Objective: To describe the relationship of laser-induced drusen reduction to change in visual function at 1 year among patients enrolled in the Choroidal Neovascularization Prevention Trial (CNVPT). Design: Comparison of groups with and without drusen reduction; follow-up of a randomized controlled trial. Participants: Evaluations of drusen and visual acuity at baseline and at 1 year were performed for 351 eyes of the 432 eyes enrolled in the CNVPT Bilateral Drusen Study and Fellow Eye Study (81%). One hundred eighty-four eyes were assigned to observation, and 167 eyes were assigned to laser treatment. Eyes with conditions that precluded an analysis of drusen reduction, such as those that developed choroidal neovascularization (CNV) within the first year, are excluded from this analysis. Methods: Change in macular drusen between initial visit and after 1 year was assessed by side- by-side grading by evaluators masked to information on visual function. Visual acuity, contrast threshold, and critical print size were measured by certified visual function examiners. Main Outcome Measures: Change in visual acuity is the primary outcome. Change in contrast threshold and change in critical print size are secondary outcome measures. Results: Laser-treated eyes with 50% or more drusen reduction at 1 year had more 1- and 2-line increases in visual acuity and less losses in visual acuity compared with laser-treated eyes with less drusen reduction or with observed eyes (P = 0.001). Similar improvements were noted for contrast threshold but not critical print size at 1 year. Conclusions: Laser-induced drusen reduction is associated with improved visual acuity and contrast sensitivity in eyes at 1 year. Longer term effects of laser-induced drusen reduction on visual function require additional observation. The overall potential value of laser treatment in eyes with high-risk drusen requires consideration of not only short-term effects on vision but also the effects of CNV and atrophy on vision.
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The majority of patients with early AMD and large drusen do not progress to central blindness, yet many describe a general deterioration of the quality of central vision over time. Focal or confluent large drusen are the clinical hallmark of a more diffuse, clinically invisible thickening of the inner collagenous layers of Bruch’s membrane, as well as acellular material surrounding the basement membrane of the retinal pigment epithelium. 24,25 Because large drusen are a known risk factor for the development of late complications of AMD 26 (geographic atrophy and CNV) and subsequent central vision loss, the CNVPT and other studies use drusen reduction as a surrogate ophthalmoscopic endpoint to monitor the effects of laser treatment to eyes with large drusen. In this study, we evaluated drusen within 500 μm of the fovea (central macula) using baseline and 1-year color fundus photographs because these images are more sensitive than fluorescein angiography in detecting drusen reduction in laser treated eyes (Lee MS, Shin DS, Javornik NB, et al. Visual acuity and drusen change over one year in CNVPT eyes assigned to laser treatment. Invest Ophthalmol Vis 39: S243, 1998). Smaller randomized pilot studies have suggested that laser treatment can reduce the incidence of CNV and result in modest gains of visual acuity in eyes with large drusen, but their limited numbers of subjects preclude a specific analysis of the effect of drusen reduction on visual function (Frennesson IC, Nilsson SE: Significant decrease in exudative complications after prophylactic laser treatment of soft drusen maculopathy in a randomized study. Invest Ophthalmol Vis Sci 38:S18, 1997). 12 Studies of the natural history of large drusen reveal that drusen may change, typically over several years, with some drusen evolving from focal to confluent lesions or even drusenoid pigment epithelial elevations and then to a gradual disappearance or fading associated with thinning and depigmentation of the overlying retinal pigment epithelium (RPE). 2,26,27 The CNVPT group and other groups have clearly demonstrated that laser photocoagulation can accelerate the disappearance of directly treated or remote large macular drusen in a significant percentage of patients. In this study, approximately 46% of eyes assigned to laser treatment demonstrated 50% or more drusen reduction at 1 year. Although other studies have not specifically used a 50% threshold for drusen reduction, our results are consistent with others describing an effect attributable to laser treatment (Friberg TR, Olk RJ, Wong KL, et al. A pilot study comparing subthreshold vs. threshold diode laser photocoagulation in the prophylaactic treatment of macular degeneration: one year follow-up. Invest Ophthalmol Vis Sci; 39:S243, 1998). 2–15 We have been intrigued by the observations of some CNVPT patients, particularly those with bilateral drusen, who report or demonstrate improved vision in their laser-treated eye (Fig 2) . Treatment bias is one potential explanation. On the other hand, it is possible that laser-induced drusen reduction may have other beneficial effects on visual function. Large drusen and the associated diffuse thickening of Bruch’s membrane have been hypothesized to play a role in the visual deterioration of patients with nonexudative AMD, perhaps acting as a hydrophobic diffusion barrier to nutrients or other metabolic exchange between the choriocapillaris and macular photoreceptors. 