy subjects and patients with pseudoexfoliation syndrome (PEX) and pseudoexfoliative glaucoma (PEXG) using the ocular response analyzer (ORA). Materials and methods: One hundred eighteen eyes of 45 healthy, 43 PEX and 30 PEXG eyes were included in to the study. Corneal biomechanical parameters measurements were obtained using ORA. The main parameters assessed were corneal hysteresis (CH), corneal resistance factor (CRF), Goldmann-correlated pressure measurement (IOPg) and corneal compensated intraocular pressure (IOPcc). Ultrasound pachymetry was used for measurement of central corneal thickness (CCT). Results: In healthy subjects, PEX and PEXG eyes’ mean CH values were 10.3 ± 1.4, 8.2 ± 1.4 and 6.8 ± 1.7 mmHg, respectively. The difference in mean CH between the PEXG and other two groups were statistically significant (p50.001). Mean CRF values were 10.3 ± 0.7, 7.9 ± 1.6 and 7.9 ± 1.9 mmHg, in healthy subjects PEX and PEXG, respectively. The difference in mean CRF between the PEX and PEXG was not statistically significant (p = 0.630), however the mean CRF was significantly higher in healthy subjects, compared to other two groups. Mean CCT were 546.3 ± 28, 525.5 ± 35 and 509 ± 36 l, in healthy subjects, PEX and PEXG, respectively. The differences on CCT were also significant among the three groups (p50.001). Conclusion: In this study, the corneal biomechanical features of subjects with PEX were found to be changed as compared to healthy controls. In these patients; CH, CRF and CCT were decreased which was more obvious in patients with PEXG in comparison to PEX patients. Keywords: Corneal biomechanics, glaucoma, ocular response analyzer, pseudoexfoliation syndrome, pseudoexfoliative glaucoma
INTRODUCTION
The pathological changes also occur in the ophthalmic arterial and venous vessels and also around the lamina cribrosa in the eye.1–5 Pseudoexfoliation syndrome is the most common identifiable cause of glaucoma.2 Accumulation of white material on the anterior lens surface is the most constant diagnostic feature of PEX. The classic pattern consists of three different zones that become visible when the pupil is fully dilated. PEX material can also be identified significantly at the pupillary border. Pigment loss of the iris epithelium in the
Pseudoexfoliation syndrome (PEX) is an age-related systemic disease characterized by the synthesis and accumulation of an abnormal fibrillar extracellular material throughout the anterior segment of the eye. PEX is recognized by the ophthalmologist during a routine biomicroscopic examination. This disease involves dysregulation of elastin synthesis and formation of irregular elastic fiber aggregates, with a concomitant significant reduction of collagen fibers.
Received 11 January 2014; revised 4 May 2014; accepted 24 May 2014; published online 20 June 2014 Correspondence: Ugur Celik, MD, Merkezefendi Mah, Mevlana Cad, Sedeftepe Evleri, Blok: 96 No: 26, Zeytinburnu, Istanbul, Turkey. Tel: +90 535 965 17 40. E-mail: [email protected]
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Corneal Biomechanics of Pseudoexfoliation region near the iris sphincter and pigment deposition on anterior chamber structures are other two important findings of PEX.2 Abnormally accumulated fibers in pseudoexfoliative glaucoma (PEXG) are claimed to disrupt the normal drainage of aqueous humor and cause intraocular pressure elevation.6 PEXG has a more serious clinical progress and worse prognosis compared to primary open angle glaucoma (POAG).2,7 Almost all the structures of anterior segment of the eye are affected in PEX. Typical exfoliative fibers have been demonstrated via electron microscopy (EM) in the corneal endothelium.8,9 Corneal endotheliopathy seen in PEX includes changes in endothelial cell density and morphologic alterations.9,10 Beside these EM findings Zheng et al.11 demonstrated the significant changes on the density of corneal basal epithelial cells, stromal keratocytes and the endothelium in PEX by using in vivo confocal microscopy. Both the endothelial and cellular structural changes of the corneal layers accompanied with changes in the extracellular matrix might affect the corneal biomechanics.12,13 Inferring from these previously reported findings, we postulated that corneal biomechanical properties in eyes with PEX might be different from those of normal subjects. Ocular response analyzer (ORA) successfully reveals the biomechanical properties of the cornea. With this device, parameters reflecting the biomechanical properties of the cornea such as corneal hysteresis (CH), corneal resistance factor (CRF), Goldmann correlated intraocular pressure measurement (IOPg) and corneal compensated intraocular pressure (IOPcc) measurements can be evaluated. CRF reflecting the elastic properties of the cornea is partially independent of intraocular pressure but it has a strong relationship between central corneal thickness (CCT). CH reflecting the viscous properties of the cornea shows the changes in the organization of collagen lamellae and it is independent of CCT. CH and CRF are good indicators to comprehend the biomechanical properties of the cornea.14–17 In this study, we aimed to investigate how corneal biomechanical properties vary in patients with PEX and PEXG in comparison to healthy subjects by using ORA.
