Principal Cause of Poor Visual Acuity after Neovascular Age-Related Macular Degeneration: Age-Related Eye Disease Study 2 Report Number 23.

PURPOSE: To analyze the principal cause for poor vision in eyes with best-corrected visual acuity (BCVA) of 20/200 or worse 2 years after neovascular age-related macular degeneration (nAMD). DESIGN: Prospective cohort study of participants enrolled in a clinical trial of oral supplements. PARTICIPANTS: Age-Related Eye Disease Study 2 (AREDS2) participants whose eyes began anti-vascular endothelial growth factor (VEGF) therapy for incident nAMD and had data available at 2 years. METHODS: Participants underwent refracted BCVA testing, ophthalmoscopic examination, and fundus photography at baseline and annual visits. Self-reports of anti-VEGF injections were collected. MAIN OUTCOME MEASURES: Principal cause of BCVA of 20/200 or worse at 2 years, detected on fundus photography grading. RESULTS: Of the 594 eligible eyes, the number with BCVA of 20/200 or worse at 2 years was 56 (9.4%). Mean BCVA was 14.9 letters (standard deviation [SD], 12.3 letters; Snellen equivalent, 20/500), versus 70.1 letters (SD, 12.8 letters; Snellen equivalent, 20/40) in the other group. Of the 55 eyes with fundus photography available at 2 years, 33 (60.0%) had central macular atrophy and 22 (40.0%) had central subretinal fibrosis assessed as the principal cause for poor vision. The group with poor BCVA had a higher proportion of non-White participants (8.9% vs. 1.7%; P = 0.006), lower BCVA 2 years earlier (mean, 38.0 letters [SD, 26.7 letters; Snellen equivalent, 20/160] vs. 71.8 letters (SD, 11.9 letters; Snellen equivalent, 20/40]; P < 0.0001), higher proportion with macular atrophy 2 years earlier (26.8% vs. 12.3%; P = 0.003), higher proportion with macular hemorrhage (25.5% vs. 13.2%; P = 0.014), and fewer anti-VEGF injections (7.6 vs. 10.2; P = 0.001). CONCLUSIONS: Visual acuity data and fundus photography were obtained in a clinical trial environment, but were related to anti-VEGF therapy given in routine clinical practice. At 2 years after starting anti-VEGF therapy, almost 1 in 10 eyes showed BCVA at the level of legal blindness. From fundus photography grading, the cause of poor vision appeared to be macular atrophy in 60% and subretinal fibrosis in 40%. These data may be useful in understanding the long-term limits to good vision in nAMD.

Liposomal hypocrellin B as a potential photosensitizer for age-related macular degeneration: pharmacokinetics, photodynamic efficacy, and skin phototoxicity in vivo.

Photodynamic therapy (PDT) has been successfully implemented as a treatment for wet age-related macular degeneration (AMD), but very few photosensitizers have been developed for clinical use. Herein, we describe a novel formulation of liposomal hypocrellin B (LHB) that was prepared by high-pressure homogenization. The encapsulation efficiency and PDT efficacy in vitro of this new preparation were found to remain nearly constant over 1 year. Moreover, LHB is rapidly cleared from the blood, with a half-life of 2.319 ± 0.462 h and a very low serum concentration at 24 h after injection. Testing in a rat model of choroidal neovascularization (CNV) showed that leakage of blood vessels in CNV lesions was significantly reduced when LHB PDT was given at a dose of 1 mg kg(-1) along with yellow laser irradiation; the damage to the collateral retina and the retinal pigment epithelium was minimal. Skin phototoxicity assays showed that only two of the 200 mice given a 4 mg per kg dose of LHB experienced an inflammatory reaction in the auricle irradiated at 24 h after dosing. These data collectively indicate that LHB may be a safe and effective photosensitizer for vascular-targeted PDT of AMD.

Omega-3 supplementation combined with anti-vascular endothelial growth factor lowers vitreal levels of vascular endothelial growth factor in wet age-related macular degeneration.

