Time-specific intraocular pressure curves in Rhesus macaques (Macaca mulatta) with laser-induced ocular hypertension.

OBJECTIVE: To detect and categorize time-specific variations in daytime intraocular pressure (IOP) found in Rhesus monkeys with laser-induced ocular hypertension. PROCEDURES: Ten male monkeys with argon laser-induced ocular hypertension in one eye were anesthetized with ketamine hydrochloride, and the IOP measured in both eyes at 7 a.m., 7.30 a.m., and then hourly until 1 p.m. with a Tonopen trade mark XL applanation tonometer. Intraocular pressure time profiles for both eyes in each animal were developed. The means +/- SD of the IOPs for both eyes were calculated for the whole 6-h study period, and the values compared statistically. The difference between the lasered eye mean IOP standard deviation and the normal eye mean IOP standard deviation for each animal during the 6-h follow-up was also calculated and compared. RESULTS: Mean IOP (+/- SD) in the glaucoma and normal eyes for the 10 animals during the 6-h study was 32.6 +/- 2.5 and 14.9 +/- 2.5 mmHg, respectively. The IOP was significantly higher in the experimental eye than in the normal eye (P = 0.0008). The mean IOP in the lasered eye did not significantly change during the study period, whereas a slight but significant increase in IOP of the normal eye over the study period was recorded (P = 0.003). The variance in IOP in the hypertensive eyes was considerably greater than that in the untreated control eyes. From 7 a.m. to 1 p.m. the IOP declined in five eyes and increased in the other five eyes with laser-induced ocular hypertension. CONCLUSIONS: The time-specific IOP variation pattern in the daytime in the laser treated eyes is significantly greater than the variation in the normotensive eyes. This shows that in order to detect statistical differences between IOP variations induced by an IOP-reducing drug, and the exaggerated spontaneous IOP variations present in the laser-induced hypertensive eye, sufficient animals should be included in any study. Understanding the time-specific IOP variation present in a group of monkeys with laser-induced ocular hypertension is essential prior to using the model for the evaluation of IOP-reducing drugs.

Corneal thickness and endothelial cell density measured by non-contact specular microscopy and pachymetry in Rhesus macaques (Macaca mulatta) with laser-induced ocular hypertension.

PURPOSE: Sustained increase in intraocular pressure (IOP) in humans results in a loss of corneal endothelial cells and an increase of corneal thickness. The effects of chronically elevated IOP on the corneal endothelium of monkeys with laser-induced ocular hypertension, a commonly used animal model of human glaucoma have not been documented. This study examined the central corneal thickness (CCT), the corneal endothelial cell density (ECD), and the corneal endothelial cell size (ACS) in Rhesus monkeys with experimental ocular hypertension. Materials and methods. Ten male monkeys with argon laser-induced ocular hypertension in one eye for an average duration of 2.4+/-0.7 years, were sedated with ketamine hydrochloride, and the CCT, ECD, and ACS measured at the center of the cornea of both eyes with a Topcon SP-2000P non-contact specular microscope (Topcon America Corporation((R)), Paramus, NJ, USA). CCT was also measured using a DHG-500 Pachette ultrasonic pachymeter (DHG Technology Inc., Exton, PA, USA). Mean and standard deviation (S.D.) of CCT, ECD and ACS for each eye was calculated and statistically compared.Results. Mean CCT in the hypertensive and normal eyes measured by specular microscopy was 0.477+/-0.023mm and 0.468+/-0.020 mm, respectively. Mean ECD in the hypertensive and normal eyes was 2601.7+/-631.8 and 3990.2+/-402.9 cells mm(-2), respectively. The mean size of the endothelial cells was 252.4+/-23.9 micro m(2) in the normal eye and 408.7+/-115.0 microm m(2) in the hypertensive eye. No significant difference in the measurement of CCT was observed between the specular microscope and the pachymeter (p=0.46). No significant difference in the mean CCT was observed between the two eyes (p=0.4820), whereas the mean ECD was significantly lower in the hypertensive eye than in the normal eye (p<0.001). The ECD was inversely related to the length of IOP elevation (p<0.001). CONCLUSIONS: No difference in the corneal thickness measurement was observed between the specular microscopy and the pachymetry techniques. Chronic ocular hypertension did not significantly affect the CCT, but caused a significant loss of endothelial cells in the center of the cornea of the laser treated eyes compared to the normotensive eyes. The duration of elevated IOP was the most important factor affecting the ECD.

[Retinal hazard from blue light emitting diode].

