Treatment of Nonexudative Age-Related Macular Degeneration with Infrared (810 nm) Diode Laser Photocoagulation

RPE. Large subfoveal drusen often are associated with decreased visual acuity, diminished contrast sensitivity, impairment of color vision, and metamorphopsia.

Approximately 90% of the severe loss of visual function from macular degeneration occurs secondary to the subsequent development of choroidal neovascularization or exudative lesions. For patients over 65 years of age with drusen present in both eyes, the risk of developing severe visual loss is estimated to be about 18% over 3-years (3–5). Patients who have already had an exudative event in one eye are at an especially high risk of losing vision in the fellow eye; this risk approaches 60% over a 5-year period (6). Because of the risks associated with drusen, investigators have sought to improve the visual prognosis of eyes with dry age-related macular degeneration by using various potentially prophylactic measures. Vitamins, minerals, and other micronutrients may reduce the risks of blindness, but the positive impact of these does not appear striking (7,8). Plasmapheresis (9), or the removal of certain unwanted components from the blood, requires complex, expensive equipment, and has not been shown to be clinically efficacious in any large controlled study despite its promotion by some advocates. Finally, pharmacological approaches that seek to prevent choroidal neovascularization using antiangiogenic drugs are also under study.

Historically, laser photocoagulation has been observed to promote the resorption of drusen even when the laser lesions are placed some distance away from the drusen themselves. However, the precise mechanism of such drusen resolution remains elusive. Duvall and Tso (10) have postulated that laser photocoagulation induces pericytes from the underlying choriocapillaris to form phagocytes, which in turn remove the amorphous drusen debris. Other research suggests that local and circulating antibodies to certain drusen components may also play a role (11).

Until recently, virtually all the clinical studies regarding the prophylactic photocoagulation of eyes with drusen have dealt with small numbers of patients and were of a pilot nature. All used laser light in the visible spectrum, usually the argon and krypton wavelengths. For example, Wetzig (12) used moderate intensity argon or krypton lesions in 42 eyes and noted that drusen resorbed in about half of the eyes over a 3-year period. Cleasby et al. (13) suggested that such prophylactic laser treatment might prevent the development of choroidal neovascularization. A favorable effect on visual acuity was suggested by Frennesson and Nilsson (14), who showed a 50% reduction in drusen area at 12 months. Improved visual acuity after laser photocoagulation was also described by Figueroa et al. (15) and by Little et al. (16). Finally, Guymer et al. (17) demonstrated improved scotopic thresholds after laser photocoagulation of eyes with high-risk clinical features of AMD.

The safety and efficacy of laser treatment placed directly over the drusen themselves versus treatment of the RPE in their vicinity has been debated. Advocates of direct treatment argue that the RPE and underlying Bruch’s membrane are thicker at the drusen site so that treatment at the drusen is less likely to induce choroidal neovascularization. Advocates of the 810-nm laser argue that very minimal lesions are clinically effective in inducing drusen absorption, even when lesions are placed in a grid without regard to precise drusen location.

II.PILOT STUDIES

A.Argon Laser Photocoagulation

The Choroidal Neovascularization Prevention Trial (CNVPT) used argon laser photocoagulation (18) to induce drusen disappearance. Patients were divided into two groups; bilat-

erally eligible patients were defined as those with at least 10 large drusen ( 63 microns in diameter) in the macula of each eye and vision of 20/40 or better. In the unilateral (fellow eye) group, one eye had to have had a previous exudative event prior to entry into the study, so that only the remaining eye with multiple large drusen was eligible for randomization. The eye to be treated was randomly selected for a bilaterally eligible patient, while in the fellow eye group, the eligible eye was randomized to either observation or treatment. Treatment was performed using argon green laser photocoagulation with 100-micron spots placed in one of four separate patterns. The intensity of lesions varied from gray-white to white depending upon the treatment protocol selected. In most cases, a C-pattern located just temporal to the foveola was placed. If there was not an observable reduction of drusen of at least 50% at 6 months’ time in the CNVPT, the eye typically was retreated with another C-pattern located nasal to the fovea to, in essence, completely surround the foveola with laser treatment.

