Ganglion cell loss and dysfunction: relationship to perimetric sensitivity.

PURPOSE: To describe two methods of neural damage quantification from perimetric data, and to discuss their theoretical implications. METHODS: A recently published model of retinal ganglion cell (GC) receptive field density is used to obtain best estimates of the receptive fields per solid degree at each stimulus point in the 24-2 test pattern array. A method of age related change compensation is proposed and a functional relationship between perimetric sensitivity and GC survival is used for loss quantification. RESULTS: Data for the 24-2 test pattern array for the right eye are presented. These can be adjusted for age related loss, but are also expressed as percentages which are considered to be age invariant. Simple models relating receptive field density to sensitivity are proposed for quantification. CONCLUSIONS: Equations relating GC receptive field densities at points in the visual field to normative data on sensitivity are proposed to estimate GC loss in glaucoma. If 1/Lambert sensitivity is <800, (29 dB), a linear relationship applies and a loss factor of 1-10, where TD is the signed total deviation in decibels, may be applied to values in a percentage chart which are provided to give the percentage loss for each stimulus. Higher sensitivities are non-linearly related. Two equations are proposed to cover the range corresponding to thresholds from 0 dB to 33 dB. Hypothetical examples are given and the relationship between visual field defects and pattern electroretinograms is discussed in quantitative terms.

The length of Henle fibers in the human retina and a model of ganglion receptive field density in the visual field.

An experimental study of lateral displacement of ganglion cells (GCs) from foveal cones in six human retinas is reported. At 406-675 microm in length, as measured in radially oriented cross-sections, Henle fibers are substantially longer than previously reported. However, a new theoretical model indicates that the discrepancies in these reports are mainly due to meridional differences. The model takes into account the effects of optical degradation and peripheral ON/OFF asymmetry and predicts a central GC:cone ratio of 2.24:1. It provides estimates of cumulative counts and GC receptive field density at 0 degrees -30 degrees along the principal meridians of the visual field.

Can pulsatile ocular blood flow distinguish between patients with and without diabetic retinopathy?

PURPOSE: Our aim was to determine if pulsatile ocular blood flow (POBF) measurements could distinguish between type 2 diabetes mellitus (DM) subjects with and without diabetic retinopathy (DR). METHODS: Ninety-eight DM subjects were recruited. POBF was measured using an Ocular Blood Flow tonometer and retinopathy was assessed using retinal digital photography. The duration of diabetes, blood pressure, glycosylated haemoglobin and plasma glucose level were also recorded. RESULTS: Seventy-two subjects had no DR and 26 subjects exhibited mild to moderate non-proliferative DR. POBF was higher in those subjects with non-proliferative DR but did not reach significance. Those subjects receiving insulin treatment had a significantly longer duration of DM, higher HbA1c and plasma glucose levels and greater incidence of non-proliferative DR compared to subjects receiving oral hypoglycaemic agents, who in turn demonstrated higher levels of these parameters than those who were controlled by diet alone (ANOVA p < 0.05 in all cases). POBF was found to increase with level of management but not significantly so. CONCLUSIONS: A single measurement of POBF does not distinguish between subjects with and without mild/moderate non-proliferative DR.

S-cone, L + M-cone, and pattern, electroretinograms in ocular hypertension and glaucoma.

Silent substitution and selective adaptation techniques were used to obtain full field S-cone and L + M-cone electroretinograms from 18 patients with ocular hypertension (OHT), 9 with normotensive glaucoma (NTG), 18 with early primary open angle glaucoma (POAG) and 19 normal controls. Pattern electroretinograms were also recorded, using a reduced check size to increase the contribution of retinal ganglion cells. In the OHT and POAG groups, statistically significant reductions (P = 0.05-0.001) were observed in the amplitudes, most notably in the late negative waves of all three types of ERG compared to the controls. These are thought to reflect ganglion cell activity. The results imply a diffusely distributed loss of activity (20-35%) affecting many retinal pathways to a similar extent in OHT and early POAG, with an additional amount (<5%) in POAG corresponding approximately to the loss associated with local field defects. The electrophysiology indicated that virtually all cases of untreated OHT have greater retinal dysfunction than the least affected cases of POAG. The NTG group showed a different pattern of loss in that the PERG was markedly affected but the S-cone ERG was not significantly reduced.