PATIENTS AND METHODS This observational, cross-sectional study was performed at Malatya State Hospital, Department of Ophthalmology in Malatya, Turkey between January 2013 and September 2013. The study population included healthy subjects as the control group, and previously diagnosed PEX and PEXG patients. Hospital’s ethics committee approved the study. An informed consent was obtained from each patient. The !
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patients having any accompanying ocular disease or previous history of any surgical intervention, dense cataract, ±4.00 D or higher spherical refractive error, 3.00 D or higher cylindrical refractive error and subjects being on corticosteroid treatment either systemically or topically were excluded from the study. The patients with chronic renal disease, hepatic disease, rheumatologic disease and diabetes were also excluded. Patients with PEX and PEXG were consecutively selected and included in the study. The diagnosis of glaucoma was based on evaluation of IOP, CCT, optic disk examination, visual field testing and evaluation of peripapillary retinal nerve fibers. PEX was defined as the presence of pseudoexfoliative material accumulation on the anterior lens capsule or at the pupillary border, pupillary ruff defects and transillumination defects of the pupillary ruff and iris sphincter. PEXG was defined as the presence of above-mentioned PEX findings with associated findings of glaucoma.7 The existence of pseudoexfoliative material was reassured after full mydriasis. All participants in the control and PEX groups had maximum IOP measured 522 mmHg and normal appearing optic disc (cup-to-disc ratios of 0.50 or less w/o vertical cupping, no cup-to-disc asymmetry, absence of any disc hemorrhage). Patients with IOP 422 mmHg and/or suspicious optic disc appearance further underwent Humphrey perimetry. All patients underwent a complete ocular examination including auto-refractometric measurement with Topcon KR 8000 auto refractor keratometer (Topcon Medical Systems, Inc), uncorrected and best-corrected visual acuities with Snellen charts, slit-lamp biomicroscopic examination, fundus examination, IOP measurement by Goldmann applanation tonometry (GAT), and detailed anterior and posterior segment evaluation. Gonioscopy with Goldmann three-mirror lens was conducted at the end of the visit. Ocular response analyzer measurements were performed prior to any contact procedures and pupillary dilatation to minimize the probable effects of applanation and dilatation on the corneal biomechanical properties. To reduce the effects of corneal diurnal variation, all examinations were performed between 09:00 and 12:00. No eye drops were used before ORA measurements. The average of the two pressure values in ORA (Pressure 1, Pressure 2) provides the IOPg reading. ORA also determines a second IOP value called IOPcc. CH, CRF, IOPcc, IOPg were measured and obtained consecutively, and only the best quality readings according to the best Waveform Score (WS) were selected for the analysis of ORA readings. All ORA readings had WS of 44.0. Central corneal thickness was measured after all non-contact measurements were completed by the help of ORA-attached handheld ultrasonic
472 S. Yazgan et al. pachymeter after instillation of one drop of topical proparacaine HCl 0.5% (Alcaine; Alcon Laboratories, UK). The instrument took three measurements from central cornea and the thinnest corneal thickness measurement was recorded.
Statistical Methods Statistical analyses were performed with SPSS 18.0 software (SPSS Inc., Chicago, IL). Distribution of data was determined by Shapiro–Wilks test. Continuous variables were expressed as mean ± SD and categorical variables as frequency and percent. Depending on the data distributions ANOVA or Kruskal–Wallis test was used to determine the differences among the three groups. p Value of 50.05 were considered statistically significant for all tests.
