George A. Cioffi

Structure and function evaluation (SAFE): II. comparison of optic disk and visual field characteristics

PURPOSE To evaluate the relationship between glaucomatous structural damage to the optic nerve and development of visual field loss with standard automated perimetry (SAP) and short wavelength automated perimetry (SWAP). DESIGN Cohort study. METHODS Patients with elevated intraocular pressure and normal SAP visual fields were enrolled in this prospective study. Stereo optic disk photographs, SAP, and SWAP visual fields were obtained annually over a period of 4 or more years. Trained readers evaluated baseline and follow-up optic disk photographs for evidence of glaucomatous damage. Standard automated perimetry and SWAP examinations were evaluated according to previously validated criteria for development of confirmed visual field changes. RESULTS Two-hundred ninety-five subjects (479 eyes) were enrolled. Following masked assessment of stereo photographs by an optic disk reading center, 272 of the 479 eyes were judged to have glaucomatous optic neuropathy at the time of study entry. Depending on the criteria employed, approximately 10% to 17.5% of all eyes developed confirmed visual field loss for SAP (conversions). Of the conversions, 75% to 80% had baseline glaucomatous optic disk damage, whereas normal and glaucomatous optic disks were equally divided (50%) among the nonconversion eyes. This difference was statistically significant (P <.003). Depending on the criteria employed, 4% to 12% of the eyes had confirmed SWAP deficits at baseline, and 4% to 8% developed confirmed SWAP defects at a follow-up examination. There was a greater percentage of eyes with a glaucomatous optic neuropathy in the group with SWAP deficits (75%-100%) than for those eyes in which SWAP remained normal (45%-60%). Some of these differences were statistically significant (P <.05). CONCLUSIONS A strong relationship exists between glaucomatous optic disk damage at study entry and the subsequent development of a confirmed glaucomatous SAP visual field defect. A higher percentage of glaucomatous optic disks were also found in patients with SWAP deficits at baseline and in those who later developed SWAP deficits. These findings support the premise that a glaucomatous optic disk is predictive of the subsequent development of glaucomatous visual field loss.

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

An in vivo model of chronic optic nerve ischemia: the dose- dependent effects of endothelin-1 on the optic nerve microvasculature

The purpose of this study was to evaluate the effects induced by chronic microapplication of endothelin-1 on the anterior optic nerve microvasculature and to determine the dose-response characteristics of endothelin-1 on this vascular bed. Daily dosages between 4.69 x 10(-4) and 9.0 x 10(-1) micrograms/day of endothelin-1 were delivered continually over 3 days, and at a constant flow rate, to the perineural region of the anterior optic nerve of 15 albino rabbits via osmotically-driven minipumps. The vasomotor effect of local endothelin-1 on the microvasculature of the optic nerve was examined using intraluminal microvascular corrosion casting technique. The vasomotor effects were quantified by measuring the relative amount of vasoconstriction of the arterioles supplying the anterior optic nerve (primary and secondary branches of the short posterior ciliary arteries). The average constriction was calculated for the endothelin-treated eyes and the untreated, contralateral eyes. The mean vasoconstriction in the endothelin treated eyes ranged from 14.7% to 30.0% and was highly correlated with the logarithmic value of the daily dose of endothelin-1 (R2 = 0.59, p = 0.00083). The interocular difference (between treated and untreated eyes) of the optic nerve vasoconstriction ranged from 0-19% (mean +/- SD: 7.23 +/- 5.7%). This interocular difference also correlated highly with the log of the daily endothelin-1 dosage (R2 = 0.80; p < 0.0001). By additionally accounting for the weight and sex in a multiple linear regression function, the correlation was markedly improved (R2 = 0.92; p < 0.0001). In conclusion, the microvasculature supplying the anterior optic nerve of the rabbit demonstrates a dose-dependent vasoconstriction with chronic local application of endothelin-1. This in vivo, experimental model offers a titratable method with which the effects of chronic vasoconstriction and vascular insufficiency on the optic nerve can be examined.

