Naim Terai

Identification of Biomechanical Properties of the Cornea: The Ocular Response Analyzer

Purpose: Several methods have been devised for measuring geometric parameters of the cornea but, until now, the biomechanics of the cornea have been largely ignored. The relatively new Ocular Response Analyzer (ORA) provides such biomechanical information. In order to correctly interpret the underlying biomechanics of ORA data, we review reported ORA measurements and provide a compendium of factors influencing these measurements, with discussion of possible explanations for ORA measurement results. Methods: This review comprised a literature search using “ocular response analyzer” and “ocular response analyser” as keywords. We reviewed and compared reported results from recent ORA studies so obtained, with an eye to understanding corneal biomechanics. Results: Several ORA biomechanical parameters of the cornea – corneal hysteresis (CH) and corneal resistant factor (CRF) – characterize the viscoelastic properties of the cornea, especially those of the ground substance. The impact on CH and CRF values of various independent factors, e.g. intraocular pressure (IOP), age, central corneal thickness (CCT), and corneal swelling, are discussed. The impact on CH and CRF of treatment-related structural changes of the cornea, i.e. those occurring after refractive surgical procedures, placement of intracorneal rings, and collagen crosslinking (CXL), as well as pathological changes of the cornea, e.g. those resulting from keratoconus, edema, and glaucoma, are discussed. Conclusions: Changes in CRF and CH may be reflective of structural changes in the ground substance of the cornea. Thus, ORA provides invaluable information for delineating biomechanical conditions pertaining to the cornea, with special regard to ocular diseases, e.g. keratoconus and glaucoma.

Detection of biomechanical changes after corneal cross-linking using Ocular Response Analyzer software.

PURPOSE To investigate biomechanical changes after corneal cross-linking (CXL) with riboflavin/ultraviolet-A (UVA) in keratoconus using the recently developed Ocular Response Analyzer (ORA, Reichert Technologies) software. METHODS Through use of the new ORA software (version 2.04), 37 new parameters derived from the best measurement signal with the highest wavescore of 4 measurements from 50 eyes of 46 patients with keratoconus were obtained before and 1 year after CXL. The parameters of 96 eyes from 96 age-matched, healthy individuals with a spherical equivalent refraction <3.00 diopters served as controls. RESULTS Corneal hysteresis (CH) and corneal resistance factor (CRF) before CXL were 7.38±1.42 mmHg and 6.16±1.42 mmHg, respectively, compared to 7.37±1.26 mmHg (P=.971) and 6.16±1.50 mmHg after CXL (P=.997), respectively. Based on these 37 new parameters, the area under peak 2 (p2area) showed a statistically significant increase from 1262.3±623.1 before CXL to 1704.3±732.3 1 year after CXL (35%; P=.001). The related value for the p2area of the healthy control group was 3374.9±1099.9. A significant negative correlation was observed between the p2area and the difference in CH-CRF values (r=-0.29, P=.001). CONCLUSIONS The area under peak 2 appears to be a more sensitive parameter to detect biomechanical changes after CXL than CH or CRF alone. After CXL, keratoconic corneas display altered biomechanical properties, which remain different to those observed in healthy corneas.

Biomechanical condition of the cornea as a new indicator for pathological and structural changes

AIM Several methods permit the measurement of geometric parameters of the cornea, but until now biomechanical conditions of the cornea have been ignored (e.g. in refractive corneal surgery). Besides the geometric condition, biomechanical properties of the cornea have been shown to influence applanation measurement of intra-ocular pressure (IOP) and epidemiological studies have identified corneal thickness as an independent risk factor for the development and progression of glaucoma. The aim of this investigation was to characterize the biomechanical properties of the cornea using the ocular response analyzer (ORA). METHODS The ocular response analyzer (ORA) is a new method available for non-contact measurement of the biomechanical properties of the cornea. We evaluated the reproducibility of measurements, the difference between static and dynamic factors and the impact of independent factors (e.g. IOP, age, CCT, swelling of the cornea) on 2,500 measurements of corneal hysteresis (CH) and corneal resistance factor (CRF). RESULTS In a large sample size we observed changes in CH and CRF after refractive surgery procedures (LASIK, UV-A cross-linking, keratoplasty) and in other corneal disorders (keratoconus, corneal dystrophies). CONCLUSIONS CRF and CH changes may reflect structural changes of the cornea. Thus, the ORA provides valuable information for a better understanding and characterization of the biomechanical condition of the cornea, especially with regard to diseases such as keratoconus and glaucoma.

The effect of caffeine on retinal vessel diameter in young healthy subjects.

Purpose:  To investigate the effect of caffeine on retinal vessel diameter before and during flicker light stimulation in young healthy subjects.

Enhanced pressure in the central retinal vein decreases the perfusion pressure in the prelaminar region of the optic nerve head.

