Subthreshold Nanosecond Laser Intervention in Age-Related Macular Degeneration: The LEAD Randomized Controlled Clinical Trial.

PURPOSE: There is an urgent need for a more effective intervention to slow or prevent progression of age-related macular degeneration (AMD) from its early stages to vision-threatening late complications. Subthreshold nanosecond laser (SNL) treatment has shown promise in preclinical studies and a pilot study in intermediate AMD (iAMD) as a potential treatment. We aimed to evaluate the safety of SNL treatment in iAMD and its efficacy for slowing progression to late AMD. DESIGN: The Laser Intervention in Early Stages of Age-Related Macular Degeneration (LEAD) study is a 36-month, multicenter, randomized, sham-controlled trial. PARTICIPANTS: Two hundred ninety-two participants with bilateral large drusen and without OCT signs of atrophy. METHODS: Participants were assigned randomly to receive Retinal Rejuvenation Therapy (2RT®; Ellex Pty Ltd, Adelaide, Australia) SNL or sham treatment to the study eye at 6-monthly intervals. MAIN OUTCOME MEASURES: The primary efficacy outcome was the time to development of late AMD defined by multimodal imaging (MMI). Safety was assessed by adverse events. RESULTS: Overall, progression to late AMD was not slowed significantly with SNL treatment compared with sham treatment (adjusted hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.33-1.14; P = 0.122). However, a post hoc analysis showed evidence of effect modification based on the coexistence of reticular pseudodrusen (RPD; adjusted interaction P = 0.002), where progression was slowed for the 222 participants (76.0%) without coexistent RPD at baseline (adjusted HR, 0.23; 95% CI, 0.09-0.59; P = 0.002), whereas an increased progression rate (adjusted HR, 2.56; 95% CI, 0.80-8.18; P = 0.112) was observed for the 70 participants (24.0%) with RPD with SNL treatment. Differences between the groups in serious adverse events were not significant. CONCLUSIONS: In participants with iAMD without MMI-detected signs of late AMD, no significant difference in the overall progression rate to late AMD between those receiving SNL and sham treatment were observed. However, SNL treatment may have a role in slowing progression for those without coexistent RPD and may be inappropriate in those with RPD, warranting caution when considering treatment in clinical phenotypes with RPD. Our findings provide compelling evidence for further trials of the 2RT® laser, but they should not be extrapolated to other short-pulse lasers.

Laser treatment of drusen to prevent progression to advanced age-related macular degeneration.

BACKGROUND: Drusen are amorphous yellowish deposits beneath the sensory retina. People with drusen, particularly large drusen, are at higher risk of developing age-related macular degeneration (AMD). The most common complication in AMD is choroidal neovascularisation (CNV), the growth of new blood vessels in the centre of the macula. The risk of CNV is higher among people who are already affected by CNV in one eye.It has been observed clinically that laser photocoagulation of drusen leads to their disappearance and may prevent the occurrence of advanced disease (CNV or geographic atrophy) associated with visual loss. OBJECTIVES: To examine the effectiveness and adverse effects of laser photocoagulation of drusen in AMD. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2015, Issue 7), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to August 2015), EMBASE (January 1980 to August 2015), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to August 2015), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 3 August 2015. SELECTION CRITERIA: Randomised controlled trials (RCTs) of laser treatment of drusen in AMD in which laser treatment had been compared with no intervention or sham treatment. Two types of trials were included. Some trials studied one eye of each participant (unilateral studies); other studies recruited participants with bilateral drusen and randomised one eye to photocoagulation or control and the fellow eye to the other group. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies and extracted data. We pooled data from unilateral and bilateral studies using a random-effects model. For the bilateral studies, we estimated the within-person correlation coefficient from one study and assumed it was valid for the others. MAIN RESULTS: The update of this review found two additional studies, totaling 11 studies that randomised 2159 participants (3580 eyes) and followed them up to two years, of which six studies (1454 participants) included people with one eye randomised to treatment and one to control. Studies were conducted in Australia, Europe and North America.Overall, the risk of bias in the included studies was low, particularly for the larger studies and for the primary outcome development of CNV. Photocoagulation did not reduce the development of CNV at two years' follow-up (odds ratio (OR) 1.07, 95% confidence interval (CI) 0.79 to 1.46, 11 studies, 2159 participants (3580 eyes), high quality evidence). This estimate means that, given an overall occurrence of CNV of 8.3% in the control group, we estimated an absolute risk reduction by no more than 1.4% in the laser group, according to the lower CI limit. Only two studies investigated the effect on the development of geographic atrophy and could not show a difference, but estimates were imprecise (OR 1.30, 95% CI 0.38 to 4.51, two studies, 148 participants (148 eyes), low quality evidence).Among secondary outcomes, photocoagulation led to drusen reduction (OR 9.16, 95% CI 6.28 to 13.4, three studies, 570 participants (944 eyes), high quality evidence) but was not shown to limit loss of 3 or more lines of visual acuity (OR 0.99, 95% CI 0.81 to 1.22, nine studies, 2002 participants (2386 eyes), moderate quality evidence).In a subgroup analysis, no difference could be shown for conventional visible (eight studies) versus subthreshold invisible (four studies) photocoagulation for the primary outcomes (P value = 0.29). The effect in the subthreshold group did not suggest a relevant benefit (OR 1.27, 95% CI 0.82 to 1.98). No study used micropulse subthreshold photocoagulation.No other adverse effects (apart from development of CNV, geographic atrophy or visual loss) were reported. AUTHORS' CONCLUSIONS: The trials included in this review confirm the clinical observation that laser photocoagulation of drusen leads to their disappearance. However, treatment does not result in a reduction in the risk of developing CNV, and was not shown to limit the occurrence of geographic atrophy or visual acuity loss.Ongoing studies are being conducted to assess whether the use of extremely short laser pulses (i.e. nanosecond laser treatment) cannot only lead to drusen regression but also prevent neovascular AMD.

