Argon Laser to Drusen

most layer of the choroid and is composed of an anastomosing sheet of large, fenestrated capillaries. The blood flow in the choroid is one of the highest in the body, largely to meet the high metabolic needs of the outer retina/RPE. Nutrients and waste products pass through the fenestrations of the choriocapillaris. Typically, the BM is not a barrier to these molecules and the RPE transports them to and from the outer retina via active and passive mechanisms (8).

Druse (plural drusen) is a German-derived word meaning nodule. Literally, drusen are crystalline nodules found in stones. In the ophthalmic literature, there have been numerous clinical and histopathological definitions of drusen (9). The lack of standard terminology for drusen makes interpretation of the literature difficult. Recently, a clinical classification and grading for AMD was developed. In this system, drusen are whitishyellow spots external to the retina or RPE (10). Hard drusen are less than 63 microns, well defined, and yellow-white. Soft drusen are greater than 63 microns. They can have indistinct and distinct borders, may coalesce to form larger, confluent drusen, and typically are white-yellow in color. Pathologically, three types of soft drusen have been described: (1) localized detachments of RPE and basal linear deposit in eyes with diffuse basal linear deposit; (2) localized detachments of the RPE and basal laminar deposit in eyes with diffuse basal laminar deposits; and (3) localized RPE detachments due to focal accumulation of basal linear deposit in eyes without diffuse basal linear deposit (11,12). Ultrastructurally, basal laminar deposits consist of membrane-bound vesicles, wide-spaced collagen, and amorphous, granular material located between the plasma membrane and basal lamina of the RPE. Basal linear deposits are located external to the RPE’s basal lamina in the inner collagenous zone. They consist of vesicular and granular electron-dense material and small foci of wide-spaced collagen (11–16). Histochemically, drusen have been shown to consist of lipids, mucopolysaccharides, and glycoconjugates (17–19).

As stated above, the RPE is a metabolically active tissue layer and, most likely, drusen are derived from RPE (20–22). Studies have demonstrated that RPE cells over time accumulate intracellular lipofuscin and other by-products of the catabolism of photoreceptor outer segments (23). It has been shown that the RPE deposits cellular material into the sub-RPE space via evagination of its plasma membrane. This probably is the deposition of the intracellular accumulation of its phagocytic by-products. These plasma-membrane- bound vesicles break down into drusenoid material (22). With normal aging, Bruch’s membrane also undergoes ultrastructural and histochemical changes (24–27). BM increases in thickness, accumulates lipids, and develops protein cross-linking. The hydraulic conductivity (flow per unit pressure) of BM in normal eyes decreases with age (26). Similar to drusen, these alterations in BM may also represent the accumulation of waste products from the RPE. The basal linear/laminar deposits and the alterations in BM may impair the flow of fluid to and from the choriocapillaris. The reduced flow of nutrients and oxygen and the impaired removal of waste products may impose a metabolic strain on the outer retina from an enlarged, hydrophobic (lipid-laden) BM and drusen may induce the formation of angiogenic factors and may promote the formation of CNV (28).

III.DRUSEN AS A RISK FACTOR FOR CNV

Laser to drusen has generated investigation because soft drusen are risk factors for CNV and subsequent visual loss. In 1973, Gass noted that nine of 49 (18%) patients with bilateral macular drusen developed visual loss in one eye secondary to “diskiform detachment

or degeneration” over an average of 4.5 years (3). Smiddy and Fine followed 71 patients with bilateral macular drusen for an average of 4.3 years. Eight eyes of seven patients (9.9%) developed exudative maculopathy. Severe visual loss ( 6 lines) occurred in seven eyes and the 5-year cumulative risk of developing severe visual loss was 12.7% (29). Holz et al. prospectively followed 126 patients with bilateral drusen and “good visual acuity.” The 3-year cumulative incidence of developing CNV or pigment epithelial detachment was 13.3% (30). The risk for CNV is higher in patients with drusen in one eye and CNV in the other eye. In Gass’ study, 31 of 91 patients lost central vision from CNV in their fellow eye over an average of 4 years (3). The Macular Photocoagulation Study Group followed 127 patients who had an extrafoveal CNV in one eye. In the fellow eye, the risk of developing a CNV was 58% over 5 years if large drusen and RPE hyperpigmentation were present. The risk dropped to 10% if no drusen or hyperpigmentation was present (31). In another study, the Macular Photocoagulation Study Group verified that large drusen are a significant independent risk factor for CNV. In this same study, the risk for CNV jumped to 87% in eyes with five or more drusen, focal hyperpigmentation, one or more large drusen, and systemic hypertension (32). In the study of Sandberg et al., 127 patients with unilateral CNV were followed for an average of 4.5 years; 8.8% per year developed CNV in their fellow eye. Macular appearance, which included large drusen, was significantly associated with CNV (33). One prospective study followed 101 patients with unilateral CNV and drusen in the fellow eye for up to 9 years. The yearly incidence of CNV varied between 5% and 11%. Significant risk factors were the number, size, and confluence of drusen (34).

