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Purpose To evaluate safety and successful use of a novel subretinal delivery system and suprachoroidal surgical approach and safety and activity of human umbilical tissue–derived cells (palucorcel) via a novel delivery system in patients with geographic atrophy (GA). Design Multicenter, open-label phase 2b study. Participants Participants were 55 to 90 years with GA secondary to age-related macular degeneration (AMD) and best-corrected visual acuity (BCVA) of 20/80 to 20/800. Exclusion criteria included neovascular AMD in the intervention eye, glaucoma with intraocular pressure of 25 mmHg or more, or other significant ophthalmologic conditions. Methods Participants received a subretinal injection of palucorcel, 3.0 × 105 cells in 50 μl, using the custom-designed delivery system and surgical procedure. Main Outcome Measures Safety assessments included treatment-emergent adverse events (AEs), immunologic assessments, and ophthalmologic evaluations. Efficacy was evaluated as change in mean number of BCVA letters from baseline, proportion of participants gaining 15 BCVA letters or more, and growth rate of GA lesions at 12 months. Results Surgery and palucorcel administration were performed in 21 participants at 8 sites by 8 different surgeons. At baseline, median total area of GA was 13.4 mm2 and median BCVA was 43 letters in the intervention eye. Eye-related AEs occurred in 76% of participants (16/21), including conjunctival hemorrhage (n = 5), retinal hemorrhage (n = 4), and vitreous floaters (n = 4). Most AEs were mild and resolved within 1 month. No serious AEs, no retinal detachment or perforation, and no significant changes in intraocular pressure occurred. At month 12, mean change in BCVA from baseline was –5.9 letters correct (standard deviation, 13.0 letters correct) in the intervention eye and –3.7 letters correct (standard deviation, 9.0 letters correct) in the fellow eye. No participants showed improvement of 15 letters or more in the intervention eye, and 3 participants lost more than 15 letters by month 1. No apparent effect of treatment was observed. Conclusions Palucorcel was delivered successfully to the targeted subretinal site using a novel delivery system and suprachoroidal approach for most participants; however, improvement in GA area, retardation of growth, or visual acuity were not demonstrated.

Purpose To investigate the natural history and genetic associations of drusenoid pigment epithelial detachment (DPED) associated with age-related macular degeneration (AMD). Design Retrospective analysis of a prospective cohort study. Participants Of the 4203 Age-Related Eye Disease Study 2 (AREDS2) participants, 391 eyes (325 participants) had DPED without late AMD at the time of DPED detection. Genetic analyses included 120 white AREDS2 participants and 145 Age-Related Eye Disease Study (AREDS) participants with DPED. Methods Baseline and annual stereoscopic fundus photographs were graded centrally to detect DPED, a well-defined yellow elevated mound of confluent drusen ≥433 μm in diameter, and to evaluate progression rates to late AMD: geographic atrophy (GA) and neovascular (NV)-AMD. Five single nucleotide polymorphisms (CFH [rs10611670], C3 [rs2230199], CFI [rs10033900], C2/CFB [rs114254831], ARMS2 [rs10490924]) and genetic risk score (GRS) group were investigated for association with DPED development. Kaplan–Meier analyses and multivariable proportional hazard regressions were performed. Main Outcome Measures Progression rates to late AMD and decrease of ≥3 lines in visual acuity (VA) from the time of DPED detection; association of rate of DPED development with genotype. Results Mean (standard deviation [SD]) follow-up time from DPED detection was 4.7 (0.9) years. DPED was associated with increased risk of progression to late AMD (hazard ratio [HR], 2.36; 95% confidence interval [CI], 1.98–2.82; P Conclusions This study replicates the results of previous natural history studies of eyes with DPED including the high rates of progression to late AMD and vision loss (regardless of progression to late AMD). The genetic associations are consistent with genes associated with AMD progression.