PURPOSE: To compare the effect of exposure time from a blue(460 nm) light emitting diode(LED) on the morphology of the outer retina and determine conditions where damage occurs. MATERIALS AND METHODS: Young adult rhesus monkeys were anesthetized, and received blue LED exposure from a modified slit-lamp. A 3 mm beam of 0.85 mW was imaged onto the retina through a lens positioned before the cornea and exposure damage was determined at time intervals for 12 to 90 min. Fundus photography, fluorescein angiography(FAG), retinal tomography(HRT), and s-cone electororetinogram(S-ERG) were recorded at baseline, 2, and 30 days. RESULTS: Two days after 40 min exposure, there was a grey, discolored region, which was over-fluorescent in FAG, and an incresse in HRT and S-ERG corresponding to the site which was exposed to LED light. In histological examination at 30 days, the LED had caused produced a marked disruption of the disks of photoreceptor cells, damaged retinal pigment epithelium(RPE) apical villi, and a loss of RPE melanin after 90 min exposure. CONCLUSION: A threshold level was found around 40 min. This morphological damage may impair function and continuous exposure to blue light is potentially dangerous to vision.

Distant cancer effects on standardised testing of peripheral vision.

BACKGROUND: Profound central-retinal visual losses have been a major presenting factor reported in cancer and melanoma associated retinopathies (CAR, MAR). However, it is well established that standardised tests of peripheral retinal function are often the most sensitive detectors of early eye disease. This is a preliminary investigation of the responsiveness of the peripheral retina to "distant" (non-eye or CNS) cancers using easily obtained standardised tests. METHODS: The design is a single blind study where test results are compared with published norms and a small age matched control group. Of 120 ambulatory cancer outpatients who were interviewed at routine follow up examinations, 111 volunteered and admitted a range of mild visual changes. 25 cancer patients completed all tests of peripheral vision function and a clinical screening. There were seven control subjects of the same age range. RESULTS: 98% (49 of 50) of eyes from the patient cohort were judged clinically normal following examinations which emphasised the central retina, fundus appearance, and static fields. On testing which emphasised the visual periphery, 46 (92%) eyes showed one or more quantitative abnormalities >2 SD from the age adjusted norm means. These abnormalities clustered mainly about dark adaptation (rod cell) sensitivity (31, 62% of measured sites), the blue sensitive retinal cells (17, 34% of measured eyes), and the oscillatory component (OP) of the electroretinogram (23, 46% of measured eyes). One control eye (7%) showed a significant dark adaptation abnormality and ERG reduction. There was no identifiable interaction between chemotherapy mode and the cancer associated retinal deficits (CARD). Antiretinal antibodies were found in sera from most patients and controls. CONCLUSION: CARD is common in the retinal periphery of many cancer patients, and is distinct from rare CAR, MAR central-retinal responses. CARD has numerous potential clinical uses which justify expanded research with more defined large samples.

Human photopic response to circulating glucose.

Circulating glucose was manipulated in young human volunteers with clinically normal vision. Fasting achieved a concentration range of 45-91 mg/dl. And sugar loading produced a range of 79-108 mg/dl. Glucose increased in all subjects. A nonparametric ANOVA provided a p=0.0005 for the significance of the concentration differences between group glucose concentrations under the two conditions in the sample. Each volunteer participated in each condition of the repeated-measures design. Clinical tests were completed before electroretinograms were recorded under photopic and scotopic adaptation conditions. Measures were made from 12 eyes. Only photopic adaptation conditions with maximal stimuli produced significant results. Inter-individual differences were robust and constrained to reduced implicit times for b-wave peaks and 30 Hz flicker implicit times. Under the elevated glucose conditions. Other variables showed very strong trends. These results confirm and extend other human indications of photopic retinal sensitivity to variations within the normal range of circulating glucose concentrations.

Mid-peripheral pattern electrical retinal responses in normals, glaucoma suspects, and glaucoma patients.

