Using the electroretinogram to understand how intraocular pressure elevation affects the rat retina

Intraocular pressure (IOP) elevation is a key risk factor for glaucoma. Our understanding of the effect that IOP elevation has on the eye has been greatly enhanced by the application of the electroretinogram (ERG). In this paper, we describe how the ERG in the rodent eye is affected by changes in IOP magnitude, duration, and number of spikes. We consider how the variables of blood pressure and age can modify the effect of IOP elevation on the ERG. Finally, we contrast the effects that acute and chronic IOP elevation can have on the rodent ERG

Selective loss of an oscillatory component from temporal retinal multifocal ERG responses in glaucoma,”

PURPOSE. To evaluate electrophysiologic function in glaucoma by using a new stimulus designed to enhance ganglion cell and optic nerve head component (ONHC) contributions to multifocal electroretinogram (mfERG) responses. METHODS. mfERGs of 16 individuals with glaucoma (POAG) and 18 normal control subjects were recorded and analyzed with a VER imaging system. The stimulus had three frames inserted between each m-sequence step: a full-field dark frame (1.0 cd/m 2 ), a full-field flash (200 cd/m 2 ), and another dark frame. Multifocal flashes were 100 cd/m 2 . The stimulus subtended approximately 40°total diameter and contained 103 scaled hexagonal elements. Signals were obtained using Burian-Allen bipolar electrodes, amplified ϫ10 6 , band-pass filtered at 10 to 300 Hz, and sampled at 1200 Hz. RESULTS. Local first-order responses (kernels) consisted of a direct component (DC) followed by an induced component (IC). Nasal-temporal response asymmetries in normal eyes were most easily observed in the IC. A small but distinct oscillation in the ICs of temporal retinal responses distinguished them from nasal IC waveforms. In individuals with glaucoma, there was less asymmetry between nasal and temporal responses, mostly because of the reduction of the oscillation in the temporal retinal ICs. The amplitude of this oscillation was 4.4 Ϯ

Factors Influencing Optical Coherence Tomography Peripapillary Choroidal Thickness: A Multicenter Study.

Purpose:To quantify peripapillary choroidal thickness (PCT) and the factors that influence it in healthy participants who represent the racial and ethnic composition of the U.S. population. Methods:A total of 362 healthy participants underwent optical coherence tomography (OCT) enhanced depth imaging of the optic nerve head with a 24 radial B-scan pattern aligned to the fovea to Bruch's membrane opening axis. Bruch's membrane, anterior scleral canal opening (ASCO), and the anterior scleral surface were manually segmented. PCT was measured at 100, 300, 500, 700, 900, and 1100 μm from the ASCO globally and within 12 clock-hour sectors. The effects of age, axial length, intraocular pressure, ethnicity, sex, sector, and ASCO area on PCT were assessed by ANOVA and univariable and multivariable regressions. Results:Globally, PCT was thicker further from the ASCO border and thinner with older age, longer axial length, larger ASCO area, European descent, and female sex. Among these effectors, age and axial length explained the greatest proportion of variance. The rate of age-related decline increased further from the ASCO border. Sectorally, the inferior-temporal sectors were thinnest (10.7%-20.0% thinner than the thickest sector) and demonstrated a higher rate of age-related loss (from 15.6% to 20.7% faster) at each ASCO distance. Conclusions:In healthy eyes, PCT was thinnest in the inferior temporal sectors and thinner PCT was associated with older age, European descent, longer axial length, larger ASCO area, and female sex. Among these associations, age had the strongest influence, and its effect was greatest within the inferior temporal sectors

A Common Glaucoma-risk Variant of SIX6 Alters Retinal Nerve Fiber Layer and Optic Disc Measures in a European Population: The EPIC-Norfolk Eye Study.

