P. M. Brennen

Identification and Assessment of Schlemm's Canal by Spectral-Domain Optical Coherence Tomography

PURPOSE Measurements of human Schlemms canal (SC) have been limited to histologic sections. The purpose of this study was to demonstrate noninvasive measurements of aqueous outflow (AO) structures in the human eye, examining regional variation in cross-sectional SC areas (on/off collector channel [CC] ostia [SC/CC] and nasal/temporal) in the eyes of living humans. METHODS SC was imaged by spectral-domain optical coherence tomography with a 200-nm bandwidth light source. Both eyes of 21 healthy subjects and one glaucomatous eye of three subjects were imaged nasally and temporally. Contrast and magnification were adjusted to maximize visualization. Cross-sectional SC on and off SC/CC was traced three times by two independent masked observers using ImageJ (ImageJ 1.40g, http://rsb.info.nih.gov/ij/ Wayne Rasband, developer, National Institutes of Health, Bethesda, MD). The mean SC area was recorded. A linear mixed-effects model was used to analyze eye, nasal/temporal laterality, and SC area on or off SC/CC. RESULTS SC area was significantly larger on SC/CCs than off (12,890 vs. 7,391 micorm(2), P < 0.0001) and was significantly larger on the nasal side than on the temporal (10,983 vs. 8,308 micorm(2), P = 0.009). SC areas were significantly smaller in glaucoma patients than in normal subjects, whether pooled (P = 0.0073) or grouped by on (P = 0.0215) or off (P = 0.0114) SC/CC. CONCLUSIONS Aqueous outflow structures, including SC and CCs, can be noninvasively assessed in the human eye. These measurements will be useful in physiological studies of AO and will be clinically useful in the determination of the impact of glaucoma therapies on IOP as well as presurgical planning.

Prophylactic Treatment of Age-Related Macular Degeneration Report Number 2: 810-Nanometer Laser to Eyes With Drusen: Bilaterally Eligible Patients

BACKGROUND AND OBJECTIVE To determine the prophylactic and therapeutic value of a single subthreshold 810-nanometer laser treatment in patients with high risk drusen as a manifestation of dry age-related macular degeneration in both eyes. PATIENTS AND METHODS The Prophylactic Treatment of Age-related Macular Degeneration study enrolled 1,278 eyes of 639 participants who were 50 years or older with at least 5 drusen 63 microm or more in diameter in each eye. Treatment consisted of the placement of an annular grid of 48 extrafoveal, subthreshold 810-nm diode laser applications centered at but sparing the foveola in one eye of each participant, with the fellow eye serving as a control. Development of choroidal neovascularization and change in best-corrected visual acuity were compared between treated and untreated eyes. RESULTS Subthreshold laser treatment did not decrease the incidence of choroidal neovascularization in treated versus untreated eyes. A modest visual acuity benefit in treated eyes was found at 24 months (1.5 letter difference; P = .04) and in the treated eyes of participants with a baseline visual acuity between 20/32 and 20/63 (4.0 letter difference; P = .0034). However, this treatment effect was not sustained at 3 years. CONCLUSION A single subthreshold 810-nanometer laser treatment to eyes of participants with bilateral high risk drusen is not an effective prophylactic strategy against choroidal neovascularization.

Is drusen area really so important? An assessment of risk of conversion to neovascular AMD based on computerized measurements of drusen.

PURPOSE To assess the relative risk of an eyes conversion to wet age-related macular degeneration (AMD) based primarily on drusen measurements obtained from analysis of digitized images. METHODS Four hundred forty-four subjects (820 eyes) enrolled in the Age-Related Eye Disease Study (AREDS I) and 78 subjects (129 eyes) from the Prophylactic Treatment of AMD trial (PTAMD) were studied retrospectively. Drusen size, distribution, drusen area, and hyperpigmentation in two central macular regions on baseline fundus images were determined using an image analysis algorithm. The relative risk for choroidal neovascularization (CNV) based on drusen area, presence of one or five large drusen, hyperpigmentation, and fellow eye status was calculated. RESULTS Odds ratios (ORs) for measured drusen area within the 1000- and 3000-μm regions were 1.644* (1.251-2.162) and 1.278 (0.927-1.762) for AREDS eyes and 0.832 (0.345-2.005) and 1.094 (0.524-2.283) for PTAMD eyes (*P < 0.05). In the 1000-μm region, respective ORs for the presence of a large druse, hyperpigmentation, and fellow eye affected were 2.60, 1.71, and 6.44* for AREDS eyes and 8.24, 1.37, and 17.56* for PTAMD eyes; for the 3000-μm region, ORs were 3.45*, 3.40*, and 4.59* for AREDS and nonsignificant, 6.58, and 11.62* for PTAMD eyes, respectively. CONCLUSIONS Total drusen area, presence of large drusen, and the presence of hyperpigmentation were not consistent risk factors for an eyes development of CNV. Risk depended on study cohort as well as location. Having an affected fellow eye was the strongest and most consistent risk factor across all models. A larger drusen area does not necessarily increase an eyes risk of conversion to CNV.