Cortical OFF-potentials from the S-cone pathway reveal neural damage in early glaucoma.

We used background adaptation and silent substitution techniques to record full-field ON and OFF-visually evoked cortical potentials (VECPs) selectively from the S-cone and L- and M-cone pathways in 15 patients with primary open angle glaucoma (POAG), and 15 normal controls. The most statistically significant (P=0.01) VECP test for POAG was a voltage change in the S-cone pathway cortical OFF-response. A sensitivity of 93% was achieved, with 60% specificity at minimum error rate. This is presumed to reflect reduced activity in the S-cone and magnocellular visual pathways, and may provide an effective method for research and monitoring change in early glaucoma.

Electrophysiological evidence of early functional damage in glaucoma and ocular hypertension.

PURPOSE: The quantification of early retinal ganglion cell damage in ocular hypertension and glaucoma. METHODS: Thirty subjects under treatment for open-angle glaucoma, 23 subjects with ocular hypertension, and 28 healthy subjects in a control group were investigated by monocular pattern electroretinogram (ERG), L&M (long and medium wavelength) cone ERG, and S (short wavelength)-cone ERG. The diagnosis of glaucoma was based on masked assessment of digital stereoscopic optic nerve head images by three glaucoma specialists. The optic nerve head and retinal nerve fiber layer was assessed by scanning laser ophthalmoscopy and optical coherence tomography. RESULTS: All types of ERG had reduced mean amplitudes in ocular hypertension and open-angle glaucoma groups compared with the control group. In the ocular hypertension group, the N95 and the L&M-pathway photopic negative response (PhNR) were significantly attenuated (by 19% and 18% compared with the control group, respectively; by 30% and 22%, respectively, in the open-angle glaucoma group compared with the control group). In the subjects with open-angle glaucoma, the pattern ERG P50-N95 was found to be the most sensitive electrophysiological test, and the cup-disc area ratio, when examined by scanning laser ophthalmoscopy, was the most sensitive imaging parameter. Modest but not statistically significant correlations were found between the imaging and electrophysiologic parameters. CONCLUSIONS: With disc appearance used for the classification of open-angle glaucoma and ocular hypertension, significant electrophysiological losses were found in both conditions. The modest correlation between the structural and electrophysiological measures suggests that these assess different aspects of the pathologic process; electrophysiology can be used to quantify retinal ganglion cell dysfunction that occurs before cell death.

Silent substitution S-cone electroretinogram in subjects with diabetes mellitus.

A defect in the blue sensitive mechanism has been reported in certain ocular and systemic diseases. For example, tritanopic colour vision defects and changes to the S-cone electroretinogram (ERG) have been demonstrated in glaucoma and diabetes mellitus. Electrophysiological methods of eliciting the S-cone ERG, however, often result in considerable L- and M-cone intrusion. We report the findings of a study employing the silent substitution S-cone ERG technique, which is thought to represent an almost pure S-cone signal, and the L'Anthony desaturated D15 colour vision test in subjects with Type 1 or 2 diabetes mellitus with no or minimal background retinopathy. The results of this study show a significantly increased S-cone ERG b-wave implicit time and significantly worse colour vision in those with background retinopathy compared with those with no diabetic retinopathy. This suggests that S-cone pathway dysfunction may be responsible for the deterioration in colour vision found in diabetes mellitus.

The effect of post prandial glucose changes on oscillatory potentials in subjects with type 2 diabetes mellitus.

