Douglas R. Anderson

The effectiveness of intraocular pressure reduction in the treatment of normal-tension glaucoma

PURPOSE In a companion paper, we determined that intraocular pressure is part of the pathogenesis of normal-tension glaucoma by analyzing the effect of a 30% intraocular pressure reduction on the subsequent course of the disease. We report an intent-to-treat analysis of the study data to determine the effectiveness of pressure reduction. METHODS One eligible eye of 145 subjects with normal-tension glaucoma was randomized either to no treatment (control) or to a 30% intraocular pressure reduction from baseline. To be eligible for randomization, the normal-tension glaucoma eyes had to show documented progression of field defects or a new disk hemorrhage or had to have field defects that threatened fixation when first presented for the study. Survival analysis compared time to progression of all randomly assigned patients during the course of follow-up from the initial baseline at randomization. In a separate analysis, data of patients developing cataracts were censored at the time that cataract produced 2 lines of Snellen visual acuity loss. RESULTS Visual field progression occurred at indistinguishable rates in the pressure-lowered (22/66) and the untreated control (31/79) arms of the study (P = .21). In an analysis with data censored when cataract affected visual acuity, visual field progression was significantly more common in the untreated group (21/79) compared with the treated group (8/66). An overall survival analysis showed a survival of 80% in the treated arm and of 60% in the control arm at 3 years, and 80% in the treated arm and 40% in the controls at 5 years. The Kaplan-Meier curves were significantly different (P = .0018). The analyses gave different results because of a higher incidence of cataract in the group that underwent filtration surgery. CONCLUSIONS The favorable effect of intraocular pressure reduction on progression of visual change in normal-tension glaucoma was only found when the impact of cataracts on visual field progression, produced largely by surgery, was removed. Lowering intraocular pressure without producing cataracts is beneficial. Because not all untreated patients progressed, the natural history of normal-tension glaucoma must be considered before embarking on intraocular pressure reduction with therapy apt to exacerbate cataract formation unless normal-tension glaucoma threatens serious visual loss.

Correlation of Asymmetric Damage With Asymmetric Intraocular Pressure in Normal-Tension Glaucoma (Low-Tension Glaucoma)

If intraocular pressure plays a role in producing visual field loss in normal-tension glaucoma, there may be a possible benefit from therapeutic efforts to lower the pressure. To see whether pressure plays a role in the production of damage, we studied 14 cases of normal-tension glaucoma with asymmetric intraocular pressure (1- to 6-mm Hg interocular difference in pressure). In 12 of these 14 cases, we found that glaucomatous cupping and field loss (damage) was greater in the eye with higher pressure. This statistically significant correspondence of the higher pressure with the greater visual damage suggests that the level of pressure is a factor in producing optic nerve damage. Other factors also must contribute to account for the few instances in which damage asymmetry did not reflect interocular pressure-difference and for the occurrence of injury at such low levels of pressure in the first place. Although benefit may be expected from therapeutic lowering of pressure in this condition, the degree of benefit, as well as the side effects from treatment required for successful lowering of pressure, remains to be documented by a future clinical trial.

Ability of Cirrus™ HD-OCT Optic Nerve Head Parameters to Discriminate Normal from Glaucomatous Eyes

PURPOSE To determine the ability of optic nerve head (ONH) parameters measured with spectral domain Cirrus HD-OCT (Carl Zeiss Meditec, Inc., Dublin, CA) to discriminate between normal and glaucomatous eyes and to compare them with the discriminating ability of peripapillary retinal nerve fiber layer (RNFL) thickness measurements performed with Cirrus HD-OCT. DESIGN Evaluation of diagnostic test or technology. PARTICIPANTS Seventy-three subjects with glaucoma and 146 age-matched normal subjects. METHODS Peripapillary ONH parameters and RNFL thickness were measured in 1 randomly selected eye of each participant within a 200 × 200 pixel A-scan acquired with Cirrus HD-OCT centered on the ONH. MAIN OUTCOME MEASURES Optic nerve head topographic parameters, peripapillary RNFL thickness, and area under receiver operating characteristic curves (AUCs). RESULTS To distinguish normal from glaucomatous eyes, regardless of disease stage, the 6 best parameters (expressed as AUC) were vertical rim thickness (VRT, 0.963), rim area (0.962), RNFL thickness at clock-hour 7 (0.957), RNFL thickness of the inferior quadrant (0.953), vertical cup-to-disc ratio (VCDR, 0.951), and average RNFL thickness (0.950). The AUC for distinguishing between normal eyes and eyes with mild glaucoma was greatest for RNFL thickness of clock-hour 7 (0.918), VRT (0.914), rim area (0.912), RNFL thickness of inferior quadrant (0.895), average RNFL thickness (0.893), and VCDR (0.890). There were no statistically significant differences between AUCs for the best ONH parameters and RNFL thickness measurements (P > 0.05). CONCLUSIONS Cirrus HD-OCT ONH parameters are able to discriminate between normal eyes and eyes with glaucoma or even mild glaucoma. There is no difference in the ability of ONH parameters and RNFL thickness measurement, as measured with Cirrus OCT, to distinguish between normal and glaucomatous eyes.