Risk Factors for Conversion to Neovascular Age-related Macular Degeneration Based on Longitudinal Morphologic and Visual Acuity Data

PURPOSE To use longitudinal quantitative morphologic and visual acuity (VA) data to investigate the risk of choroidal neovascularization (CNV) event occurrence in eyes with dry age-related macular degeneration (AMD). DESIGN Prospective observational study. PARTICIPANTS A total of 513 participants (844 eyes) followed longitudinally in one center enrolled in the Age-Related Eye Disease Study (AREDS) or the Prophylactic Treatment of AMD Study (PTAMD). METHODS We assessed images of previously obtained fundus photographs for the presence of macular pigmentation, drusen area, and drusen distribution (number and size), and fellow eye CNV status at baseline. Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity at each visit and the age of each subject were obtained. We used a longitudinal logistic mixed-effects model with random intercepts fitted to event occurrences to assess risk on a per eye basis. MAIN OUTCOME MEASURES Odds ratios for CNV event. RESULTS Thirty-one subjects (6.0%) had events. Only VA changes over time and follow-up interval showed statistically significant effects. Several statistical models that included VA at the previous visit were used. In 2 models, 3 categories of VA were used: ≤ 75 letters, >75 and ≤ 85 letters, and >85 letters. Two categories were used for follow-up: ≤ 3 years versus >3 years or ≤ 1 year versus >1 year. In the first model with categorization at 3 years, a decrease in acuity from the >85 letter category to ≤ 75 letters increased the odds of CNV by 16.9 times (P = 0.022). In the model with categorization at 1 year, a decrease in acuity from the >85-letter category to ≤ 75 letters increased the odds of CNV by 21.4 times (P = 0.0175). Differences between the follow-up intervals were significant (P = 0.043) and indicated a more than 7-fold increase in the odds. Changes in morphologic features of the macula did not show significant effects. CONCLUSIONS A decrease in VA to ≤ 75 ETDRS letters in an eye with an initial ETDRS baseline acuity of >85 letters increases the likelihood of CNV by approximately 20-fold. This likelihood also increases with aging.

Comparison of StratusOCT and Cirrus HD-OCT imaging in macular diseases.

BACKGROUND AND OBJECTIVE The Cirrus HD-OCT (Carl Zeiss Meditec, Dublin, CA) device is a spectral-domain optical coherence tomography system that allows faster data acquisition than the previous generation StratusOCT (Carl Zeiss Meditec, Dublin, CA), which is a time-domain device. The authors compared images from both units to determine the clinical usefulness of spectral-domain optical coherence tomography technology in patients with macular diseases. PATIENTS AND METHODS Six consecutive patients were imaged with both the Cirrus HD-OCT and the StratusOCT devices and the images were compared. RESULTS Cirrus HD-OCT images were typically more useful than StratusOCT images for assessing fine architectural details in macular pathology. The Cirrus HD-OCT software also facilitated a better understanding of three-dimensional data volumes. CONCLUSIONS Commercially available spectral-domain optical coherence tomography is a clinically useful tool for visualizing and understanding macular diseases and offers benefits not inherent in previous generation machines.

Analysis of the relationship between drusen size and drusen area in eyes with age-related macular degeneration.