Disappearance of soft drusen and subsequent development of choroidal neovascularization following macular hole surgery: a case report.

BACKGROUND: Drusen are important risk factor for neovascular age-related macular degeneration (AMD) and have a dynamic nature as they can enlarge, newly form, or disappear over time. There have been few reports on drusen regression or choroidal neovascularization (CNV) development after macular hole surgery. We report, to our knowledge, the first case of both drusen regression and subsequent CNV development within 7 months of successful macular hole surgery. CASE PRESENTATION: A 73-year-old woman presented with a stage 3 full-thickness macular hole and large, confluent soft macular drusen in the right eye and a neovascular age-related macular degeneration (AMD) in the fellow eye. Four months after the successful macular hole surgery, significant regression of drusen was seen, especially in the temporal area to the fovea. Three months later, the patient developed CNV and her best-corrected visual acuity decreased to 20/100, despite further regression of macular drusen. CONCLUSIONS: Macular hole patients with macular soft drusen need to be carefully followed up after surgery for possible drusen regression and CNV development.

Long-term SD-OCT/SLO imaging of neuroretina and retinal pigment epithelium after subthreshold infrared laser treatment of drusen.

PURPOSE: The purpose of this study was to determine the long-term effect of subthreshold diode laser treatment for drusen in patients with nonexudative age-related macular degeneration with spectral domain optical coherence tomography combined with simultaneous scanning laser ophthalmoscope. METHODS: Eight eyes of four consecutive age-related macular degeneration patients with bilateral drusen previously treated with subthreshold diode laser were imaged with spectral domain optical coherence tomography/scanning laser ophthalmoscope. Abnormalities in the outer retinal layers' reflectivity as seen with spectral domain optical coherence tomography/scanning laser ophthalmoscope were retrospectively analyzed and compared with color fundus pictures, and autofluorescence images were acquired immediately before and after the laser treatment. RESULTS: A focal discrete disruption in the reflectivity of the outer retinal layers was noted in 29% of the laser lesions. The junction in between the inner and outer segment of the photoreceptor was more frequently affected, with associated focal damage of the outer nuclear layer. Defects of the retinal pigment epithelium were occasionally detected. These changes did not correspond to threshold burns on color fundus photography but corresponded to focal areas of increased autofluorescence in the majority of the cases. CONCLUSION: Subthreshold diode laser treatment causes long-term disruption of the retinal photoreceptor layer as analyzed by spectral domain optical coherence tomography/scanning laser ophthalmoscope. The concept that subthreshold laser treatment can achieve a selected retinal pigment epithelium effect without damage to rods and cones may be flawed.

Subthreshold laser treatment for reticular pseudodrusen secondary to age-related macular degeneration.