Purpose To analyze the prevalence, incidence, and clinical characteristics of eyes with geographic atrophy (GA) in age-related macular degeneration (AMD), including clinical and genetic factors affecting enlargement. Design Prospective cohort study within a controlled clinical trial. Participants Age-Related Eye Disease Study 2 (AREDS2) participants, aged 50–85 years. Methods Baseline and annual stereoscopic color fundus photographs were evaluated for GA presence and area. Analyses included GA prevalence and incidence rates, Kaplan-Meier rates, mixed-model regression, and multivariable analysis of the square root of GA, area adjusted for covariates, including clinical/imaging characteristics and genotype. Main Outcome Measures (1) Presence or development of GA; (2) change in the square root of GA area over time. Results At baseline, 517 eyes (6.2%) of 411 participants (9.8%) had pre-existing GA (without neovascular AMD), with the following characteristics: 33% central, 67% noncentral; and the following configurations: 36% small, 26% solid/unifocal, 24% multifocal, 9% horseshoe/ring, and 6% indeterminate. Of the remaining 6530 eyes at risk, 1099 eyes (17.3%) of 883 participants developed incident GA without prior neovascular disease during mean follow-up of 4.4 years. The Kaplan-Meier rate of incident GA was 19% of eyes at 5 years. In eyes with incident GA, 4-year risk of subsequent neovascular AMD was 29%. In eyes with incident noncentral GA, 4-year risk of central involvement was 57%. GA enlargement rate (following square root transformation) was similar in eyes with pre-existing GA (0.29 mm/year; 95% confidence interval 0.27–0.30) and incident GA (0.28 mm/year; 0.27–0.30). In the combined group, GA enlargement was significantly faster with noncentrality, multifocality, intermediate baseline size, and bilateral GA (P Conclusions Analyses of AREDS2 data on natural history of GA provide representative data on GA evolution and enlargement. GA enlargement, which was influenced by lesion features, was relentless, resulting in rapid central vision loss. The genetic variants associated with faster enlargement were partially distinct from those associated with risk of incident GA. These findings are relevant to further investigations of GA pathogenesis and clinical trial planning.

Purpose To characterize histologic changes in the optic nerve and the retina of an end-stage retinitis pigmentosa (RP) patient after long-term implantation with the Argus II retinal prosthesis system. Methods Serial cross sections from the patient's both eyes were collected postmortem 6 years after implantation. Optic nerve from both eyes were morphometrically analyzed and compared. Retina underneath and outside the array was analyzed and compared with corresponding regions in the fellow eye. Results Although the optic nerve of the implant eye demonstrated significantly more overall atrophy than the fellow eye (P < 0.01), the temporal quadrant that retinotopically corresponded to the location of the array did not show additional damage. The total neuron count of the macular area was not significantly different between the two eyes, but the tack locations and their adjacent areas showed significantly fewer neurons than other perimacular areas. There was an increased expression of glial fibrillary acidic protein (GFAP) throughout the retina in the implant eye versus the fellow eye, but there was no significant difference in the cellular retinaldehyde-binding protein (CRALBP) expression. Except for the revision tack site, no significant increase of inflammatory reaction was detected in the implant eye. Conclusion Long-term implantation and electrical stimulation with an Argus II retinal prosthesis system did not result in significant tissue damage that could be detected by a morphometric analysis. Translational Relevance This study supports the long-term safety of the Argus II device and encourages further development of bioelectronics devices at the retina-machine interface.

To evaluate safety and successful use of a novel subretinal delivery system and suprachoroidal surgical approach and safety and activity of human umbilical tissue-derived cells (palucorcel) via a novel delivery system in patients with geographic atrophy (GA).Multicenter, open-label phase 2b study.Participants were 55 to 90 years with GA secondary to age-related macular degeneration (AMD) and best-corrected visual acuity (BCVA) of 20/80 to 20/800. Exclusion criteria included neovascular AMD in the intervention eye, glaucoma with intraocular pressure of 25 mmHg or more, or other significant ophthalmologic conditions.Participants received a subretinal injection of palucorcel, 3.0 × 10Safety assessments included treatment-emergent adverse events (AEs), immunologic assessments, and ophthalmologic evaluations. Efficacy was evaluated as change in mean number of BCVA letters from baseline, proportion of participants gaining 15 BCVA letters or more, and growth rate of GA lesions at 12 months.Surgery and palucorcel administration were performed in 21 participants at 8 sites by 8 different surgeons. At baseline, median total area of GA was 13.4 mmPalucorcel was delivered successfully to the targeted subretinal site using a novel delivery system and suprachoroidal approach for most participants; however, improvement in GA area, retardation of growth, or visual acuity were not demonstrated.

