Dynamic Drusen Remodelling in Participants of the Nutritional AMD Treatment-2 (NAT-2) Randomized Trial.

PURPOSE: To evaluate the dynamic remodeling of drusen in subjects with unilateral neovascular age-related macular degeneration (AMD) receiving a three-year course of oral docosahexaenoic acid (DHA) or placebo. SETTING: Institutional setting. METHODS: Three hundred subjects with age-related maculopathy and neovascular AMD in the fellow eye were randomly assigned to receive either 840 mg/day DHA or placebo for 3 years. Main outcome measures of this post-hoc sub-group analysis were progression of drusen number, total diameter, and total area on fundus photography, and their association with DHA supplementation, socio-demographic and genetic characteristics. RESULTS: Drusen progression was analyzed in 167 subjects that did not develop CNV (87 that received DHA and 80 that received placebo). None of the drusen remodeling outcomes were significantly associated with DHA supplementation. Total drusen diameter reduction in the inner subfield was significantly associated with age (older patients: r = -0.17; p = 0.003). Women showed a tendency to decreased total drusen diameter in the inner subfield with CFH polymorphism (p = 0.03), where women with TT genotype tended to have a greater reduction in drusen diameter than other genotypes (CC and CT). Drusen area in the inner subfield was more reduced in older patients (r = -0.17) and in women (p = 0.01). Drusen number showed no significant trends. CONCLUSIONS: Dynamic drusen remodeling with net reduction in drusen load over three years was found in patients with exudative AMD in one eye and drusen in the other eye (study-eye). This reduction was correlated with increased age and female gender, and showed a tendency to be influenced by CFH genotype, but did not appear to be affected by DHA supplementation. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN98246501.

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.

Changes in visual acuity in patients with wet age-related macular degeneration treated with intravitreal ranibizumab in daily clinical practice: the LUMIERE study.

PURPOSE: To survey compliance with recommended intravitreal ranibizumab treatment protocols in daily clinical practice in France, with reference to outcomes. METHODS: A retrospective, descriptive, observational study in patients with subfoveal wet age-related macular degeneration treated with ranibizumab. All historical data for the study period, including demographic, treatment, and disease details and visual acuity measurements (baseline, Month 3, and Month 12), were recorded retrospectively at least 12 months after the beginning of treatment. RESULTS: In 551 patients followed by 16 ophthalmologists, 12 months of intravitreal ranibizumab treatment induced a mean visual acuity gain of 3.2 ± 14.8 Early Treatment Diabetic Retinopathy Study-equivalent letters. Fewer than 40% of patients received the recommended treatment of initial 3 monthly injections. More than 50% had to wait >8 days between diagnosis and treatment. At Month 3, visual acuity gain was greater in patients who had received recommended induction and in whom treatment was initiated quickly. At Month 12, the induction-related effect had largely disappeared but the time-to-treatment effect persisted. Patients had an average of 5.1 injections (2.6 during induction period). No patients were monitored monthly as stipulated in the guidelines. CONCLUSION: Although poor compliance with recommendations has been reflected in mediocre outcomes, there is evidence that practice is improving.

Macular edema in central retinal vein occlusion: correlation between optical coherence tomography, angiography and visual acuity.

To analyze the characteristics and the course of macular edema secondary to central retinal vein occlusion (CRVO) using optical coherence tomography (OCT) and to determine correlations between clinical, tomographic and angiographic data, in particular including retinal ischemia. In this retrospective study, 53 consecutive patients with CRVO were included. At each follow-up visit, patients underwent complete ophthalmological examination, including best-corrected visual acuity (BCVA) and OCT. Fluorescein angiography was performed at baseline and on demand during follow-up. 243 OCTs were analyzed. Mean age was 61 years and mean follow-up 13 months. The first structural change, observed very early after the onset of the occlusion, was a diffuse increase at the level of the outer nuclear layer without change at the level of the inner retina. This early change seemed characteristic of retinal vein occlusion. Cystoid spaces were subsequently observed in all retinal layers and were combined with serous retinal detachment in 51 %. During the first 6 months, central retinal thickness was higher in ischemic CRVO (mean, 691 µm) than in non-ischemic CRVO (mean, 440 µm, p < 0.01). In eyes with foveal thickness (central retinal thickness without subretinal fluid) of 700 µm or greater, peripheral ischemia was present in 69 % of eyes, final BCVA was 20/200 or less in 75 % and never reached 20/40 during follow-up. The integrity of the junction of the photoreceptors' inner and outer segments was correlated with a better prognosis (p < 0.05). Foveal thickness was inversely correlated to BCVA at each visit and could have a prognostic value. OCT examination in CRVO revealed useful data for the diagnosis of CRVO and its prognosis. The largest macular edemas seemed to be the hallmark of ischemic CRVO.

