Baseline characteristics of the transient pattern electroretinogram in non-human primates: inter-ocular and inter-session variability.

This study assessed the inter-ocular and inter-session variability of the transient pattern electroretinogram (PERG) in a group of non-human primates. The transient PERG was measured both eyes of 29 non-human primates, and again after three months in 23 eyes of 23 of these animals. Signals were elicited using a contrast (90%, 75 cdm(-2)) reversing (5 reversals sec(-1)) checkerboard pattern (0.56 cpd). PERGs were also measured for stimuli of varied spatial frequency (n=8, 0.07-2.22 cpd), contrast (n=4, 20-100%), mean luminance (n=4, 4.7-75 cdm(-2)) and defocus (n=5, +1, +2, +3 diopters). The inter-eye and inter-session limits-of-agreement (LOA; 95%) were determined for each PERG parameter. Variability was also compared with previous studies using the coefficient-of-variability (COV). Pharmacological blockade of the inner retinal contributions to the PERG measured under these conditions was conducted in one animal using intravitreal injection of tetrodotoxin (approximately 6 microM) and N-methyl-D-aspartic acid (approximately 6 microM). The N95 component of the primate transient PERG showed spatial tuning, with a peak between 0.14 and 0.28cpd. This spatial tuning was not as apparent for the P50 component. A linear relationship between P50 and N95 amplitude was found with contrast and mean luminance. Both components were attenuated with the introduction of +2 diopters or more of defocus. The inter-session COV for the P50 and N95 components were 23.8 and 19.2%, respectively, while the LOA were 58 and 46%, respectively. The N95:P50 ratio had smaller inter-session variability, was robust to changes in contrast, mean luminance and defocus, and was effective for characterization of inner-retinal dysfunction after pharmacologic block.

Depth of penetration of scanning laser Doppler flowmetry in the primate optic nerve.

OBJECTIVES: To estimate the measuring depth of the blood flow and to establish the vascular contributions to these measurements with scanning laser Doppler flowmetry (SLDF) of the primate anterior optic nerve. METHODS: Optic nerve blood flow in each eye of 8 monkeys was measured using SLDF before and following surgical occlusion of the central retinal artery (n = 4) or posterior ciliary arteries (n = 4). The regional blood flow in both eyes was determined using a nonradioactive microsphere method. RESULTS: The blood flow in the nerve fiber layer (NFL), including the prelaminar region, was measured with microspheres after central retinal artery occlusion; it was significantly reduced (-83%) with no significant change in the combined laminar and retrolaminar regions. The blood flow measured with SLDF had a 51% reduction. After posterior ciliary artery occlusion, the blood flow in the NFL was measured with microspheres and was not significantly affected (+2%); neither was that measured with SLDF (-12%). However, there was a 51% reduction in the laminar and retrolaminar regions when microspheres were used. The mean +/- SD tissue thickness of the NFL was 359 +/- 16 microm and 353 +/- 54 microm in each group. CONCLUSIONS: Scanning laser Doppler flowmetry measures blood flow principally in the NFL of the anterior optic nerve, which is primarily supplied by the central retinal artery. Blood flow in the laminar and retrolaminar regions makes a small contribution to the SLDF measurement, with an NFL thickness between 300 and 400 microm. CLINICAL RELEVANCE: Scanning laser Doppler flowmetry is used for the noninvasive evaluation of ocular microcirculation in diseases such as glaucoma. Because of the dual blood flow supply in the optic nerve and the limited penetration power of the laser, the instrument primarily measures the microcirculation on the surface of the optic nerve, which is largely supplied by the central retinal artery rather than the ciliary arteries.

Predictive value of a 1-day, 1-eye trial on the 1-month ocular hypotensive response of latanoprost 0.005%.

