Intraocular Pressure-Lowering Efficacy of a Sustained-Release Bimatoprost Implant in Dog Eyes Pretreated with Selective Laser Trabeculoplasty.

Purpose: To assess the intraocular pressure (IOP)-lowering effect of a biodegradable bimatoprost implant following selective laser trabeculoplasty (SLT) in a canine model. Methods: Unilateral SLT was performed in 11 normotensive, treatment-naive beagle dogs. IOP was measured at baseline (pre-SLT) and weekly post-SLT (≤10 weeks). After IOP returned to baseline or at 10 weeks (whichever occurred first), a sustained-release bimatoprost implant was administered bilaterally in the anterior chamber of each animal. IOP was measured weekly for 4 weeks and then every 2 weeks up to week 42. Results: The main outcomes included the IOP change (%) from baseline, calculated in both eyes in the overall population, SLT responder subgroup (defined by peak IOP reduction from baseline ≥3 mmHg or ≥15% for >1 week post-SLT), and SLT nonresponder subgroup (defined by peak IOP reduction from baseline <3 mmHg or <15%). The bimatoprost implant lowered IOP similarly in both the SLT-treated and fellow SLT-naive eyes. Following bimatoprost implant administration, the mean (standard deviation [SD]) peak IOP reduction from baseline was 34.4% (8.5%) in SLT-treated eyes and 35.7% (5.9%) in fellow SLT-naive eyes. The bimatoprost implant lowered IOP comparably (P > 0.17) in eyes that responded to SLT (mean [SD] peak IOP reduction, 34.6% [10.7%]; n = 6) and those that did not (mean [SD] peak IOP reduction, 34.1% [6.1%]; n = 5). Conclusion: The bimatoprost implant effectively lowered IOP in eyes pretreated with SLT, regardless of response to SLT. The current data suggest that eyes previously treated with SLT can still benefit from the intracameral bimatoprost implant.

Contrast Sensitivity in Early to Intermediate Age-Related Macular Degeneration (AMD).

PURPOSE: Previous studies indicated that advanced age-related macular degeneration (AMD) affects contrast sensitivity (CS) in humans. The CS results for early/intermediate AMD patients are contradictory. The purpose of this study was to determine if CS testing discriminates early/intermediate AMD patients with normal acuity from normal patients. METHODS: Forty-nine subjects (25 control and 24 early/intermediate AMD patients) were chosen for this project. The age (p = .16) and acuity (p = .34) was not significantly different between the groups. The average simplified AREDS AMD grade for the AMD patients was 2.75 ± 1.03. Three CS functions employing a descending method of limits were measured at the fovea (1. stationary stimulus and, 2. 16 Hz counter-phase stimulus under photopic conditions and 3. the stationary stimulus viewed through a 2 log unit neutral density filter (mesopic condition, background luminance of 1 cd/m2)) and at 4 deg right or left of the fovea with a horizontally oriented sine wave grating (5 deg diameter) viewed on a VPixx monitor (luminance of 100 cd/m2). RESULTS: The early AMD patients were no different from the control patients for any test condition. The intermediate AMD patients were significantly different from the control patients for the mesopic CS function (p = .05). Post-hoc 2-sample t-tests for the intermediate AMD patients were significantly different from the control patients under the stationary photopic and mesopic conditions for the 1.5 cycle per degree stimulus. CONCLUSIONS: Group differences in CS were only found in intermediate AMD patients. The loss in CS increased for the intermediate AMD patients under low light levels. Thus, CS may not be the optimal test to discriminate early AMD from control patients so other tests measured under dark adapted conditions should be investigated.

A nonhuman primate model of blue light-induced progressive outer retina degeneration showing brimonidine drug delivery system-mediated cyto- and neuroprotection.