Latanoprost Treatment for Glaucoma: Effects of Treating for 1 Year and of Switching From Timolol

PURPOSE To determine the efficacy and safety of latanoprost treatment for 1 year in glaucoma patients, and to evaluate the effects of switching from timolol to latanoprost therapy. METHODS Latanoprost 0.005% was topically applied once daily without masking for 6 months in 223 patients with elevated intraocular pressure after previous treatment with latanoprost once daily or 0.5% timolol twice daily for 6 months in a multicenter, randomized, double-masked, parallel group study. RESULTS Compared with baseline values before treatment, a significant (P < .0001) diurnal reduction in intraocular pressure of 6 to 8 mm Hg was maintained with minimal fluctuation for the duration of treatment. When treatment was switched from timolol to latanoprost, intraocular pressure was reduced by 1.5 +/- 0.3 mm Hg (mean +/- SEM; 8% change in intraocular pressure; 31% of the intraocular pressure reduction produced by timolol; P < .001) compared with the change in intraocular pressure in patients remaining on latanoprost therapy. Of the patients initially enrolled, 95% successfully completed treatment. There was a slight overall increase in conjunctival hyperemia in patients who switched from timolol to latanoprost, but no change in those who continued latanoprost. The timolol-induced reduction of resting heart rate returned to baseline levels after switching to latanoprost. Of the 247 patients treated with latanoprost during the masked and/or open-label studies, 12 (5%) demonstrated a definite (n = 4) or possible (n = 8) increase in iris pigmentation. CONCLUSIONS Latanoprost is a well-tolerated ocular hypotensive agent that appears to be more effective than timolol in reducing intraocular pressure. The increase in iris pigmentation appears to be harmless but requires further investigation.

Psychophysical investigation of ganglion cell loss in early glaucoma.

Purpose:To evaluate ganglion cell loss in early glaucoma using a variety of psychophysical tests and to identify optimal perimetric technique(s) for detection of early glaucomatous visual function loss. Methods:Five perimetric tests, short wavelength automated perimetry (SWAP), temporal modulation perimetry (TMP), frequency doubling technology perimetry (FDT), detection acuity perimetry (DAP), and resolution acuity perimetry (RAP) were compared in their ability to discriminate between normal individuals and patients with early glaucoma or glaucoma suspects. Comparisons were also made by their ability to produce repeatable defects. The tests examined different visual functions that are likely to be mediated by different retinal ganglion cell subpopulations, thereby permitting examination of hypotheses of ganglion cell death in early glaucoma. Results:All visual field tests demonstrated high performance in separating glaucoma patients from normal individuals. SWAP, TMP, FDT, and DAP provided the greatest discrimination between normal individuals and high- and low-risk glaucoma suspects. However, SWAP, TMP, and FDT obtained better consistency across the various analysis approaches (global indices and pointwise) than DAP and RAP. Of all the test types, FDT exhibited the highest proportion of repeatable abnormal test locations, with poor confirmation rates achieved by DAP and RAP. Conclusion:The performance of SWAP, FDT, and TMP suggests that these test types may all be suitable for detection of early loss of visual function in glaucoma. Ganglion cell subpopulations with lower levels of redundancy and/or those with larger cell sizes offer the most parsimonious explanation for earliest ganglion cell losses occurring in glaucoma.

Impact of Systemic Blood Pressure on the Relationship between Intraocular Pressure and Blood Flow in the Optic Nerve Head of Nonhuman Primates