RESULTS In the study, 118 eyes of 118 patients were evaluated. In control group, 45 eyes of 45 subjects; in PEX group 43 eyes (in 29 subjects with bilateral PEX one eye was randomly selected; in 14 subjects with unilateral PEX, the eye involved was selected for the study) and in PEXG group 30 eyes (in 18 subjects with bilateral PEX one eye was randomly selected; in 12 subjects with unilateral PEX, the eye involved was selected for the study) were evaluated. (Table 1)
TABLE 1 Demographics of the groups. Control
PEX
PEXG
p Value
Gender, n (%) 0.141 Male 26 (57.8%) 27 (62.8%) 17 (56.7%) Female 19 (42.2%) 16 (37.2%) 13 (43.3%) Age (year, 67.83 ± 6.75 74.12 ± 7.60 73.50 ± 5.36 0.076 mean ± SD) 0.02 ± 1,9 0.03 ± 1,7 0.08 ± 1,7 0.117 Refractive error (SE,D)a SE, spherical equalent; D, diopter; SD, standard deviation.
The mean age was 67.83 ± 6.75 for Group 1 (range 55–85 years), 74.12 ± 7.60 for Group 2 (range 56–85 years) and 73.50 ± 5.36 for Group 3 (range 60–80 years). There was not any statistical difference in age and gender distribution among the three groups (p = 0.076, p = 0.141, Table 1). No statistical difference was determined among the mean spherical equivalent values of the groups (p = 0.117, Table 1). In PEXG group, three subjects were newly diagnosed and were not using any medication. Five subjects have been on topical monoteraphy (prostaglandin analogue). Of the remaining 22 subjects, 7 subjects were using a prostaglandin-timolol combination drug therapy as topical treatment, 10 subjects topical carbonic anhydrase inhibitor-timolol combination and 5 subjects a prostaglandin analogue-topical carbonic anhydrase inhibitor-timolol combination treatment. The comparison of results of the three groups were shown in Table 2 for ORA parameters. In CH values, there was a significant difference among the three groups (p50.001). CH was significantly lower in patients with PEXG compared with both PEX syndrome and normal subjects. (Table 2) The average CH value was 1.9 mmHg lower in PEX group compared to control group, whereas in PEXG group CH value was 3.2 lower than that of the control group. For CRF values, there was also a significant difference among the three groups (p50.001). CRF values were highest in the control group and lowest in PEXG group. Although there was not statistically significant difference between PEX and PEXG group (p = 0.630), the comparison between the control and PEX group and, the control and PEXG group demonstrated statistically significant difference (P150.001, P250.001; respectively). Mean CRF values were 2.3 mmHg lower in PEX group and 2.5 mmHg lower in PEXG group compared to control group. With regard to CCT values, the differences of the three groups were also statistically significant. Mean CCT value was highest in control group and lowest in PEXG group. Dual group comparisons showed higher CCT values in control group compared to both PEX and PEXG group (P150.001, P250.001, respectively).
TABLE 2 Measurements and comparisons of the groups.
CHa (mmHg) CRFb (mmHg) CCTc (mm) IOPccd (mmHg) IOPge (mmHg) GATf (mmHg)
Control (group 1)
PEX (group 2)
PEXG (group 3)
Pair 1*
Pair 2*
Pair 3*
p Value**
10.3 ± 1.5 10.3 ± 1.7 546.3 ± 28 15.9 ± 2.8 15.4 ± 3.2 15.2 ± 3.15
8.2 ± 1.4 7.9 ± 1.6 525.5 ± 35 16.5 ± 2.7 13.3 ± 3.1 13.4 ± 3.10
6.8 ± 1.7 7.9 ± 1.9 509 ± 36 20.2 ± 4.2 15.9 ± 4.2 15.7 ± 4.02
50.001 50.001 50.001 0.33 50.001 50.001
50.001 50.001 50.001 50.001 0.632 0.232
50.001 0.630 0.016 50.001 50.001 50.001
50.001 50.001 50.001 50.001 50.001 50.001
Pair 1, Group 1 and Group 2 comparison; Pair 2, Group 1 and Group 3 comparison; Pair 3, Group 2 and Group 3 comparison. p*, all groups comparison (one-way ANOVA test); **Bonferroni adjusted Mann–Whitney U test or Tukey test. a Corneal hysteresis, bcorneal resistance factor, ccentral corneal thickness, dcornea compensated intra ocular pressure, eGoldmann correlated intra ocular pressure, fintraocular pressure Goldmann applanation tonometry. Current Eye Research
Corneal Biomechanics of Pseudoexfoliation The difference between PEX and PEXG groups was statistically significant as well (p = 0.016). Mean IOPcc values were 0.4 mmHg higher in PEX group and 5.2 mmHg higher in PEXG group compared to control group. Mean IOPg values were 2.1 mmHg lower in PEX group, and 0.5 mmHg higher in PEXG group compared to control group. Mean GAT values were 1.8 mmHg lower in PEX group but 0.5 mmHg higher in PEXG group compared to control group (Table 2).