Geographic atrophy (GA) is an advanced form of age-related macular degeneration (AMD) characterized by atrophy of the retinal pigment epithelium (RPE), loss of photoreceptors, and disruption of choriocapillaris. Excessive light exposure is toxic to the retina and is a known risk factor for AMD. We first investigated the effects of blue light-induced phototoxicity on RPE and photoreceptors in nonhuman primates (NHPs, a model of progressive retinal degeneration) and then evaluated the potential cyto- and neuroprotective effects of the brimonidine drug delivery system (Brimo DDS). In the first set of experiments related to model development, parafoveal lesions of varying severity were induced using blue light irradiation of the retina of cynomolgus monkeys to evaluate the level of phototoxicity in the RPE and photoreceptors. RPE damage was assessed using fundus autofluorescence imaging to quantify areas of hypofluorescence, while thinning of the outer nuclear layer (ONL, photoreceptor nuclei) was quantified using optical coherence tomography (OCT). Photoreceptor function was assessed using multifocal electroretinography (mfERG). RPE damage progressively increased across all lesion severities from 2 to 12 weeks, as did the extent of ONL thinning. Lesions of high severity continued to show reduction in mfERG amplitude, reaching a statistically significant maximum reduction at 12 weeks. Collectively, the first set of experiments showed that blue light irradiation of the NHP eye resulted in progressive retinal degeneration identified by damage to RPE, ONL thinning, and disrupted photoreceptor function - hallmarks of GA in humans. We then used the model to evaluate the cyto- and neuroprotective effects of Brimo DDS, administered as a therapeutic after allowing the lesions to develop for 5 weeks. Placebo DDS or Brimo DDS were administered intravitreally and a set of untreated animals were used as an additional control. In the placebo DDS group, hypofluorescence area continued to increase from baseline, indicating progressive RPE damage, while progression was significantly slowed in eyes receiving Brimo DDS. Likewise, ONL thinning continued to progress over time in eyes that received the placebo DDS, but was reduced in Brimo DDS-treated eyes. Pharmacologically relevant brimonidine concentrations were sustained in the retina for up to 26 weeks following Brimo DDS administration. In summary, Brimo DDS demonstrated cyto- and neuroprotective effects in a novel NHP GA model of progressive retinal degeneration.

Comparison of contrast sensitivity in macaque monkeys and humans.

Contrast sensitivity functions reveal information about a subject's overall visual ability and have been investigated in several species of nonhuman primates (NHPs) with experimentally induced amblyopia and glaucoma. However, there are no published studies comparing contrast sensitivity functions across these species of normal NHPs. The purpose of this investigation was to compare contrast sensitivity across these primates to determine whether they are similar. Ten normal humans and eight normal NHPs (Macaca fascicularis) took part in this project. Previously published data from Macaca mulatta and Macaca nemestrina were also compared. Threshold was operationally defined as two misses in a row for a descending method of limits. A similar paradigm was used for the humans except that the descending method of limits was combined with a spatial, two-alternative forced choice (2-AFC) technique. The contrast sensitivity functions were fit with a double exponential function. The averaged peak contrast sensitivity, peak spatial frequency, acuity, and area under the curve for the humans were 268.9, 3.40 cpd, 27.3 cpd, and 2345.4 and for the Macaca fascicularis were 99.2, 3.93 cpd, 26.1 cpd, and 980.9. A two-sample t-test indicated that the peak contrast sensitivities (P = 0.001) and areas under the curve (P = 0.010) were significantly different. The peak spatial frequencies (P = 0.150) and the extrapolated visual acuities (P = 0.763) were not different. The contrast sensitivities for the Macaca fascicularis, Macaca mulatta, and Macaca nemestrina were qualitatively and quantitatively similar. The contrast sensitivity functions for the NHPs had lower peak contrast sensitivities and areas under the curve than the humans. Even though different methods have been used to measure contrast sensitivity in different species of NHP, the functions are similar. The contrast sensitivity differences and similarities between humans and NHPs need to be considered when using NHPs to study human disease.

Visibility through atmospheric haze and its relation to macular pigment.

