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.

Regression of early diabetic macular oedema is associated with prevention of dark adaptation.

HYPOTHESIS: Dark-adapted rods consume oxygen at high rates and light adaptation decreases this oxygen burden and can have therapeutic effects on diabetic macular oedema (DMO). METHODS: Patients with mild non-proliferative diabetic retinopathy (DR) and early, untreated non-sight-threatening DMO slept for 6 months wearing masks that illuminated the eyelid of one closed eye by 505 nm light. Exclusion criteria were any concomitant eye disease, DR >ETDRS grade 35, and other systemic diseases. PRIMARY OUTCOME: change of OCT retinal thickness in the local region where oedema was present. RESULTS: A total of 34 out of 40 patients completed the study. Mean baseline OCT macular cube thickness was equivalent for study and fellow eyes. But study eyes had a greater mean thickness in the central subfield zone 1 (282±53 µm) vs (256±19 µm) the fellow eyes. Twenty-eight study eyes showed intraretinal cysts compared with nine in the fellow eyes. At 6 months, only 19 study eyes had cysts while cysts were seen in 20 fellow eyes. After 6 months, the worst affected ETDRS zone and the central subfield zone 1 reduced in thickness in study eyes only by 12 µm (95% CI 20 to -7, P=0.01). The secondary outcomes of change in visual acuity, achromatic contrast sensitivity, and microperimetric thresholds improved significantly in study eyes and deteriorated in fellow eyes. CONCLUSIONS: Sleeping in dim light that can keep rods light adapted may reverse the changes of DMO.

A preliminary trial to determine whether prevention of dark adaptation affects the course of early diabetic retinopathy.

UNLABELLED: This study was designed to determine whether a new form of treatment of diabetic retinopathy (DR) was acceptable to patients and whether reduction in the maximal activity of rods in diabetes could affect the progress of DR. METHODS: In 12 patients, trans-lid retinal illumination of one eye was employed during sleep to prevent the depolarisation of rods and thus reduce their metabolic activity. TECHNIQUES: A headband was used to place a source of chemical light over one eye, with its fellow as a control. MEASUREMENTS: Colour contrast thresholds were measured before and after a period of treatment in treated eyes, and the changes were compared to those in untreated fellow eyes, and areas of 'dark retinal anomalies' (microaneurysms, dot haemorrhages) were measured at the same time points. RESULTS: Patients found this intervention to be acceptable, and no adverse effects were noted. In the majority of cases, and for each outcome measure, the treated eyes improved relative to their fellows. The intervention significantly reduced the tritan thresholds in treated eyes relative to their fellows (P=0.03), and the area of dark retinal anomalies decreased in treated eyes and increased in untreated eyes, with a similar probability. CONCLUSIONS: The study showed that this intervention is safe. Although the study was not powered to study efficacy, the results are promising and consistent with other reports that indicate the retina in DR is suffering from hypoxia; however, further trials should be undertaken.

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.

Colour vision testing as an aid to diagnosis and management of age related maculopathy.

AIM: To provide a simple test that detects the onset of age related maculopathy (ARM), and can be used to monitor its severity. METHODS: Colour contrast sensitivity was measured using computer graphics techniques. Colour thresholds were measured along tritan and protan colour confusion axes in the presence of dynamic luminance noise. Thresholds were determined separately for two sizes of optotypes (6.5 degrees and 1.5 degrees). Natural pupils were used. Normal values for the test have been established. RESULTS: In all patients with unilateral age related macular degeneration, the smaller optotype was invisible in that eye and in almost all, the larger optotype could not be seen. In the symptomless fellow eyes (with ARM) the larger optotype thresholds were raised. The degree of loss was larger for tritan. For the smaller optotype, protan thresholds were elevated in the majority of patients. Tritan losses were greater and disproportionate to the loss seen with the larger optotype. Every person including those with minimal fundal changes had tritan test results for 1.5 degree optotypes >2 SD above the normal mean. Tritan thresholds varied with the severity of the ARM. CONCLUSIONS: The test is sensitive, simple and quick to administer, and easy for patients. Therefore, it should be useful in detecting and monitoring elderly people with age related changes in their fundi before irreversible loss of vision has occurred.