PURPOSE: To determine the influence of omega-3 supplementation on vitreous vascular endothelial growth factor A (VEGF-A) levels in patients with exudative age-related macular degeneration (wet AMD) receiving intravitreal anti-VEGF treatment. DESIGN: Prospective, randomized, open-label, single-center, clinical trial, consecutive interventional case series. METHODS: The study included 3 cohorts with wet AMD and a control group with epiretinal membrane or macular hole. Twenty wet AMD patients being treated with anti-VEGF were randomized to daily supplementation of antioxidants, zinc, and carotenoids with omega-3 fatty acids (docosahexaenoic acid and eicosapentaenoic acid; group 1, n = 10) or without omega-3 fatty acids (group 2, n = 10). They were compared with an anti-VEGF treatment-naïve wet AMD group (group 3, n = 10) and an epiretinal membrane or macular hole group (group 4, n = 10). Primary outcome was vitreal VEGF-A levels (at the time of anti-VEGF injection). Secondary outcomes were plasma VEGF-A and central foveal thickness. Patients with new submacular hemorrhage or any other treatment within 3 months were excluded. Final analyses included 9, 6, 7, and 8 patients in groups 1 through 4, respectively. RESULTS: Patients receiving omega-3s (group 1) had significantly lower levels of vitreal VEGF-A (141.11 ± 61.89 pg/mL) when compared with group 2 (626.09 ± 279.27 pg/mL; P = .036) and group 3 (735.48 ± 216.43 pg/mL; P = .013), but similar levels to group 4 (235.81 ± 33.99 pg/mL; P = .215). All groups showed similar values for plasma VEGF-A and central foveal thickness measurements. CONCLUSIONS: This study demonstrated that omega-3 supplementation combined with anti-VEGF treatment is associated with decreased vitreal VEGF-A levels in wet AMD patients.

Oral docosahexaenoic acid in the prevention of exudative age-related macular degeneration: the Nutritional AMD Treatment 2 study.

OBJECTIVE: To evaluate the efficacy of docosahexaenoic acid (DHA)-enriched oral supplementation in preventing exudative age-related macular degeneration (AMD). DESIGN: The Nutritional AMD Treatment 2 study was a randomized, placebo-controlled, double-blind, parallel, comparative study. PARTICIPANTS: Two hundred sixty-three patients 55 years of age or older and younger than 85 years with early lesions of age-related maculopathy and visual acuity better than 0.4 logarithm of minimum angle of resolution units in the study eye and neovascular AMD in the fellow eye. METHODS: Patients were assigned randomly to receive either 840 mg/day DHA and 270 mg/day eicosapentaenoic acid (EPA) from fish oil capsules or the placebo (olive oil capsules) for 3 years. MAIN OUTCOME MEASURES: The primary outcome measure was time to occurrence of choroidal neovascularization (CNV) in the study eye. Secondary outcome measures in the study eye were: incidence of CNV developing in patients, changes in visual acuity, occurrence and progression of drusen, and changes in EPA plus DHA level in red blood cell membrane (RBCM). RESULTS: Time to occurrence and incidence of CNV in the study eye were not significantly different between the DHA group (19.5±10.9 months and 28.4%, respectively) and the placebo group (18.7±10.6 months and 25.6%, respectively). In the DHA group, EPA plus DHA levels increased significantly in RBCM (+70%; P<0.001), suggesting that DHA easily penetrated cells, but this occurred unexpectedly also in the placebo group (+9%; P = 0.007). In the DHA-allocated group, patients steadily achieving the highest tertile of EPA plus DHA levels in RBCM had significantly lower risk (-68%; P = 0.047; hazard ratio, 0.32; 95% confidence interval, 0.10-0.99) of CNV developing over 3 years. No marked changes from baseline in best-corrected visual acuity, drusen progression, or geographic atrophy in the study eye were observed throughout the study in either group. CONCLUSIONS: In patients with unilateral exudative AMD, 3 years of oral DHA-enriched supplementation had the same effect on CNV incidence in the second eye as did the placebo. However, RBCM fatty acid measurements revealed that CNV incidence was significantly reduced in DHA-supplemented patients showing a steadily high EPA plus DHA index over 3 years. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Combination therapy with low-dose transpupillary thermotherapy and intravitreal ranibizumab for neovascular age-related macular degeneration: a 24-month prospective randomised clinical study.