PURPOSE The pressure in the central retinal vein (CRVP) has been shown to be higher in glaucoma patients than in controls. Until now, these measurements have been performed in arbitrary units or in units of ophthalmodynamometric force. In our study, a contact lens dynamometer, calibrated in mm Hg, was used to calculate the retinal perfusion pressure. METHODS A total of 27 patients with primary open angle glaucoma (POAG) and 27 healthy control subjects were included in the study. The IOP measurement included Goldmann applanation tonometry, whereas the pressure enhancement measurement consisted of contact lens dynamometry. results: the pressures are given in mm hg, and are expressed as the mean ± SD for the control subjects versus the POAG patients: IOP 14.4 ± 2.7 vs. 15.4 ± 2.9, systolic blood pressure 141 ± 20.1 vs. 153 ± 16.5 (P = 0.013), central retinal vein threshold pressure (CRVTP) 11.9 ± 3.8 vs. 16.8 ± 5.0, CRVP 15.0 ± 2.7 vs. 17.9 ± 4.2, and retinal perfusion pressure (PPret) standard 84 ± 12.2 vs. 94 ± 9.1 and new 83 ± 12.2 vs. 91 ± 9.6. The differences in PPret between using the new versus the standard method are 0.55 ± 1.33 vs. -2.5 ± 3.89 (P = 0.041 and P = 0.002, respectively). The PPret was at least 5.0 mm Hg lower in 5 of the 27 POAG patients when the new calculation method was used. CONCLUSIONS The perfusion pressure in the retina and prelaminar region of the optic nerve head (ONH) may be lower than expected because the CRVP may be higher. The pressure measurement in the central retinal vein may be a step toward a better understanding of ONH pathophysiology.

short-term effect of topical antiglaucoma medication on tear-film stability, tear secretion, and corneal sensitivity in healthy subjects

Background: The purpose of this study was to investigate the short-term effect of topical antiglaucoma medication on tear-film stability, tear secretion, and corneal sensitivity in healthy subjects. Methods: In this prospective, double-blind crossover trial, break-up time and basal secretion (Jones test) were measured 60 minutes before, and 30, 60, and 90 minutes after topical antiglaucoma drop application in 30 healthy subjects. Corneal sensitivity was measured 60 minutes before, and five, 10, and 15 minutes after drop application using a Cochet–Bonnet esthesiometer. Results: Reduction of break-up time in the latanoprost group was −23.8% after 30 minutes (P = 0.21), −26.7% after 60 minutes (P = 0.03) and −51.4% after 90 minutes (P ≤ 0.003), which was statistically significant. Reduction of break-up time in all other treatment groups was not statistically significant. The Jones test revealed a significant reduction of basal secretion after application of brimonidine (−17.8%, P = 0.002; −22.5%, P < 0.001; −30.5%, P < 0.001), followed by apraclonidine (−10%, P = 0.06; −20.1%, P = 0.02; −22.1%, P = 0.002), latanoprost (−2.4%, P = 0.64; −18.6%, P = 0.001; −20.1%, P = 0.001) and dorzolamide (−0.5%, P = 0.9; 14.3%, P = 0.018; −17.3%, P = 0.004) at 30, 60, and 90 minutes after drop application. Reduction of basal secretion in all other treatment groups was not statistically significant. Conclusion: Latanoprost showed the most statistically significant reduction in break-up time, and brimonidine showed the most significant reduction in basal secretion of all the glaucoma medications used in this study. In conclusion, our data may be helpful for treatment decisions in glaucoma patients who also suffer from ocular surface problems.

Influence of high-dose cortisol on the biomechanics of incubated porcine corneal strips.

PURPOSE To investigate the change in biomechanical properties of the cornea induced by high-dose hydrocortisone. METHODS The influence of hydrocortisone was investigated in 12 fresh porcine corneas incubated in culture medium of 2.5 muM of hydrocortisone for 7 days. Twelve additional porcine corneas incubated in culture medium without hydrocortisone for the same time served as the control group. Strips of cornea were cut and the stress-strain relationship was measured in a biomaterial tester. Youngs modulus was calculated. RESULTS After incubation, the thickness of the cornea was 1120+/-130 mum in the control group and 1320+/-90 mum in the hydrocortisone group. The hydrocortisone-treated corneas were 18% thicker compared to the control corneas. However, the difference in the biomechanical stress value at 10% strain was significantly larger. In the control group, the stress value measured 122+/-40 kPa, and in the hydrocortisone group, it measured 77+/-19 kPa (P=.003), representing a reduction of the corneal stiffness by 37% due to hydrocortisone treatment. Youngs modulus was reduced by 42.8% from 2.90+/-1.10 MPa in the control group to 1.66+/-0.49 in the hydrocortisone group. CONCLUSIONS Hydrocortisone is a modulating factor of the biomechanical properties of the cornea. The significance of the cortisol status of the patient and its influence on the biomechanical stability of the cornea should be considered in the development of keratectasia in keratoconus or after refractive surgery.