PURPOSE: To determine if a 1-day, 1-eye trial of latanoprost 0.005% was predictive of the 1-month intraocular pressure response in patients with uncontrolled open-angle glaucoma on maximally tolerated medical therapy without latanoprost. METHODS: One eye of 39 consecutive patients was enrolled in prospective trial of latanoprost 0.005%. An investigator masked to treatment eye and intraocular pressure result measured intraocular pressure at 1 day and 1 month after treatment. The diagnostic precision of the 1-day, 1-eye trial for the 1-month result was determined at a 10%, 20%, and 30% reduction from baseline intraocular pressure. RESULTS: Treatment produced a mean +/- SD (range) decrease in intraocular pressure from 20.9 +/- 4.6 (14 to 35) mm Hg to 16.6 +/- 3.6 (9 to 26) mm Hg at 24 hours (P <.0001, paired t test). This reduction in intraocular pressure was similar at 1 month with mean +/- SD (range) intraocular pressure of 16.1 +/- 3.1 (9 to 22) mm Hg (P <.0001, paired t test). The accuracy of the 1-day, 1-eye trial for the 1-month response at a 10%, 20%, and 30% reduction of intraocular pressure from baseline intraocular pressure was 96% (chi square = 29.5, P <.001), 74% (chi square = 8.4, P =.004), and 80% (chi square = 10.2, P =.001), respectively. CONCLUSION: A 1-day, 1-eye trial of latanoprost 0.005% is predictive of the 1-month intraocular pressure response in patients with uncontrolled open-angle glaucoma.

The topographic relationship between multifocal electroretinographic and behavioral perimetric measures of function in glaucoma.

PURPOSE: To study the spatial relationship between local functional abnormalities found using multifocal electroretinography (MERG) and those measured using standard automated perimetry (SAP) in a group of glaucoma patients with well-defined, localized visual field loss. METHODS: MERG's were measured for 15 patients with longstanding, stable, localized SAP visual field loss and for 27 normal controls using VERIS Science (EDI, San Mateo, CA). Most glaucoma patients had substantial asymmetry of visual field defects across the horizontal midline so that within-eye comparisons of MERG changes could be made in addition to comparisons between glaucoma and healthy, aged-matched controls. RESULTS: For the glaucoma patient group as a whole, conventional measurements of MERG responses, such as peak-to-trough amplitude, peak implicit time, and scalar-product density, did not reveal abnormalities that spatially corresponded to local sensitivity losses determined by SAP visual field thresholds. Some of the patients had MERG abnormalities (e.g., reduced amplitudes) in areas of advanced SAP visual field loss that indicated local retinal dysfunction. On average, glaucoma patients were missing a MERG component that resembled the optic nerve head component as described by Sutter and Bearse. CONCLUSIONS: Different MERG components may be affected at different stages of glaucoma, perhaps reflecting a diversity of pathophysiologic mechanisms. This may complicate spatial and temporal relationships between abnormalities found using the MERG and behavioral perimetry, particularly when conventional measurements of MERG responses are used to characterize a diverse patient group/disease.

Three common assumptions about ocular blood flow and glaucoma.

Although substantial indirect evidence exists to link altered ocular blood flow to glaucoma, it must be remembered that the validity of investigations in this area depends on acceptance of three basic assumptions: 1) ischemia directly causes or increases the susceptibility of the optic nerve to glaucomatous damage; 2) optic nerve vascular anatomy and physiology allows identification of the critical vascular beds in optic nerve disease; and 3) current measurement techniques provide the ability to monitor important vascular beds. The hypotheses underlying these assumptions are examined.

Measurement of ocular blood flow.

Many of these techniques have been adapted to investigate hemodynamic alterations, not only in glaucoma, but in diverse disorders such as diabetic retinopathy, macular degeneration, retinal dystrophies, and nonglaucomatous optic neuropathies. However, each of these techniques has limitations and there is not a single methods that provides comprehensive measurements for all the ocular tissues. Our enhanced understanding of ocular vascular anatomy has helped to direct our hemodynamic investigations of the various vascular beds within the eye. However, many of the techniques have lacked validation (reproducibility and accuracy) prior to clinical implementation. Understanding the limitations and the theoretical assumptions of each of these techniques will allow more prudent application in the clinical arena in the future.