DISCUSSION Corneal hysteresis is a corneal biomechanical marker measured by ORA device. CH gives an idea about the viscosity of the cornea, thus it reflects the changes in the corneal stromal collagen organization. The ability to measure this effect is the key to the understanding of biomechanical properties of the cornea and their influence on IOP measurement process.7,15–18 CH is not affected by the CCT.7,15–18 On the other hand, CRF is providing information about the elasticity of the cornea and it is strongly linked to CCT.7,16–18 Approximately 5% of pseudoexfoliation syndrome has been known to develop progressive glaucoma in 5 years, and this rate is increasing to 15% within 10 years.19,20 In spite of the technological improvements, it is still unknown how it produces a glaucomatous damage. In vivo, confocal microscopic studies indicated that in subjects with one eye showing clinical proves of pseudoexfoliation, PEX material may be found without any clinical findings in the follow eyes as well.11,21 Currently, it is known that, pseudoexfoliation syndrome is not only an ophthalmologic problem but is a multifactorial systemic disease.2 In different studies, a significant relationship between cardiovascular disease, cardiovascular mortality and PEX has also been reported.22–24 While assessing the clinical findings of our study thoroughly, CH values were highest in the control group whereas they were lowest in PEXG group and this difference was statistically significant. Also, the comparison of CH values between PEX and PEXG group showed that CH values were significantly lower in PEXG group. Similarly, CRF values in control group were highest and in PEXG were lowest. In PEX group, CRF values were slightly higher than PEXG group but the difference was not significant. Considering the CCT, the values were highest in the control group and lowest in PEXG group. The dual comparison for PEXG and PEX groups showed CCT values being significantly higher in PEX group. According to analysis of the results of these three measurements, the decrease of CCT parallels with the decrease of CH and CRF in pseudoexfoliation syndrome. !
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Our clinical findings were confirmed by the study held by Zheng et al.11 They showed the pathological changes in PEX by using in vivo confocal microscopy. In the related study, a control group, a unilateral PEX group and the contralateral eye of those patients were evaluated and all the layers of cornea were screened by confocal microscopy. According to results of this study; the density of basal epithelial cells, stromal keratocytes and endothelial cells were found to be significantly decreased in PEX group and in their contralateral eye. Thus, the decrease in CCT was thought to be related to the apoptosis of keratocytes. Albeit the results of study held by Cankaya and Yenerel et al. showed no difference in CCT values of PEX and PEXG groups; various clinical studies indicated that CCT were thinner in eyes with PEX and PEXG.8,11,25–27 Similar to our study results, Yenerel et al.26 found that the CH and CRF were significantly lower in eyes with PEX, while Cankaya et al. and Ayala et al. found only CH being lower in pseudoexfoliative eyes.25,26,28 The altered biomechanical properties in PEX are supported by the confocal microscopic studies demonstrating the stromal changes and extracellular material deposition in eyes with PEX.23,29 In present study, when IOP values were evaluated; GAT and IOPg results were similar. There was not a significant difference for GAT and IOPg values between control group and PEXG, whereas GAT and IOPg values were significantly lower in PEX group. Furthermore, IOPcc values were statistically higher in PEXG group however there was not statistical difference between control group and PEX group in respect to IOPcc values. These findings suggest that, GAT and IOPg values, known as being effected by CCT and by corneal biomechanical features, are inadequate for a reliable IOP measurement. On the other hand, IOPcc values, known as not being affected by corneal features, provide real and reliable IOP measurement for three groups. Thus, paralleling with the decrease of CCT values in pseudoexfoliative eyes, IOP measurements seem to be either normal or lower than the real values when