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.

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.

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.

Early worsening of diabetic retinopathy due to intensive glycaemic control.

The prevalence of diabetes and diabetic retinopathy is increasing around the world. Glycaemic control is important in reducing the long-term risk of complications of diabetes, however intensive glycaemic control, particularly in patients with longstanding and poorly controlled diabetes, is associated with the risk of early worsening of diabetic retinopathy and vision loss. We present two clinical cases to illustrate the presentation of early worsening and to highlight a role for intravitreal anti-vascular endothelial growth factor therapies in ameliorating this phenomenon, as well as a review of the current understanding of this phenomenon. We emphasise the importance of identifying individuals at risk of early worsening of diabetic retinopathy and recommend regular ophthalmological review during the period of intensive glycaemic control to ensure optimal visual outcomes.

Interpretation of Subretinal Fluid Using OCT in Intermediate Age-Related Macular Degeneration.

PURPOSE: To determine the natural history of asymptomatic, subretinal fluid (SRF) in intermediate age-related macular degeneration (iAMD) and highlight the entity of nonexudative detachment of the neurosensory retina (NEDNR). DESIGN: Prospective, observational case series. PARTICIPANTS: Cases of iAMD with bilateral drusen >125 µm who were participating in a longitudinal study, in whom spectral-domain (SD)-OCT imaging detected asymptomatic SRF. METHODS: Participants underwent clinical examinations every 6 months with multimodal imaging that included infrared reflectance, fundus autofluorescence, and SD-OCT. The grading center identified eyes with SRF. Eyes with SRF ≤30 µm were monitored more regularly, whereas eyes with SRF >30 µm underwent fluorescein angiography (FA) and indocyanine green angiography (ICGA). Subretinal fluid without evidence of neovascularization or polyp was termed "NEDNR". All cases of SRF underwent swept-source OCT angiography (SS-OCTA) to determine if choroidal neovascularization (CNV) was present and were then followed prospectively. MAIN OUTCOME MEASURES: Natural history of iAMD eyes with SRF that had no evidence of neovascularization during the monitoring period of 30 to 54 months. RESULTS: Sixteen eyes of 12 patients with iAMD developed asymptomatic SRF over a follow-up period of 30 to 54 months. Four eyes developed occult CNV on FA and were no longer followed in this study. Four eyes developed SRF ≤30 µm, and 8 eyes developed SRF >30 µm, with 11 of the 12 eyes developing subretinal hyperreflective material (SHRM). None of these 12 eyes showed any evidence of neovascularization at the initial detection of SRF and were termed "NEDNR". During the follow-up period of 12 to 36 months after the onset of SRF, only 1 eye developed exudative CNV. The remaining 11 eyes failed to demonstrate any abnormal choroidal vasculature on SS-OCTA, including 4 eyes with cuticular drusen in which SHRM developed into a large subfoveal vitelliform-like deposit. CONCLUSIONS: Multimodal imaging is helpful for the interpretation and management of asymptomatic SRF in iAMD. In some eyes, all imaging, including SS-OCTA, failed to demonstrate subclinical neovascularization, and we use the acronym NEDNR to describe these cases. This phenotype within iAMD needs to be recognized and monitored to determine if and when treatment might be needed.

Factors promoting success and influencing complications in laser-induced central vein bypass.