Purpose To determine the feasibility and safety of bilateral simultaneous vitreoretinal surgery in pediatric patients. Design International, multicenter, interventional, retrospective case series. Participants Patients 17 years of age or younger from 24 centers worldwide who underwent immediate sequential bilateral vitreoretinal surgery (ISBVS)—defined as vitrectomy, scleral buckle, or lensectomy using the vitreous cutter—performed in both eyes sequentially during the same anesthesia session. Methods Clinical history, surgical details and indications, time under anesthesia, and intraoperative and postoperative ophthalmic and systemic adverse events were reviewed. Main Outcome Measures Ocular and systemic adverse events. Results A total of 344 surgeries from 172 ISBVS procedures in 167 patients were included in the study. The mean age of the cohort was 1.3±2.6 years. Nonexclusive indications for ISBVS were rapidly progressive disease (74.6%), systemic morbidity placing the child at high anesthesia risk (76.0%), and residence remote from surgery location (30.2%). The most common diagnoses were retinopathy of prematurity (ROP; 72.7% [ P P = 0.02). There were no reported intraoperative ocular complications. During the immediate postoperative period, 2 eyes from different patients demonstrated unilateral vitreous hemorrhage (0.6%). No cases of endophthalmitis, choroidal hemorrhage, or hypotony occurred. Mean total anesthesia time was 203±87 minutes. There were no cases of anesthesia-related death, malignant hyperthermia, anaphylaxis, or cardiac event. There was 1 case of reintubation (0.6%) and 1 case of prolonged oxygen desaturation (0.6%). Mean follow-up after surgery was 103 weeks, and anatomic success and globe salvage rates were 89.8% and 98.0%, respectively. Conclusions This study found ISBVS to be a feasible and safe treatment paradigm for pediatric patients with bilateral vitreoretinal pathologic features when repeated general anesthesia is undesirable or impractical.

Background: The safety and efficacy of subretinally transplanted human central nervous system stem cells (HuCNS-SCR) in subjects with geographic atrophy (GA). Methods: Twenty-two eyes of 11 subjects with bilateral GA due to age-related macular degeneration (AMD) were enrolled in this IRB-approved, multicenter, prospective Phase I/II open-label clinical trial. For each subject, the eye with the worst best-corrected visual acuity was selected for treatment and considered the study eye; the fellow eye was treated as a control for this analysis. A total of 0·25 X 106 or 1·0 X 106 HuCNS-SC cells were directly infused into the subretinal space, superotemporal to the fovea near the junctional zone outside the area of GA. Subjects were followed for 12 months and the GA was monitored with fundus autofluorescence (FAF) imaging. Total GA area in both eyes was measured at baseline and month 12 by certified graders and sectoral (clock hour)/directional GA progression rates with respect to the foveal center were computed, and compared between study and control eyes. Findings: Although there was a numerical difference and trend, no statistically significant difference was observed in the overall 12 month enlargement in GA area between study and fellow eyes (1·07 ± 0·84 vs. 2·08 ± 1·97 mm2, P=0·08). However, the month 12 sectoral/directional GA growth rate for the superotemporal region (i.e. toward the location of HuCNS-SC transplantation) showed a significantly slower progression rate in study eyes compared to the same region in fellow eyes (0·06 ± 0·11 vs. 0·21 ± 0·13 mm2, P=0·03). The progression rate in the superotemporal quadrant of the study eye was also significantly slower than in the other three quadrants of the study eye combined (P=0·003). Interpretation: In this Phase I/II trial, HuCNS-SC transplantation was well tolerated and appeared to be associated with slower expansion of the GA lesion in the transplanted quadrant. Trial Registration: NCT01632527. Funding Statement: The clinical study was supported in full by the original trial sponsor, StemCells, Inc. Declaration of Interests: Financial disclosure: Dr. Sadda receives research support from Carl Zeiss, Meditec, Optos, Genentech, and Allergan. He has served as a consultant for Genentech, Allergan, Alcon, Novartis, and Roche. Dr. Birch receives research support from Nightstar, Allergan, AGTC, 4D Molecular Therapeutics, and ProQR Therapeutics. He has served as a consultant for Nightstar, AGTC, Nacuity Pharmaceuticals, Editas Medicine, Acucela, Foundation Fighting Blindness, and ProQR Therapeutics. All other authors declare no conflicts of interest. Ethics Approval Statement: All study procedures were approved by the institutional review boards (IRBs) of the participating clinical centers, and the research adhered to the tenets set forth in the Declaration of Helsinki. Informed consent was obtained from all subjects after explanation of the study procedures and the expected risks and benefits.