Numerous pathological studies have shown the correlation of drusen and AMD. Spraul and Grossniklaus examined 51 eyes with AMD and 40 age-matched control eyes. Soft, confluent, and large drusen and basal (linear) deposits correlated with AMD (15). Curcio and Millican demonstrated that basal linear deposits and large drusen are 24 times more likely to be found in eyes with AMD than age-matched control eyes (13).

IV. ARGON LASER PHOTOCOAGULATION

To understand how laser results in drusen resorption, it is necessary to examine the cellular effects of argon laser on the outer retina, RPE, BM, and choriocapillaris. The argongreen laser emits a wavelength of 514 nm. This laser wavelength is largely absorbed by the melanin of the RPE and choroid. Absorption of the laser light elevates the tissue temperature 10–20 C and causes denaturation of proteins. This thermal effect is called photocoagulation (35,36). The histopathological characteristics of an argon laser burn depend on the power, spot size, and duration of the laser burn. Smiddy et al. examined the light microscopic changes to a human retina 24 h after argon laser application. The juxtafoveal region was treated with laser spots 200 microns in size and 0.5 s in duration. The power ranged between 200 and 400 milliwatts (mW). Histopathologically, there was a choroidal infiltrate of mononuclear and polymorphonuclear cells. The choriocapillaris (CC) was acellular at the center of the burn. The RPE was disrupted and the outer and inner retinal nuclear layers were pyknotic. The ganglion and nerve fiber layers were also affected (37). Thomas et al. conducted a similar study. They examined a human eye 24 h after argon laser. One laser spot of power 310 mW, 100 microns, and 0.5 s was applied in the superonasal quadrant. There was variable RPE necrosis and advanced CC necrosis. A second argon laser burn of 210 mW, 500 microns, and 0.5 s in the peripapillary region demonstrated significant RPE disruption, CC necrosis, and BM disruption (38).

There have been a number of studies with argon laser on cynomologus monkeys, whose fovea is similar to the human fovea. Smiddy et al. placed a 13-spot burn in the juxtafoveal region of a cynomologus monkey with argon green laser and examined the histopathological effects at 1 and 7 days. They used a 200-micron spot size, 0.2-s duration, and power between 100 and 200 mW. The desired reaction was a laser burn that turned the retina light gray. At day 1, the ganglion cell layer was partially preserved but all deeper layers were necrotic with RPE hyperplasia. At day 7, there was disruption of the retina up to the ganglion cell layer (39). In a second study, Smiddy et al. demonstrated that the RPE undergoes cellular proliferation after argon laser (40). Peyman et al. examined the histopathological effects of argon blue-green laser to the parafoveal area of cynomologus monkeys. They used a 100-micron spot size, 0.1-s duration, and a power of 100 mW. At day 1, there was coagulative necrosis of the RPE, outer nuclear layer, and outer plexiform layer. The choroid was minimally affected. At days 12 and 21, glial tissue had replaced the outer retina. There was an inflammatory infiltrate and the RPE was hyperplastic. If the power was increased to 320 mW, the basement membrane was ruptured and choroidal hemorrhages developed (41). Coscas and Soubrane treated the parafoveal region of adult baboons with argon green laser and examined the light and electron microscopic changes at 1 h, 3 weeks, and 6 weeks. As in the above studies, they showed disruption of the outer retina, necrosis of the RPE, and a macrophage response. Depending on the laser settings, there was variable involvement of the choriocapillaris (42). In a review of macular photocoagulation, Swartz states, “The histologic characteristics of a moderate argon-green burn show a typical cone-shaped lesion sparing the inner retina” (43). The laser intensities of these studies exceed those in most human laser-to-drusen trials.