GAT is used for IOP measurement. As a matter of fact, a case series presented by Rao et al.30 indicated that five pseudoexfoliative eyes of three patients had advanced glaucomatous damage, thin cornea but normal intraocular pressure (523 mmHg) when the pressure measurements are done using GAT. The association between corneal biomechanical changes and glaucoma was studied previously. In a prospective longitudinal study, Medeiros et al. reported that the CH measurements were significantly associated with risk of glaucoma progression. Eyes with lower CH had faster rates of visual field loss than those with higher CH and this study also supported the role of CH as an important factor to be considered in the assessment of the risk of progression in patients
474 S. Yazgan et al. with glaucoma. Daniel et al. also reported that CH was closely related to visual field changes rather than to structural markers of glaucoma damage as measured by optical coherent topography (OCT). The results of the present study indicates that the change in biomechanical features of cornea starts before the pathophysiological glaucomatous process develops in patients with PEX. It has been known that, even if the IOP values were within normal range, the glaucomatous process might still develop.2,6 These results may suggest that, in PEX, the phenomenon may not only be related to the increase in IOP but also to the structural changes that affect the entire globe; and thus the optic nerve damage becomes even more pronounced with the damage to optic nerve vessels. It is known that CRF and CH values are affected by age. With the effect of ageing, the bonds between the corneal collagen fibers are increasing in number and thus the cornea becomes more rigid and strong in structure. However, this hardening reduces the visco-elastic response of the cornea. Kida et al.31 examined the effect of ageing on the corneal biomechanical properties and diurnal variation of biomechanical properties. The results of this study showed that, CH and CRF values decrease with age and show diurnal variations. In our study, the mean age of all three groups were found to be similar (p40.05), by which the effect of age were excluded. ORA measurements were performed between the hours 09:00–12.00 in the morning to exclude the diurnal changes. Evaluation of the visual field and retinal nerve fiber thickness besides the ORA findings could resulted in valuable data on PEX and PEXG, however it has been the limitation of our study. In addition, the small number of PEXG eyes receiving different antiglaucomatous medication limited the assessment and comparison of biomechanical parameters of those groups. The early detection of PEX/PEXG with ORA findings needs long term prospective studies involving larger patient cohorts. In conclusion, in the present study, corneal biomechanical features of subjects with PEX were found to be changed as compared to healthy controls. In these patients; CH, CRF and CCT were found to be lower which was more obvious in patients with PEXG in comparison to PEX patients.
DECLARATION OF INTEREST This study was not supported by any of the company. None of the authors has financial or proprietary interests in any material or method mentioned. These data have not been previously published.
REFERENCES 1. Thorleifsson G, Magnusson KP, Sulem P, Walters GB, Gudbjartsson H, Stefansson H, et al. Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma. Science 2007;317:1397–1400. 2. Schlotzer-Schrehardt U, Naumann GO. Ocular and systemic pseudoexfoliation syndrome. Am J Ophthalmol 2006;141:921–937. 3. Schlotzer-Schrehardt UM, Koca MR, Naumann GO, Volkholz H. Pseudoexfoliation syndrome. Ocular manifestation of a systemic disorder? Arch Ophthalmol 1992; 110:1752–1756. 4. Streeten BW, Li ZY, Wallace RN, Eagle Jr RC, Keshgegian AA. Pseudoexfoliative fibrillopathy in visceral organs of a patient with pseudoexfoliation syndrome. Arch Ophthalmol 1992;110:1757–1762. 5. Schlotzer-Schrehardt U, Kuchle M, Hofmann-Rummelt C, Kaiser A, Kirchner T. Latent TGF-beta 1 binding protein (LTBP-1); a new marker for intra-and extraocular PEX deposits. Klin Monbl Augenheilkd 2000;216:412–419. 6. Bhat S. Pseudoexfoliation syndrome: an identifiable cause of open angle glaucoma. KJO 2010;22:330–335. 