PURPOSE: A common missense variant in the SIX6 gene (rs33912345) is strongly associated with primary open-angle glaucoma (POAG). We aimed to examine the association of rs33912345 with optic disc and retinal nerve fiber layer (RNFL) measures in a European population. METHODS: We examined participants of the population-based EPIC-Norfolk Eye Study. Participants underwent confocal laser scanning tomography (Heidelberg Retina Tomograph II, HRT) to estimate optic disc rim area and vertical cup-disc ratio (VCDR). Scanning laser polarimetry (GDxVCC) was used to estimate average RNFL thickness. The mean of right and left eye values was considered for each participant. Genotyping was performed using the Affymetrix UK Biobank Axiom Array. Multivariable linear regression with the optic nerve head parameter as outcome variable and dosage of rs33912345 genotype as primary explanatory variable was used, adjusted for age, sex, disc area, axial length, and intraocular pressure. We further repeated analyses stratified into age tertiles. RESULTS: In total, 5433 participants with HRT data and 3699 participants with GDxVCC data were included. Each "C" allele of rs33912345 was associated with a smaller rim area (-0.030 mm [95% CI -0.040, -0.020]; P=5.4×10), a larger VCDR (0.025 [95% CI 0.017, 0.033]; P=3.3×10) and a thinner RNFL (-0.39 μm [95% CI -0.62, -0.15]; P=0.001). The RNFL association was strongest in the oldest age tertile, whereas rim area and VCDR associations were strongest in the youngest and oldest age tertiles. CONCLUSIONS: The protein-coding SIX6 variant rs33912345, previously associated with POAG, has a functional effect on glaucoma-associated optic nerve head traits in Europeans.EPIC-Norfolk infrastructure and core functions are supported by grants from the Medical Research Council (G1000143) and Cancer Research UK (C864/A14136). The clinic for the third health examination was funded by Research into Ageing (262). Genotyping was funded by the Medical Research Council (MC_PC_13048). Mr Khawaja is supported by a Moorfields Eye Charity grant. Miss Chan is a joint Medical Research Council/Royal College of Ophthalmologists Research Fellow, and received additional support from the International Glaucoma Association. Professor Foster has received additional support from the Richard Desmond Charitable Trust (via Fight for Sight) and the Department for Health through the award made by the National Institute for Health Research to Moorfields Eye Hospital and the UCL Institute of Ophthalmology for a specialist Biomedical Research Centre for Ophthalmology

Predicting Progressive Glaucomatous Optic Neuropathy Using Baseline Standard Automated Perimetry Data

PURPOSE. To test the hypothesis that specific locations and patterns of threshold findings within the visual field have predictive value for progressive glaucomatous optic neuropathy (pGON). METHODS. Age-adjusted standard automated perimetry thresholds, along with other clinical variables gathered at the initial examination of 168 individuals with high-risk ocular hypertension or early glaucoma, were used as predictors in a classification tree model. The classification variable was a determination of pGON, based on longitudinally gathered stereo optic nerve head photographs. Only data for the worse eye of each individual were included. Data from 100 normal subjects were used to test the specificity of the models. RESULTS. Classification tree models suggest that patterns of baseline visual field findings are predictive of pGON with sensitivity 65% and specificity 87% on average. Average specificity when data from normal subjects were run on the models was 69%. CONCLUSIONS. Classification trees can be used to determine which visual field locations are most predictive of poorer prognosis for pGON. Spatial patterns within the visual field convey useable predictive information, in most cases when thresholds are still well within the classically defined normal range. (Invest Ophthalmol Vis Sci. 2009;50:674 -680

Relationship between the magnitude of intraocular pressure during an episode of acute elevation and retinal damage four weeks later in rats