A complete ophthalmic examination is not routinely performed on infants with Miller–Dieker syndrome (MDS, chromosome 17p13.3 microdeletion). The authors present the cases of four cousins with MDS who also carried a 16p13.3 microduplication (not associated with Rubinstein–Taybi syndrome). Retinopathy of prematurity-like proliferative peripheral retinopathy (PPR) was detected in two male first cousins, but was not detected in the female half-cousins. PPR in the first infant resolved by 4 months, but the second infant's PPR progressed, requiring photocoagulation followed by lens-sparing vitrectomy. While ocular abnormalities are more prevalent and severe in other lissencephalopathies, the PPR in these MDS infants underscores the sight-saving potential of performing an ophthalmologic exam with early molecular testing for all lissencephaly infants.

Rand Spencer,1 Steven Fisher,2 Geoffrey P Lewis,3 Terri Malone4 1Texas Retina Associates, Dallas, TX, USA; 2Molecular, Cellular, and Developmental Biology, 3Center for the Study of Macular Degeneration, Neuroscience Research Institute, University of California, Santa Barbara, CA, 4Cell Therapy, Janssen Research & Development, LLC, Spring House, PA, USA Background: A 70-year-old woman with retinitis pigmentosa experienced an epiretinal membrane (ERM) formation and a tractional retinal detachment (RD) following subretinal administration of palucorcel (CNTO 2476), a novel human umbilical tissue-derived cell-based therapy, as part of a Phase I study. The clinical course and results of a histologic examination of the ERM, which was peeled during surgery to repair the RD, are described here.Methods: In this open-label, first-in-human, Phase I study (NCT00458575), two of seven subjects developed RD, with an ERM formation reported in a woman receiving a targeted dose of 3.0×105 palucorcel administered via a transvitreal route. A sample of the ERM was retained for analysis following the ERM peeling procedure. Clinical outcomes and ERM histology, based on immunocytochemistry analyses and fluorescence in situ hybridization (FISH) staining, were evaluated.Results: We first noted the RD and formation of the ERM at 26 days after palucorcel administration. The ERM was cellular and contained multiple cell types, including Müller glial cells, immune cells, neurites, retinal pigment epithelial cells, and palucorcel. The majority of cells were not actively dividing. FISH staining showed a subset of Y chromosome-positive cells in the ERM from this woman, supporting the presence of palucorcel (derived from umbilical cord tissue of male neonate). Palucorcel did not differentiate into Müller glia, immune cells, neurites, or retinal pigment epithelial cells.Discussion: The development of an ERM containing both subject (self) cells and palucorcel suggests that palucorcel egress in the vitreal cavity after retinotomy may contribute to ERM formation and RD and that an alternative delivery method will be required before further studies are conducted. Subsequent clinical research using alternative subretinal delivery methods for palucorcel in other indications suggests that membrane development does not occur when palucorcel is delivered without retinal perforation. Keywords: cell therapy, epiretinal membrane, retinitis pigmentosa

Retinal tacks, first developed for the treatment of complex retinal detachments, have more recently been used for the fixation of epiretinal electrode arrays as part of implanted visual prostheses. Here, we report on the clinical experience of extracting four such tacks after chronic implantation. The ability to safely extract retinal tacks ensures that epiretinal devices can be repositioned or removed if necessary. Custom-built, titanium alloy retinal tacks were mechanically removed from the posterior coats after prolonged implantation (up to 19 months). The resulting wound was characterized by clinical evaluation, fundus photography, and fluorescein angiography while being monitored for stability over time. The wounds were also compared to earlier published reports of the healing response around retinal tacks in human subjects. Tack extraction was accomplished successfully, without complication, in all four subjects. The wound site was readily identified by pale scar tissue. No change in the wound size or appearance was noted over many months of post-operative observation (up to 22 months after explant). No adverse effects on overall ocular health were detected. Extraction of retinal tacks from subjects implanted with epiretinal prostheses can be performed without significant complication. The long-term healing response appears to be stable and localized in eyes afflicted with retinitis pigmentosa or choroideremia. There was also minimal, if any, impact on the local circulatory system. These cases suggest that the use of retinal tacks for anchoring epiretinal visual prostheses does not preclude safe repositioning or removal of the device more than a year after implant.