PURPOSE Studies suggest that reduced ocular perfusion pressure in the optic nerve head (ONH) increases the risk of glaucoma. This study tested a hypothesis that the magnitude of blood flow change in the ONH induced between two same intraocular pressure (IOP) alterations depends on the level of mean systemic blood pressure (BP). METHODS In eight anesthetized rhesus monkeys, systemic BP was maintained at either a high, medium, or low level (n = 6 each, ranging from 51-113 mm Hg); IOP was rapidly altered from 10 to 30 mm Hg and then to 10 mm Hg manometrically. Blood flow in the ONH (BF(ONH)) was repeatedly measured with a laser speckle flow graph for 10 minutes at each IOP level period. The BF(ONH) and relative changes to the baselines at each measured time point were calculated and compared longitudinally among the three BP groups. RESULTS There was no statistically significant difference in mean baseline BF(ONH) across the BP groups. In the high-BP group, BF(ONH) had no significant change during the IOP alterations. However, the same IOP alterations caused a significant BF(ONH) change in the two lower BP groups. The duration of the BF(ONH) changes from baseline to a peak and to a steady state was significantly delayed in the two lower, but not the higher, BP groups. CONCLUSIONS Systemic BP plays an important role in maintaining the normal autoregulation of the ONH, and it became deficient in the lower BP groups. In patients with glaucoma, a normal, sustained BP may be important to prevent worsening glaucoma.

Intravitreal Colchicine Causes Decreased RNFL Birefringence without Altering RNFL Thickness

PURPOSE To test the hypothesis that longitudinal differences between retinal nerve fiber layer (RNFL) birefringence, measured by scanning laser polarimetry (SLP), and RNFL thickness, measured by optical coherence tomography (OCT), are informative about the state of axonal degeneration. METHODS Colchicine was injected into the vitreous cavity of one eye in each of six vervet monkeys (Chlorocebus sabaeus; estimated vitreal concentration: 1 mM, n = 3; 2 mM, n = 1; 10 mM, n = 2); an equivalent volume (approximately 0.1 mL) of sterile saline was injected into fellow control eyes. RNFL birefringence was measured by SLP before injection and every 10 minutes after injection for 2 hours. RNFL thickness was measured by OCT before injection and 2 hours later. After isolating each retina, biopsy specimens were obtained from the inferotemporal arcade region, approximately 2 mm from the center of the optic disc, using a 2-mm trephine and were processed for transmission electron microscopy (TEM). Retinas were then flat-mounted and stained with an antibody against polymerized beta-III-tubulin. RESULTS RNFL birefringence measured by SLP decreased over time in all six colchicine-injected eyes, appearing to reach a plateau of -20% +/- 7% (P < 0.0001) approximately 100 minutes after injection. There were no significant differences between quadrants (P = 0.44) and no apparent dose effect (P = 0.87). The change in vehicle-injected control eyes was -3% +/- 3% (P = 0.06; NS). The change in RNFL thickness measured by OCT was +1% +/- 4% (P = 0.81; NS) in colchicine-injected eyes and +6% +/- 6% (P = 0.13; NS) in control eyes. There was no evidence of macular edema by fundus biomicroscopy, stereo fundus photography, or OCT. TEM revealed disorganization of microtubules, swelling of mitochondria, and blurred axonal membrane borders in colchicine-injected eyes. Flat-mounted retinas stained with an antibody against polymerized beta-III-tubulin showed only a mild reduction of peripapillary stain intensity in the colchicine-injected eyes compared with controls. CONCLUSIONS Intravitreal injection of colchicine caused microtubule disruption within the axons of the RNFL in nonhuman primate eyes. This was manifest as a reduction of RNFL birefringence, without alteration of RNFL thickness, suggesting that such discrepancies can be informative about the status of axonal degeneration.

Predicting the Onset of Glaucoma: The Confocal Scanning Laser Ophthalmoscopy Ancillary Study to the Ocular Hypertension Treatment Study