After 1 year, the CNVPT study showed paradoxically that treated eyes in the fellow eye group unfortunately had a significantly higher incidence of choroidal neovascularization than observed eyes (16.9% vs 3.2%). Hence, the study was prematurely halted for safety reasons and the protocol and goals were reassessed. Ultimately, the study was relaunched as a larger randomized trial excluding patients who had, at entry, a diskiform process in one of their eyes. Thus, the fellow eye group of patients was excluded from further study.

B.Infrared (810 nm) Diode Laser Photocoagulation

Concurrently, a group of investigators was evaluating the use of 810-nm infrared laser to prophylactically treat eyes with drusen (19). Very importantly, this group also sought to study the effect of altering the intensity of the laser lesion at the time of treatment. Virtually no retinal photocoagulation studies had prospectively randomized laser lesion intensity to evaluate the effect of minimal versus more typical intensities on clinical outcomes.

1.Study Method

In the infrared diode pilot study, 29 eyes of 152 patients aged 50 years or older met the following inclusion criteria and were randomized: at least five large drusen ( 63 microns in size) in the macula, no substantial geographic atrophy, or confounding ocular diseases, and best corrected visual acuity of 20/63 or better as measured on ETDRS acuity charts. Unilateral patients must have had a previous diskiform or exudative event in one of their eyes while the fellow eye met eligibility criteria (Fig. 3, left), whereas in bilateral patients, both eyes met all eligibility criteria (Fig. 3, right).

Randomization for the study was performed as follows: unilaterally eligible patients had their eligible eye randomized to either treatment or observation and bilaterally eligible patients had one of their eyes randomly selected for treatment with the other eye serving as a control. In all cases, laser treatment consisted of placement of 48 125-micron diameter spots in an annular pattern (Fig. 4) grouped to surround but to avoid the foveola. Retreatments were not allowed. Laser lesion intensity was itself randomized to either threshold or subthreshold levels. The threshold laser lesion protocol required the placement of 48 spots that were barely visible directly after placement whereas the subthreshold treatment protocol called for the use of clinically invisible lesions, which remained invisible even hours after placement. This was accomplished by creating a test laser lesion of 0.2 s duration outside of the macula and increasing the laser power from a minimal amount until the retinal

Figure 3 (Left) An eligible patient in the unilateral group has one eye affected by end-stage exudative AMD while the eligible eye has at least 5 drusen 63 microns in size or larger and visual acuity of 20/63 or better. (Right) A bilaterally eligible patient has 5 or more drusen 63 microns and 20/63 visual acuity or better in each eye.

Figure 4 The placement of 48 125-micron laser lesions was done in a grid that surrounded the foveola whereby the lesions were placed in an annulus whose inside radius was one-half an optic disk diameter and whose outside radius was 11/2 disk diameters.

lesion could be just barely detected. Keeping the laser power settings constant, the duration of the laser pulse was decreased to 0.1 s, which halved the energy applied to produce the lesion. A subthreshold lesion resulted. These lesions could not be seen directly after treatment. However, they could be placed with reasonable accuracy by dividing the target area into four quadrants and then placing 12 lesions in each section of the treatment annulus. Clinical conformation of lesion placement could be confirmed by fluorescein angiography.

2.Results

Choroidal Neovascularization. At 24 months, the infrared diode pilot study, showed no statistically significant difference in choroidal neovascular event rates in treated versus observed eyes in either the unilaterally eligible or bilaterally eligible patient groups (see Table 1). These results are in contrast to the increased risk of choroidal neovascularization found by the CNVPT study at 12 months in treated eyes of unilaterally eligible patients. The event rates for observed eyes in the unilaterally and bilaterally eligible patients were 27% and 4.6%, respectively, at 24 months. Hence, the risk of choroidal neovascularization was about six times greater in those patients who had already had a previous event in one of their eyes (unilateral group) compared to patients who had both eyes eligible at entry. Prophylactic diode laser treatment did not increase or decrease a patient’s chances of developing an exudative event within the follow-up period of 24 months.