Electrical activity in visual cortex associated with combined auditory and visual stimulation in temporal sequences known to be associated with a visual illusion.

When a subject views a visual stimulus paired with a brief click, a second click occurring approximately 80 ms later produces the hallucination of a second visual stimulus. We have used combinations of visual and sound stimuli to evoke cortical activity and have recorded the associated event-related potentials. We have recorded EPs in a conventional manner, and have calculated from multichannel recordings the Laplacian derivations to determine if the currents were generated in primary visual cortex. Clicks alone do not cause significant activity in V1, but if paired with pattern stimulation, modify the evoked potential. The timing of this extra activity almost certainly excludes "feed back" activation from higher centres, and can most simply be explained if sound-activated thalamo-cortical input can rapidly produce extra activity in 'primed' visual cortex. This finding has general implications for cortical function, for the generation of the hallucination and for 'blindsight'.

Symptomatic abnormalities of dark adaptation in patients with EFEMP1 retinal dystrophy (Malattia Leventinese/Doyne honeycomb retinal dystrophy).

PURPOSE: To investigate the nature of symptomatic visual disturbance in patients with EFEMP1 retinal dystrophy in the absence of geographic atrophy or choroidal neovascularization. METHODS: Patients presenting to a tertiary referral centre underwent clinical evaluation, fluorescein angiography, colour contrast sensitivity, focal, pattern, and standard electroretinography, electrooculography, scotopic threshold perimetry and dark adaptometry. RESULTS: Clinical features included reduced central vision, difficulty passing from light to dark, and diffuse submacular and peripapillary deposits, which were hyperfluorescent by fluorescein angiography. Colour contrast thresholds were abnormal in all six patients studied and both pattern and focal electroretinograms were abnormal in five of six patients. The scotopic and mixed rod-cone single flash ERG was normal but two patients demonstrated reduced oscillatory potentials and one had borderline delayed 30 Hz responses. Scotopic thresholds were elevated and rod-mediated dark adaptation kinetics were markedly prolonged in all six patients when measured over the central visible confluent deposits. CONCLUSIONS: In patients with EFEMP1 retinal dystrophy with confluent macular deposits, scotopic sensitivity is reduced and dark adaptation kinetics are prolonged over the macular deposits but are normal elsewhere. These results emphasize the localised nature of functional deficits in some patients with EFEMP1 retinal dystrophy and correlate well with the patient's visual symptoms. Symptomatic visual dysfunction may precede the development of clinically evident geographic atrophy or choroidal neovascularization in this disorder.

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.

Effect of alcohol and light on the retinal pigment epithelium of normal subjects and patients with retinal dystrophies.

BACKGROUND: Light absorbed by photoreceptors causes oscillations in the voltage across the retinal pigment epithelium (RPE). This is the basis of the clinical test, electro-oculography (EOG). We have previously shown that alcohol causes a sequence of voltage changes which are so precisely the same as those caused by light that they must be produced by the same RPE machinery. There is good evidence that alcohol produces its effect by a direct action on the RPE. Consequently, in diseases associated with loss of photoreceptors, alcohol should continue to produce the voltage changes of the EOG unless secondary changes have occurred in the RPE. METHODS: The alcohol response in patients with retinitis pigmentosa (RP) was investigated using EOG. RESULTS: In no patient with RP was there any alcohol rise. CONCLUSION: In patients with RP secondary abnormalities of function of the RPE must occur.

The electroretinogram in diabetic retinopathy.

Electroretinography (ERG) is an objective method of evaluating retinal function. Since its introduction to clinical practice in the 1940s, it has become a useful and routine diagnostic clinical tool in ophthalmology. This review summarizes the role of ERG as a clinical technique for evaluating the progression of diabetic retinopathy and as a research tool for increasing our understanding of the pathophysiology of diabetic retinopathy. Most studies show unequivocally that the different types of ERG tests detect local abnormalities or widespread pathology, even in very early stages of the disease. It seems plausible that measurements from ERG recordings, particularly the oscillatory potentials, may be useful for predicting progression from nonproliferative to the more sight-threatening stages--preproliferative or proliferative--of diabetic retinopathy. Some recent work implies that the ERG can also be a useful diagnostic method for discriminating between eyes with diabetic retinopathy and those without the condition.