There have been no histopathological studies on human eyes examining the effects of laser on drusen. However, there have been a number of studies involving primates. Duvall and Tso applied argon-green laser directly to drusen in two eyes of a rhesus monkey and noted the light microscopic and ultrastructural characteristics of drusen resorption. At 0–2 days, there was outer-segment retinal disruption, RPE necrosis, and fibrin deposition. The drusen were still present. At 3–8 days, two types of macrophages were present. One type was in the outer retina and subretinal space and their appearance was consistent with blood-borne monocytes. The second type of macrophage contained cell processes that surrounded the drusen material. These cell processes were traced by serial sectioning to the pericytes of the choriocapillaris. At 9 days and beyond, there was resorption of the drusen. Blood-borne monocytes were densely packed in the subretinal space. The cell processes of the choroidal pericytes contained drusenoid material. The authors postulated that the fibrin deposition from the laser photocoagulation initiated a phagocytic response, which resulted in clearance of the drusen by choroidal pericytes. Perry et al. examined the choroidal microvascular response to argon laser in cats. They demonstrated activation of the endothelial cells in the choriocapillaris after laser photocoagulation (44). Della et al. treated a rhesus monkey with soft large drusen. They used an argon laser to apply a grid pattern in the macula. Six weeks after laser, the directly treated drusen had disappeared (45).

V.THEORIES ON DRUSEN REDUCTION AND CNV PREVENTION

Drusen disappearance after laser photocoagulation is clearly documented in the literature. (46–59). However, the mechanism of drusen disappearance is not well understood. Several

theories have been proposed: (1) phagocytosis of drusen; (2) decreased deposits by removal of RPE; (3) release of soluble mediators; (4) thinning of Bruch’s membrane; and (5) mechanical alteration of the structure of Bruch’s membrane. It is clear from the above studies that argon laser induces an inflammatory response and the intensity of the reaction depends on the laser settings. The laser settings in the studies, as well as the laser subjects, are variable, which makes interpretation difficult (6,37–40,42–44,48). Furthermore, in most of the clinical studies of laser to drusen, the calibrated intensity is minimal whitening. This is different from the above studies where stronger intensities where evaluated. However, despite these limitations, we can postulate that laser-induced phagocytosis of drusen occurs. Blood-borne inflammatory cells may ingest the drusen material. Studies certainly indicate their presence after laser. Duvall and Tso noted drusenoid material in cell processes after laser photocoagulation and attributed the origin of these cell processes to choroidal pericytes (48). Dysfunctional RPE, destroyed by laser, is replaced by proliferating RPE, (40). The RPE has phagocytic ability and the proliferating RPE may be involved in drusen resorption (52). Also, the removal of dysfunctional RPE cells may halt further drusen development and allow removal of accumulated material. After laser-induced tissue damage, the RPE and other cells may produce soluble mediators. For instance, Glaser et al. showed that RPE cells release an inhibitor of neovascularization (60). These soluble mediators may enhance the natural processes that result in spontaneous drusen resorption (3,61). They might also account for the observation that drusen distant from laser burns disappear after photocoagulation.

Bruch’s membrane in AMD eyes is diffusely thickened and hydrophobic. The structural effect on BM by argon laser is variable. Thomas et al. showed that BM’s integrity depended on the energy density of the laser (38). Photocoagulation may thin the abnormally thick BM and, in theory, improve its hydraulic conductivity. The increased metabolic transport could improve drusen clearance and decrease drusen formation. The laser could also exert a mechanical effect on BM, causing contraction of collagen and elastin (similar to laser trabeculoplasty) and improving egress of material through a more permeable BM. Peyman et al. showed that photocoagulation may improve perioxidase diffusion from the vitreous to the choroid (62).

Similar to drusen reduction, it is unclear how laser to drusen might prevent CNV. Some of the same theories on the mechanism of drusen reduction apply to CNV prevention. Improved transport of nutrients across BM might reduce the metabolic strain on the RPE/outer retina and stop the production of angiogenic factors from the RPE. Indeed, laser might even induce the production of vasoinhibitory growth factors from the RPE. Gass postulated that laser “tacks” down the RPE to BM, eliminating a potential cleavage plane for CNV (3). Proliferating RPE, induced by the laser, may envelop early CNV and prevent further growth.