Linking Structure and Function in Glaucoma

The glaucomas are a group of relatively common optic neuropathies, in which the pathological loss of retinal ganglion cells causes a progressive loss of sight and associated alterations in the retinal nerve fiber layer and optic nerve head. The diagnosis and management of glaucoma are often dependent on methods of clinical testing that either, 1) identify and quantify patterns of functional visual abnormality, or 2) quantify structural abnormality in the retinal nerve fiber layer, both of which are caused by loss of retinal ganglion cells. Although it is evident that the abnormalities in structure and function should be correlated, propositions to link losses in structure and function in glaucoma have been formulated only recently. The present report describes an attempt to build a model of these linking propositions using data from investigations of the relationships between losses of visual sensitivity and thinning of retinal nerve fiber layer over progressive stages of glaucoma severity. A foundation for the model was laid through the pointwise relationships between visual sensitivities (behavioral perimetry in monkeys with experimental glaucoma) and histological analyses of retinal ganglion cell densities in corresponding retinal locations. The subsequent blocks of the model were constructed from clinical studies of aging in normal human subjects and of clinical glaucoma in patients to provide a direct comparison of the results from standard clinical perimetry and optical coherence tomography. The final formulation is a nonlinear structure-function model that was evaluated by the accuracy and precision of translating visual sensitivities in a region of the visual field to produce a predicted thickness of the retinal nerve fiber layer in the peripapillary sector that corresponded to the region of reduced visual sensitivity. The model was tested on two independent patient populations, with results that confirmed the predictive relationship between the retinal nerve fiber layer thickness and visual sensitivities from clinical perimetry. Thus, the proposed model for linking structure and function in glaucoma has provided information that is important in understanding the results of standard clinical testing and the neuronal losses caused by glaucoma, which may have clinical application for inter-test comparisons of the stage of disease.

Collaborative normal tension glaucoma study

Purpose of review Before this study was done, there was a difference of opinion concerning whether intraocular pressure (IOP) was involved in producing optic nerve damage when there was glaucomatous damage to the optic nerve and characteristic visual field loss, even though the IOP was in the statistically normal range. This article reviews the findings of a collaborative study aimed at finding the answer to this question. Recent findings The level of pressure influences the course of normal tension glaucoma, as evidenced by a slower rate of incident visual field loss in cases with 30% or more lowering of intraocular pressure. The rate of progression without treatment is highly variable, but often slow enough that half of the patients have no progression in 5 years. A faster rate occurs in women, in patients with migraine headaches, and in the presence of disc hemorrhages. Some patients may experience greater benefit from lowering of IOP than others, but further research is needed to be able to identify those most likely to benefit. Summary As a group, patients with normal tension glaucoma benefit from lowering of IOP. Variable rate of deterioration, as well as lack of progression in a substantial number in 5 years, suggest that treatment should be individualized according to the stage of disease and rate of progression. Traits that help predict risk and rate of progression and response to treatment are beginning to become known and, when fully known, will help guide management decisions.

Factors that predict the benefit of lowering intraocular pressure in normal tension glaucoma

PURPOSE To study whether the benefit of lowering of intraocular pressure (IOP) varies according to certain traits. DESIGN Randomized clinical trial, secondary analysis. METHODS Visual field data were analyzed from 144 subjects (144 eyes) randomized not to receive IOP-lowering treatment or to have the IOP lowered by 30%. Survival analyses were applied to compare times to progression between groups. Changes in mean deviation global index over time were compared with multilevel random effects models. RESULTS By univariate analysis, the most readily demonstrated treatment benefit occurred in patients without baseline disk hemorrhage, of female gender, with family history of glaucoma, without family history of stroke, without personal history of cardiovascular disease, and with mild disk excavation; IOP lowering benefited females with migraine (P <.05) but perhaps without eliminating all migraine-associated risk. CONCLUSIONS It is suggested that different factors may contribute to the glaucomatous optic neuropathy in different cases of normal tension glaucoma, interacting with IOP to different degrees and, thereby, affecting the magnitude of benefit of IOP lowering. Further study is required to establish interactions that would have implications for understanding the disease mechanisms in glaucomatous cupping, for guiding development of new treatment modalities, and for making clinical decisions regarding prognosis and management of individual patients.