[Color vision in relation to age: a study of normal values]. / Farbensehen in Abhängigkeit vom Alter: eine Normwertstudie.

BACKGROUND: It is difficult to quantify thresholds in most colour vision tests, and this is especially the case for tritan hues, where a strong age-related increase of threshold has been reported. With the development of computer-graphic methods it is possible to remove brightness clues caused by lens absorption. This study attempts to give normative values for colour contrast thresholds and assess the age related changes therein. PATIENTS AND METHODS: 115 patients aged between 6 & 71 years were tested for central and peripheral colour contrast sensitivity. No patient had any systemic or eye disease. As a preliminary, heterochromatic flicker balance between the luminosities of the R and G and B and G phosphors was established, so that all colours subsequently generated were isoluminant for the person tested. Then, using a modified binary search technique, colour contrast thresholds were established using both 2 degree optotypes, for central vision, and a ring, 12.5 degrees in radius for peripheral vision. In the latter case, the observer had to name the position of the missing quadrant in the ring. Stimuli were presented for 200 msec at 1 Hz. Colours were modulated on protan, deutan or tritan colour axis. RESULTS: No correlation between age and central colour vision thresholds was observed. By contrast a significant but only minor increase of peripheral colour vision threshold was observed for the peripheral protan and tritan axis. DISCUSSION: The present system removes luminance clues from colour vision tests and permits both central and peripheral retina to be tested. The results are simple in that the influence of age can be neglected. The variability of threshold results is small, and it is easy to detect the relatively large changes associated with disease. Since high-quality monitors are standardised and calibrated, providing the stimulus parameters described are adhered to, the results given here for upper limits of normal may be used for other similar systems.

The effect of neodymium: YAG capsulotomy on contrast sensitivity and the evaluation of methods for its assessment.

OBJECTIVE: To determine the most appropriate method for measuring the effect on contrast sensitivity of neodymium:YAG (Nd:YAG) posterior capsulotomy for early posterior capsular opacification (PCO). DESIGN: Prospective comparison of five different methods for luminous contrast sensitivity testing in patients undergoing capsulotomy. PARTICIPANTS: Sixteen patients with PCO involving the visual axis and visual acuities of 20/40 or better were recruited sequentially. INTERVENTION: All patients were tested with each of the five tests before and after Nd:YAG capsulotomy. MAIN OUTCOME MEASURES: The contrast sensitivity function was measured with variable contrast sine wave gratings using the Vistech VCTS 6500, Mentor B-VAT-II and a computer graphics system. Peak contrast sensitivity at 3 cyc/deg was compared with two letter tests, the Pelli-Robson chart, and a computer that generated optotypes. RESULTS: Significant generalized improvement that was not frequency selective was measured over the entire contrast sensitivity function after capsulotomy. The five tests did not significantly differ (P > 0.05) in their measurement of peak contrast sensitivity (3 cyc/deg) improvement after capsulotomy. Letter-based tests showed better agreement and lower variance than gratings tests. Visual acuity and contrast sensitivity improvement were poorly correlated. CONCLUSIONS: This study shows that contrast sensitivity is adequately documented by a single measurement at 3 cyc/deg, is an informative supplement to visual acuity, and that little extra information is to be gained by measuring further spatial frequencies in eyes with PCO. Peak contrast sensitivity is best determined using a letter-based test.

Comparison of methods to assess visual impairment from glare and light scattering with posterior capsule opacification.

