Hypoxia and Dark Adaptation in Diabetic Retinopathy: Interactions, Consequences, and Therapy.

In diabetes, retinal blood flow is compromised, and retinal hypoxia is likely to be further intensified during periods of darkness. During dark adaptation, rod photoreceptors in the outer retina are maximally depolarized and continuously release large amounts of the neurotransmitter glutamate-an energetically demanding process that requires the highest oxygen consumption per unit volume of any tissue of the body. In complete darkness, even more oxygen is consumed by the outer retina, producing a steep fall in the retinal oxygen tension curve which reaches a nadir at the depth of the mitochondrial-rich rod inner segments. In contrast to the normal retina, the diabetic retina cannot meet the added metabolic load imposed by the dark-adapted rod photoreceptors; this exacerbates retinal hypoxia and stimulates the overproduction of vascular endothelial growth factor (VEGF). The use of nocturnal illumination to prevent dark adaptation, specifically reducing the rod photoreceptor dark current, should ameliorate diabetic retinopathy.

The pathogenesis of early retinal changes of diabetic retinopathy.

Recent successful trials of antibodies to vascular endothelial growth factor (VEGF) in diabetic retinopathy implicate this cytokine as a major cause of diabetic retinopathy (DR) and diabetic macular oedema (DME). The mechanisms which cause VEGF to be over-expressed to cause the vasculopathy are not entirely clear. This review explores the earliest changes to the retina in DR and the factors that predispose or prevent DR, including sleep apnoea, receptor degenerations laser treatment and VEGF polymorphism. The review also presents the evidence that retinal hypoxia, existing in the earliest stages, causes DR. This hypoxia is much increased by dark adaptation, indicating a new and possibly superior therapy.

Age-related macular degeneration.

Age-related macular degeneration is a common cause of blindness. Its incidence is increasing, partly due to the advancing age of the population in North America and Europe, but there is no doubt that the age-adjusted rates are also increasing, which points to some environmental influence. The condition is characterized by the appearance of retinal deposits called drusen. These and other changes form a barrier between the retinal pigment epithelium and the choroidal circulation. As a result, new vessels may grow from the choroid and penetrate the retina. These new vessels are delicate and can leak or bleed. Such episodes occur in the "wet" form of age-related macular degeneration and cause the well known disciform degeneration, which in turn leads to distortion of the image and rapid loss of vision. Even when this does not happen, areas of retina may atrophy, probably due to anoxia: this is the "dry" form of the disease, also called geographic atrophy. In trials, scattered laser burns have been applied to the retina but the long-term benefits of this are as yet uncertain. New micro-pulse lasers are coming into use which may be more effective. Surgical treatments include translocation of the retina and photodynamic therapy. Medical therapies attracting attention are intraocular injections of anti-angiogenic drugs, such as ranibizumab. These need further evaluation, as does the role of diet. Within a few years blindness due to age-related macular degeneration may be reduced by combining dietary control, screening for visual loss, and medical and surgical methods of treatment.

Spare the rod and spoil the eye.

This review presents a new unified view of the pathogenesis of three common causes of acquired retinal degenerative disease-diabetic retinopathy, age related macular degeneration, and retinopathy of prematurity. In these three conditions, angiogenesis has a predominant role in the development of sight threatening pathology. Angiogenesis is controlled by among other factors the expression of vascular endothelial growth factor (VEGF), which in turn is regulated by absolute and relative lack of oxygen. The severe pathological manifestations of these three conditions are not part of a general underlying disease process because they are peculiar to the eye, and the profound hypoxia that develops in normal retina during dark adaptation (rod driven hypoxia) is an adequate and elegant additional factor to explain their pathogenesis. A large number of experimental reports support this conclusion, although rod driven anoxia is not generally considered as a causal factor in ocular disease. However, the hypothesis can be critically tested, and also suggests novel methods of treatment and prevention of these conditions that may be simpler and more inexpensive than current therapies and that have a smaller potential for adverse effects.

The human electro-oculogram: interaction of light and alcohol.