There is a lack of treatment aimed at the regression of reticular pseudodrusen (RPD) secondary to age-related macular degeneration (AMD). The aim of this prospective, pilot study is to evaluate the safety and short-term efficacy of subthreshold laser treatment (SLT) in patients affected by RPD secondary to dry AMD (dAMD). Twenty eyes of 20 patients (mean age 78.4 ± 6.8 years) with RPD secondary to dAMD were prospectively enrolled. All patients were treated in an extrafoveal area of 1.27 mm2 using end-point management yellow subthreshold laser and followed for 3 months. Best-corrected visual acuity was 0.140 ± 0.09 LogMAR at the baseline and no changes were observed during the follow-up (p = 0.232). No significant worsening was disclosed before and after the treatment analyzing the macular sensitivity of the treated area (p = 0.152). No topical and/or systemic side effects were disclosed during the 3-month follow-up. The distribution among the RPD stages changed after the treatment (p < 0.001). In detail, in the treated area, we observed a significant increase in the number of Stage 1 RPD during the follow-up (p = 0.002), associated with a significant decrease of Stage 3 RPD (p = 0.020). Outer nuclear layer (ONL) thickness analysis showed a significant increase after the treatment associated with RPD regression (p = 0.001). End-point management SLT appears a safe treatment for RPD secondary to dAMD, showing short-term safety outcomes. Our results suggest that SLT could be effective in inducing a RPD regression in terms of RPD stage and ONL thickening.

Subthreshold Nanosecond Laser in Age-Related Macular Degeneration: Observational Extension Study of the LEAD Clinical Trial.

PURPOSE: To evaluate the long-term effect of subthreshold nanosecond laser (SNL) treatment on progression to late age-related macular degeneration (AMD). DESIGN: Observational extension study of a randomized, sham-controlled trial. PARTICIPANTS: Two hundred twelve participants with bilateral large drusen. METHODS: The Laser Intervention in the Early Stages of AMD (LEAD) study was a 36-month trial where participants were randomized to receive SNL or sham treatment in 1 eye at 6-monthly intervals up to 30 months. After the completion of the LEAD study, the 2 largest recruiting sites offered remaining participants an opportunity to enroll in a 24-month observational extension study. This study thus examined all participants from these 2 sites who were enrolled in the LEAD study at baseline, including the additional observational data. MAIN OUTCOME MEASURES: Time to develop late AMD, defined on multimodal imaging, between those randomized the SNL or sham treatment. RESULTS: Overall, no significant difference was found in the rate of progression over a 60-month period in those randomized to the SNL compared with the sham group (adjusted hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.36-1.09; P = 0.098), similar to the findings at 36 months in the LEAD Study. However, evidence of treatment effect modification continued to emerge based on the coexistence of reticular pseudodrusen (RPD; P = 0.007, adjusted interaction). Namely, progression was slowed significantly with SNL treatment for those without coexistent RPD (adjusted HR, 0.34; 95% CI, 0.16-0.71; P = 0.004), but it was not significantly different for those with RPD (adjusted HR, 1.81; 95% CI, 0.67-4.88; P = 0.239). CONCLUSIONS: A 24-month observational extension study to the LEAD Study confirmed that SNL treatment did not significantly reduce the overall rate of progression to late AMD in a cohort with intermediate AMD. However, the persistence of a potential beneficial treatment effect in those without coexistent RPD over a longer follow-up duration of an additional 24 months without additional treatment is encouraging. These findings provide further justification for future trials to examine the potential value of SNL treatment for slowing progression in intermediate AMD.

Laser treatment of drusen to prevent progression to advanced age-related macular degeneration.