OBJECTIVE To evaluate the predictive ability of baseline confocal scanning laser ophthalmoscopy (CSLO) Glaucoma Probability Score (GPS) for the development of primary open-angle glaucoma (POAG) and to compare it with the Moorfields regression analysis (MRA) classification, other topographic optic disc parameters, and stereophotograph-based cup-to-disc ratio. DESIGN Longitudinal, randomized clinical trial. PARTICIPANTS We included 857 eyes of 438 participants in the CSLO Ancillary Study to the Ocular Hypertension Treatment Study (OHTS) with good quality baseline CSLO images. METHODS The ability of baseline GPS, MRA, and optic disc parameters to predict the development of POAG was evaluated in univariate and multivariable proportional hazard ratio analyses. Likelihood ratios and positive and negative predictive values were compared. MAIN OUTCOME MEASURES The POAG end point as determined by repeatable changes in the visual field or optic disc. RESULTS Sixty-four eyes of 50 CSLO Ancillary Study participants developed POAG. Median time to reach a POAG end point was 72.3 months. The 93 eyes of 388 participants not reaching endpoint were followed for a median of 124.9 months. Baseline GPS identified many more eyes as outside normal limits than the MRA. In multivariable analyses, all regional and global baseline GPS indices were significantly associated with the development of POAG; hazard ratios (95% confidence interval) ranged from 2.92 to 3.74 for an outside normal limits result. The MRA indices were also significantly associated with the development of POAG in multivariable analyses. In addition, the predictive ability of baseline GPS, MRA and stereometric parameters were similar to the predictive ability of models using photograph-based horizontal cup-to-disc ratio. CONCLUSIONS These results suggest that baseline GPS, MRA, and stereoparameters alone or when combined with baseline clinical and demographic factors can be used to predict the development of POAG end points in OHTS participants and are as effective as stereophotographs for estimating the risk of developing POAG in ocular hypertensive subjects.

ISCHEMIC MODEL OF OPTIC NERVE INJURY

PURPOSE It is proposed that the anterior optic nerve is specifically susceptible to microcirculatory compromise contributing to the development of glaucomatous optic neuropathy. METHODS Ischemic optic neuropathy was induced by delivering endothelin-1 (ET-1) to the retrobulbar space in one eye of 12 primates for 6 to 12 months. Regional ganglion cell axonal sizes and densities were compared with the normal, contralateral eyes. RESULTS Without changes of intraocular pressure, mean axonal density was significantly decreased in ET-1 eyes compared to controls (P = .03, paired t test). Two-way matched-pair analysis of variance showed a significant effect of ET-1 on overall axonal density (P < .0001). Among the animals with significant axonal loss, the mean axonal loss was 11.6%, and loss varied from 4% to 21%. Axonal loss was commonly localized within specific quadrants. Five animals were examined for preferential axonal size loss. As a group, there appears to be a tendency toward preferential large axonal loss, but the mean axonal loss of large and small axons did not meet significant differences (P = .1) However, examination of individual animals with significant loss shows significantly greater loss of large axons as compared to the small axons in three of the animals. CONCLUSIONS Chronic optic nerve ischemia causes demonstrable and localized damage of the optic nerve, without intraocular pressure elevation. There is preferential loss of large retinal ganglion cell axons in animals with significant axonal loss. Ischemia-induced focal axonal loss is similar to human glaucoma and may represent a differential regional vulnerability.

Estimating normal optic nerve axon numbers in non-human primate eyes.

PURPOSE The goal of the present study is to develop a semi-automated method to estimate accurately, with minimum variance, the total number of axons by counting a subset of the axons within a primate optic nerve. METHODS Using an imaging analysis system, axons in 50% of the area of cross-sections of the retrobulbar optic nerve from five adult Rhesus monkeys were counted and extrapolated as an estimate of total axon number of the optic nerves. Both neural and non-neural areas were sampled. With the coordinates of the counts topographically registered, axon numbers within areas ranging from 1 to 50% were resampled. A Monte Carlo and theoretical estimate of the standard deviation of the total axon count for each sampled area was computed. RESULTS The mean cross-sectional area of the five optic nerves counted was 7.26 +/- 0.6 mm2, and the mean total axon count of the optic nerve area was 1,304,8168 +/- 89,112. When sampling less than 8% of the optic nerve, the standard deviation within the individual of the total estimated axon number increased sharply. CONCLUSION With this technique, the variance within each individual increased only slightly when the counting area was reduced from 50 to 8%, but increased sharply when the counted area became less than 8%. While counting less than 8% of the optic nerve area gives a good estimation of total axon count, the effect of a substantial increase in the standard deviation on the statistical power needed to differentiate group differences will depend on the study design.