PURPOSE: To investigate the production of the voltage changes evoked in the retinal pigment epithelium (RPE) by light and alcohol and the interaction of these agents. METHODS: The eye movement potential in humans was intermittently recorded to standard horizontal excursions for long periods during which either retinal illumination was altered or ethyl alcohol was administered by the oral, intragastric, or intravenous route. In other experiments, both light and alcohol were administered. RESULTS: Alcohol and light produced near identical corneofundal voltage changes (positive and then negative) over more than 40 minutes. Differences in timing between alcohol and light increases are explicable by the delays in alcohol absorption. Weak background light suppressed the effect of light steps, and low levels of background alcohol suppressed the response to subsequent doses. Backgrounds of one agent did not affect the voltage changes caused by the other. Minimal alcohol effects were seen after administration of 1 g orally or 270 mg intravenously--that is, doses that produced undetectable changes in breath alcohol. The semisaturating oral dose was approximately 20 mg/kg. CONCLUSIONS: Alcohol and light act through separate pathways to form a final common pathway inside the RPE cell that is responsible for triggering the timing of the slow oscillatory changes of EOG voltage. The sensitivity and duration with which alcohol affects the RPE are comparable with the effect of melatonin or dopamine, although only the former interacts with light similarly to alcohol. Transient modulation of the acetylcholine (Ach) neuronal receptor occurs at similar sensitivity, but all other known actions of alcohol require higher concentrations than this RPE action.

The electro-oculographic responses to alcohol and light in a series of patients with retinitis pigmentosa.

PURPOSE: Alcohol produces changes in the electro-oculogram (EOG) similar to those caused by light, but indirect evidence indicates that alcohol directly affects the retinal pigment epithelium (RPE). An investigation of the alcohol-induced increase (termed the alcohol rise in this study) in patients with disease of the photoreceptors was therefore of interest. METHODS: Standard EOGs were recorded after oral administration of alcohol in a group of patients with retinitis pigmentosa (RP). RESULTS: The average response of 17 patients to alcohol was a slow decrease of potential, which contrasts with the normal alcohol rise. In patients with considerable residual peripheral field, alcohol produced a small increase of voltage, followed by a prolonged decrease. The slower decrease in the EOG voltage was evident in patients with small fields and could be seen even in those who had lost all visual function. Light caused small increments of EOG voltage (termed light rises), again related to the field size. CONCLUSIONS: It is probable that the intracellular signaling system that causes the alcohol and light rises is lost in RP.

A simple grating test for contrast sensitivity: preliminary results indicate value in screening for glaucoma.

Using a new test, in which patients are asked to view printed sinusoidal gratings of varying contrast, we have established normal population values and have investigated a small series of glaucomatous patients. In these, test scores are higher than the normal range and increase with the severity of the disease. Patients with raised intraocular tension, normal discs, and no field loss may give abnormal results. The test can be scored so that a very sharp distinction may be made between normal and glaucomatous eyes. The test is simple, quick to perform, portable, and can be done in almost any situation.

Pattern ERG in amblyopia.

The authors have recorded pattern ERGs in 62 amblyopic children. In 12 who were occluded up until the morning of the test, the occluded eye response was reduced, and the ratio ([response amplitude of amblyopic eye]/[response amplitude of fellow eye]) was greater than unity. In the remainder, the ratio was considerably less than unity. Ratios of less than 1.0 were found for anisometropic, esotropic, exotropic, and microtropic amblyopes. The ratio was not related to visual acuity or to squint but was higher in those children whose vision was improved by orthoptic treatment. In a group of older children recalled to the clinic, the ratio was 1.0 in those who had maintained equal visual acuity and was less than unity in those children whose acuity had regressed after treatment, or had not improved during treatment. The reduction of the pattern ERG in amblyopes occurs without a corresponding reduction in the focal ERG. In adult amblyopes, the relationship between loss of acuity, loss of grating contrast sensitivity, and the reduction in the PERG is complex and may differ according to the type of amblyopia.

Temporal and spatial properties of suppressive rod-cone interaction.

