IMPORTANCE Intravitreal gene therapy is regarded as generally safe with limited mild adverse events, but its systemic effects remain to be investigated. OBJECTIVE To examine the association between immune response and intraocular inflammation after ocular gene therapy with recombinant adeno-associated virus 2 carrying the ND4 gene (rAAV2/2-ND4). DESIGN, SETTING, AND PARTICIPANTS This secondary analysis of an open-label, dose-escalation phase 1/2 randomized clinical trial of rAAV2/2-ND4 included data from February 13, 2014 (first patient visit), to March 30, 2017 (last patient visit at week 96), the first 2 years after injection. Patients older than 15 years with diagnosed ND4 Leber hereditary optic neuropathy (LHON) and visual acuity of at least counting fingers were enrolled in 1 of 5 cohorts. Four dose cohorts of 3 patients each were treated sequentially. An extension cohort of 3 patients received the dose of 9 × 10 10 viral genomes per eye. INTERVENTIONS Patients received increasing doses of rAAV2/2-ND4 (9 × 10 9 , 3 × 10 10 , 9 × 10 10 , and 1.8 × 10 11 viral genomes per eye) as a single unilateral intravitreal injection. Patients were monitored for 96 weeks after injection; ocular examinations were performed regularly, and blood samples were collected for immunologic testing. MAIN OUTCOMES AND MEASURES A composite ocular inflammation score (OIS) was calculated based on grades of anterior chamber cells and flare, vitreous cells, and haze according to the Standardization of Uveitis Nomenclature. The systemic immune response was quantified by enzyme-linked immunospot (cellular immune response), enzyme-linked immunosorbent assay (IgG titers), and luciferase assay (neutralizing antibody [NAb] titers). RESULTS The present analysis included 15 patients (mean [SD] age, 47.9 [17.2] years; 13 men and 2 women) enrolled in the 5 cohorts of the clinical trial. Thirteen patients experienced intraocular inflammation after rAAV2/2-ND4 administration. Mild anterior chamber inflammation and vitritis were reported at all doses, and all cases were responsive to treatment. A maximum OIS of 9.5 was observed in a patient with history of idiopathic uveitis. Overall, OIS was not associated with the viral dose administered. No NAbs against AAV2 were detected in aqueous humor before treatment. Two patients tested positive for cellular immune response against AAV2 at baseline and after treatment. Humoral immune response was not apparently associated with the dose administered or with the immune status of patients at baseline. No association was found between OISs and serum NAb titers. CONCLUSIONS AND RELEVANCE In this study, intravitreal administration of rAAV2/2-ND4 in patients with LHON was safe and well tolerated. Further investigations may shed light into the local immune response to rAAV2/2-ND4 as a potential explanation for the observed intraocular inflammation.

The standardized sterile technique in an operation room with laminar airflow showed very low rates of endophthalmitis at three European sites.

PURPOSE. It has been shown that lutein and zeaxanthin accumulate in the macula where they enhance contrast sensitivity and may reduce the risk of progression to advanced age-related macular degeneration (AMD). Furthermore, omega-3 long-chain polyunsaturated fatty acids (PUFA) might further reduce this risk. However, controversy exists regarding whether PUFA may reduce the bioavailability of lutein.METHODS. This was a prospective 12-month, randomized, open label study evaluating the effect of supplementation with lutein, other antioxidants, and minerals on contrast sensitivity (CS) and macular pigment optical density (MPOD) in patients with age-related maculopathy. A total of 79 patients were randomized to either lutein (10 mg) and antioxidant supplement or lutein and antioxidant supplement in combination with PUFA. Patients received supplementation for a period of 6 months and were followed for a total of 12 months.RESULTS. Serum lutein and zeaxanthin increased significantly by the first follow-up visit at 1 month, and remained elevated throughout the intervention period of 6 months in the luteinonly group but not in the luteinþPUFA group. Macular pigment optical density and CS increased significantly in the lutein-only group (P < 0.005) but not in the luteinþPUFA group (P ¼ 0.059) compared to baseline. Best-corrected visual acuity remained unchanged during the entire study period in both groups.CONCLUSIONS. Addition of PUFA may reduce the bioavailability of lutein and therefore lessen the beneficial effect on macular pigment and CS. This needs to be considered when prescribing lutein supplements to patients with low lutein levels. (ClinicalTrials.gov number, NCT00563979.)