VI. UNCONTROLLED STUDIES AND CASE REPORTS

Since Gass described the disappearance of drusen after laser photocoagulation, a number of case reports and uncontrolled clinical studies have examined the prophylactic treatment of drusen. Cleasby et al. treated 29 eyes in patients with “exudative senile maculopathy (ESM)” in the fellow eye. They treated one eye of 25 patients with “nonexudative senile maculopathy (NSM)” in both eyes. They defined NSM as the presence of drusen, retinal pigment atrophy, and clumping and/or cholesterol deposits in the macula in individuals

older than 50. They used the argon laser to directly treat drusen “within a broad ring around the fovea.” The desired intensity was a minimally visible reaction in the retina. The laser parameters were a spot size of 50–100 microns, power between 100 and 150 mW, and duration of 0.05–0.1 s. The number of applications was approximately 200–300 shots. In the group of 29 patients with ESM in one eye, three developed ESM in the treated eye over an average follow-up of 28.4 months. This represented a 4.4% yearly rate of ESM formation, which is less than the natural history of AMD. In the NSM group, neither the control eyes nor the treated eyes developed ESM over an average follow-up of 27.3 months. All 25 treated eyes and five control eyes showed a reduction in drusen. There were no reported complications from the laser (47). Despite a small number of patients, no control group for the ESM eyes, and no randomization for NSM eyes, this study suggested prophylactic laser to drusen might be beneficial.

Wetzig treated 42 eyes of 27 patients with prophylactic laser in a retrospective, nonrandomized study. All patients had macular soft drusen and recent visual changes (visual loss or metamorphopsia). The vision ranged from 20/20 to 20/400. Only 25% of eyes had a best-corrected prelaser visual acuity of 20/40 or better. The mean age at treatment was 69 years. Eyes with CNV or hemorrhagic/exudative changes were excluded. Thirty-one eyes were treated with krypton red laser, one eye with a combination of xenon and krypton, eight eyes with argon laser, and two eyes with a combination of argon and krypton laser. Both eyes were treated in some patients and several eyes were retreated. The desired intensity of the laser reaction was a faint, white-gray spot. The spots, approximately 50–75, were applied in a scatter pattern around the fovea. The vision improved, remained stable, or worsened by one line in 22 eyes (52%) over an average follow-up of 3.7 years. Twelve percent developed choroidal neovascularization. The drusen disappeared in these treated eyes, usually beginning at 3 months (58). Wetzig published a follow-up of these patients 6 years after the original publication. The average follow-up time was 120 months. Thirty-three percent of the treated eyes remained stable or lost one line of visual acuity, 21% lost two to three lines, and 46% lost three or more lines. Twenty-one percent of treated eyes developed CNV during the follow-up and several patients developed progressive enlargement of the treatment scars. There was no control group but seven eyes with drusen were untreated. In this untreated group, three eyes retained 20/40 or better visual acuity, two eyes lost two or more lines, and two eyes worsened to 20/400 or less. This study was limited, as it was a retrospective, nonrandomized study with a small number of eyes. Also, it included many patients with poor vision and selected patients with visual symptoms. These patients may have harbored subtle occult CNV. Overall, this study did not show a clear beneficial effect of prophylactic laser (59).

Figueroa et al. treated 20 patients with argon laser. Group 1 consisted of 14 patients with bilateral drusen. One eye was randomly assigned to receive laser treatment. Group 2 consisted of six patients with CNV in one eye and drusen in the fellow eye. The ages ranged from 55 to 80 years and the average follow-up was 18 months. Drusen temporal to the fovea were directly treated with the argon green laser at a power of 100 mW, duration of 0.1 s, and spot size of 100 microns. The desired laser intensity was calibrated to achieve a light gray-white lesion. The mean number of laser spots was 30. Treated drusen disappeared at approximately 2 months while surrounding, untreated drusen disappeared at a mean of 10 months. Visual acuity improved in 30% of eyes by one line or more. This was secondary to the resorption of untreated subfoveal drusen. The visual acuity remained unchanged in 65% of eyes and decreased in 5% (one eye). The one eye that worsened developed a choroidal neovascular membrane away from the laser scars (49). Figueroa et al. updated

these results and presented new data in a second publication (50). The laser settings were the same as described above. All treated drusen disappeared at an average of 3.5 months. In all but three patients, the untreated drusen resolved at an average of 8.6 months. The drusen disappearance progressed in a temporal-to-nasal direction. Superonasal drusen persisted the longest time. Two of the 30 control eyes in Group 1 (bilateral drusen) demonstrated spontaneous drusen resolution. After an average of 3 years, one control eye and no treated eyes developed a choroidal neovascular membrane. Three fellow eyes (18%) in Group 2 developed CNV. In one eye, the CNV developed adjacent to the laser scars. Again, it was difficult to draw any conclusions from this study because of the small numbers. But, despite drusen resorption, the laser prophylaxis did not appear to prevent CNV in Group 2.