AIM: To compare the effect of combined low-dose transpupillary thermotherapy (TTT) and intravitreal ranibizumab with sham TTT and intravitreal ranibizumab in patients with neovascular age-related macular degeneration (AMD). METHODS: A 24-month, double-masked, randomised, active-controlled clinical trial. 100 patients with primary neovascular AMD were randomly assigned (1:1) to receive intravitreal ranibizumab and sham TTT or intravitreal ranibizumab and low-dose TTT. After an initial loading phase of ranibizumab patients were assigned to receive quarterly low-dose TTT (136 mW/mm) or sham TTT for 24 months. Retreatment with ranibizumab was allowed in both treatment groups using a variable dosing regimen. The primary endpoint was the number of intravitreal injections with ranibizumab. Secondary endpoints included change in best corrected visual acuity (BCVA), central retinal thickness (CRT) and lesion area. RESULTS: In the per protocol (PP) population (78 patients) the mean number of ranibizumab injections was 8.0 in the sham TTT group versus 6.3 in the TTT group (p<0.05). The mean number of injections between 0-12 months and 13-24 months was 4.8 versus 4.6 (p>0.05) and 3.2 versus 1.7 (p<0.01) in the sham TTT and TTT groups, respectively. There was no statistically significant difference in BCVA (+4.0 vs +0.9 ETDRS letters), CRT (-49.9% vs -36.4%) or lesion area (-0.3% vs -10.6%) between the treatment groups at the final examination. The results of the intent-to-treat population (92 patients) were similar to the PP population. CONCLUSIONS: Treatment with low-dose TTT significantly reduced the number or intravitreal injections of ranibizumab over 24 months. The results suggest that low-dose TTT can serve as an adjuvant in combination with intravitreal ranibizumab for neovascular AMD. CLINICAL TRIAL REGISTRATION NUMBER: The trial is registered at http://clinicaltrials.gov (no NCT00599222).

Clinical evidence of intravitreal triamcinolone acetonide in the management of age-related macular degeneration.

Triamcinolone acetonide (TA) is one of the first pharmacologic compounds evaluated for the treatment of choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). The most important effects of TA consist in the stabilisation of the blood-retinal barrier and the down-regulation of inflammation. TA also has anti-angiogenic and anti-fibrotic properties. The peculiar characteristic of being well tolerated by ocular tissues and the capability to remain active for many months after a single intravitreal injection, make this drug a safe and effective alternative. In the past decade, intravitreal injection of TA (IVTA) has emerged as a useful treatment of several ocular diseases such as uveitis, macular edema secondary to retinal vasculature disease, neovascularisation and vitreoretinopathy. In this paper, we review all the available evidence of its use in AMD as mono-therapy or in combination with other treatments, and we discuss which role TA will play in the treatment of AMD in the future. The first experiences with IVTA as monotherapy for the treatment of exudative AMD reported a positive outcome in transiently reducing the leakage from CNV. However, in the long-term follow-up, IVTA as monotherapy had no effect on the risk of severe visual acuity loss, despite a significant anti-angiogenic effect found 3 months after the treatment. Consequently, studies using the combination of IVTA and photodynamic therapy (PDT), which acts synergistically, were performed. They reported to improve vision and to reduce the number of re-treatments with PDT. A large number of publications confirmed the positive synergic role of combining TA and PDT (therapies) for the treatment of all types of CNV: classic or predominantly classic, occult or minimally classic and RAP (Retinal Angiomatous Proliferation) lesions. The advantages registered with the use of IVTA plus PDT compared to PDT alone were partially limited by the side effects, such as the rapid evolution of cataract. Nevertheless, cataract surgery may stimulate the development of CNV (result in stimulating CNV). However, in large, randomized, clinical trials on combination therapy of TA and PDT, visual acuity failed to show an improvement, even though the lesion size and subretinal fluid had decreased, compared to controls treated with PDT alone. Some authors reported an increased risk of developing macular atrophy after the combination therapy with IVTA and PDT. Reduction of the PDT fluence rate in association with the use of steroids resulted in reducing the risk of macular atrophy and in a better visual acuity outcome. The introduction of anti-VEGF-based drugs has revolutionized the treatment of AMD and has replaced all the previous therapies used for CNV. Visual improvement becomes an expectation in a higher proportion of patients, previously limited to minimizing vision loss. Anti-VEGF therapy also resulted in superior visual improvement compared to all types of combination therapy with IVT and PDT. Nevertheless, anti-VEGF monotherapy also has many limitations due to the need of repetitive treatments, increased costs and tachyphylaxis. Treatment regimens involving TA in combination therapy with anti-VEGF and PDT may preserve benefits for substantially longer periods. A question remains open on whether a combination treatment with anti-VEGF, triamcinolone and/or PDT may be a treatment option in patients with exudative AMD, by offering, with one cycle of therapy, functional VA benefits comparable to those observed with continued monthly anti-VEGF therapy. Further trials, of higher scientific significance, are needed to study the potential of these treatment options.

Care of patients undergoing intra-vitreal therapy.

This article discusses the role of the ophthalmic nurse in the care of patients with wet age-related macular degeneration who are undergoing intra-vitreal therapy. It provides an overview of the condition, its classification, clinical features, aetiology, diagnosis and treatment, and explains the implications for future nursing practice. A proactive, evidence-based and holistic approach to nursing care is emphasised throughout the article.