BACKGROUND: Drusen are amorphous yellowish deposits beneath the sensory retina. People with drusen, particularly large drusen, are at higher risk of developing age-related macular degeneration (AMD). The most common complication in AMD is choroidal neovascularisation (CNV), the growth of new blood vessels in the centre of the macula. The risk of CNV is higher among patients who are already affected by CNV in one eye.It has been observed clinically that laser photocoagulation of drusen leads to their disappearance and may prevent the occurrence of advanced disease (CNV or geographic atrophy) associated with visual loss. OBJECTIVES: To examine the effectiveness and adverse effects of laser photocoagulation of drusen in AMD. SEARCH STRATEGY: We searched CENTRAL, MEDLINE and EMBASE on 14 November 2008. SELECTION CRITERIA: Randomised controlled trials (RCTs) of laser treatment of drusen in AMD in which laser treatment had been compared with no intervention or sham treatment. Two types of trials were included. Some trials studied one eye of each patient (unilateral studies); other studies recruited patients with bilateral drusen and randomised one eye to photocoagulation or control and the fellow eye to the other group. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies and extracted data. We pooled data from unilateral and bilateral studies using a random-effects model. For the bilateral studies, we estimated the within-patient correlation coefficient from one study and assumed it was valid for the others. MAIN RESULTS: We found nine studies which randomised 2216 people: four unilateral trials, three bilateral trials and two trials that included both a unilateral and a bilateral study arm.Overall, the studies were of moderate quality. Only half of the trials reported adequate allocation sequence generation, allocation concealment and masking of visual acuity outcome assessors.Although two (of the nine) studies reported significant drusen disappearance at two years, photocoagulation did not appear to affect the development of CNV at two years follow up (nine studies, 1767 people followed up, odds ratio (OR) 1.04, 95% CI 0.71 to 1.51) or the loss of three or more lines of visual acuity (six studies, 1628 people followed up, OR 1.17, 95% CI 0.75 to 1.82). AUTHORS' CONCLUSIONS: The trials included in this review confirm the clinical observation that laser photocoagulation of drusen leads to their disappearance. However, there is no evidence that this subsequently results in a reduction in the risk of developing CNV, geographic atrophy or visual acuity loss.

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.

Preventing Progression in Nonexudative Age-Related Macular Degeneration With Subthreshold Laser Therapy: A Systematic Review.

BACKGROUND AND OBJECTIVE: Age-related macular degeneration (AMD) is the leading cause of irreversible blindness among the elderly in developed countries. Subthreshold retinal laser therapy is a new technique that targets drusen - a marker of nonexudative AMD - without causing incidental retinal damage associated with conventional laser photocoagulation. This review summarizes published literature on subthreshold retinal laser therapy as prophylactic treatment of nonexudative AMD. PATIENTS AND METHODS: A literature search of the PubMed, Medline, and Embase databases was conducted from January 1997 to April 2018. Studies were analyzed based upon study design, laser parameters, drusen reduction, changes in visual acuity (VA), and the development of choroidal neovascularization (CNV) and/or geographic atrophy (GA). RESULTS: Twelve studies involving 2,481 eyes treated with subthreshold retinal laser therapy were included in this review. Treatment led to increased drusen reduction, and studies with significant VA improvement were associated with significant drusen reduction. There was no significant change in the risk of developing CNV or GA. CONCLUSIONS: Subthreshold retinal laser therapy is effective for reducing drusen and potentially improving vision in patients with nonexudative AMD. This therapy does not show benefits in reducing development of CNV or GA. Thus, its long-term efficacy to prevent progression to advanced AMD cannot yet be recommended. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:e61-e70.].

Secondary and Exploratory Outcomes of the Subthreshold Nanosecond Laser Intervention Randomized Trial in Age-Related Macular Degeneration: A LEAD Study Report.

PURPOSE: To evaluate the secondary and exploratory outcomes of the Laser Intervention in Early Stages of Age-Related Macular Degeneration (LEAD) study, a 36-month trial of a subthreshold nanosecond laser (SNL) treatment for slowing the progression to late age-related macular degeneration (AMD) in its early stages. DESIGN: Multicenter, randomized, sham-controlled trial. PARTICIPANTS: Two-hundred ninety-two patients with bilateral large drusen. METHODS: Participants were randomly assigned to receive SNL or sham treatment to the study eye at 6-month intervals. MAIN OUTCOME MEASURES: The secondary outcome measure of the LEAD study was the time to development of late AMD, defined by multimodal imaging in the non-study eye. The exploratory outcome measures were the rate of change in best-corrected visual acuity (BCVA), low-luminance visual acuity, microperimetric mean sensitivity, drusen volume in the study and non-study eyes, and participant-reported outcomes based on the Night Vision Questionnaire and Impact of Vision Impairment questionnaire. RESULTS: Progression to late AMD in the non-study eye was not significantly delayed with SNL treatment (hazard ratio, 0.83; 95% confidence interval, 0.40-1.71; P = 0.611). There was no evidence of effect modification based on the coexistence of reticular pseudodrusen; interaction P = 0.065). There was no significant difference between study groups in the rate of change of low-luminance visual acuity, microperimetric mean sensitivity, and drusen volume in the study or non-study eyes, and Night Vision Questionnaire and Impact of Vision Impairment questionnaire scores (all P ≥ 0.167). The rate of BCVA decline was slightly higher for participants in the SNL group compared with the sham treatment group in the study eye (-0.54 and 0.23 letters/year, respectively; P < 0.001) but not the non-study eye (-0.48 and -0.56 letters/year, respectively; P = 0.628). CONCLUSIONS: Subthreshold nanosecond laser treatment of one eye did not have an effect on delaying progression to late AMD in the fellow eye and did not, in general, have an impact on the exploratory structural, functional, and participant-reported outcomes.