Recordings were obtained from rods and horizontal cells of Xenopus, using an eyecup preparation. The enhancement of cone signals produced by rod backgrounds was measured using flickering red spots of varying intensity and diameter, and the experiments were repeated with cone stimuli consisting of alteration of wavelengths of 660 and 605 nm, adjusted for equal effects on rods or cones ("silent substitution"). Rods responded to red flicker with discrete wavelets up to 5 Hz. The characteristics of suppressive rod-cone interaction (SRCI) depend on the precise stimulus parameters. In particular, the reported low-pass attenuation of SRCI is absent with silent substitution. An analysis of the responses to backgrounds in horizontal cells, and the effects of the red light flashes in rods, led to the conclusion that the characteristics of SRCI are determined partially by the fact that "cone" stimuli excite rods and vice versa. This result simplifies the mechanism of SRCI and permits a comparison between the studies of SRCI using electroretinograms and horizontal cells.

Evidence from human electroretinogram A and off responses that color processing occurs in the cones.

PURPOSE: To investigate two apparent anomalies of the human electroretinogram: the "on" and "off" components of the cone based PIII are unequally sized, and transitions from red to green, which are electroretinographically silent, yield reverse transitions (green to red) in which a-waves develop. METHODS: Ganzfeld electroretinograms were obtained with intense 100 msec flickering flashes from red and green light-emitting diode. Such stimuli light-adapt the retina, and the responses are caused by the excitation of long and medium wavelength cones. RESULTS: In the 10-20 msec after the beginning of a flash (black to green or black to red) the beginning of rapid receptor-generated a-wave is seen. Ten to twenty milliseconds after the end of the flash, the beginning of a rapid positive-going off response, also derived from receptors can be seen. If the retina is stimulated by the abrupt change from one wavelength of light to another (eg, from "green" to "red"), at times > 20 msec after the change there are always slow changes in potential (presumably caused by postsynaptic activity) regardless of the relative intensities of red and green. However, if the two light intensities are adjusted appropriately, 10-20 msec after the transition from green to red no electroretinographic a-wave (or off response) develops--the transition is "silent." When the transition reverses (changes back from red to green), an a-wave occurs. In the same way if a red-to-green transition is made silent by altering the relative light intensities, the green-to-red reversal evokes an a-wave. This occurs for numerous pairs of red and green intensities. Rod intrusion or minor electroretinogram components do not explain this result. The relative red:green intensity in two color-anomalous subjects is different to that in three normal subjects. The rule for a silent transition is that the decrease in excitation in one cone type should be twice the increase in excitation in the second cone type. CONCLUSIONS: The most likely cause is a reduction in the amplitude of cone receptor potentials 20-50 msec after the onset of the stimulus, caused by a sign-reversing feedback mechanism such as that described in amphibians. This implies that the chromatic signals for color vision required by theorists are partly generated in the cones.

Peripheral color contrast. A new screening test for preglaucomatous visual loss.

A new test of peripheral color contrast is described. A high-definition color monitor driven by a personal computer with a graphics interface card displays an annulus subtending 25 degrees at the eye. The color contrast between the annulus and the background can be varied. Forty-five degrees of the annulus is randomly removed in one of four quadrants. Patients are asked to identify the position of the gap while fixating a central spot. The minimum color contrast between annulus and background at which the identification is possible is between 13-16% for the protan, deuteran, and tritan axis in normal subjects. This threshold value changes little with age, refractive error, or pupillary aperture, and test-retest variability is low. Testing one eye takes only 1-2 min. The test was applied to ocular-hypertensive and glaucomatous patients. All patients with glaucoma had thresholds greater than two standard deviations (SD) above the normal mean. In addition, 97% of glaucoma patients had thresholds greater than four SDs, and 95% had thresholds more than five SDs above the normal mean. Most patients with ocular hypertension and clinical signs indicating a low or medium risk of conversion to glaucoma had thresholds under the upper limit of normal. High-risk patients with ocular hypertension fell into two groups. One approximated to normal; the other had elevated thresholds, which in many cases were more than four SDs above the normal mean. The epidemiologic consequences of this test are discussed.

Electrode comparison in pattern electroretinography.