Anterior optic nerve microvascular changes in human glaucomatous optic neuropathy.

The microvascular changes in the anterior optic nerve in human glaucomatous eyes were examined by selective methylmethacrylate microvascular corrosion castings following cannulation of the central retinal artery and posterior ciliary arteries in 11 normal eyes and 9 glaucomatous eyes. The resulting castings were examined with scanning electron microscopy. Microvascular changes were found in the anterior optic nerves of all the glaucomatous eyes with visual function loss. These findings include areas of capillary filling defects within the anterior optic nerve and a decreased numbers of feeding arteriolar vessels to the anterior optic nerve. In the prelaminar and laminar regions, the typical capillary patterns are lost and laminar striations are not present. Juxtapapillary choroidal and retinal avascular areas were also identified in two of the glaucomatous eyes. Selective microvascular corrosion casting is an excellent method to examine the three-dimensional microvasculature of the anterior optic nerve. Microvascular changes in the anterior optic nerve may play a role in the development of glaucomatous optic neuropathy.

The relationship between structural and functional alterations in glaucoma: a review.

This article reviews the relationships between structural changes and visual function losses produced by glaucomatous damage. Structural characteristics of the optic nerve head and retinal nerve fiber layer include both qualitative and semi-quantitative clinical assessment methods as well as quantitative imaging techniques. Visual function properties include standard (white-on-white) automated perimetry and new techniques such as short wavelength automated perimetry and motion displacement threshold perimetry. Previous investigations consistently report a significant relationship between structural and functional deficits in glaucoma, with structural changes usually being reported to occur earlier than functional losses. In cases of focal damage, there appears to be a good topographic relationship between structural and functional losses. Several optic nerve head and retinal nerve fiber layer measures are reported to be good predictors of glaucomatous visual field loss. However, previous investigations of structure-function relationships in glaucoma are limited by the small number of patients evaluated in most studies, the lack of well-defined inclusion/exclusion criteria as well as detailed descriptions of the patient population, and the paucity of prospective longitudinal studies that have been performed.

Frequency doubling perimetry and the detection of eye disease in the community.

PURPOSE: Frequency Doubling Technology (FDT) perimetry is a novel perimetric test that provides rapid screening (45 to 60 seconds) and full-threshold (4 to 5 minutes) testing for detection of vision loss. The purpose of this study was to determine the specificity and sensitivity of FDT perimetry for the detection of ocular disease. METHODS: A total of 130 participants (257 eyes of 42 men and 88 women) recruited from the community completed FDT perimetry, standard achromatic automated perimetry (SAP), anterior segment biomicroscopy, tonometry, and dilated ophthalmoscopy. FDT results were considered abnormal if 1 point was abnormal (depressed below the 5% level on the screening protocol C-20-5). SAP was considered abnormal if the glaucoma hemifield test or pattern standard deviation was outside normal limits (P < .05) or a hemifield cluster of 3 depressed points on the pattern deviation probability plot (P < .05) was present. An abnormal eye examination was defined as the presence of an abnormality in the anterior segment, lens, or posterior segment that was likely to cause a visual field defect or the presence of glaucomatous or other optic neuropathy. RESULTS: The mean age (+/- SD) of participants was 55.5 years (+/- 10.3). Ethnic groups, as reported by participants, included 77 (59%) African Americans, 40 (31%) Caucasians, and 13 (10%) in other groups. On clinical examination, 116 eyes (45%) were normal, 9 eyes (3.5%) had a cataract with best corrected visual acuity worse than 20/30, 16 eyes (6%) had open-angle glaucoma, and 17 eyes (7%) had retinal findings or lesions that were likely to cause a visual field defect. For FDT perimetry, 22 (8.6%) of 257 tests were unreliable, and for SAP, 65 (25.3%) of 257 tests were unreliable. The sensitivity and specificity of FDT perimetry for detecting an abnormal clinical examination were 55% and 90% and for detecting an abnormal examination that included an abnormal SAP, 64% and 86%. CONCLUSIONS: FDP demonstrated reasonable discriminatory power for detecting eye disease.