Drusen Disappearance. A total of 43.6% of eyes treated with subthreshold lesions exhibited a 50% reduction in macular drusen area over 24 months compared to 62.3% of eyes treated with more intense (visible) threshold lesions. Overall, at 24 months, diode laser treatment resulted in a 50% reduction in drusen level in 68.3% of eyes compared to virtually no reduction (3.3%) in observed eyes over the same time period. As shown in Figure 5, it was apparent that more intense lesions led to more rapid resolution of drusen, whereas use of more gentle subthreshold spots also resulted in drusen resorption, but at a slower rate.

Figure 5 Graph showing the influence of the intensity of the laser lesions used and the time to 50% resolution of drusen area. Subthreshold 811-nm diode laser-treated patients require a longer time, on average, to achieve drusen resorption but at 24 months following treatment, the percentage of eyes showing substantial drusen resorption is similar, regardless of laser treatment intensity.

Visual Improvement. Although changes in the clinical appearance of drusen can be striking after photocoagulation (Fig. 6), such changes have little relevance to the patient unless they are accompanied by improved visual acuity or reduction of risk of long-term visual loss. A subset of patients in the PTAMD pilot in whom two lines of improvement was possible (20/32–20/63 vision at entry) was analyzed at 24 months. A total of 15.4% of all treated eyes (18.2% of visual treated and 12.5% of subthreshold treated) enjoyed two lines of improvement after 2 years compared to 0% of observation eyes. In the bilateral study arm, 41 patients had initial acuity of 20/32–20/63 and 24.4% of these eyes showed two lines of improvement after treatment compared to 0% of fellow eyes. This visual improvement was statistically significant to the p 0.002 level. These visual results are in harmony with results from several smaller studies that suggest a visual benefit to prophylactic laser treatment to eyes with drusen (15,16,20).

Theoretical Considerations. The 810-nm-diode wavelength has certain properties that may make it a preferable choice over visible argon or krypton wavelengths for the treatment of drusen. The infrared laser may produce less blood–retinal barrier breakdown because of greater tissue penetration and less thermal disruption, particularly at lower energy levels (21). Pollack et al. (22) concluded that subclinical diode laser photocoagulation of the retina limits damage to the photoreceptors compared to more intense threshold lesions. However, some authors (22) have suggested that the placement of minimal intensity laser lesions is difficult to accomplish in a reproducible manner because of heterogeneity

Figure 6 (Left) The right fundus of a patient with multiple, large macular drusen. (Center) Twelve months after treatment with subthreshold laser lesions, drusen resorption has been dramatic. (Right) Fluorescein angiogram of same eye 2 years after treatment. The subthreshold laser scars are virtually undetectable. See also color insert, Fig. 19.6 left and center.

in the RPE cells themselves. Funatsu et al. (23) suggested that diode laser photocoagulation produces a greater increase in preretinal oxygen partial pressure than argon laser photocoagulation, giving the former a theoretical advantage in preventing choroidal neovascularization. Whether or not these potential advantages have clinical relevance remain to be established.

III.PTAMD STUDY

Based on the pilot data, a large multicentered, randomized, controlled trial was initiated using only subthreshold 810-nm-diode laser lesions placed in a single treatment session. To date, approximately 600 patients have enrolled in this study, which is called Prophylactic Treatment of Age-Related Macular Degeneration (PTAMD) Trial. Endpoints being evaluated include choroidal neovascular event rates in both the bilateral and unilateral patient groups, alterations of drusen area and drusen distribution, and changes in best corrected visual acuity.