AimTo evaluate the optical coherence tomography angiography (OCTA) features of fellow eyes of patients with unilateral choroidal neovascularisation (CNV) associated with chronic central serous chorioretinopathy (CSCR).MethodsMedical records of patients with chronic CSCR who had undergone OCT angiography of both the eyes were reviewed. Patients with evidence of unilateral CNV detected by conventional imaging (OCT, fluorescein angiography and/or indocyanine green angiography) were included in the study. The OCT and OCTA characteristics of fellow eyes were analysed.ResultsForty patients (80 eyes—40 fellow eyes) with chronic CSCR with evidence of CNV in one eye were included. Mean age of the patients was 54.9±9.9 years and 82.5 % were males. Twenty-five (62.5%) fellow eyes had flat irregular pigment epithelial detachment on OCT, out of which 21 had internal hyper-reflectivity. A definite vascular network was picked up by OCTA in 9 of these 40 fellow eyes (22.5%) which was not detected on conventional imaging. In addition, two eyes had an ill-defined hyper-reflectivity, which could not be classified as a definite network at that point of time. The networks detected on OCTA in fellow eyes were mostly inactive, suggesting a subclinical neovascularisation.ConclusionOne-fourth of fellow eyes showed vascular network which could not be diagnosed on conventional imaging which highlights the importance of imaging both the eyes of chronic CSCR for early detection of CNV using OCTA. Further longitudinal studies are needed to assess the clinical course of such subclinical vascular networks in CSCR.

We aimed to evaluate the neuroprotective efficacy of rasagiline in pseudophakic patients who had surgery for macula-off rhegmatogenous retinal detachment (RRD). This was a 6-month, prospective, randomized, double-blind, placebo-controlled pilot study. Patients presenting with acute macula-off RRD were recruited and randomized 1:1 to receive rasagiline 1 mg/day or placebo for 7 days. Bestcorrected visual acuity (BCVA) and optical coherence tomography were acquired 1 day before as well as 2 days, 3 weeks, 3 months and 6 months after surgery. We screened 26 patients with RRD whereof 23 were eventually included and randomized. The primary outcome was final BCVA. Secondary outcomes included central retinal thickness (CRT) and adverse events (AE). We evaluated photoreceptor cells (prc) recovery through morphological measurements. The baseline characteristics were comparable between groups. BCVA significantly improved in both groups (letters gained: rasagiline 61.5 ± 18.1 vs placebo 55.3 ± 29.2, p = 0.56), but no significant inter-group difference was found at any visit. CRT was stable 3 weeks after surgery onwards, with no inter-group difference. No treatment-emergent AE occurred. Significant prc restoration was observed from 3 weeks to 6 months after surgery, without inter-group difference at either visit. Ellipsoid zone integrity (β = 0.517, p = 0.008) and foveal bulge (β = 0.387, p = 0.038) were significant predictors of good final BCVA. In conclusion, perioperative oral treatment with rasagiline 1 mg/day for 7 days did not show significant benefits on visual or anatomical outcomes in macula-off RRD patients. Rhegmatogenous retinal detachment (RRD) refers to separation of the neurosensory retina from the retinal pigment epithelium (RPE) due to accumulation of subretinal fluid through one or more retinal breaks 1. Currently, surgical repair is the only available treatment. Foveal detachment (macula-off) occurs in 54.5% of all RRD patients and is a major factor influencing visual recovery after successful surgical repair 2. As a result of deprived metabolic supply from the RPE and choroidal vasculature, photoreceptor (prc) death is the ultimate cause of vision loss after RRD 3. This is particularly relevant in the macula, where the density of prc is the highest and maximal visual acuity is achieved. Arguably, visual acuity recovery is significantly limited due to prc loss. Apoptosis was believed to be the major cause involved in prc death. However, recent evidence demonstrated that non-apoptotic forms of cell death (autophagy and necrosis), mitochondrial outer membrane permeabilization and inflammation raised by the interaction between dying cells and phagocytes all play a role in prc death after RRD 4. Accordingly, strategies targeting these pathways may be effective in prc rescue after RRD. Rasagiline [N-propargyl-1-(R)-aminoindan] is a second-generation propargylamine pharmacophore that selectively and irreversibly inhibits monoamine oxidase B (MAO-B). It has been an approved drug for the treatment of Parkinson's d...