PURPOSE: To evaluate the factors influencing the successful creation of a laser-induced chorioretinal venous anastomosis (L-CRA) and those involved in the development of complications. DESIGN: Interventional cohort study. PARTICIPANTS: Fifty-five patients with a nonischemic central retinal vein occlusion (CRVO) who were randomized to receive an L-CRA from the total of 108 who completed the follow-up period of the Central Vein Bypass Study. METHODS: Patients who were randomized to L-CRA were followed up for an 18-month period. They were stratified in 2 sets of 2 cohorts: those who did or did not demonstrate an L-CRA and those who did or did not demonstrate neovascular complications at the site of the L-CRA. Subgroup analysis was performed to determine what factors influenced the creation of an L-CRA and the development of complications at each individual laser site. MAIN OUTCOME MEASURES: Identification of systemic and local ocular factors associated with increased success rates of L-CRA creation and those involved with an increased risk of neovascular complications. RESULTS: Younger age (P = 0.03), better baseline visual acuity (P = 0.04), and the absence of hypertension (P = 0.001) were systemic features associated with an increased chance of demonstrating a successful L-CRA at each site, whereas sex and duration of the CRVO were not. The position of the L-CRA site did not influence the outcome; however, evidence of rupture of the vein wall at the time of the attempt was associated with a higher chance of success (P = 0.008). Increased risk of neovascularization, which occurred at 12 sites in 10 eyes, was associated with higher central venous pressure before treatment (P = 0.03), prolonged fluorescein transit time (P = 0.0001), and the presence of some capillary nonperfusion (P = 0.01). CONCLUSIONS: Younger age, better baseline visual acuity, and the absence of hypertension were associated with an improved success rate, as was evidence of rupture of the vein wall. High baseline central venous pressure, prolonged fluorescein transit time, and the presence of any retinal ischemia were associated with a higher incidence of neovascular complications. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

The Central Retinal Vein Bypass Study: a trial of laser-induced chorioretinal venous anastomosis for central retinal vein occlusion.

PURPOSE: To evaluate the effectiveness of a laser-induced chorioretinal venous anastomosis (L-CRA) as a treatment for nonischemic central retinal vein occlusion (CRVO). DESIGN: Prospective, randomized, controlled, multicenter clinical trial. PARTICIPANTS: A total of 113 consecutive patients with a nonischemic CRVO of >3 months' duration and visual acuity of < or =20/50. METHODS: Patients were randomized to L-CRA (58 patients) or conventional care (55 patients). They underwent standardized retinal photography, fluorescein angiography, and ophthalmic examinations, together with standardized assessments of best-corrected visual acuity, performed by masked visual acuity assessors using Early Treatment Diabetic Retinopathy Study protocols. Analysis was performed by intention-to-treat. MAIN OUTCOME MEASURES: The primary outcome measure was change in visual acuity at 18 months. Secondary outcomes were progression of retinal ischemia and rates of adverse events. RESULTS: A total of 53 control patients and 55 treatment patients completed the study. The 2 groups were comparable for age, age- and gender-adjusted mean visual acuity, and most other parameters. In the treated group of 55 patients, 42 (76.4%) developed an L-CRA. Over the 18-month follow-up period, treated eyes had an 8.3 letter mean improvement from baseline compared with control eyes (P = 0.03). Treated eyes that developed a functional L-CRA achieved an 11.7 letter mean improvement from baseline over the control group after 18 months (P = 0.004). Conversion to the ischemic CRVO category occurred in 20.8% of control eyes and in 9.6% of treated eyes overall (P = 0.33). Of the treated group who developed an L-CRA where the retinal ischemia was due to progression of the CRVO, 4.9% progressed to the ischemic category (P = 0.03). Neovascularization developed at the site of the L-CRA in 10 of 55 treated eyes (18.2%). Vitrectomy surgery was required by 5 of 55 treated eyes (9.1%) because of macular traction or nonresolving vitreous hemorrhage. CONCLUSIONS: Chorioretinal venous anastomosis was created in 76.4% of eyes with nonischemic CRVO in this study. Eyes that developed an anastomosis had a significant improvement (11.7 letters) in final visual acuity after 18 months, compared with eyes in the control group (P = 0.004). Complications were managed successfully with careful follow-up and early intervention.

Cataract surgery in high-risk age-related macular degeneration: a randomized controlled trial.