Vascularisation of the macula takes place between 24 and 27 weeks post-conception. Preterm birth may affect the formation of the foveal avascular zone (FAZ) and foveal depression, and displacement of inner retinal layers away from the incipient fovea.To examine whether vascular abnormalities accompany an inner retinal abnormality, and whether they are coincident.High-density spectral domain optical coherence tomography volume scans were obtained from 24 preterm children and 34 full-term controls (5-16 years). Matlab programs were used to quantify total retinal thickness, thickness of individual retinal layers and metrics of foveal morphology. Summed voxel projections for the ganglion cell layer-inner nuclear layer were used to identify the FAZ.Preterm children had significantly smaller FAZ diameters than controls (p0.0001). The foveal pits of preterm children were significantly shallower and less steep (p0.0001) and total retinal thickness at the fovea was significantly increased (p0.0001) compared to controls. The ganglion cell layer-inner plexiform layer and outer nuclear layer were significantly (p≤0.0001) thicker in preterm children than in controls.Preterm birth results in abnormal foveal vascularisation, a failure of the inner retinal neurons to migrate away from the fovea, and an elevated outer nuclear layer ratio. The spatial coincidence of inner retinal and vascular abnormalities in preterm children supports the hypothesis that aspects of foveal development are interdependent.

Purpose Midgestation is a critical period in the formation of the foveal avascular zone. The authors evaluated the effects of preterm birth on foveal structure in children with regressed retinopathy of prematurity. Methods Children with regressed retinopathy of prematurity with normal-appearing posterior poles (n = 26) and full-term control children (n = 56) were investigated. Frequency-domain optical coherence tomography 9-mm line scans across the fovea were obtained from right eyes. Using a customized segmentation program in MATLAB, total retinal thickness and the thickness of individual retinal layer regions were measured at the fovea (0°) and throughout ± 8°. Results Total thickness of the fovea in the retinopathy of prematurity group (287.7 ± 47.6 μm) was greater than that in the control group (230.1 ± 18.2 μm). Bilinear fitting was performed to examine the relationship between total thickness and gestational age. Before 28 weeks, foveal thickness decreased with gestational age (14.3 μm/week); after 28 weeks, foveal thickness decreased only slightly (2.73 μm/week). Inner retinal layers contributed to the difference in thickness between groups more than outer layers. Foveal thickness was correlated with gestational age at birth but not with visual acuity or refractive error. Conclusion Preterm birth before 28 weeks of gestational age was associated with a failure of the inner retinal layers to migrate away from the fovea, resulting in increased foveal thickness.

The purpose was to study the congenital cytomegalovirus (CMV), which is the most common cause for congenital infection in the United States, affecting nearly 40,000 infants per year. There is no widely accepted treatment protocol for congenital CMV infection despite recent clinical trials with antiviral medications ganciclovir and valganciclovir.We present a case report of an infant with severe congenital CMV infection with presentation of chorioretinitis in both eyes at 5 months of age.The child did not receive treatment with ganciclovir during hospitalization after birth despite severe manifestations of CMV infection. Treatment was again withheld after diagnosis of retinitis because of immunocompetent status, potential side effects of ganciclovir treatment, and location of retinitis in the retinal periphery of both eyes. The retinitis resolved during a period of 3 months.This case shows that CMV retinitis in infants with congenital CMV infection can be delayed in presentation and can resolve without treatment. It shows the need for more consistent monitoring for chorioretinitis in infants with congenital CMV infection.

The aim of this study is to analyze the impact of ophthalmic and neonatal factors on motor development in extremely low birth weight (ELBW) children.Sixty-four ELBW children at least 3 years of age were recruited. Visual acuity (VA) was assessed using the Teller acuity cards (TACs) and a letter test, if possible. A validated questionnaire assessing 25 fine (part A) and 20 gross motor (part B) skills was administered to the parents. Data were collected on retinopathy of prematurity (ROP) zone, intraventricular haemorrhage (IVH), length of stay in hospital, and number of days on oxygen.Abnormal TAC acuity was associated with significantly lower scores on both parts A and B (part A: 21.5 versus 11.8, p0.001; part B: 17.5 versus 13.2, p0.001). Linear regression demonstrates a significant direct relationship between letter acuity and score A only (p = 0.03, r(2) = 0.179). Neither length of hospital stay, number of days ventilated, nor a history of IVH were associated with score A or B. However, the presence of ROP zone 1 was associated with a lower score A (p = 0.03).In this ELBW cohort VA and ophthalmic factors were the only factors associated with scores of development, particularly fine motor development.