28,29 Laser-induced drusen reduction might improve macular nutrient/waste product exchange or other metabolic exchange, 11 such as heat transfer, restore the RPE-Bruch membrane-choroid complex to more normal anatomy, and reapproximate photoreceptors to subjacent tissues, debride dysfunctional RPE cells, 6,7 stimulate choroidal pericytes to become macrophages with associated cellular and paracrine activity, 30 alter the humoral milieu to stimulate photoreceptor function or retard selective photoreceptor senescence, 31 or quite simply reduce photoreceptor optical aberration induced by a topographically irregular substrate. It is conceivable that laser-induced drusen reduction may affect visual function via one or more of these mechanisms. At this time, however, these theories relating drusen reduction and the potential mechanisms of improved visual function remain hypothetical. In this study, the effect of drusen reduction on improvement in visual acuity at 1 year in the LASER ≥ 50% group compared with the LASER < 50% and OBS < 50% groups was maintained when other factors affecting change in visual acuity were accounted for in a multiple regression model. The similarities of the distributions of change in visual acuity between the LASER < 50% and OBS < 50% are intriguing (Figs 1 and 3) . The laser treatment advantage persisted when the data were segregated into the CNVPT Bilateral Drusen Study or the Fellow Eye Study. Other investigators have noted that the improvement in vision for eyes with drusen reduction may diminish over time, possibly due to advancing cataract, or that an eye may experience accelerated loss of vision despite drusen reduction. 8,32 Therefore, these data regarding improved visual function in eyes with laser-induced drusen reduction are preliminary, and longer follow-up for eyes enrolled in the CNVPT is warranted. Other studies have described visual impairment in eyes with early AMD using other tests of contrast sensitivity, central visual field sensitivity, and recovery of vision after exposures to bright light compared with age-matched control subjects without AMD. 33,34 Clearly, best-corrected visual acuity provides only one aspect of the visual world of a patient with AMD. Thus, our data demonstrating improved contrast threshold in patients experiencing significant drusen reduction after laser treatment, while preliminary, are encouraging. Critical print size, the size of reading print below which the reading speed slows, did not follow the pattern of improvement noted for visual acuity and contrast threshold in eyes with ≥ 50% drusen reduction. The reasons for this are unclear but may be related to the fact that reading speed is a more complex and dynamic task than simply discerning high-contrast (visual acuity) or low-contrast (contrast threshold) letters statically. Fortunately, approximately 55%–62% of all eyes maintained or improved their critical print size at 1 year. To focus on the issue of the effects of drusen reduction on visual function, this study specifically excluded one important group of eyes in the CNVPT—those that developed CNV within the first year with or without laser treatment. In our preliminary reports, we noted an increased incidence of CNV in laser-treated eyes in the Fellow Eye Study but not in the Bilateral Drusen Study. Interestingly, this imbalance of CNV in laser-treated eyes in the Fellow Eye Study had not resulted in significant vision loss in the short term; 14 perhaps these predominantly occult CNV lesions will diminish visual function over time, or it may be that these laser-associated CNV lesions may have a relatively benign course. Clearly, this is a critical piece of information that is needed to assess completely the overall potential value of laser treatment to eyes with large drusen. Thus, the results of this report, while encouraging, do not justify laser treatment of eyes with large drusen outside the context of a well-designed clinical trial. Our group will continue to follow CNVPT patients for a total of 4 years to collect more information on patients enrolled in the CNVPT Bilateral Drusen and the Fellow Eye Studies. The imbalance of CNV events in the Fellow Eye Study has prompted us to focus on patients with high-risk bilateral drusen. Our plan is to commence, in early 1999, the Complications of Age-Related Macular Degeneration Prevention Trial (CAPT), a multicenter randomized controlled clinical trial sponsored by the National Eye Institute. This trial’s specific aim is to determine the potential value of laser treatment to eyes with AMD and bilateral large drusen. From the public health perspective, focusing on patients with bilateral large drusen is rational in view of a recent report that a prophylactic intervention in this group that is 30% effective would halve the rate of legal blindness from AMD. 35 Finally, CAPT will permit further study of the potential beneficial effects of drusen reduction on visual function and the impact of these changes on patient quality of life in a large group of patients with bilateral large drusen.