Sarks et al. treated 18 eyes of 16 patients with bilateral drusen and one eye of 10 patients with exudative changes in the other eye. Patients were 55 years or older and followed for a mean of 16.8 months. Inclusion criteria included visual acuity 20/40 or better and no evidence of atrophy or CNV. A ring of 40–50 nonconfluent laser burns was applied approximately 1500 microns from the foveal center. Drusen were not directly targeted. The argon green laser settings were a spot size of 100 microns, duration from 0.05 to 0.1 s, and a power calibrated to produce “a barely discernible whitening of the RPE.” In 14 of the 16 patients with bilateral drusen, only one eye was treated. In these treated eyes, the vision remained stable in 10 eyes and improved in four eyes. The vision decreased in four eyes and remained stable in 10 eyes in the untreated group. Overall, in the two treated groups, visual acuity improved in 12 eyes (40%), remained unchanged in 16 eyes (53%) and worsened in two eyes (7%). Visual improvement was secondary to foveal drusen resorption, which occurred in all treated eyes and not at all in the untreated eyes. Two treated patients developed choroidal neovascular membranes. They developed at 7 and 8 months in retina adjacent to laser burns. Expansion of laser-induced atrophy was minimal in this study (57).

Guymer et al. treated one eye of 12 patients at high risk for visual loss secondary to AMD. All 12 treated eyes demonstrated macula drusen and visual acuity of 20/40 or better. Ten patients had end-stage lesions in one eye and two patients had bilateral soft confluent drusen. Twelve laser spots were placed in a ring 750–1000 microns from the fovea. The argon green laser settings were a spot size of 200 microns, duration of 0.2 s, and power calibrated to achieve faint blanching of the RPE (80–300 mW). The average follow-up was 16 months. Visual acuity remained the same or improved in 11 patients. Nine of the 11 patients had a reduction in drusen size, number, and confluence. One patient lost four lines secondary to CNV membrane development. This membrane did not originate from a laser site. Two patients developed profound atrophy at the laser site and four others developed RPE pigmentary changes at the laser sites. This study showed that a small number of laser applications could promote drusen disappearance. It also showed no correlation between resolution of drusen and improvement or deterioration of dark-adapted retinal thresholds (54).

Sigelman published a case report of a 58-year-old woman with a diskiform scar secondary to AMD in the right eye and confluent soft drusen in the left eye. The patient’s vision dropped to 20/40 with metamorphopsia in the left eye. There was no CNV but an increased density and size of foveal drusen. Using a wavelength of 576 nm (yellow), power of 180 mW, duration of 0.3 s, and spot size of 200 microns, he directly treated drusen and also applied a parafoveal grid for a total of 56 spots. Treated and untreated drusen disappeared and the vision returned to 20/20 1 year after treatment (63).

VII. CONTROLLED STUDIES

Information from the above studies confirmed that laser can promote drusen reduction. However, the visual benefit of prophylactic laser was not proven. These reports do not provide enough evidence to support laser treatment in eyes with drusen outside the context of a clinical trial. Frennesson and Little conducted small randomized trials. The Choroidal Neovascularization Prevention Trial (CNVPT) is the largest clinical trial to date. These studies are described below.

Frennesson and Nilsson conducted a randomized, prospective study of prophylactic laser treatment (51). One eye of 13 patients with bilateral soft drusen was treated. In a second group, the fellow eye of six patients with a diskiform lesion in the other eye was treated. The control group consisted of 19 patients who had been randomized to observation. The groups were matched for age and visual acuity but there were more men in the treatment group. The visual acuity in all treated eyes was 20/25 or better. Patients with macular pigment clumping, atrophy, pigment epithelial detachments, or exudative AMD were excluded. A horseshoe-shaped grid pattern with direct drusen treatment as well as scatter treatment was applied with argon green laser. Laser parameters were a spot size of 200 microns, duration of 0.05 s, and power of 100–200 mW. The number of laser spots varied from 51 to 154. The intensity was calibrated to achieve a “grayish reaction.” Drusen area on color fundus photographs and fluorescein angiograms was calculated at baseline and follow-up for both groups. Follow-up results were published at 6 months, 12 months, and 3 years (51–53). The mean drusen area significantly decreased in the treated eyes and significantly increased in the control eyes. Over 3 years, five eyes (33%) in the control group developed CNV, while no eyes did in the treatment group. This study demonstrated that laser treatment promotes drusen resorption, which had also been shown in the above studies. Importantly, it suggested that laser prophylaxis might prevent the exudative complications of AMD. However, as with the above studies, the sample size was small and the confidence interval large, which made it difficult to draw valid conclusions (53).