In recent years, there has been great interest in recording the pattern electroretinogram (PERG) in glaucomatous and diabetic populations. The Dawson, Trick, and Litzkow thread electrode (DTLTE) and the gold foil electrode (GFE), commonly used for recording PERGs, were compared for variations in amplitude of response, test-retest variability, and patient comfort. Two study centers collected data on a total of 32 normal subjects. The subjects from the London center showed a slight (but not significant) preference for the DTLTE, and the Houston subjects also found the DTLTE to be significantly more comfortable (chi-square = 39, P less than 0.001). In both study groups, the GFE was found to produce a statistically larger amplitude of response than that obtained with the DTLTE. Significant differences were found regardless of the slow (transient, 3.1 Hz; F = 6.24; P = 0.0192) or fast (steady state, 8.3 Hz; F = 18.38; P = 0.0001) stimulus-presentation rate. Larger differences between the two electrodes occurred under steady-state conditions. Although there is no consensus as to the optimum recording conditions to obtain the subtle PERG, it appears the the GFE records larger responses than the DTLTE. However, test-retest data confirmed that the GFE records twice the amplitude of the DTLTE, and it also produced twice the variability (average percent difference over time for GFE, 15%; for DTLTE, 8%).

A gold foil electrode: extending the horizons for clinical electroretinography.

A gold foil ERG electrode is described. The device is inexpensive and simple to fabricate. Since it is hooked over the lower lid and makes minimal touch contact with the inferior limbal area, it can be used in circumstances which require prolonged testing of retinal function or in eyes with corneal pathology. Because the optics of the eye are not compromised, it is possible, with the use of appropriate stimuli and response-averaging techniques, to record local EFGs from relatively small retinal areas.

Grating test of contrast sensitivity in patients with retrobulbar neuritis.

A retrospective study of 57 patients with retrobulbar neuritis (RBN) was carried out with a new test of contrast sensitivity that utilizes printed sinusoidal gratings. For 21 patients suffering from multiple sclerosis, visual abnormality was detected in 18 "affected" eyes and 12 apparently unaffected eyes. For the 36 patients with RBN, abnormalities were detected in 29. In seven of these cases, the grating test showed bilateral impairment. The grating test seemed to be a more sensitive indicator of demyellinization than other psychophysical tests. In 24 of the patients with the least severe disease, the grating test was compared with the visual evoked response. The probability of making a positive diagnosis was .54 for the evoked potential alone, and .71 for the grating test alone.

Color vision defects in ocular hypertension and glaucoma. Quantification with a computer-driven color television system.

In order to detect early defects of color vision caused by increased intraocular pressure, a computer graphics device and color monitor system were used to measure color contrast sensitivity. The system determines the threshold chrominance of a colored grating in which there is no change in luminance. The study included 13 control subjects aged 10 to 57 years and 19 patients with ocular hypertension or glaucoma aged 20 to 58 years. In the 13 eyes with visual field loss, color contrast sensitivity was profoundly reduced when the grating colors fell on a tritan color confusion line. In the eyes without visual field loss, tritan color contrast sensitivity was reduced to an average level considerably below the extreme limits of the control group. These results were compared with those of other color vision tests and diagnostic criteria for glaucoma. The findings suggest that among the tests used, color contrast sensitivity testing was able to discriminate most effectively between patients who had retinal damage and the normal population.

Using argon laser blue light reduces ophthalmologists' color contrast sensitivity. Argon blue and surgeons' vision.

Color contrast sensitivity was measured in laser operators before and after laser use. After argon blue-green laser treatment sessions, sensitivity was reduced for colors lying along a tritan color-confusion line for several hours. This acute effect is due to specular "flash-backs" from the aiming beam off the surface of the contact lens. It is caused only by argon 488-nm light, when the aiming beam intensity is high. In addition, a correlation has been demonstrated between the number of years of laser experience and a chronic reduction in tritan color contrast sensitivity. It is suggested that repeated acute changes caused by the argon lasers may cause cumulative effects and produce a chronic threshold elevation. A simple method of eliminating the acute effect is documented.

Autosomal dominant pattern dystrophy of the retina associated with a 4-base pair insertion at codon 140 in the peripherin/RDS gene.