PURPOSE: To compare 2 glare tests to determine their relative usefulness in the assessment of posterior capsule opacification (PCO) and to evaluate the potential benefits of combined visual, acuity, contrast sensitivity, and glare testing. SETTING: Teaching hospital ophthalmology department. METHODS: Sixteen patients had glare, visual acuity, and contrast sensitivity testing before and after neodymium:YAG (Nd:YAG) capsulotomy. Results with the Brightness Acuity Tester (BAT, Mentor), which measures disability glare, and the Straylightmeter (Foundation for Eye Research, The Netherlands), which quantifies forward scatter by direct compensation techniques, were compared. The correlation between glare, ETDRS visual acuity, and Pelli-Robson contrast sensitivity was determined. RESULTS: Pretreatment visual acuity was significantly correlated with contrast sensitivity (P < .01). However, visual acuity and contrast sensitivity were poorly correlated with both the BAT and Straylightmeter (P > .05), indicating that visual acuity is predictive of contrast sensitivity but a poor predictor of glare. Glare was significantly improved (Straylightmeter, P < .0001; BAT, P < .05) following capsulotomy. While the Straylightmeter consistently measured precapsulotomy forward scatter that improved with treatment, corresponding BAT disability glare was unmeasurable in 18.8% of patients with PCO, as their visual acuities improved rather than deteriorated with glare testing. CONCLUSIONS: Glare testing provided more information than contrast sensitivity when combined with visual acuity in the evaluation of PCO. Glare related to PCO is better assessed using the Straylightmeter because the BAT may yield aberrant disability glare results.

Does dark adaptation exacerbate diabetic retinopathy? Evidence and a linking hypothesis.

The paper reviews evidence that before any change in diabetics' fundi, changes occur to blood flow, ERG and visual functions. In the case of colour vision and contrast sensitivity, the changes are partially reversed by breathing oxygen, and therefore are the result of retinal hypoxia. There are also other evidences that hypoxia is a major factor in the development of diabetic retinopathy (DR). Therefore in diabetics with early retinopathy, but normal photopic vision, functional disturbance might appear in dark adaptation, since in such circumstances, (as shown by Linsenmeier and his colleagues) the already low retinal PO2 markedly decreases. This hypothesis has been tested and results consistent with the hypothesis (and with a number of older reports) have been obtained. The significance of this finding to early DR is discussed, and a mechanism suggested whereby prolonged periods of hypoxia during dark adaptation could generate changes in retinal capillaries. Such periods occur each night, and their elimination in diabetics could be therapeutic.

Incidence of idiopathic full-thickness macular holes in fellow eyes. A 5-year prospective natural history study.

PURPOSE: This study aimed to determine the incidence of idiopathic full-thickness macular hole (FTMH) in normal fellow eyes and to evaluate the role of electrodiagnostic and psychophysical tests in identifying eyes at risk. PATIENTS AND METHODS: A prospective longitudinal natural history study of a cohort of patients with unilateral holes and normal, asymptomatic fellow eyes without posterior vitreous detachment was conducted. Subjects underwent baseline examination, pattern reversal electroretinography, electro-oculography (EOG), and color contrast sensitivity (CCS) testing for protan, deutan, and tritan thresholds and were recalled for clinical examination at 18 months and 5 years. RESULTS: At baseline, 114 patients were examined. Eighty were available for review at 18 months, of whom 6 had full-thickness macular holes develop in the fellow eye. At 5 years, 67 of the remaining 74 patients who had not developed holes at 18 months were re-examined and a further 5 were found to have holes develop in the fellow eye. A posterior vitreous detachment without hole formation had developed in 20 fellow eyes at 5 years. Although mean pattern reversal electroretinography and EOG responses were within normal limits in affected and fellow eyes at baseline, mean CCS protan, deutan, and tritan thresholds were elevated significantly in affected eyes at baseline (P = 0.0001). Unaffected fellow eyes showed normal mean protan and deutan thresholds, but significantly elevated mean tritan thresholds (P = 0.01) at baseline. Mean tritan CCS loss was, however, similar in fellow eyes in which holes later developed and in fellow eyes in which holes did not. CONCLUSIONS: The Kaplan-Meier estimated risk of fellow eye involvement is 15.6% (range, 8.4%-22.3%; P = 0.05) at 5 years. Although electrodiagnostic and psychophysical testing was not predictive of fellow eye involvement, tritan CCS loss at baseline, in apparently normal fellow eyes, may indicate subclinical foveal dysfunction, the nature of which is unclear.