Little et al. randomized one eye of 27 patients with bilateral confluent soft drusen to prophylactic treatment. The mean age of patients was 69.7 years. The minimal visual acuity was 20/60 and the mean follow-up time 3.2 years. Foveal atrophy, pigment epithelial detachments, and exudative changes were exclusionary criteria. Drusen were directly treated. Laser settings for the dye laser (577–620 nm) were a spot size of 100–200 microns, power of 100–200 mW (calibrated to induce a slight lightening of the RPE/outer retina), and duration of 0.05–0.1 s. No laser spots were applied within 300 microns of the foveal center and rarely within 500 microns. Twenty-three to 526 laser spots were applied. Thirtyseven percent of eyes were treated with more than one session. Six treated eyes and no control eyes improved (2) or more lines. Sixteen treated and 17 control eyes remained stable. Five treated and 10 control eyes lost two or more lines. Drusen resorption within 1500 microns of the fovea occurred “more completely” in the treated eyes than control eyes in 22 eyes. In five eyes of both groups, there was equal drusen disappearance. Four control patients and two treated patients developed CNV. Laser scar enlargement occurred in three eyes. It was again difficult to draw conclusions from this study because of a small sample size but visual acuity and drusen resorption were significantly better in the treated eyes (56).

The Choroidal Neovascularization Prevention Trial is the largest pilot study to date to examine the potential treatment benefit of laser to drusen (46,55,64). A total of 156 patients without exudative AMD and with 10 or more large drusen ( 63 microns) in each eye

Figure 4 Six-month color fundus photographs show no significant change in drusen in either eye. Visual acuity remains 20/30 OU. See also color insert, Fig. 18.4.

Figure 5 Twelve-month color fundus photographs show marked resolution of drusen in the treated left eye. The right eye remains stable with no significant change in dursen. Visual acuity is 20/30 OD and 20/20 OS. See also color insert, Fig. 18.5.

A B

Figure 6 (A) Baseline fundus photograph demonstrating multiple, large drusen. The eye was treated with 20 laser spots in the temporal macula per the CNVPT protocol. (B) Six months later there is significant drusen reduction and the vision has changed from 20/32 to 20/25. See also color insert, Fig. 18.6A, B.

sidered as having occurred only when there was evidence of dye leakage on fluorescein angiography. Changes in drusen characteristics also were assessed through a comparison of photographs taken at baseline and the particular follow-up visit under consideration. These comparisons were performed to determine whether the total area of drusen was the same as, more, or less than at baseline and whether there were new areas of drusen or areas of drusen that had disappeared. Each eye was also graded for reduction of 50% or more in the area of drusen relative to baseline (65).

The CNVPT protocol specified that eyes assigned to treatment be retreated at 6 months if the area of drusen had not decreased by 50% from baseline. At 6 months, 28% of 78 eyes in the Bilateral Drusen Study and 41% of 37 eyes in the Fellow Eye Study had a 50% reduction in drusen and were exempt from retreatment. By 12 months, 54% of 35 eyes in the Bilateral Drusen Study and 27% of 11 in the Fellow Eye Study had a 50% reduction. One eye in the observed group had a 50% reduction in drusen area. Less than 10% of treated eyes and more than 90% of observed eyes showed no reduction in the area of drusen at 12 months (46).

