Michael Haustein

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.

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.

Comparison of Travoprost and Bimatoprost plus Timolol Fixed Combinations in Open-Angle Glaucoma Patients Previously Treated with Latanoprost plus Timolol Fixed Combination

PURPOSE To compare the ocular hypotensive effect of bimatoprost plus timolol and travoprost plus timolol fixed combinations in glaucoma patients whose disease was controlled but had not reached their target intraocular pressure (IOP) with the fixed combination of latanoprost plus timolol. DESIGN A 2 × 3-month, multicenter, prospective, randomized, double-masked, cross-over clinical trial. METHODS Eighty-nine open-angle glaucoma (OAG) patients were included. After a 6-week run-in period with latanoprost plus timolol, patients were randomized to either travoprost plus timolol or bimatoprost plus timolol for 3 months. Patients then switched to the opposite therapy for 3 additional months. The primary end point was the comparison of mean daily IOP after 3 months of each treatment. RESULTS At baseline, mean IOP was 16.5 mm Hg (95% confidence interval, 16.0 to 17.0 mm Hg) with treatment with latanoprost plus timolol. Both bimatoprost plus timolol and travoprost plus timolol statistically significantly reduced the mean IOP from baseline (P < .0001). Mean IOP at month 3 was statistically significantly lower in the bimatoprost plus timolol group compared with the travoprost plus timolol group (14.7 mm Hg [95% confidence interval, 14.3 to 15.3 mm Hg] vs 15.4 mm Hg [95% confidence interval, 15.0 to 15.9 mm Hg]; P = .0041). IOP was lower during bimatoprost plus timolol treatment at all time points and statistical significance was reached at 8 am, 11 am, and 5 pm, but not at 2 pm and 8 pm. Both treatments showed similar tolerability profile. CONCLUSIONS Bimatoprost plus timolol and travoprost plus timolol can provide additional IOP-lowering effect in patients not fully controlled with latanoprost plus timolol. The observed additional IOP reduction was greater with bimatoprost plus timolol with a similar tolerability profile.

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.

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).

Diabetes mellitus affects biomechanical properties of the optic nerve head in the rat.

Background: To investigate the effect of diabetes on the biomechanical behavior of the optic nerve head (ONH) and the peripapillary sclera (ppSc) in streptozocine-induced diabetic rats. Methods: Diabetes mellitus was induced in 20 Wistar rats using streptozocine. Twenty-five nondiabetic rats served as controls. Eyes were enucleated after 12 weeks and 2 strips of one eye were prepared containing ONH or ppSc. The stress-strain relation was measured in the stress range of 0.05–10 MPa using a biomaterial tester. Results: At 5% strain the stress of the ONH in diabetic rats was 897 ± 295 kPa and in the control group it was 671 ± 246 kPa; there was a significant difference between both groups (p = 0.011). The stress of the diabetic ppSc (574 ± 185 kPa) increased compared to that of the nondiabetic ppSc (477 ± 171 kPa), but this did not reach statistical significance (p = 0.174). The calculated tangent modulus at 5% strain was 11.79 MPa in the diabetic ONH and 8.77 MPa in the nondiabetic ONH; there was a significant difference between both groups (p = 0.006). The calculated tangent modulus at 5% strain was 7.17 MPa in the diabetic ppSc and 6.12 MPa in the nondiabetic ppSc, without a statistically significant difference (p = 0.09). Conclusion: In contrast to the ppSc, the ONH of diabetic rats showed a significant increase in stiffness compared to nondiabetic rats, which might be explained by nonenzymatic collagen cross-linking mediated by advanced glycation end products due to high blood glucose levels in diabetes. Further studies are needed to investigate if these biomechanical changes represent a detrimental risk factor for intraocular pressure regulation in diabetic glaucoma patients.

The effect of low-density lipoprotein apheresis on ocular microcirculation in patients with hypercholesterolaemia: a pilot study

Aim To investigate the effect of low-density lipoprotein (LDL) apheresis on ocular microcirculation in patients with hypercholesterolaemia. Methods Six patients with hypercholesterolaemia were included in this study. The diameter of retinal vessels was measured continuously with the retinal vessel analyser before and after LDL apheresis. After baseline assessment a monochromatic luminance flicker was applied to evoke retinal vasodilation. Flicker response was then analysed 50, 70 and 120 s after baseline measurement. In addition, cholesterol, high-density lipoprotein, LDL and triglyceride levels were obtained to find a possible correlation between changes in retinal vessel diameter and lipid metabolism before and after apheresis. Results The mean diameter of the arterioles at baseline was 107.6±2.1 μm and the mean diameter of the venules at baseline was 132.8±3.2 μm. The diameter of the arterioles after apheresis increased to 111.2±2.3 μm after 50 s, 113.2±2.6 μm after 70 s and 113.7±2.6 μm after 120 s, showing a trend to statistical significance at all time points (p=0.046, p=0.028 and p=0.028, respectively). The mean diameter of the venules after apheresis increased to 138.8±5.9 μm after 50 s, 139.8±6.3 μm after 70 s and 141.2±6.0 μm after 120 s, showing a trend to statistical significance at all time points (all p=0.028). Conclusions Changes in retinal vascular diameter seem to be associated with the systemic effect of a single LDL apheresis. Vasodilatation of the arterioles and the venules improved after LDL apheresis, indicating an improvement of ocular perfusion in patients with hypercholesterolaemia.

Contact Lens Dynamometry: The Influence of Age

PURPOSE To examine the influence of age on systolic (systOAP) and diastolic (diastOAP) blood pressure in the ophthalmic artery (OA) measured by a new contact lens dynamometer (CLD). METHODS In a prospective cross-sectional clinical trial, 106 eyes of 106 patients (58 women, 48 men) were examined. A nearly uniform age distribution was achieved by recruiting subjects in seven age groups, with at least 12 in each decade. Blood pressure in the OA was measured with a new CLD. Arterial blood pressure at the upper arm was measured by cuff, according to the Riva-Rocci (RR) METHOD: Main outcome measures were: SystOAP and diastOAP in the OA and systolic (systRR) and diastolic (diastRR) pressures in the subclavian artery. RESULTS The blood pressures showed the following linear regression equations in association with age: systRR (mm Hg) = 115 + 0.45 × age (years) (R = 0.50; P < 0.00001); diastRR (mm Hg) = 72 + 0.28 × age (years) (R = 0.42; P < 0.00001); systOAP (mm Hg) = 61 + 0.93 × age (years) (R = 0.74; P < 0.0001); and diastOAP (mm Hg) = 44 + 0.37 × age (years) (R = 0.57; P < 0.0001). CONCLUSIONS The relative slopes of the regression lines relating age to diastolic and systolic pressures are steeper in the ophthalmic than in the subclavian artery, indicating that the pressures in the ophthalmic artery increase faster with age than do the associated pressures in the subclavian artery, as measured by the standard sphygmomanometry. This phenomenon may be explained by progressive stiffening of the walls in the carotid and ophthalmic arteries. The effect of age should be taken into account whenever interpreting ophthalmodynamometric measurements for clinical diagnostic purposes.

Statins affect ocular microcirculation in patients with hypercholesterolaemia

Purpose:  To investigate the effect of statins on ocular microcirculation in patients with hypercholesterolaemia.