Effect of brimonidine on optic nerve blood flow in rabbits.

PURPOSE: Brimonidine is a highly selective alpha2-adrenoreceptor agonist that lowers intraocular pressure. The aim of the present study was to analyze in vivo the vasomotor effects and the influence of brimonidine on blood flow within the optic nerve, by means of intraluminal microvascular corrosion casting technique and intravascular injection of colored microspheres. METHODS: New Zealand white rabbits received either brimonidine tartrate 0.2% or placebo (vehicle) topical drops in one eye for 4 weeks. Intraocular pressures were measured at baseline and 4 weeks. The anterior optic nerve microvasculature of four rabbits was examined with corrosion castings for regions of focal vasoconstriction. Optic nerve blood flow was determined in 16 rabbits by means of nonradioactive colored microspheres. RESULTS: The vasoconstriction values of the short posterior ciliary arterial branches in the brimonidine eyes were 16.7%+/-3.7%. In the fellow untreated eyes, the mean vasoconstriction was 16.6%+/-2.4%. In the placebo-treated eyes, the average constriction was 15.9%+/-3.2%; the fellow eyes showed a mean constriction value of 16.1%+/-5.3%. There was no statistical difference between any of the groups (P = .2). The optic nerve blood flow in the brimonidine-treated rabbits was 0.18+/-0.06 ml/mg/min and 0.17+/-0.04 ml/mg/min in the treated and the fellow eyes, respectively. The difference between the optic nerve blood flow in the brimonidine-treated eyes and the optic nerve blood flow in all of the untreated eyes (0.19+/-0.06 ml/mg/min) also was not statistically different (P = .82). CONCLUSIONS: Long-term application of brimonidine 0.2% does not affect the blood flow or vasomotor activity of the anterior optic nerve.

Glaucoma surgery: are there new perspectives in perioperative pharmacology?

The literature directed at perioperative pharmacologic advances in relation to glaucoma filtration surgery is reviewed. The successful use of subconjunctival anesthesia demonstrates a new alternative in preoperative glaucoma surgical anesthesia. The intraoperative use of the antimetabolites mitomycin C and 5-fluorouracil in both traditional filtration and glaucoma drainage implantation surgery has been expanded. The use of the antifibrinolytic agents urokinase and recombinant tissue plasminogen activator adds a new and controversial dimension to postoperative pharmacologic therapy.

The influence of ocular pulsatility on scanning laser Doppler flowmetry.

PURPOSE: To determine the effect of the cardiac cycle on scanning laser Doppler flowmeter measurements of retinal capillary blood flow in rhesus monkeys and humans. METHODS: Multiple scanning laser Doppler flowmetry images of rhesus monkey and human retinal capillary blood flow over a range of heart rates were obtained. Average flow values were determined for the 64 scan lines that compose the two-dimensional flow map. Cutaneous blood flow was measured simultaneously with a laser Doppler flowmeter. The temporal relationships between retinal capillary blood flow, peripheral arterial pulse, and cutaneous blood flow were determined. In addition, human retinal capillary blood flow in a 10 x 10-pixel area during different phases of the cardiac cycle was compared. RESULTS: Regular oscillations in human and rhesus monkey retinal capillary blood flow are evident as alternating bright and dark horizontal bands in scanning laser Doppler flowmetry images. These fluctuations are temporally correlated with cutaneous blood flow. Linear regression of actual vs predicted heart rate based on peaks in retinal capillary flow yielded r = 0.999 in a rhesus monkey and 0.938 in a human. Retinal capillary blood flow in a 10 x 10-pixel area fluctuated as much as 50% depending on the phase of the cardiac cycle. CONCLUSIONS: The alternating bright and dark banding pattern observed in scanning laser Doppler flowmetry scans of retinal capillary blood flow is related to the cardiac pulse. The errors introduced by pulse-related fluctuations in retinal capillary blood flow are significant and must be minimized or corrected for accurate and reproducible measurements of ocular hemodynamics.