[Prophylactic laser treatment to macular soft drusen in age-related maculopathy of updated results].

OBJECTIVE: To investigate the follow-up results of the prophylactic laser treatment to macular soft drusen in age-related macular degeneration. METHODS: Prospective, 10 persons with bilateral soft drusen and with good visual acuity were observed for 8 years. 10 eyes were treated. The fellow eyes were as control group. Fluorescein angiography and Amsler test were studied after 8 years. Scanning laser ophthalmoscope was performed after 2 years. Some of them were performed multifocal ERG to test the macular function after 3 years. RESULTS: There is no choroidal neovascularization in both the laser group and the control group. There is no differences in the best corrected visual acuity after 8 years. All eyes had good fovea fixation. Light sensitivity of both eyes had no significant difference to be found by scanning laser ophthalmoscope. The latencies and amplitude densities of the N1 and P1 waves in the central first ring remained unchanged at 3 years post-treatment (before treatment t = -0.779, 0.722, -0.491, 0.286; after treatment t = 1.342, 0.043, 0.937, 0.350; P > 0.05) compared with the fellow eyes. CONCLUSIONS: There is no impairment to be found in the macula after preventive laser treatment. The treatment did not demonstrate a clinically significant benefit for choroidal neovascularization in eyes of people with bilateral large drusen.

[Assessment of the clinical and functional results of laser coagulation of retinal drusen in the central zone of the eye grounds].

Macular drusen are known to be a major risk factor of age-related macular degeneration (ARMD) of the retina. The use of laser coagulation of macular drusen to prevent the progression of a dystrophic process remains to be disputable question so far. This paper presents the clinical and functional results of laser coagulation of macular drusen in 30 patients with bilateral retinal ARMD. The routine ophthalmological study, photorecording, fluorescence angiography of the fundus of the eye, optic coherent tomography, and electrophysiological studies indicated macular drusen regression, increased visual acuity, and better electrophysiological parameters. Choriodal neovascularization and exudative complications did not develop in both the early and late follow-up periods.

Photobiomodulation reduces drusen volume and improves visual acuity and contrast sensitivity in dry age-related macular degeneration.

PURPOSE: To evaluate the efficacy of photobiomodulation (PBM) treatment for patients with dry age-related macular degeneration (AMD). METHODS: Assessments on 42 eyes with dry AMD (age related eye disease study (AREDS) 2-4) were conducted. Multiwavelength light emitting diode (LED) light comprising of yellow (590 nm), red (670 nm) and near-infrared (790 nm) bandwidths was applied to subjects' eyes for a treatment course of 3 weeks. Outcome measures were changes in best-corrected visual acuity (BCVA), contrast sensitivity (CS), drusen volume and central drusen thickness. RESULTS: Significant improvement in mean BCVA of 5.90 letters (p < 0.001) was seen on completion of the 3-week treatment and 5.14 letters (p < 0.001) after 3 months. Contrast sensitivity improved significantly (log unit improvement of 0.11 (p = 0.02) at 3 weeks and 3 months (log unit improvement of 0.16 (p = 0.02) at three cycles per degree. Drusen volume decreased by 0.024 mm3 (p < 0.001) and central drusen thickness was significantly reduced by a mean of 3.78 µm (p < 0.001), while overall central retinal thickness and retinal volume remained stable. CONCLUSION: This is the first study demonstrating improvements in functional and anatomical outcomes in dry AMD subjects with PBM therapy. These findings corroborate an earlier pilot study that looked at functional outcome measures. The addition of anatomical evidence contributes to the basis for further development of a non-invasive PBM treatment for dry AMD.

Prophylactic treatment of age-related macular degeneration report number 1: 810-nanometer laser to eyes with drusen. Unilaterally eligible patients.