PURPOSE: A major factor limiting the visibility of distant targets is veiling attributed to atmospheric scattering, known commonly as haze. It has been suggested that yellow filters (in this case, the macular pigments, MPs) could selectively absorb this haze, thus extending visual range. This study is an empirical test of the visibility hypothesis. METHODS: Twelve subjects had their full contrast sensitivity function (CSF) (represented by six spatial frequencies) assessed in the presence of two background conditions: simulated blue haze and short wave-deficient light. Contrast sensitivity at the peak of the CSF (7.5 cycles per degree) was measured in the presence of the same two backgrounds as the full CSF, with the addition of a broadband xenon background condition in a separate sample of 25 subjects. RESULTS: Simulated blue haze was found to uniformly reduce the CSF in the 12 subjects for whom the full CSF was assessed. Therefore, only the peak was measured in the larger sample of 25 subjects. Macular pigment density was significantly related to energy at threshold for both the haze and xenon backgrounds but not the short wave-deficient background. Thus, subjects with higher levels of MP could withstand more light before losing sight of the target. CONCLUSIONS: This result is consistent with previous modeling of the visibility hypothesis as well as visual range improvements seen when using an artificial MP filter.

The influence of filtering by the macular carotenoids on contrast sensitivity measured under simulated blue haze conditions.

PURPOSE: Distant objects are often obscured as a result of wavelength-dependent scattering in the atmosphere. This scattered light, which is mostly short-wave, effectively forms a veiling luminance (or background light) against which a target must be detected and discriminated. The macular pigment (MP) carotenoids could reduce the effective background intensity by selectively filtering out short wavelengths which would increase the contrast of the object in the retinal image, thus improving visibility. This Visibility hypothesis was originally posited by Wooten and Hammond (2002). This study represents a first empirical test of the hypothesis. METHODS: Five young healthy subjects were evaluated. MP optical density (OD) was measured using HFP. Visibility was assessed by measuring contrast sensitivity thresholds at 8 cycles/deg (CST) using an optical system that passed xenon-light through the sine-wave grating. Blue haze was simulated using an ecologically valid broad-spectrum filter. Changes in MP density were simulated using a variable path length filter with an oil-based carotenoid solution that mimicked the absolute absorption spectrum of MP. RESULTS: The average baseline CST was 0.004. Adding 0.25OD of simulated MP lowered the average threshold to 0.003 (25%). An additional 0.25OD decreased thresholds an additional 10% and the effect reached a plateau at about 0.50. DISCUSSION: The largest improvement (about 25%) in contrast occurred with the initial, and relatively modest, addition of 0.25OD units of simulated MP suggesting that the largest improvements may be linked to initial increases in MPOD.

Macular pigment: a test of the acuity hypothesis.

PURPOSE: Schültze, in 1866, originally proposed that macular pigment (MP) could improve acuity by reducing the deleterious effects associated with the aberration of short-wave (SW) light. Although proposed well more than a century ago, the hypothesis has never been empirically tested. The authors chose to begin evaluating the acuity hypothesis by measuring MP levels, gap, and hyperacuity in the same observers. METHODS: Eighty healthy young subjects were assessed. Forty subjects were assigned to the gap acuity experiment and 40 to the hyperacuity experiment. Peak MP optical density (MPOD) was measured using heterochromatic flicker photometry (HFP). Resolution and hyperacuity were measured as the minimum perceivable gap between two solid black lines (1'' width) vertically separated and as a vernier offset, respectively. These targets were presented on a 0.5 degrees circular diffusing background that appeared either white (17 cd/m2) or yellow (16 cd/m2). The yellow background was produced by using light-emitting diodes (LEDs) with a peak lambda = 570 nm. The white background was produced by combining the yellow with a blue LED (peak lambda = 460 nm). The subject's head (5.33 m from the stimulus) was stabilized with a head-rest assembly, and the adaptive state was controlled with the use of a constant white surround (11 cd/m2). Thresholds were determined based on probit analysis of psychometric functions generated using a two-alternative forced-choice procedure. RESULTS: MPOD ranged from 0.14 to 1.00 measured at 30' eccentricity. Gap and hyperacuity measures each varied by a factor of approximately 5 to 6. Average gap acuity (N = 38) for the white condition (filtered by MP) was 31.2'' (SD = 9.4) and did not differ from the average (N = 38) for the yellow condition (not filtered by MP), which was 32.1'' (SD = 10.9). Similarly, average hyperacuity for the white condition (7.0''; SD = 2.9) did not differ from that of the yellow condition (6.8''; SD = 3.5). CONCLUSIONS: MPOD did not correlate significantly with gap or hyperacuity measured in the yellow or white conditions. These data, therefore, do not support the predictions of the acuity hypothesis.