AIMS: Reliance on intraocular pressure, optic nerve cupping changes, nerve fibre layer integrity, and visual field changes may delay treatment of glaucoma since irreversible changes may have already occurred at the time of diagnosis. Abnormal pattern electrical retinal responses (PERR or PERG) have been demonstrated in patients with ocular hypertension (no visual field changes) and glaucoma when visual stimulation was presented to the central field. Since glaucomatous visual field changes tend to occur first in the mid-periphery, the use of PERR outside of the central field may offer an earlier indication of glaucomatous involvement. METHODS: Glaucoma suspects and glaucoma patients were derived from a university practice. Normal subjects were recruited from non-patient volunteers. Alternating bar gratings were presented in the supranasal, supratemporal, infratemporal, and infranasal visual field. Six spatial frequencies, from 0.25 to 6.0 cycles per degree, were used for normal volunteers; three spatial frequencies, from 0.38 to 1.5 cycles per degree, were presented to suspects and glaucoma patients. Time of onset of the first negative (N35) and first positive peak (P50) and the amplitude consisting of the absolute difference between the first negative peak and first positive peak (P50 amplitude) are reported. Age corrected values were determined for normals, suspects, and glaucoma patients for each spatial frequency and for each quadrant in the visual field. RESULTS: Mean P50 amplitudes from normal subjects showed spatial tuning in all quadrants with reduced low frequency attenuation. Normals demonstrated a small decline in amplitude with age. Glaucoma patients demonstrated an age corrected reduction in amplitude and early implicit times. Glaucoma suspects had values between those of normal and glaucoma subjects. P50 amplitudes were weakly correlated with increasing cup to disc diameter ratio. A glaucoma patient with asymmetric visual field loss demonstrated significant diminution of the PERR bilaterally. CONCLUSION: The PERR, using mid-peripheral stimulation, may be a sensitive tool for the early detection of glaucoma. Further refinements can speed clinical data acquisition and enhance signal to noise ratio.

Signs of glaucoma in rhesus monkeys from a restricted gene pool.

PURPOSE: To investigate the distribution of intraocular pressure (IOP) and cup properties in a colony of rhesus monkeys that has had no outside genetic input since 1938 (approximately 12 generations). This sample of sequestered monkeys is significantly larger than any previously reported. Comparisons are made with a sample of random-source monkeys to develop population estimates defining the limits of normalcy. METHODS: The IOP and cup/disc ratio estimates were collected from 701 eyes of 354 adult rhesus monkeys from the closed colony on Cayo Santiago, Puerto Rico. Results for IOP were compared with the normal rhesus IOP population distribution function calculated from an earlier sample of genetically heterogeneous rhesus. RESULTS: The mean +/- standard deviation IOP in the Cayo Santiago monkeys (15.8+/-3 mmHg) related well to the calculated "normal" rhesus distribution (14.5+/-2 mmHg) below and around the mean IOP only. Above the mean rhesus IOP, the samples from the Cayo monkeys were strongly skewed: 129 eyes had IOP more than two standard deviations above the normal mean IOP, and 54 eyes had IOP more than three standard deviations above the normal mean IOP. Cup/disc ratio estimations tended to cluster as higher values in the higher IOP quartiles. Some eyes with IOP below the mean had cup/disc ratios > 0.5. Values for IOP that were more than two standard deviations above the mean and cup/disc ratios > 0.4 were not uniformly distributed across social groupings, although incidence of high IOP was more than 25% in one group. CONCLUSION: After 12 generations with the same genetic pool, expression of ocular hypertension and large optic disc cups is high but not uniform.

Diurnal intraocular pressure curves in healthy rhesus macaques (Macaca mulatta) and rhesus macaques with normotensive and hypertensive primary open-angle glaucoma.

PURPOSE: The authors identify any diurnal intraocular pressure (IOP) variation in healthy Cayo Santiago macaques, as well as Cayo Santiago macaques with normotensive and hypertensive primary open-angle glaucoma (POAG), to further evaluate their potential value as a model for human POAG. METHODS: Twenty-four monkeys (eight animals each of the healthy control, normotensive glaucoma, and hypertensive glaucoma groups) were sedated with ketamine hydrochloride and the IOP measured hourly from 8:00 AM until 3:00 PM with a Tonopen XL applanation tonometer (Mentor, Norwell, MA, U.S.A.). Mean IOP time profiles, mean IOPs at each observation time, and linear trends in mean IOP over time were compared among groups. Intraocular pressure rate-of-change over time and residual variation about the regression line for each individual eye were analyzed. Cup/disc ratio (C/D) was compared with baseline IOP, IOP profile mean and slope, and IOP residual variation. RESULTS: A significant group and time effect on mean IOP (p = 0.0001 and 0.011, respectively), with highest values at 2:00 PM or 3:00 PM, and a significant increasing linear trend in mean IOP over time in the hypertensive group were observed (p = 0.012). Intermediate readings between control and hypertensive mean IOPs were identified for the normotensive glaucoma group. The biggest range of IOP variation was found in the hypertensive glaucoma monkeys. Higher variations in IOP did not lead to an increase in C/D. CONCLUSIONS: This study provides evidence that the Cayo Santiago macaques are a valuable model for human normotensive and hypertensive POAG.