BACKGROUND AND OBJECTIVE To examine the relationship between drusen counts and drusen area in eyes with age-related macular degeneration, and to correlate drusen areas between fellow eyes. PATIENTS AND METHODS Digital images from 378 patients (756 eyes) were analyzed using a validated drusen detection algorithm. Total drusen area and the number of drusen of various sizes (small: < 62 microns, intermediate: 63-124 microns, large: 125-249 microns, etc) were recorded for the central 1,000- and 3,000-micron diameter macular regions. Correlations were assessed using structural equation models. RESULTS For the 1,000-micron region, the number of intermediate drusen was more highly correlated to total drusen area than the number of large drusen (R = 0.91 vs 0.82); this difference was statistically significant. The correlation coefficients for drusen area between fellow eyes was 0.73. CONCLUSION The number of large drusen does not correlate better with total drusen area than drusen of other sizes. The number of large drusen is not necessarily a good surrogate for total drusen area.

Author Response: Is Drusen Area Really So Important?

We appreciate Dr Ying’s questions and comments regarding our paper and acknowledge his criticism. Our results indicated that an increase in drusen area does not necessarily impart an additional risk for choroidal neovascularization (CNV). We pointed out that the risk of an event in our study does increase with increasing drusen area but it did not do so without limits, as we discussed in our concluding paragraph. We are well aware of the publications from Age-Related Eye Disease Study (AREDS) as the UPMC Eye Center was one of the 11 original centers in this pivotal trial and Dr Friberg was the principal investigator at our site. In the Table 2 provided by Dr Ying in his letter query, the drusen are characterized and the area categories increase from 0 to greater than 1 disc area of drusen in the central 3000 micrometers of the macula. Essentially, his categorical table covers subjects with no or very few small drusen, which are typically category 1 AREDS subjects, to category 3 subjects with many drusen. The event rate for choroidal neovascularization in his table entries increases from 0.1% to 8.6%, to 12.2%, and finally to 12.9%. We graphed his extracted data here in Figure A. The slope of the plotted curve is steep initially and then flattens as the equivalent drusen area reaches that equal to approximately 70 large drusen. In Figure 1 in our IOVS article, we estimated the probability of neovascularization versus drusen area in the 3000-micrometer region of regard in fellow eye not affected AREDS eyes and show it with a dotted line. That figure is reproduced here (Fig. B). These figures are similar. Flattening of the slope to zero in our published curve occurs at approximately 0.80 mm, which is equivalent to an area of approximately 60 large drusen. Before this drusen area is reached, the slope is steeper, indicating increased risk of CNV with increasing drusen area. Essentially, the relationship between drusen area and risk in both our figure and that derived from Dr Ying’s table depends upon the region of the curve to which one is referring. We also pointed out that using categories to denote drusen area rather than using continuous data yields statistical results that can be skewed or biased and are generally not as robust. We did not assert that drusen area is never important. However, we challenge the implicit historical assumption that an increasing drusen area in a subject’s eye exposes it to an ever-increasing risk of conversion to CNV. This is important clinically, as retinal specialists often see patients with drusen spread across the entire posterior pole. As more drusen develop, our study results refute the notion that this increase necessarily makes this eye more susceptible to CNV. Conversely, a reduction in drusen area in eyes with an already large area may not reduce an eye’s risk of conversion. This would be the case if an eye’s drusen area falls within the region of the curve where the slope is zero. Furthermore, our results also indicate that in eyes whose fellow eye is affected (dashed line in our curve), the slope may even turn negative, so a greater drusen area might possibly reduce risk. Our Prophylactic Treatment of Age-Related Macular Degeneration (PTAMD) subjects had more drusen to start with than AREDS subjects. The criticism regarding small numbers is valid as we so stated. However, we also pointed out that we used multiple models, and we found rather consistent results across Figure. (A) Plot of CNV versus the number of large drusen from the table provided by Dr. Ying. His data are extracted from the AREDS. Note that the slope is initially steep and then levels off, indicating that the effect of increasing drusen area on the CNV event rate is diminishing. (B) Plot of the probability of a CNV event versus total drusen area based on our drusen area measurements for AREDS subjects at our center. The region of regard was the central 3000 micrometers of the macula. The dotted line plots eyes of subjects where the fellow eye had not been affected by a CNV event at baseline. The slope is initially steep and then flattens out when a drusen area of about 0.80 mm is reached.