Purpose The Argus II Retinal Prosthesis System (Second Sight Medical Products, Inc, Sylmar, CA) was developed to restore some vision to patients blind as a result of retinitis pigmentosa (RP) or outer retinal degeneration. A clinical trial was initiated in 2006 to study the long-term safety and efficacy of the Argus II System in patients with bare or no light perception resulting from end-stage RP. Design Prospective, multicenter, single-arm clinical trial. Within-patient controls included the nonimplanted fellow eye and patients’ native residual vision compared with their vision with the Argus II. Participants Thirty participants in 10 centers in the United States and Europe. Methods The worse-seeing eye of blind patients was implanted with the Argus II. Patients wore glasses mounted with a small camera and a video processor that converted images into stimulation patterns sent to the electrode array on the retina. Main Outcome Measures The primary outcome measures were safety (the number, seriousness, and relatedness of adverse events) and visual function, as measured by 3 computer-based, objective tests. Secondary measures included functional vision performance on objectively scored real-world tasks. Results Twenty-four of 30 patients remained implanted with functioning Argus II Systems at 5 years after implantation. Only 1 additional serious adverse event was experienced after the 3-year time point. Patients performed significantly better with the Argus II on than off on all visual function tests and functional vision tasks. Conclusions The 5-year results of the Argus II trial support the long-term safety profile and benefit of the Argus II System for patients blind as a result of RP. The Argus II is the first and only retinal implant to have market approval in the European Economic Area, the United States, and Canada. © 2016 American Academy of Ophthalmology

© 2015 American Academy of Ophthalmology. Purpose Retinitis pigmentosa (RP) is a group of inherited retinal degenerations leading to blindness due to photoreceptor loss. Retinitis pigmentosa is a rare disease, affecting only approximately 100 000 people in the United States. There is no cure and no approved medical therapy to slow or reverse RP. The purpose of this clinical trial was to evaluate the safety, reliability, and benefit of the Argus II Retinal Prosthesis System (Second Sight Medical Products, Inc, Sylmar, CA) in restoring some visual function to subjects completely blind from RP. We report clinical trial results at 1 and 3 years after implantation. Design The study is a multicenter, single-arm, prospective clinical trial. Participants There were 30 subjects in 10 centers in the United States and Europe. Subjects served as their own controls, that is, implanted eye versus fellow eye, and system on versus system off (native residual vision). Methods The Argus II System was implanted on and in a single eye (typically the worse-seeing eye) of blind subjects. Subjects wore glasses mounted with a small camera and a video processor that converted images into stimulation patterns sent to the electrode array on the retina. Main Outcome Measures The primary outcome measures were safety (the number, seriousness, and relatedness of adverse events) and visual function, as measured by 3 computer-based, objective tests. Results A total of 29 of 30 subjects had functioning Argus II Systems implants 3 years after implantation. Eleven subjects experienced a total of 23 serious device- or surgery-related adverse events. All were treated with standard ophthalmic care. As a group, subjects performed significantly better with the system on than off on all visual function tests and functional vision assessments. Conclusions The 3-year results of the Argus II trial support the long-term safety profile and benefit of the Argus II System for patients blind from RP. Earlier results from this trial were used to gain approval of the Argus II by the Food and Drug Administration and a CE mark in Europe. The Argus II System is the first and only retinal implant to have both approvals.

Docosahexaenoic acid (DHA) continues to be evaluated and recommended as treatment and prophylaxis for various diseases. We recently assessed efficacy of high-dose DHA supplementation to slow vision loss in patients with X-linked retinitis pigmentosa (XLRP) in a randomized clinical trial. Because DHA is a highly unsaturated fatty acid, it could serve as a target for free-radical induced oxidation, resulting in increased oxidative stress. Biosafety was monitored during the 4-year trial to determine whether DHA supplementation was associated with identifiable risks.Males (n = 78; 7-31 years) meeting entry criteria were enrolled. The modified intent-to-treat cohort (DHA = 33; placebo = 27) adhered to the protocol ≥ 1 year. Participants were randomized to an oral dose of 30 mg/kg/d DHA or placebo plus a daily multivitamin. Comprehensive metabolic analyses were assessed for group differences. Treatment-emergent adverse events including blood chemistry metabolites were recorded.By year 4, supplementation elevated plasma and red blood cell-DHA 4.4- and 3.6-fold, respectively, compared with the placebo group (P0.00001). Over the trial duration, no significant differences between DHA and placebo groups were found for vitamin A, vitamin E, platelet aggregation, antioxidant activity, lipoprotein cholesterol, or oxidized LDL levels (all P0.14). Adverse events were transient and not considered severe (e.g., gastrointestinal [GI] irritability, blood chemistry alterations). One participant was unable to tolerate persistent GI discomfort.Long-term, high-dose DHA supplementation to patients with XLRP was associated with limited safety risks in this 4-year trial. Nevertheless, GI symptoms should be monitored in all patients taking high dose DHA especially those with personal or family history of GI disturbances. (ClinicalTrials.gov number, NCT00100230.).