Intravitreal ranibizumab for macular oedema secondary to retinal vein occlusion: a retrospective study of 34 eyes.

PURPOSE: To evaluate the efficacy and the safety of intravitreal ranibizumab injection (Lucentis) in eyes with macular oedema secondary to central retinal vein occlusion (CRVO) or branch retinal vein occlusion (BRVO). METHODS: The files of consecutive patients (34 eyes, 15 CRVO, 19 BRVO) were retrospectively analysed. Intravitreal injections of 0.5 mg ranibizumab were administered; retreatment was based on acuity visual changes and optical coherence tomography findings. Patients received 2-4 injections (mean, 2.1). Mean follow-up was 7 months. RESULTS: After the first injection, mean best-corrected visual acuity (BCVA) improved from 20/160 to 20/80 and mean central retinal thickness (CRT) decreased significantly from 549 to 301 µm (p < 0.01). For each injection, BCVA improvement was on average nine letters (p < 0.01) and macular oedema reduction was 195 µm CRT (p < 0.01). The decrease in CRT was similar in CRVO and BRVO, but the improvement in BCVA was larger in BRVO. No local or systemic adverse effect was detected. Final visual acuity was correlated to initial visual acuity and to visual acuity measured after the first injection. The change in CRT was correlated to the number of injections and to initial CRT. CONCLUSION: Intravitreal injections of ranibizumab appeared to be a safe and effective option in the treatment of macular oedema secondary to retinal vein occlusion. Nevertheless, because the natural course has demonstrated a possible improvement in vision in almost one quarter of affected eyes at 3 years, further controlled and prospective studies are necessary to compare this treatment to the natural course with a longer follow-up.

Steroids and macular edema from retinal vein occlusion.

PURPOSE: The possibility of applying long-lasting steroids, such as triamcinolone and subsequently dexamethasone implant, directly in the eye, without the systemic side effects observed after their oral or intravenous administration, aroused great enthusiasm among ophthalmologists. METHODS AND RESULTS: The SCORE study, a multicenter clinical trial, compared the efficacy and safety of 1-mg and 4-mg doses of preservative-free intravitreal triamcinolone with observation in central retinal vein occlusion (CRVO) participants with macular edema secondary to perfused CRVO. This study marked a turning point in the management of retinal vein occlusion (RVO), since it was the first report on an effective treatment of macular edema due to CRVO. But in branch retinal vein occlusion (BRVO), the SCORE study showed no difference in visual acuity for the standard care group compared with the triamcinolone groups; however, the rates of adverse events (particularly elevated intraocular pressure and cataract) were highest in the 4-mg group. The authors concluded that laser grid photocoagulation should remain the benchmark against which other treatments should be compared. The Geneva Study, a randomized, controlled, clinical trial, conducted to evaluate the safety and efficacy of an intravitreal implant that delivers sustained levels of dexamethasone (Ozurdex™), studied the largest group of RVO patients with macular edema (1267 patients), including 35% CRVO and 65% BRVO. The study demonstrated that this slow-release device could both reduce the risk of vision loss and improve the speed and incidence of visual improvement in eyes with macular edema secondary to CRVO and BRVO, with fewer side effects, such as elevation of intraocular pressure or cataract. Other ongoing studies evaluate the safety and efficacy of anti-vascular endothelial growth factor injection; preliminary results showed that these therapies are effective in decreasing macular edema and improving visual acuity, with fewer ocular adverse effects, but their duration of action seems limited. CONCLUSIONS: These recent studies result in a great change in the management of macular edema from RVO. Unfortunately, long-term studies on safety and efficacy are not yet available, and further studies will have to show whether the short-term benefits are only transient or may finally lead to a long-lasting improvement in vision.

PLEKHA1-LOC387715-HTRA1 polymorphisms and exudative age-related macular degeneration in the French population.