OBJECTIVE: To determine the effects of subthreshold 810-nm-diode laser treatment on the rate of development of choroidal neovascularization (primary end point) and the effect on visual acuity (VA) in participants with multiple large drusen in one eye and a preexisting neovascular age-related macular degeneration (AMD) lesion in the other. DESIGN: Multicenter, prospective, randomized controlled trial. PARTICIPANTS: Two hundred forty-four patients > or =50 years of age and with a neovascular or advanced AMD lesion in one eye and, in the fellow "study" eye, (1) at least 5 drusen > or = 63 mum in diameter, (2) Early Treatment Diabetic Retinopathy Study best-corrected VA (BCVA) of 20/63 or better, and (3) no evidence of neovascularization at baseline. METHODS: Patients were randomized to treatment or observation of their study eye at each of 22 centers. At each visit, the protocol specified that BCVA, a complete retinal examination, and fluorescein angiography be documented. Treated eyes had a grid of 48 extrafoveal, subthreshold diode (810 nm) laser spots, 125 mum in diameter, placed in an annulus outside of the foveola. Patients were seen at baseline and at 3, 6, 12, 18, 24, 30, and 36 months after randomization. No retreatments were allowed. MAIN OUTCOME MEASURES: Development of choroidal neovascularization (as confirmed by fluorescein angiography) and change in BCVA. RESULTS: Throughout follow-up, the rate of choroidal neovascularization events in treated eyes consistently exceeded that in observed eyes. At 1 year, the difference was 15.8% versus 1.4% (P = 0.05). Most of the intergroup differences in choroidal neovascularization events occurred during the first 2 years of follow-up. Treated eyes showed a higher rate of VA loss (> or =3 lines) at 3- and 6-month follow-ups relative to observed eyes (8.3% vs. 1% and 11.4% vs. 4%, respectively; Ps = 0.02, 0.07). After 6 months, no significant differences were observed in VA loss between groups. CONCLUSION: Prophylactic subthreshold 810-nm-diode laser treatment to an eye with multiple large drusen in a patient whose fellow eye has already suffered a neovascular event places the treated eye at higher risk of developing choroidal neovascularization. We advise against using prophylactic subthreshold diode laser treatment in these eyes.

Prophylactic laser treatment hastens choroidal neovascularization in unilateral age-related maculopathy: final results of the drusen laser study.

PURPOSE: The Drusen Laser Study evaluated macular laser to prevent choroidal neovascularization (CNV) and vision loss in high-risk age-related maculopathy (ARM). DESIGN: Prospective, interventional, randomized, controlled clinical trial in five hospital centers. METHODS: Patients in the unilateral group had neovascular ARM and drusen in the study eye. Study eyes were randomized to laser-treated or no-laser groups. For patients in the bilateral drusen group, eyes were randomized to right eye, laser or no laser; and left eye, alternative. Laser treatment comprised 12 argon spots. Outcome was best-corrected visual acuity and CNV signs, which were monitored for 3 years. RESULTS: In the unilateral group, vision loss occurred in 21 (28.8%) of 73 patients in laser vs 13 (19.7%) of 66 no-laser patients (P=.214). Incidence of CNV was 27 (29.7%) of 91 in laser vs 15 (17.65%) of 85 no-laser patients (P=.061). CNV onset was approximately 6 months earlier in laser-treated compared with no-laser patients (P=.05). In the bilateral group, vision loss occurred in six (8.3%) of 72 laser-treated vs 10 (13.9%) of 72 fellow eyes (P=.3877). CNV incidence was 12 (11.6%) of 103 in laser-treated vs seven (6.8%) of 103 fellow eyes (P=.225). There was no difference in onset of CNV. CONCLUSIONS: Results do not support prophylactic laser of the fellow eye of patients with neovascular ARM. Its role in patients with bilateral drusen remains unclear.

Laser burn intensity and the risk for choroidal neovascularization in the CNVPT Fellow Eye Study.