Ocular perfusion pressure in glaucoma

This review article discusses the relationship between ocular perfusion pressure and glaucoma, including its definition, factors that influence its calculation and epidemiological studies investigating the influence of ocular perfusion pressure on the prevalence, incidence and progression of glaucoma. We also list the possible mechanisms behind this association, and discuss whether it is secondary to changes in intraocular pressure, blood pressure or both. Finally, we describe the circadian variation of ocular perfusion pressure and the effects of systemic and topical medications on it. We believe that the balance between IOP and BP, influenced by the autoregulatory capacity of the eye, is part of what determines whether an individual will develop optic nerve damage. However, prospective, longitudinal studies are needed to better define the role of ocular perfusion pressure in the development and progression of glaucoma.

Intraocular Pressure Reduction in Normal-tension Glaucoma Patients

BACKGROUND In a collaborative study, patients with untreated normal-tension glaucoma were randomly assigned to a marked intraocular pressure reduction group or to a no therapy group. It was anticipated that medical therapy and laser trabeculoplasty would generally not achieve adequate pressure lowering and that fistulizing surgery would be required. This hypothesis was examined using current observations in the study. METHODS Patients randomized to the therapy group had a pressure reduction of at least 30% from their last prerandomization level. This was achieved within 6 months by means of fistulizing surgery or with pilocarpine and/or laser trabeculoplasty. Beta-blockers and adrenergic agonists were excluded from both eyes. RESULTS Of 30 patients with documented stable 30% pressure reduction, 17 (57%) achieved this with topical medication and/or laser trabeculoplasty: 8 with pilocarpine alone, 2 with laser trabeculoplasty alone, and 7 with laser trabeculoplasty after initial topical medication. The remaining 13 (43%) patients required a single fistulizing procedure. There was no statistically significant difference between the mean follow-up time for the nonfistulized group (533.8 +/- 437.6 days) and for the fistulized group (502.7 +/- 344.7 days). Both treatment groups had similar baseline profiles. CONCLUSION Marked pressure reduction can be achieved and maintained on a long-term basis by means other than fistulizing surgery in a large proportion of patients with untreated normal-tension glaucoma.

Estimating the Rate of Retinal Ganglion Cell Loss in Glaucoma

PURPOSE To present and evaluate a new method of estimating rates of retinal ganglion cell (RGC) loss in glaucoma by combining structural and functional measurements. DESIGN Observational cohort study. METHODS The study included 213 eyes of 213 glaucoma patients followed up for an average of 4.5 ± 0.8 years with standard automated perimetry visual fields and optical coherence tomography. A control group of 33 eyes of 33 glaucoma patients underwent repeated tests over a short period to test the specificity of the method. An additional group of 52 eyes from 52 healthy subjects followed up for an average of 4.0 ± 0.7 years was used to estimate age-related losses of RGCs. Estimates of RGC counts were obtained from standard automated perimetry and optical coherence tomography, and a weighted average was used to obtain a final estimate of the number of RGCs for each eye. The rate of RGC loss was calculated for each eye using linear regression. Progression was defined by a statistically significant slope faster than the age-expected loss of RGCs. RESULTS From the 213 eyes, 47 (22.1%) showed rates of RGC loss that were faster than the age-expected decline. A larger proportion of glaucomatous eyes showed progression based on rates of RGC loss rather than based on isolated parameters from standard automated perimetry (8.5%) or optical coherence tomography (14.6%; P < .01), while maintaining similar specificities in the stable group. CONCLUSIONS The rate of RGC loss estimated from combining structure and function performed better than either isolated structural or functional measures for detecting progressive glaucomatous damage.

The histologic basis of optic disk pallor in experimental optic atrophy

We studied the clinical and microscopic appearances of the optic nerve head in squirrel monkeys with optic nerve degeneration produced by optic nerve transection at the orbital apex. The ophthalmoscopic development of optic disk pallor coincided with the loss of nerve fiber bundles and the rearrangement of the remaining disk astrocytes into dense parallel layers across the nerve head. No astrocytic mitoses were observed and the estimated volume of astrocytes increased only slightly from normal. Among the astrocytes in atrophic disks, many capillaries had patent lumens and ultrastructurally normal endothelial cells. Pallor of the optic disk seems to result from a decrease in the transmission of light into the cytoarchitecture of the atrophic nerve head, not from the absence of capillaries or from extensive astrocytic proliferation.