PURPOSE: Identification of genetic factors for age-related macular degeneration (AMD) is of crucial importance in this common cause of blindness. Exudative AMD is rapidly progressive and usually associated with severe prognosis. Our purpose was to investigate this association on locus 10q26 in a case-control study including French patients specifically affected with exudative AMD. METHODS: Polymorphisms rs4146894:G>A of Pleckstrin Homology Domain-containing Protein Family A member 1 (PLEKHA1) gene, rs10490924:G>T at LOC387715, and rs11200638:G>A of HTRA1 (HTRA serine peptidase 1) gene were analyzed in AMD cases (n=118, age=72.3+/-3.8 years old) and healthy controls (n=116, age=72.0+/-3.8 years old). RESULTS: PLEKHA1 polymorphism was associated with AMD. The A allele frequency was 0.67 in cases versus 0.41 in controls, (p=0.0001). After age and sex adjustment, the odds ratio for risk of AMD was 9.1 (4.0-20.9, 95% CI, p=0.0001) for the AA genotype and 2.6 (1.3-5.5, 95% CI, p=0.04) for the AG genotype, conditional on HTRA1. Association was even stronger and independent with HTRA1. The A allele frequency was 0.51 in cases versus 0.22 in controls, (p=0.0001). The odds ratio was 15.5 (5.5-43.9, 95% CI, p=0.0001) for the AA genotype and 3.4 (1.9-6.1, 95% CI, p=0.0001) for the AG genotype. No further information was obtained from LOC387715 due to virtually complete linkage disequilibrium with HTRA1 polymorphism in cases (D'=1.0) and controls (D'=0.98). Although a role for PLEKHA1 could not be totally excluded, there was a four times higher AMD risk was associated with haplotype "A-T-A" involving "PLEKHA1-LOC387715-HTRA1" risk alleles. CONCLUSIONS: Compared to PLEKHA1, HTRA1/LOC387715 genetic variations were independently and strongly associated with exudative AMD in the French population. Chromosome-10 genetic variants appear as potentially useful risk markers for early detection of AMD.

Effect of calcium dobesilate on progression of early diabetic retinopathy: a randomised double-blind study.

BACKGROUND: The study was carried out to confirm the effect of calcium dobesilate (CaD) compared to placebo (PLA) on the blood-retinal barrier (BRB) permeability in early diabetic retinopathy (DR). METHODS: Adults with type II diabetes and early diabetic retinopathy (below level 47 of ETDRS grading and PVPR between 20 and 50x10(-6)/ min, plasma-free fluorescein) were included in this double-blind placebo-controlled study. Treatment was 2 g daily for 24 months. The primary parameter, posterior vitreous penetration ratio (PVPR), was measured every 6 months by fluorophotometry. Secondary parameters were fundus photography, fluorescein angiography and safety assessments. Metabolic control was performed every 3 months. RESULTS: A total of 194 patients started the treatment (98 CaD, 96 PLA) and 137 completed the 24-month study (69 CaD, 68 PLA). Both treatment groups were comparable at baseline, with ETDRS level 10 in about 59% of patients. Mean PVPR change from baseline after 24 months was significantly (P=0.002) lower in the CaD group [-3.87 (SD 12.03)] than in the PLA group [+2.03 (SD 12.86)], corresponding to a 13.2% decrease in the CaD group and a 7.3% increase in the PLA group. PVPR evolution was also analysed by HbA1c classes (<7%, between 7 and 9%, > or =9%) and results confirmed the superiority of CaD independently of the diabetes control level. A highly significant difference [CaD: -3.38 (SD 13.44) versus PLA: +3.50 (SD 13.70)] was also obtained in a subgroup of patients without anti-hypertensive and/or lipid-lowering agents (P=0.002 at 24 months). A further analysis of the secondary parameters showed significant changes in favour of CaD in the evolution from baseline to the last visit of haemorrhages (P=0.029), DR level (P=0.0006) and microaneurysms (P=0.013). Regarding safety, only 2.5% (n=5 patients/ events) of all adverse events reported were assessed as possibly or probably related to the test drug, while all serious adverse events were reported as unlikely. There was no statistical difference between groups. CONCLUSION: Calcium dobesilate 2 g daily for 2 years shows a significantly better activity than placebo on prevention of BRB disruption, independently of diabetes control. Tolerance was very good.

Stage 3 macular hole: role of optical coherence tomography and of B-scan ultrasonography.

PURPOSE: To analyze the various aspects of Stage 3 macular hole with optical coherence tomography (OCT) and B-scan ultrasonography. DESIGN: Observational case series. METHODS: Patients referred for full-thickness macular hole were prospectively screened with OCT and B-scan ultrasonography. OCT examination analyzed the diameter of the hole, the posterior hyaloid, the surrounding retina, and the inconstant presence of a pseudo-operculum. B-scan ultrasonography permitted the distinction between stage 3 and stage 4 holes, based on the detachment of the posterior hyaloid. RESULTS: The study included 62 eyes with stage 3 holes. On OCT, the typical aspect with a hyaloid detached from the macular area was observed in 37% of the eyes (group 3C). In 42% of the eyes (group 3B), a focal adherence was visible at the margin of the hole, as in stage 2 macular hole, but the hole was long-standing, large, and noneccentric. In 21% of the eyes, the hyaloid was not visible anterior to the retina but was still adherent to it (group 3A). In the absence of B-scan ultrasonography, these OCT features could be confused with a stage 4 macular hole. No difference in the size of the hole was observed between subgroups. CONCLUSION: OCT can show various aspects of stage 3 macular holes. B-scan ultrasonography was useful for assessing the location of the posterior hyaloid and to distinguish stage 3 from stage 4 macular holes. These features may provide additional information on the pathogenesis of macular hole and may have therapeutic implications.