Impaired retinal function in young labrador retriever dogs heterozygous for late onset rod-cone degeneration.

Xenon-flash d.c.-electroretinograms were recorded from dark adapted, rod-cone degenerate homozygote affected (n = 6), heterozygote carrier (n = 3) and control retinas (n = 4) at 3 and 4 months of age, starting at 0.6 log units below control PII threshold. One log unit higher stimuli were necessary to evoke PII in heterozygote and affected retinas compared to controls. Unique to the heterozygotes, double peaked PII responses that were evoked by -2 log relative units intensity stimulation were significantly (P = 0.028) lower in amplitude than those of controls. PII amplitudes of homozygotes were significantly (P = 0.005) lower in amplitude than those of controls at both ages examined in response to -2 and 0 log relative intensity stimulation. No differences were found in scotopic threshold response amplitudes or times to peak between the three groups. Homozygote affected PII times to peak were significantly (P = 0.005) shorter in relation to controls at -2 log units. Findings suggest that heterozygotes exhibit an impaired retinal function which can be demonstrated at 3 and 4 months in this mutant.

The late positive retinal potential in dogs.

The late positive potential of the mammalian electroretinogram has been called the 'PI' or the 'c-wave' potential. It is unusual among retinal potentials because its peak implicit time increases in response to increasing stimulus intensity and because it cannot be demonstrated consistently in small samples of normal humans or normal dogs. We recorded wideband (DC-1 kHz) responses from 34 normal Beagles or dogs of similar size. Of the 34, 11 produced a late positive potential set that satisfied the criteria for c-waves. Multiple aspartate injections always increased c-wave amplitude and stimulus-response linearity in all 'producers'. Non-producers were never converted to producer status by aspartate blocking of the inner retina. Interaction of late positive and negative potentials and the possible influence of normal individual variations in the trans-epithelial potential are discussed. Individual mammal c-wave production is controlled by outer retinal phenomena which vary between individuals.

Early morphometry of a retinal dystrophy in Labrador retrievers.

Retinal morphometry was assessed in 7 dogs from a colony of Labrador Retrievers with dystrophic retinas at 1,2,3,4 and 18 months of age. Rod outer segment length and outer nuclear layer width were measured in the central, midperipheral and peripheral retina at six locations along the vertical meridian. Early striking regional differences in onset and rate of progression were characteristic for this inherited retinal degeneration. Notably, some areas of the retina developed fully and normally before degenerating. The central parts of the vertical meridians showed slightly disorganized rod outer segments already at 1 month of age and they were significantly shorter than those of control animals at 3 and 4 months (p < 0.01 and p < 0.001, respectively). The rod outer segments of the midperipheral and peripheral regions were, however, comparable to control animals as late as at 4 months of age. At 18 months the rod outer segments of dystrophic animals were significantly shorter in all retinal regions (p < 0.0005). At the age the outer nuclear layer of the dystrophic animals had become significantly thinner than that of control animals in all retinal regions (p < 0.001), indicating a clear visual cell loss. It is reasonable to characterize this as a retinal degeneration having a relatively slow progression, which enhances its relevance to conditions of clinical significance.

Chronic ocular hypertension alters local retinal responsiveness.

Electrophysiological responses of the retina and visual cortex to a series of grating stimuli (6-768 minutes of arc) were recorded in seven sessions using normal beagles, 21 sessions using beagles afflicted with inherited ocular hypertension, and 12 sessions using rhesus monkeys. A 15 degrees field centred around the animal's area centralis or fovea was used to stimulate the central retina. A 30 degrees field, centred on the same spot, was then used to stimulate the larger area. Two recording series were completed on each animal, with both field sizes presented in each recording session. The first recording took place 30 minutes after and the second 2 hours after the injection of thiamylal sodium. Only the signals from the toroidal 15 degrees of the retina of the hypertensive dogs were remarkably larger during the second recording (p = 0.001). No significant differences were found between the two recordings from the retinas of normal dogs or monkeys, nor were there any significant differences between the two recordings from above the cortex in any group. Several hypotheses are proposed to explain the basis for the interaction of thiamylal with the more peripheral retinal function in clinically glaucomatous dogs.

Primary open angle glaucomas in the rhesus monkey.