7. Ritch R, Schlo¨tzer-Schrehardt U. Exfoliation syndrome. Surv Ophthalmol 2001;45:265–315. 8. Schlo¨tzer-Schrehardt U, Ku¨chle M, Do¨rfler S, Naumann GOH. Corneal endothelial involvement in pseudoexfoliation syndrome. Arch Ophthalmol 1993;111:666–674. 9. Miyake K, Matsuda M, Inaba M. Corneal endothelial changes in pseudoexfoliation syndrome. Am J Ophthalmol 1989;108:49–52. 10. Brooks AM, Grant G, Robertson IF, Gillies WE. Progressive corneal endothelial cell changes in anterior segment disease. Aust NZ J Ophthalmol 1987;15:71–78. 11. Zheng X, Inoue Y, Shiraishi A, Hara Y, Goto T, Ohashi Y. In vivo confocal microscopic and histological findings of unknown bullous keratopathy probably associated with pseudoexfoliation syndrome. BMC Ophthalmol. 2012;12:17. 12. Hjortdal JO, Jensen PK. Extensibility of the normohydrated human cornea. Acta Ophthalmol Scand 1995;73: 12–17. 13. de Voogd S, Ikram MK, Wolfs RC, Jansonius NM, Witteman JCM, Hofman A, de Jong FH. Is diabetes mellitus a risk factor for open-angle glaucoma? Ophthalmology 2006;113:1827–1831. 14. Sullivan-Mee M, Billingsley SC, Patel AD, Halverson KD, Alldredge BR, Qualls C. Ocular response analyzer in subjects with and without glaucoma. Optom Vis Sci 2008; 85:463–470. 15. Chihara E. Assessment of true intraocular pressure: the gap between theory and practical data. Surv Ophthalmol 2008;53:203–218. 16. Kotecha A. What biomechanical properties of the cornea are relevant for the clinician? Surv Ophthalmol 2007;52: 109–114. 17. Kotecha A, Elsheikh A, Roberts CR, Zhu H, GarwayHeath DF. Corneal thickness- and age-related biomechanical properties of the cornea measured with the ocular response analyzer. Invest Ophthalmol Vis Sci 2006;47: 5337–5347. 18. Luce DA. Determining in vivo biomechanical properties of the cornea with an ocular response analyzer. J Cataract Refract Surg 2005;31:156–162. 19. Henry JC, Krupin T, Schmitt M, Lauffer J, Miller E, Ewing MQ et al. Long-term: follow up of pseudoexfolialion and the development of elevated intraocular pressure. Ophthalmology 1997;94:545–550. Current Eye Research
Corneal Biomechanics of Pseudoexfoliation 20. Konstm ACP. Glaucoma in eyes with exfoliation syndrome. 3rd International Glaucoma Syposium – ICS. Prague, Czech Republic, March 21–25, 2001. 21. Martone G, Casprini F, Traversi C, Lepri F, Pichierri P, Caporossi A. Pseudoexfoliation syndrome: in vivo confocal microscopy analysis. Clin Exp Ophthalmol 2007;35: 582–585. 22. French DD, Margo CE, Harman LE. Ocular pseudoexfoliation and cardiovascular disease : a national cross-section comparison study. N Am J Med Sci 2012;4:468–473. 23. Demir N, Ulus T, Yucel OE, Kumral ET, Singar E, Tanboga HI. Assessment of myocardial ischaemia using tissue Doppler imaging in pseudoexfoliation syndrome. Eye (Lond) 2011;25:1177–1180. 24. Shrum KR, Hattenhauer MG, Hodge D. Cardiovascular and cerebrovascular mortality associated with ocular pseudoexfoliation. Am J Ophthalmol 2000;129:83–86. ¨ zcelik D, Demirdogen E, 25. Cankaya AB, Anayol A, O Yilmazbas P. Ocular response analyzer to assess corneal biomechanical properties in exfoliation syndrome and exfoliative glaucoma. Graefes Arch Clin Exp Ophthalmol 2012;250:255–260.
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2015 Informa Healthcare USA, Inc.
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26. Yenerel NM, Gorgun E, Kucumen RB, Oral D, Dinc UA, Ciftci F. Corneal biomechanical properties of patients with pseudoexfoliation syndrome. Cornea 2011; 30:983–986. 27. Inoue K, Okugawa K, Oshika T, Amano S. Morphological study of corneal endothelium and corneal thickness in pseudoexfoliation syndrome. Jpn J Ophthalmol 2003;47: 235–239. 28. Ayala M. Corneal hysteresis in normal subjects and in patients with primary open-angle glaucoma and pseudoexfoliation glaucoma. Ophthalmic Res 2011;46: 187–191. 29. Sbeity Z, Palmiero PM, Tello C, et al. Non-contact in vivo confocal scanning laser microscopy in exfoliation syndrome, exfoliation syndrome suspect and normal eyes. Acta Ophthalmol 2011;89:241–247. 30. Rao A. Normotensive pseudoexfoliation glaucoma: a new phenotype? Semin Ophthalmol 2012;27:48–51. 31. Kida T, Liu JH, Weinreb RN. Effects of aging on corneal biomechanical properties and their impact on 24-hour measurement of intraocular pressure. Am J Ophthalmol 2008;146:567–572.
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