OBJECTIVE: To explore the relationship between laser burn intensity and the subsequent risk for development of choroidal neovascularization (CNV) in eyes assigned to the treatment group of the Fellow Eye Study (FES) of the Choroidal Neovascularization Prevention Trial (CNVPT), using computerized methods for laser burn quantitation, and to examine the association between laser burn intensity and (1) drusen reduction and (2) visual acuity. METHODS: Color fundus images before and immediately after laser treatment in the CNVPT FES were available for 53 of 59 eyes. Prelaser and postlaser treatment images were analyzed using custom-developed computer software, allowing for laser burn identification and quantitation. As measures of laser burn intensity, we derived integrated burn rating (IBR) (the integral of the normalized intensity difference divided by the burn pixels), and the maximum burn intensity (MAX). We identified CNV using fluorescein angiography. A Cox proportional hazards model was fit to the time to development of CNV. Baseline and 6-month color photographs were used to determine reduction in drusen. Visual acuity was measured using a standardized protocol. RESULTS: The IBR and MAX spanned 4.5 logarithm units. After adjusting for smoking history and predominant drusen size, the risk ratio for CNV per logarithm unit of increasing laser burn intensity for each measure was 2.0 (P =.05) for MAX and 1.7 (P =.07) for IBR. When patients were divided into high- and low-intensity treatment groups of equal size, the high-intensity group had more drusen reduction (57% vs 32%; P =.14). There was no effect of laser intensity on change in visual acuity at 6 months. CONCLUSION: Higher-intensity prophylactic laser applications appear to be associated with a greater risk for development of CNV and with more extensive drusen reduction.

Laser treatment in subjects with high-risk clinical features of age-related macular degeneration. Posterior pole appearance and retinal function.

OBJECTIVES: To verify that a few laser lesions in the posterior pole can cause drusen to resolve in patients with age-related macular degeneration, and to document central retinal sensitivity as drusen resolve. DESIGN: In a pilot study, 12 patients considered to be at high risk for sight-threatening complications from age-related macular degeneration were treated with 12 argon laser lesions in the posterior pole, with review for 12 to 24 months. RESULTS: Choroidal neovascularization developed in 1 patient 8 months after treatment, with consequent loss of central vision. In 9 of the remaining 11 patients, high-risk characteristics of drusen were reduced. Four patients had retinal pigment epithelial depigmentation, and all maintained 20/40 visual acuity at 12 months. One patient lost 3 lines of vision due to geographic atrophy after 12 months. Scotopic retinal threshold was elevated before treatment in 8 patients, compared with an age-matched comparison group. Of these, 4 patients underwent retesting 3 to 6 months after treatment, and all had improved thresholds, but only 1 patient sustained the improvement at 12 months. At 12 months, 3 of the 8 patients showed an improvement in their mean retinal threshold. Of those in whom the mean retinal threshold worsened, the mean elevation in threshold was not more than 0.6 log units. CONCLUSIONS: A few laser lesions in the posterior pole leads to resolution of drusen. There does not appear to be an increased risk for choroidal neovascularization. Retinal threshold measurements show no indication of geographic atrophy at 1 year, but cannot be excluded as a late outcome. Laser treatment may reduce the risk for profound sight-threatening lesions in age-related macular degeneration.

Mapping retinal fluorescein leakage with confocal scanning laser fluorometry of the human vitreous.

OBJECTIVE: To demonstrate an objective, quantitative, and sensitive method of mapping retinal fluorescein leakage into the vitreous while simultaneously imaging the retina. METHODS: A prototype Zeiss confocal scanning laser ophthalmoscope was modified to obtain fluorometric measurements from 18 optical planes across the retina and cortical vitreous, separated from each other by 150 microm, and parallel to the retinal surface. After intravenous administration of fluorescein, an axial graphic of equivalent fluorescein concentration in the vitreous may be obtained from any region of interest. After correcting for fluorescence levels in the retina and choroid and plasma levels of free fluorescein, permeability values of the blood-retinal barrier to fluorescein were obtained from 1512 regions measuring 75 x 75 microm, from a total 3150 x 2700-microm area of the fundus, generating a detailed map of retinal fluorescein leakage. The method was assessed in vitro and in 7 healthy subjects who underwent scans during separate visits. Depth resolution and influence of chorioretinal fluorescence were further tested in 2 patients with multiple drusen and in 2 eyes after vitrectomy. Fourteen eyes from 7 patients with diabetes and nonproliferative retinopathy were also examined. Lateral resolution was tested in 3 diabetic eyes that underwent focal photocoagulation. Four eyes from 2 patients with diabetes and minimal retinopathy were examined at 3-month intervals. All eyes examined had less than 2 diopters of astigmatism. RESULTS: Characteristics of the modified confocal scanning laser fluorometer included a lower limit of detection equal to 0.40 Eq ng/mL and depth precision of +/-15 microm. Values for the blood-retinal barrier permeability index in healthy subjects, measured 30 minutes after a single intravenous pulse of fluorescein (14 mg/kg), ranged from 1.3 +/- 0.4 x 10(-6) cm/s over the foveal avascular zone to 2.2 +/- 0.6 x 10(-6) cm/s over vessels in the retina. Diabetic eyes with retinopathy showed higher values, ranging from 1.4 to 15.0 x 10(-6) cm/s. Vitrectomized eyes and eyes with multiple drusen showed the validity of the correction algorithm demonstrating that measurements of fluorescence in the vitreous are not influenced by the chorioretinal fluorescence level. Argon laser photocoagulation burns placed in the diabetic retina demonstrated a lateral resolution on the order of 75 to 100 microm. Intravisit and intervisit reproducibility was +/-10.2% and +/-13%, respectively. CONCLUSIONS: This new method measures localized alterations of the blood-retinal barrier and allows for direct correlation with retinal anatomy. Its most interesting feature is the ability to map retinal fluorescein leakage while simultaneously imaging the retina. This capability is expected to improve our understanding and management of retinal disease.