PURPOSE: To investigate the effect of elevated plasma glucose levels on oscillatory potentials (OPs) in patients with diabetes mellitus. METHOD: 15 patients with type 2 diabetes mellitus, with no ophthalmoscopically visible signs of diabetic retinopathy (NDR), were recruited, mean (SD) age 65.1 (10.91) years and duration 5.95 (4.95) years. Plasma glucose levels and OPs were recorded before, during and after a meal tolerance test (MTT), at times 0, 90 and 210 min. OPs were recorded following 5 min adaptation to a blue mesopic background (1.17 cd m(-2)), and elicited using a white 5 ms stimulus flickering at 5 Hz frequency over the blue background. RESULTS: Plasma glucose increased significantly from 0 to 90 min during the MTT. This corresponded with an increase in mean amplitude of OP1-4, and a significant increase in the summed amplitudes. Summed OP amplitudes were 14.52 microv and 18.38 microv at time 0 and 90 min respectively. Between times 90 and 210 min plasma glucose levels decreased significantly back to baseline. OP1 and OP2 amplitudes increased slightly and OP3 and OP4 amplitudes decreased markedly, resulting in a non-significant reduction of the summed amplitudes. No significant changes in latencies were seen. CONCLUSIONS: Summed OP amplitudes, which are known to reflect the efficiency of the retinal circulation, increased with elevated plasma glucose. This effect was not immediately reversible. Latencies appear not to be affected.

The S-cone electroretinogram: a comparison of techniques, normative data and age-related variation.

The blue sensitive mechanism in human colour vision is highly susceptible to damage in ocular disease. There is a need for objective methods to assess this and several methods of recording the blue cone (S-cone) electroretinogram (ERG) have been described. We therefore compared a silent substitution technique (SST) and a selective adaptation technique (SAT) using a novel combination of optical filters, on 24 normal subjects. The age-related variation in the S-cone ERG was also investigated in a further 73 normal subjects. S-cone ERGs elicited by SAT were of higher amplitude, (p < 0.001) with smaller coefficients of variation than those elicited with SST. The SST method has already been shown to be highly sensitive in primary open angle glaucoma and, unlike SAT, has no significant age related variation. However, the results of this study suggest that the new, SAT method may prove to be more convenient and effective in clinical practice, provided that age norms are applied.

The construction of a model eye for investigation of laser-tissue interactions in scanning laser ophthalmoscopy.

PURPOSE: To develop a model eye to study laser-tissue interactions during retinal imaging with scanning ophthalmoscopy. METHODS: A model eye was designed to match the optical properties of the human eye based on the Bennett and Rabbetts schematic eye. RESULTS: Alterations in axial length resulted in changes in refractive error similar to those in the human eye (3.70 D for 1 mm in axial length). Perfusion-fixed retinal tissue could be successfully imaged using the Heidelberg Retina Tomograph and Optical Coherence Tomograph to provide images that are similar in quality to those obtained. CONCLUSIONS: The model eye should be a valuable tool for investigating laser-tissue interactions during scanning laser ophthalmoscopy and the derivation of digital retinal and tomographic images. This model should also enable a determination of the accuracy with which digital imaging techniques, such as the optical coherence tomograph and Heidelberg Retina Tomograph, measure retinal structure.

Ocular optics, electroretinography and primary open angle glaucoma.

Advancing the knowledge of ocular image quality is important in the development of new tests for the earlier detection of primary open angle glaucoma (POAG). Loss of blue sensitivity is an important feature of POAG; however, it is difficult to separate this loss from the effects of wavelength related intraocular light scatter and media absorption. A technique for recording the S-cone electroretinogram is described which may solve these problems. The effect of scattered light is avoided by a Ganzfeld stimulus and the absorption of short wavelength light is compensated by a photometric balancing of blue and green stimuli using the M-cone response. The modulation transfer function of the eye has enabled the true spatial tuning function of the retina to be determined by pattern electroretinography (PERG). This has demonstrated the role of retinal ganglion cells in the generation of the PERG. These techniques are shown to be highly sensitive tests in the early stages of POAG.