Rhesus monkeys from the closed Cayo Santiago colony of the University of Puerto Rico demonstrate elevated (> or = 22 mm Hg) intraocular pressure in a pattern which significantly favours certain maternal lineage groupings. The colony had remained genetically pure since 1938. Of nine matriarchal lineages (matrilines) examined, two had an incidence of ocular hypertension of more than 40% and six of more than 10%. Information on 18 matrilines is currently located in the colony data base which identifies each individual and its vital statistics. In 1990, six animals were moved to the laboratory in Florida. Among those from a low incidence matriline, we found abnormal optic nerve cups, pallor, reduced function of (mainly peripheral) fields, progression and loss of optic nerve axons in the presence of ocular hypertension. In another individual where the cup/disc ratio for the right eye was 0.7 and left eye 0.4 and outflow facility was normal, we excluded all other causes of optic nerve atrophy, and low tension glaucoma was diagnosed. This female was from a matriline with a low incidence of ocular hypertension. Relatively rapid aging (3-4 years/human year) monkeys with ocular hypertension and familial clustering produce a near ideal glaucoma research model.

Primary open-angle glaucoma alters retinal recovery from a thiobarbiturate: spatial frequency dependence.

Electrophysiological responses of the retina to a series of grating stimuli (6-768 min of arc/phase) were recorded in seven sessions using normal Beagles and in 21 sessions using Beagles afflicted with inherited glaucoma. A 15 degrees and a 30 degrees field, centered around the animal's area centralis, were used to stimulate the central retina. Two recording series were completed on each animal, with both stimulus sizes presented in each recording session. The first recording took place 30 min, and the second 2 hr, after the injection of thiamylal sodium. The signals recorded from the toroidal 15 degrees of the retina of the glaucomatous dogs during the second recording were significantly larger than those of the first recording. This difference was found only for the larger (> 48 min of arc/phase) gratings. No significant differences were found between the first and second recordings from the central 15 degrees of glaucomatous dogs, nor at any site in the normal dogs.

Optic nerve aplasia.

Optic nerve aplasia is a rare congenital defect invariably associated with other ocular or systemic disorders. We examined a 3-year-old girl with monocular microphthalmos who had optic nerve aplasia on histopathologic examination of the eye after enucleation. Magnetic resonance imaging verified the presence of unilateral optic nerve aplasia, and demonstrated hemichiasmal hypoplasia on the affected side and bilateral optic tracts. The visually evoked cortical response revealed increased signals over the occipital cortex ipsilateral to the aplastic nerve, suggesting misdirection of axons from the temporal retina of the normal eye. The visual pathway in unilateral optic nerve aplasia may assume a primitive form of neuronal organization characterized by an increase in contralateral retinogeniculostriate projection.

A primate model for age related macular drusen.

A closed colony of semi-free-ranging rhesus monkeys maintained in isolation since 1938 by the Caribbean Primate Research Center (CPRC) is being studied as a model for age related macular drusen. Of examined colony animals 57.7% of the monkeys and 47.3% of their eyes have drusen. The prevalence and severity of drusen are linearly related to increasing age and are significantly higher in specific maternal lineages (matrilines). An electrophysiological estimate indicates loss of function associated with drusen. Prevalence of drusen in CPRC females is almost twice that of males, while the prevalence among CPRC animals in general appears to be several times that of monkeys from continental US facilities. Evidence suggests that the frequency of endstage lesions is also similar to that in human populations. The CPRC matriline monkeys appear to provide the best model yet reported for human age related macular drusen.

Pigment epithelial function in canine retina.

The lateral distribution and temporal changes in the eye standing potential of 15 dogs with normal eyes (as determined by use of an ophthalmoscope and electroretinography) were measured by use of noninvasive methods. The standing potential was converted to an alternating potential by controlled eye movement. The light peak occurred 6 minutes after a stimulus intensity increase of 4 log units. The ratios of the highest measured voltage after the light step divided by the voltage measured immediately before the light step ranged from 1.27 to 2.07 (mean 1.74 +/- SEM, 0.064). The responses typically decayed slowly after the light peak. The potential after the light peak did not return to prelight step values during the observation period. The field potential of the standing potential decreased nonlinearly in temporal direction from the outer canthus.

The quantity of rhodopsin in human eyes.

The content of rhodopsin in the eyes of 15 donors (30 eyes) was determined. Both retinal and pigment epithelial fractions were collected from each globe, extracted using 1% CTAB, and the rhodopsin difference spectrum of each fraction was obtained separately. The total amount of rhodopsin, obtained by summing the amounts recovered from the retinal and PE fractions, ranged from 2.00 to 11.94 (median: 6.40) nmoles/eye. Previously reported mean values of about 3.5 to 4.0 nmoles per retina have been obtained using a variety of methods. The present higher values, perhaps largely dependent on procedural details described herein, appear plausible given the known concentrations of rhodopsin in rod outer segments, rod outer segment volumes, and number of rods in the human retina.