Drusen in age-related macular degeneration: pathogenesis, natural course, and laser photocoagulation-induced regression.

Drusen are subretinal pigment epithelial deposits that are characteristic of but not uniquely associated with age-related macular degeneration (AMD). Age-related macular degeneration is associated with two types of drusen that have different clinical appearances and different prognoses. Hard drusen appear as small, punctate, yellow nodules and can precede the development of atrophic AMD. Areolar atrophy of the retinal pigment epithelium (RPE), choriocapillaris, and outer retina develop as the drusen disappear, but drusen can regress without evidence of atrophy. Soft drusen appear as large (usually larger than 63 microm in diameter), pale yellow or grayish-white, dome-shaped elevations that can resemble localized serous RPE detachments. They tend to precede the development of clinically evident RPE detachments and choroidal neovascularization. Drusen characteristics correlated with progression to exudative maculopathy include drusen number (five or more), drusen size (larger than 63 microm in diameter), and confluence of drusen. Focal hyperpigmentation in the macula and systemic hypertension also are associated with an increased risk of developing choroidal new vessels (CNVs). Large drusen are usually a sign of diffuse thickening of Bruch's membrane with basal linear deposit, a vesicular material that probably arises from the RPE, constitutes a diffusion barrier to water-soluble constituents in the plasma, results in lipidization of Bruch's membrane, and creates a potential cleavage plane between the RPE basement membrane and the inner collagenous layer of Bruch's membrane through which CNVs can grow. Disappearance of drusen spontaneously and in areas adjacent to laser photocoagulation scars was first noted by Gass (Gass JD: Arch Ophthalmol 90:206-217, 1973; Trans Am Acad Ophthalmol Otolaryngol 75:580-608, 1971). Subsequent reports have confirmed these observations. Photocoagulation-induced drusen regression might prevent patients with drusen from developing exudative maculopathy. The mechanism for spontaneous drusen regression probably involves RPE atrophy. The mechanism for photocoagulation-induced drusen regression is unknown. If photocoagulation-induced drusen regression is anatomically similar to atrophy-associated drusen regression, then the former will be associated with dissolution of basal linear deposit and a residuum of basal laminar deposit. Sarks and coworkers (Sarks JP, Sarks SH, Killingsworth MC: Eye 11:515-522, 1997) proposed that this in turn will eliminate the potential cleavage plane between the RPE basement membrane and inner collagenous layer of Bruch's membrane through which CNVs grow, thus retarding the growth of CNVs.

Hyperfluorescent plaque lesions in the late phases of indocyanine green angiography: a possible contraindication to the laser treatment of drusen.

PURPOSE: To highlight the possible role of indocyanine green angiography in predicting future exudative changes in eyes that are candidates for drusen laser treatment. METHODS: In a 56-year-old woman, fluorescein and indocyanine green angiography were performed before drusen laser treatment. RESULTS: The treated eye had a suspicious lesion at baseline indocyanine green angiography and a nonsuspicious fluoroangiographic pattern. Seven months after treatment, the patient developed choroidal neovascularization and pigment epithelial detachment in the treated eye. CONCLUSION: To decrease the risk of macular exudative changes that may be related to laser treatment, eyes that are candidates for drusen laser treatment should be examined before treatment, not only by fluorescein angiography, but also by indocyanine green angiography.