PURPOSE: To determine relationship between the magnitude of intraocular pressure (IOP) during a fixed-duration episode of acute elevation and the loss of retinal function and structure 4 weeks later in rats. METHODS: Unilateral elevation of IOP (105 minutes) was achieved manometrically in adult Brown Norway rats (9 groups; n = 4 to 8 each, 10-100 mm Hg and sham control). Full-field ERGs were recorded simultaneously from treated and control eyes 4 weeks after IOP elevation. Scotopic ERG stimuli were white flashes (-6.04 to 2.72 log cd.s.m(-2)). Photopic ERGs were recorded (1.22 to 2.72 log cd.s.m(-2)) after 15 min of light adaptation (150 cd/m(2)). Relative amplitude (treated/control, %) of ERG components versus IOP was described with a cummulative normal function. Retinal ganglion cell (RGC) layer density was determined post mortem by histology. RESULTS: All ERG components failed to recover completely normal amplitudes by 4 weeks after the insult if IOP was 70 mmHg or greater during the episode. There was no ERG recovery at all if IOP was 100 mmHg. Outer retinal (photoreceptor) function demonstrated the least sensitivity to prior acute IOP elevation. ERG components reflecting inner retinal function were correlated with post mortem RGC layer density. CONCLUSIONS: Retinal function recovers after IOP normalization, such that it requires a level of acute IOP elevation approximately 10 mmHg higher to cause a pattern of permanent dysfunction similar to that observed during the acute event. There is a 'threshold' for permanent retinal functional loss in the rat at an IOP between 60 and 70 mmHg if sustained for 105 minutes or more

Electrophysiology in glaucoma : assessment

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The fast oscillation of the electrooculogram reveals sensitivity of the human outer retina/retinal pigment epithelium to glucose level

AbstractThe effect of acute blood glucose elevations on human outer retinal function was examined. Electrooculograms were recorded as the background light cycled on/off with a 2-min period, eliciting rapid changes in the corneo-retinal standing potential known as the fast-oscillation of the electrooculogram. Recordings were made while subjects fasted and after they consumed 100 g of d-glucose. In all subjects, blood glucose levels strongly affected fast oscillation amplitude, which reflects photoreceptor-driven changes in RPE cell chloride concentration. The sensitivity of RPE metabolism to glucose fluctuations may relate to changes in the blood-retinal barrier that are known to occur in diabetes (e.g. macular edema)

Does optic nerve head surface topography change prior to loss of retinal nerve fiber layer thickness: a test of the site of injury hypothesis in experimental glaucoma.

PURPOSE:To test the hypothesis that optic nerve head (ONH) deformation manifesting as changes in its mean surface height precedes thinning of the peripapillary retinal nerve fiber layer (RNFL) in experimental glaucoma (EG). METHODS:68 rhesus macaque monkeys each had three or more baseline imaging sessions under manometric intraocular pressure (IOP) control to obtain average RNFL thickness (RNFLT) and the ONH surface topography parameter mean position of the disc (MPD). Laser photocoagulation was then applied to the trabecular meshwork of one eye to induce chronic, mild-to-moderate IOP elevation and bi-weekly imaging continued. Event analysis was applied to determine for each parameter when an 'endpoint' occurred (signficant change from baseline) for eight different endpoint criteria. Specificity was assessed in the group of 68 fellow control eyes. Classical signal detection theory and survival analysis were used to compare MPD with RNFLT. RESULTS:Regardless of the endpoint criterion, endpoints were always more frequent for MPD than for RNFLT. The discriminability index (d') was 2.7 ± 0.2 for MPD and 1.9 ± 0.2 for RNFLT (p<0.0001). Endpoints were reached by MPD an average of 1-2 months earlier than by RNFLT (p<0.01). At the onset of the first specific, detectable MPD change in EG eyes, there was still no significant change in RNFLT on average (p=0.29) and only 25% of individual eyes exhibited signficant reduction. In contrast, at onset of signficant RNFLT change, MPD had already changed an average of 101 µm from baseline (p<0.0001) and 71% of the individual eyes had exhibited significant change. The magnitude of MPD change was more than could be explained on the basis of axon loss alone. CONCLUSIONS:This study demonstrates that the average surface height of the ONH changes prior to any detectable loss of average peripapillary RNFL thickness in non-human primate eyes with experimental glaucoma