Background Hospital-nursery lighting has been suggested as a factor in causing retinopathy of prematurity. Despite ongoing debate, a causal relation has not been established. Methods We conducted a prospective, randomized, multicenter study of the effects of light reduction on 409 premature infants with birth weights of less than 1251 g and gestational ages of less than 31 weeks. Two hundred five infants were exposed to reduced light, and 204 to typical nursery lighting. The amount of light reaching the infants' eyes was reduced within 24 hours after birth by placing goggles on the infants that reduced visible-light exposure by 97 percent and ultraviolet-light exposure by 100 percent. The babies wore the goggles until 31 weeks' postconceptional age or 4 weeks after birth, whichever was longer. Once the goggles were removed, ophthalmologists masked to the treatment assignments assessed the infants for retinopathy of prematurity at least biweekly for up to 13 weeks. Results There were 188 infants in the gro...

AIMS—To examine the effects of light on retinal development and function in preterm infants as measured by the electroretinogram (ERG). Secondary outcomes included visual acuity testing, the incidence of retinopathy of prematurity, and general wellbeing, reflected in feeding tolerance, rate of weight gain, and length of hospital stay. METHODS—Eligibility criteria for enrolment were birthweight ⩽ 1250 g and gestational age ⩽ 31 weeks. Sixty one infants were randomly allocated by 6 hours after birth to a control or treatment group which wore 97% light filtering goggles for a minimum of four weeks or until the infant reached 31 weeks postmenstrual age. RESULTS—There were no significant differences between the two groups in the numbers of electroretinograms performed at 36 weeks of postmenstrual age. Although the sample size was not large enough to exclude clinically important differences in secondary outcomes, no significant differences were observed between the groups in visual acuity testing at 4-6 months corrected age, incidence of retinopathy of prematurity, weight gain, or length of stay. CONCLUSION—These data support the safety and feasibility of this intervention. A much larger study will be needed to determine whether light reduction to the eyes of very low birthweight infants will reduce the incidence of retinopathy of prematurity or enhance general wellbeing. Keywords: light exposure; retinal development; electroretinogram

Traditionally, hereditary macular degenerations have been distinguished from age-related forms of macular degeneration that typically begin after the age of 50. We describe here three different juvenile hereditary macular degeneration syndromes for which there are characteristic clinical macular anatomic appearances. Stargardt macular dystrophy (STGD) [1–3], Best macular dystrophy (BMD) [2, 4, 5] and juvenile X-linked retinoschisis (JXRS) [2, 6–8], the so-called juvenile macular degenerations, were initially characterized by distinctive fundus findings [187]. The genetic basis of these conditions was recognized early on. They have been the focus of much interest lately, in part because they are among the most frequent causes of blindness in children, and in part because an understanding of the underlying mechanisms may be relevant for the much more common age-related forms of macular dystrophy. Other forms of juvenile hereditary retinal dystrophies, such as Leber’s congenital amaurosis, rod cone monochromacy, and blue cone monochromacy, in which a macular degeneration is not a pathognomonic clinical anatomic characteristic are reported elsewhere (e.g., 4). We do not include a focus on cone degenerations which are panretinal in nature and are treated elsewhere.

Ever since Dewar [1] first recorded electrical potentials from the human eye in 1877, electroretinography (ERG) has held promise as an objective measure of retinal function. Over the intervening years, it has become possible to relate the components of full-field, focal, multifocal, and pattern ERGs to their cellular origins within the retina. Thus, each of these tests can provide specific information about retinal disease.