Frequency doubling technology perimetry using a 24--2 stimulus presentation pattern.

PURPOSE: To assess whether smaller targets and a 24-2 stimulus presentation pattern would improve the ability of frequency doubling technology (FDT) perimetry to detect and characterize early glaucomatous visual field loss. METHODS: One hundred normal subjects between the ages of 20 and 85 participated in this study. In addition, 53 patients who either had early glaucomatous visual field loss (n = 23) or were high-risk glaucoma suspects with normal conventional visual fields (n = 30) were evaluated with the commercial version of FDT perimetry (full threshold test) with 17 stimuli (four 10 degrees diameter square targets per quadrant and a central 5 degrees circular target) and a custom version of FDT perimetry using 54 stimuli (4 degrees targets with 6 degrees grid spacing) arranged in a 24-2 stimulus presentation pattern. RESULTS: The custom FDT test using a 24-2 stimulus presentation pattern had a similar dynamic range, and demonstrated normal aging characteristics and test-retest reliability that were similar to the commercial version of FDT perimetry using 17 larger stimuli. Both FDT tests showed an age-related sensitivity reduction of approximately 0.6 dB per decade, and exhibited an average test-retest reliability of 1 to 1.5 dB. The custom 24-2 FDT perimetry test had a greater variation of sensitivity with eccentricity than the commercial version of FDT perimetry that was probably related to the difference in stimulus size. The custom 24-2 FDT perimetry test had a greater percentage of abnormal test locations than the commercial FDT test for both early glaucomas and high-risk glaucoma suspects. CONCLUSIONS: FDT perimetry can be performed with smaller targets using a presentation pattern that is similar to conventional automated perimetry. In comparison to the commercially available 17 target display, the 24-2 stimulus pattern appears to have modestly higher sensitivity for detection of early glaucomatous loss and provides better characterization of the pattern of visual field loss, but the test takes approximately twice as long.

Latanoprost in glaucoma associated with Sturge-Weber syndrome: benefits and side-effects.

PURPOSE: This study was conducted to evaluate the ocular hypotensive efficacy, safety, and side effects of latanoprost 0.005% administered as adjunctive therapy in patients with Sturge-Weber syndrome (SWS) and glaucoma. METHODS: Commercially available latanoprost 0.005% was added as a single drop once daily to other antiglaucoma medications. Intraocular pressure (IOP) was measured at 1, 3, and 6 months of treatment. A successful response was defined as a reduction of at least 20% in IOP at the final follow-up evaluation without additional medical or surgical therapy and no adverse events related to latanoprost. RESULTS: 18 eyes of 18 patients with SWS and glaucoma were enrolled from 9 clinical centers. Mean baseline IOP was 28.4 +/- 7.1 mmHg (range, 17-42 mmHg). Using Kaplan-Meier analysis, a successful response to latanoprost was observed in 3 of 18 (16.7%) patients at the 6-month interval. Seven (38.9%) patients required surgery; three (16.7%) patients required additional medical therapy, seven (38.9%) patients had no change in therapy. One (5.6%) patient discontinued latanoprost treatment because of intolerable conjunctival hyperemia. Two successfully treated patients had significantly greater episcleral vessel engorgement after initiation of latanoprost therapy. CONCLUSION: Patients with SWS and glaucoma respond poorly to adjunctive latanoprost therapy and often require additional medical or surgical intervention. Increased episcleral vascular engorgement might result in greater operative risks should filtration surgery become necessary in these patients.