Recruitment was halted for both the Bilateral Drusen Study and the Fellow Eye Study because of increased rates of CNV formation in the Fellow Eye Study. In the Fellow Eye Study, there were 10 treated eyes and two observed eyes with CNV development (p 0.02). In the Bilateral Drusen Study, there were four treated eyes and two observed eyes that developed CNV (p 0.69) (46). The estimated cumulative proportion of eyes with CNV in each treatment group was calculated. For eyes in the Bilateral Drusen Study, the estimated percentage of eyes with CNV at 1 year was 5% in the treated group and 2% in the observed group (p 0.42). The relative risk estimate was 2.00 (95% confidence interval: 0.37, 10.96). For eyes in the Fellow Eye Study, the estimated percentage of eyes with CNV at 1 year was 24% in the treated group and 2% in the observed group (p 0.02). The relative risk estimate was 4.86 (95% confidence interval: 1.10, 21.57). Thus, although a statistically significant imbalance of CNV between treatment and observed groups was noted for the Fellow Eye Study, this was not the case for the Bilateral Drusen Study (64).

The simultaneous influence of selected baseline covariates and treatment group on the incidence of CNV was examined with the Cox proportional hazards model. The intensity of the laser burns applied at baseline and 6 months had been graded for 74% of the eyes assigned to laser treatment. Eleven of these eyes had developed CNV. Four of the 11 eyes had burns graded as below the intensity standard. The other seven eyes had laser burns graded as meeting the intensity standard. From this information, laser intensity as determined in the CNVPT did not seem to have a significant effect on the development of CNV. Patient age, gender, hypertension status, aspirin use, vitamin and mineral supplement usage, cigarette smoking history, drusen number and size, and presence of focal hyperpigmentation were also examined. None of the factors other than treatment group had a significant effect on the incidence of CNV (65).

Only one (7%) of the 14 eyes assigned to treatment that developed CNV had a lesion with a purely classic pattern of fluorescein leakage on angiography; this eye had a lesion1 disk area that appeared to emanate from a treatment burn. The majority of eyes, laser treated or control, that developed CNV revealed at least some occult pattern of leakage (Fig. 7A and B). At the time the CNV was first documented, three (21%) of the 14 eyes assigned to treatment had subfoveal involvement and nine (90%) of the 10 eyes for which location could be determined accurately had CNV within the general area of laser treatment. All but one of the eyes in the group assigned to treatment had been treated under the Laser

A

B

Figure 7 (A) Color fundus photograph 6 months after CNVPT laser treatment showing submacular fluid and the visual acuity has dropped from 20/20 to 20/60. (B) Fluorescein angiography shows a fibrovascular pigment epithelial detachment. See also color insert, Fig. 18.7A.

20 protocol. Three of the four eyes that developed CNV in the group assigned to observation had subfoveal involvement (64).

Because follow-up of patients in the CNVPT remains limited beyond 1 year, only preliminary information regarding visual acuity and change in visual acuity are available. In the Bilateral Drusen Study, there was little change in the distribution of visual acuity through 12 months. In the Fellow Eye Study, the proportion of observed eyes with 20/20 or better visual acuity decreased over follow-up time, while the proportion of such eyes in the treated group remained relatively stable.

The distributions of the change in visual acuity at follow-up examinations through 18 months were examined. There were no substantial differences between treated and untreated eyes in the Bilateral Drusen Study at any of the follow-up times. The eyes in the Fellow Eye Study showed a different pattern. There was a higher percentage of eyes with a decrease in visual acuity in the group assigned to observation at 12 and 18 months. The difference achieved nominal statistical significance (p 0.02) at 18 months. The reasons for the loss of two or more lines of visual acuity at 18 months for the six observed eyes were investigated. Two of the eyes had increased pigment, nongeographical atrophy, or

drusen; and one each developed CNV, was classified ineligible at baseline because of geographical atrophy within 500 microns of the foveal center, or had a drusenoid pigment epithelial detachment. No reason for the loss in visual acuity could be identified for one eye. Four of the eyes in the Fellow Eye Study assigned to treatment that developed CNV had not yet had additional follow-up after the CNV was noted and only two had 12 months of follow-up.

Interestingly, a comparison of eyes with laser-induced drusen reduction to eyes without drusen reduction showed that eyes with drusen reduction had modest improvements of visual acuity at 1 year (55). These preliminary results do not justify laser treatment of drusen, particularly since eyes that developed CNV were excluded from this analysis, but they certainly are intriguing early observations. Longer follow-up is required.

With the efforts of 16 clinical centers from around the country, the CNVPT Study Group has enrolled 276 patients. The increased incidence of CNV in lasertreated eyes of the Fellow Eye Study prompted the halting of new recruitment in December 1996. Follow-up will continue to determine whether the relative rates of CNV in laser-treated and control eyes will change or remain consistent with the preliminary data described above. Most importantly, these patients will be followed to determine long-term visual results.