BACKGROUND: To investigate if cataract surgery causes progression, from high-risk early age-related macular degeneration (AMD) to choroidal neovascularization (CNV), in the postoperative period. METHODS: Randomized controlled trial. Patients, with visually significant cataract and fundus features of early AMD at high risk of progression to CNV, were randomized into two groups and were evaluated at baseline and 6 months. The study patients (n = 27) underwent immediate cataract surgery. The control group (n = 29) comprised patients who had cataract surgery deferred until after the 6-month visit. Assessment included visual acuity, quality of life (QoL) and fundus fluorescein angiography (FFA). RESULTS: Of 68 eligible eyes, 60 participated and 56 completed the study. Three referred eyes (3.2%) were ineligible on the basis of a pre-existing, unsuspected occult CNV that was detected by baseline FFA. All three cases had end-stage exudative AMD in the fellow eye. Of the study eyes in the immediate surgery arm (n = 27), one (3.7%) developed CNV compared with none (0/29) in the deferred arm (chi(2); P = 1.0) at 6 months. In the operated group, there was a 2.8-line improvement in logMAR visual acuity and 2.1-fold average gain in QoL at 6 months. CONCLUSIONS: No increased short-term risk of progression of AMD to CNV in high-risk fundi following uncomplicated phacoemulsification surgery was found. A low threshold for performing preoperative imaging in patients with AMD, especially in those with exudative AMD in the fellow eye, to exclude undetected CNV is recommended. Provided there is no CNV, there are distinct benefits of cataract surgery in people with early AMD.

Longitudinal analysis of low-molecular weight fluorophores in type 1 diabetes mellitus.

OBJECTIVES: Circulating low molecular weight (<10 kDa) fluorophores (LMW-F) measured by non-specific fluorescence spectroscopy may detect small advanced glycation end-products (AGEs) not recognized by other assays. This longitudinal study assessed correlates of LMW-F and predictive power of LMW-F levels for vascular health in Type 1 diabetes (T1DM) patients. METHODS: Fasting patients with T1DM (n=37) were studied twice at intervals of 12-60 months (mean+/-SD, 33+/-15 months). LMW-F levels were also measured once in 112 healthy control subjects. RESULTS: Relative to controls, LMW-F levels were higher in diabetic subjects at initial and final time points (mean+/-SD), 5.4+/-1.9 AU/ml and 4.5+/-1.8 AU/ml respectively vs. 3.8+/-2.1 AU/ml; p=0.0001 and p=0.06). Baseline LMW-F levels predicted subsequent hs-CRP and oxLDL/LDL values. LMW-F levels decreased significantly over time in diabetes (5.4+/-1.9 vs. 4.5+/-1.8 AU/ml; p=0.02). Rises in LMW-F levels in individual diabetic subjects correlated significantly with worsening renal function (BUN), glycemia (HbA1c) and with vascular dysfunction (systemic vascular resistance). CONCLUSIONS: LMW-F levels predict levels of inflammation and oxidation in T1DM. Changes in LMW-F levels in T1DM reflect variations in glycemia and renal function. Biochemical characterization of LMW-F would facilitate understanding of the potential utility of LMW-F as a therapeutic target.

Complications of diabetes in urban Indigenous Australians: the DRUID study.

AIMS: To accurately assess the management and complications of type 2 diabetes in urban Indigenous Australians and compare the risk of complications with a general Australian population (AusDiab Study). METHODS: The Darwin Region Urban Indigenous Diabetes (DRUID) Study included 1004 volunteers aged >/=15 years; diabetes status was classifiable for 866. The assessment of diabetic complications and metabolic control was performed in participants with known diabetes (KDM) and diabetes newly diagnosed by the study (NDM) using an interviewer-administered questionnaire and clinical examination. RESULTS: Among 172 DRUID participants eligible for complications assessment, 135 were assessed, including 99 KDM (mean age 53 years) and 36 NDM (mean age 47 years). Percentages of KDM participants meeting therapeutic targets were: HbA1c<7%, 29%; blood pressure<130/80mmHg, 45%; total cholesterol<5.5mmol/L, 65%. Among KDM, 39% had albuminuria, 21% retinopathy, 12% peripheral vascular disease (PVD), 9% neuropathy. Factors independently associated with diabetic complications were: albuminuria-HbA1c, systolic blood pressure; retinopathy-diabetes duration; PVD-age. Compared to AusDiab participants after adjusting for other risk factors, DRUID participants had 2-3-fold increased risk of albuminuria and PVD and a non-significant increased risk of neuropathy, but no increased risk of retinopathy. CONCLUSIONS: Urban Indigenous Australians with diabetes are relatively young and have poor glycaemic control. Compared to the general Australian population with type 2 diabetes, they have greater adjusted risk of albuminuria and PVD but not retinopathy. Urgent action is required to prevent diabetes at a population level and improve diabetes management in this high-risk population.