In designing a prophylactic study, the number of patients required to show potential efficacy is an important figure unlike a therapeutic trial when an intervention or placebo is randomly given to patients identified with a given disease. A prophylactic trial requires a larger patient population. That is, only a minority of patients with AMD would be expected to develop CNVM over a few years’ time. Historical estimates can be used, but the data from an available pilot study are partially useful, if the pilot used essentially the same entry criteria and methodology. The choroidal neovascular membrane event rates at 24 months for the PTAMD pilot study are shown in Table 1. If we look only at observed eyes, the unilateral observed eyes had an event rate of 27% over 2 years, or approximately 15% per year; in the bilateral group, the rate was 4.6% over 2 years, or roughly 3% per year. If we then require a 95% confidence interval for detecting significant differences ( 0.05) and a power of 90% (90% confident that if we detect no difference that indeed no difference is present or B 0.10), we can calculate the estimated number of patients needed in the PTAMD trial. Assume that a patient will be followed for 5 years and that prophylactic treatment reduces the CNVM by a modest 20%. We then would need approximately 200

Figure 7 Using a drusen analysis software program, drusen located within the large circle (left) (alzer 1 ring) are selected for analysis and the area of regard is displayed (center). A drusen detection algorithm identifies and displays the drusen it found in false color (right). See also color insert, Fig. 19.7.

patients in the unilaterally eligible group and 2700 patients in the bilaterally eligible group to show such differences. Note that because the CNVM event rate for eyes having already had an exudative event is about six times higher than for an eye of a patient with drusen in both eyes, substantially fewer patients are needed to show treatment efficacy in unilaterally eligible patients. Hence, the continued inclusion of such patients in the PTAMD should facilitate obtaining results over a shorter period of time, in contrast to the CAPT study, which excludes such patients.

IV. FUTURE CONSIDERATIONS

Studies evaluating the effect of laser photocoagulation on drusen disappearance are somewhat hampered by imprecise methods of measuring the drusen themselves. Typically, the total area of drusen in the macula is not a criterion for entry into a study, because methodology to measure drusen area is either rudimentary or depends on the time-consuming placement of templates on images to calculate or measure drusen diameter. Difficulties are compounded by the presence of large geographic patches of confluent drusen. Hence, data relating to drusen disappearance should be considered to be gross estimates rather than objective and precise. Furthermore, the published risk of visual loss in eyes with drusen are projections based on rather gross categorizations of drusen size and extent. Eyes exhibiting even a single large drusen in the macula but far from the fovea have been grouped, in some studies, with eyes that harbor scores of large drusen in the posterior pole. The failure to quantitate drusen size, drusen area, and drusen location is potentially a serious flaw in virtually all clinical studies on the subject, whether the study evaluated the effects of photocoagulation on eyes with drusen or whether it calculated visual loss risk data as a function of the presence of drusen. Automated methods of drusen categorization may make such studies more quantitative and less subjective (Fig. 7).

V.SUMMARY

The presence of drusen in an eye is a significant risk factor for future visual loss from AMD, and in particular from choroidal neovascularization. Prophylactic infrared laser

using an 810-nm-diode laser was placed in a grid pattern of 48 spots at a single session to promote drusen disappearance in a prospective randomized pilot study. In the pilot diode laser study, the intensity of laser lesions to be used in a patient’s eye was randomized to either threshold (barely visible after placement) or subthreshold (not clinically visible) treatment. At 24 months, there was no significant difference in choroidal neovascular event rates between treated and observed eyes, whether the patient was treated with threshold or subthreshold laser intensity.

In contrast to a similar large pilot study that used argon laser treatment to promote drusen disappearance, diode laser treatment did not lead to significantly higher choroidal neovascular membrane event rates in any patient group. Threshold laser lesions led to a more rapid disappearance of drusen than lighter, subthreshold lesions but both were effective. Overall, diode laser treatment resulted in a 50% reduction of drusen levels in 68% of treated eyes at 24 months.

A total of 15% of patients in the pilot study who had initial visual acuity between 20/32 and 20/63 showed at least two lines of visual acuity improvement after diode laser treatment. A large multicenter randomized study, the Prophylactic Treatment of AgeRelated Macular Degeneration (PTAMD), is underway to determine the potential longterm benefits of 810-nm subthreshold laser treatment for patients who have dry AMD and multiple drusen.

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