Effect of latanoprost and timolol on the histopathology of the human conjunctiva

Aim: To investigate the effect of timolol and latanoprost on the extracellular matrix organisation, inflammatory infiltration, and expression of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) in the human conjunctiva. Methods: Conjunctival biopsies were obtained from the inferior fornix during routine cataract surgery from 20 patients with primary open-angle glaucoma, who had received a monotherapy either with timolol or latanoprost, and from 10 non-glaucomatous patients. Specimens were investigated by light microscopy, immunohistochemistry using antibodies against MMP-1,-3, TIMP-2,-3 and CD 68 antibodies and by quantitative transmission electron microscopy. Results: The number of collagen fibres was significantly decreased in latanoprost-treated conjunctival specimens compared with timolol-treated eyes (p<0.01) but showed no difference to controls. Amorphous material was increased in both treated groups compared with controls (p<0.001) but was less in latanoprost-treated specimens compared with timolol-treated eyes (p<0.001). Optically clear spaces, probably containing glycosaminoglycans, were significantly reduced in both treated groups—with less of a reduction in latanoprost—compared with timolol-treated eyes (p<0.001). A marked upregulation of MMP-1 and MMP-3 and moderately increased staining for TIMP-2 and TIMP-3 was found in epithelial cells and subepithelial stromal cells of latanoprost-treated eyes. A moderate infiltration with macrophages and inflammatory cells was observed in timolol-treated eyes. Conclusions: Latanoprost-treated conjunctival specimens showed a decreased stromal collagen density and a less pronounced inflammatory infiltration. The upregulation of MMP-1 and MMP-3 in latanoprost-treated eyes might explain the reduced extracellular matrix accumulation in the conjunctival stroma. Therefore, latanoprost therapy might have a more favourable effect on the outcome of glaucoma filtering surgery.

Diameter of retinal vessels in patients with diabetic macular edema is not altered by intravitreal ranibizumab (lucentis).

Purpose: To investigate the effect(s) of intravitreally injected ranibizumab on retinal vessel diameter in patients with diabetic macular edema. Methods: Participants of this prospective study were 14 men and 16 women (30 eyes) aged 60 ± 11 years (mean ± standard deviation), all with clinically significant diabetic macular edema. Treatment comprised 3 intravitreal injections of ranibizumab given at 4-week intervals. Examinations were conducted before the first (baseline), before the second (Month 1), before the third (Month 2) injections, and 3 months after baseline (Month 3). Measured parameters included systemic blood pressure, static retinal vessel analysis (central retinal artery equivalent and central retinal vein equivalent), and dynamic retinal vessel analysis, as measured by the change in vessel diameter in response to flicker stimulation during three measurement cycles. Flicker stimulation was accomplished using a 50-second baseline recording, followed by an online measurement during 20-second flicker stimulation and 80-second online measurements in both arteriolar and venular vessel segments. Results: Static retinal vessel analysis showed a reduction of central retinal artery equivalent from 186.25 ± 51.40 &mgr;m (baseline) to 173.20 ± 22.2 &mgr;m (Month 1), to 174.30 ± 27.30 &mgr;m (Month 2), and to 170.56 ± 22.89 &mgr;m (Month 3), none of which was statistically significant (P = 0.23, 0.12, and 0.14, respectively). Central retinal vein equivalent was reduced from 216.21 ± 25.0 &mgr;m (baseline) to 214.48 ± 25.4 &mgr;m (Month 1), to 214.80 ± 24.30 &mgr;m (Month 2), and to 211.41 ± 24.30 &mgr;m (Month 3), revealing no statistically significant differences between examination time points (P = 0.54, 0.06, and 0.24, respectively). Dynamic vessel analysis yielded a mean retinal arterial diameter change of +1.47% ± 2.3 (baseline), +1.91% ± 2.5 (Month 1), +1.76% ± 2.2 (Month 2), and +1.66% ± 2.1 (Month 3), none of which showed statistically significant differences (P = 0.32, 0.49, and 0.70, respectively). Mean retinal venous diameter changes were +3.15% ± 1.7 (baseline), +3.7% ± 2.3 (Month 1), +4.0% ± 2.0 (Month 2), and +4.95% ± 1.9 (Month 3), none of which showed statistically significant differences (P = 0.12, 0.17, and 0.14, respectively). Central retinal thickness, as measured by spectral domain optical coherence tomography, decreased significantly from 435.2 ± 131.8 &mgr;m (baseline) to 372.3 ± 142.8 &mgr;m (Month 3), P = 0.01. Regression analysis of arteriolar and venular diameters indicated that there was no significant correlation between these 2 parameters (r = 0.053; P = 0.835 and r = 0.06; P = 0.817, respectively). Also, no significant correlation was observed between the difference in the central retinal thickness and change in arteriolar or venular dilatation (r = 0.291, P = 0.241 and r = 0.06, P = 0.435, respectively). Conclusion: Intravitreally applied ranibizumab did not significantly affect retinal vessel diameter in patients with diabetic macular edema. Decline in the central foveal thickness after ranibizumab therapy, as measured by spectral domain optical coherence tomography, was not linked to any change in retinal vessel diameter or dilatatory response, neither for arterioles nor venules.

Morphological and functional differences between normal-tension and high-tension glaucoma.

Purpose:  To compare visual field (VF) and nerve fibre loss in patients with normal‐tension (NTG) and high‐tension glaucoma (HTG) at an equal level of glaucomatous structural damage of the optic nerve head (ONH).