OBJECTIVE: To define the phenotype of a retinal dystrophy associated with a 4-base pair insertion at codon 140 of the peripherin/RDS gene. PATIENTS: Six affected members spanning two generations of a single family were examined. Five were studied in detail electrophysiologically and psychophysically. METHODS: Psychophysical testing included color vision testing, photopic and scotopic static threshold perimetry, and dark adaptometry. Electrophysiological testing included flash and pattern electroretinography, as well as electrooculography. RESULTS: Clinical findings ranged from subtle pigmentary changes at the level of the retinal pigment epithelium to more widespread pigmentary changes associated with choroidal neovascularization. Those with severe fundus changes exhibited greater abnormalities in psychophysical and electrophysiological testing than those with minimal fundus changes. CONCLUSIONS: This particular peripherin/RDS gene mutation is associated with dominantly inherited pattern dystrophy of the retina. The phenotypic expression is variable in a manner not explained by age.

Chromosome 19q cone-rod retinal dystrophy. Ocular phenotype.

OBJECTIVE: To describe the phenotype in a family with dominantly inherited cone-rod dystrophy with chromosome assignment to a 19q locus, and to correlate this with current classifications of this retinal dystrophy. DESIGN: A detailed clinical examination including Goldmann perimetry was undertaken in all family members. Six members under the age of 30 years underwent dark-adapted electroretinography, color contrast-sensitivity measurement, dark-adapted static perimetry, and dark adaptometry. PATIENTS: The study included 34 affected and 22 unaffected patients in four generations of a pedigree that manifested autosomal dominant cone-rod retinal dystrophy linked to a chromosome 19q locus by genetic linkage analysis. RESULTS: Loss of visual acuity occurred in the first decade of life, onset of night blindness occurred after 20 years of age, and little visual function remained after the age of 50 years. Central and, later, peripheral retinal fundus changes were associated with central scotoma, pseudoaltitudinal field defects, and finally global loss of function. Psychophysical and electrophysiologic testing before the age of 26 years showed more marked loss of cone than rod function. CONCLUSIONS: The phenotype associated with this mutation does not fit well into previous subtypes of cone-rod dystrophy. Further studies will be needed to correlate specific genetic mutations in this group of conditions with the various clinical phenotypes.

Dominant retinitis pigmentosa associated with two rhodopsin gene mutations. Leu-40-Arg and an insertion disrupting the 5'-splice junction of exon 5.

OBJECTIVE: To determine the phenotypes of two families in which retinitis pigmentosa cosegregates with a rhodopsin (RHO) gene mutation: a leucine-to-arginine change at codon 40 (Leu-40-Arg) in one family, and a 150-base pair insertion that disrupts the RHO 5'-splice junction of exon 5 in another. PATIENTS: Three affected members of each family. RESULTS: The Leu-40-Arg mutation was associated with the onset of night blindness in the first decade of life. By the fourth decade, severe retinal functional loss was evident on dark-adapted static threshold perimetry, and electroretinographic responses were absent or barely detectable. In contrast, the RHO 150-base pair insertion was associated with the later onset of mild night vision difficulties; in two individuals, mild night vision difficulties were first noticed in the second decade while a third, a 25-year-old woman, was asymptomatic. Dark-adapted static threshold perimetry of this latter individual revealed a "regional" or class 2 pattern of retinal functional loss associated with equal loss of rod and cone electroretinographic responses. CONCLUSION: The RHO Leu-40-Arg mutation causes symptomatic retinal dysfunction by the end of the first decade while the insertion disrupting the 5'-splice junction of RHO exon 5 causes later onset "regional" or class 2 retinal dysfunction.

The pattern electroretinogram (PERG) in ocular hypertension and glaucoma.

Studies of normal subjects and of patients with optic nerve disorders suggest that one of the components of the pattern electroretinogram (PERG), the second negative wave, is related to optic nerve function and appears to be diminished even when the condition is relatively mild, with little alteration of visual acuity. It is known that significant loss of nerve fibers may occur prior to the development of visual field loss. We have investigated the PERGs of a group of subjects with early glaucoma and ocular hypertension, comparing them with normal subjects, and have found a selective reduction in the second negative wave in patients with evidence of optic nerve dysfunction. The PERG may prove helpful in discriminating those patients with ocular hypertension who are destined to develop visual field loss unless medical or surgical therapy were to be employed.