The initial increased incidence of CNV in laser-treated eyes in the Fellow Eye Study is intriguing. Although fellow eyes are known to be at a higher risk for development of CNV than eyes with bilateral drusen, the results thus far with laser treatment were unexpected. Interestingly, fellow eyes and bilateral drusen eyes were similar from the standpoint of clinical fundus features as measured in the CNVPT. It may be that some of the fellow eyes harbored undetected CNV, which was then stimulated by laser photocoagulation. We did not perform indocyanine green (ICG) angiography in this study, although recent reports have suggested that eyes with drusen may demonstrate plaque lesions that go on to frank CNV (66). Fellow eyes may represent a group of patients with more advanced AMD who are less amenable to prophylaxis, as suggested by Sarks et al. (20,57). Other groups have specifically targeted macular drusen with laser treatment while the CNVPT treatment strategy resulted in laser treatment between and sometimes directly on drusen. It is possible that differences in laser intensity or laser treatment strategy could account for the increased rate of CNV observed in the CNVPT Fellow Eye Study.

VIII. COMPLICATIONS

The above studies showed that prophylactic laser to drusen can be associated with CNV and atrophy. Furthermore, Hyver et al. reported the development of a granular subfoveal material after laser photocoagulation. The patient had CNV in one eye and large, confluent soft drusen in the fellow eye. Twenty-four burns were placed in the temporal macula. There was no direct drusen treatment. The burn intensity was calibrated to create barely visible whitening. Using a 630-nm wavelength, the setting was a power of 200 mW, duration of 0.05 s and spot size of 200 microns. Ten months after treatment the visual acuity had dropped from 20/25 to 20/60 and there was a granular subfoveal material. There was no CNV on fluorescein angiography (67). The Drusen Laser Study reported seven eyes that developed CNV after laser photocoagulation for drusen. No control eyes in this randomized, controlled trial developed CNV (68). Brancato et al. reported a case of CNV that developed 7 months after prophylactic laser to drusen. The patient had a baseline fluorescein

(FA) and (ICG) angiography. The FA had no CNV but the ICG showed a suspicious one-disk area of hyperfluorescence. The drusen temporal to the fovea were directly treated with krypton red laser. At 7 months, the patient’s vision dropped secondary to an occult CNV by fluorescein angiography. The ICG showed a two-disk-area plaque of hyperfluorescence whose border corresponded to the lesion observed on the baseline ICG. The laser was felt to have possibly exacerbated an underlying occult CNV (66). Indeed, laser photocoagulation is used to induce experimental CNV (69). Seven days after krypton photocoagulation to the posterior fundus of rats, Pollack et al. showed full-thickness defects in BM. It was unclear whether laser photocoagulation or cellular processes caused the defects (70). Regardless, full-thickness breaks are associated with CNV development.

IX. FUTURE DEVELOPMENTS

Because the randomized results from the CNVPT Bilateral Drusen Study and the results from the other groups suggest no harm and possibly even visual benefit, the CNVPT Study Group is planning a definitive trial of laser treatment in patients with bilateral drusen. At this time, our inability to manage exudative AMD effectively and the potential public health impact of a prophylactic therapy for AMD are very compelling reasons to continue to investigate this potential therapy. It is estimated that a 33% reduction of the rate of development of CNV in patients with bilateral drusen could halve the rate of bilateral blindness in this population (4).

The Complications of Age-Related Macular Degeneration Prevention Trial (CAPT), a National Eye Institute sponsored clinical trial, will enroll 1000 patients with bilateral drusen and assign one eye of each patient to light laser photocoagulation and the other eye to observation. Approximately 24 clinical centers around the United States will participate to determine the value of this therapy. As in the CNVPT, visual acuity will be the primary outcome of interest.

X.SUMMARY

A prophylactic treatment for AMD is highly desirable and would have significant public health impact. Laser photocoagulation to eyes with large drusen can induce dissolution of drusen. Although the optimal laser delivery characteristics are not known, lower intensity laser is preferred. Laser-induced drusen reduction may effect modest improvements in visual function.

The overall value of laser to drusen still requires study within the context of well-de- signed clinical trials. We need to evaluate results from definitive clinical trials before we can routinely recommend laser to drusen for our patients.

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