In an effort to minimize surgical and visual morbidity of cryotherapy for retinopathy of prematurity (ROP), 18 eyes of 13 patients with 3 to 7 clock hours of stage 3 ROP with "plus" disease were treated by cryotherapy applications limited to the avascular retina adjacent to the areas of stage 3 disease. In 17 of 18 eyes, this limited use of cryotherapy was sufficient to cause regression of ROP without further treatments. After at least 3 months follow-up, ROP outcome showed a normal macular appearance in 16 eyes; two eyes developed macular dragging; no retinal detachments occurred.

In the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity (ROP), 4099 infants weighing less than 1251 g at birth underwent sequential ophthalmic examinations, beginning at age 4 to 6 weeks, to monitor the incidence and course of ROP. Overall, 65.8% of the infants developed ROP to some degree; 81.6% for infants of less than 1000 g birth weight. As expected, ROP incidence and severity were higher in lower birth weight and gestational age categories. Black infants appeared less susceptible to ROP, of all severity categories, than nonblack infants. The timing of retinal vascular events correlated more closely with postconceptional age than with postnatal age, implicating the level of maturity more than postnatal environmental influences in governing the timing of these vascular events. These results include the current incidence of various severity stages of ROP found in the United States and provide new. insight into the development of ROP.

Fifteen eyes believed to be at increased risk for macular hole formation underwent vitrectomy in an attempt to prevent macular hole formation. Full-thickness macular holes have not developed in 10 of 11 eyes with stage 1 macular holes. Four eyes were noted to have small full-thickness foveal defects (stage 2 macular holes) at the time of vitrectomy. Two of the four eyes have not progressed to macular hole formation and have 20/25 visual acuity. All patients have been followed for a minimum of 13 months (median, 18 months). The 12 eyes that have not experienced macular hole formation have had a significant (P less than 0.001) improvement in vision with seven (58%) attaining visual acuity of 20/25 or better. The postoperative foveal electroretinogram (ERG) amplitude was higher than the preoperative amplitude in five of the six eyes tested.

PURPOSE Docosahexaenoic acid (DHA) was supplemented in a single-site, placebo-controlled, randomized clinical trial designed to slow vision loss associated with X-linked retinitis pigmentosa (XLRP); the DHAX Trial. We previously reported no significant differences between supplemented and placebo groups in intent-to-treat analysis of primary ERG outcomes. Assessed herein are hypothesis-generating measures of ancillary visual function outcomes in participants fully adhering to trial protocol. METHODS Male participants with XLRP (range, 7-31 years) received 30 mg DHA/kg/d (n = 29) or placebo (n = 22) for 4 years. Visual outcomes were measured annually and red blood cell (RBC) DHA determined every 6 months. RESULTS Oral DHA supplementation increased mean RBC-DHA levels by 4-fold (P < 0.0001) over placebo. No group differences in progression were found for visual acuity (P = 0.11), shape discrimination (P = 0.18), or fundus appearance (P = 0.70). Optical coherence tomography (OCT) became available during year 2 of the trial; no group differences were seen in ellipsoid zone constriction (P = 0.87) over 2 years. Yearly rates of progression were reduced for dark-adapted thresholds (P = 0.06) and visual field sensitivity for foveal, macular, peripheral, total, and ellipsoid zone regions by DHA supplementation (P = 0.039, P = 0.031, P < 0.0001, P < 0.0001, and P = 0.033). Rates of visual field sensitivity decline were dependent on RBC-DHA (P = 0.046 to

Purpose Low docosahexaenoic acid (DHA) in X-linked retinitis pigmentosa (XLRP) may influence retinal function. The goals of this study were to elevate blood DHA levels and determine the effect on the rate of disease progression. Design In a 4-year prospective randomized clinical trial, male patients with XLRP (mean age=16 years; range=4–38 years) received DHA (400 mg/d; n=23; +DHA group) or placebo (n = 21) capsules. Methods Red blood cell (RBC)-DHA concentrations were assessed every 6 months. Full-field cone electroretinograms (ERGs; the primary outcome measure), visual acuity, dark-adaptation, visual fields, rod ERGs, and fundus photos were recorded annually. Results In the +DHA group, RBC-DHA increased 2.5-fold over placebo levels (70 vs 28 mg DHA/l). Repeated measures analysis of variance for cone ERG showed a significant main effect of year ( P P = .16). Preservation of cone ERG function correlated with RBC-DHA ( P = .018), and there was less change in fundus appearance in the +DHA group ( P = .04). Neither visual acuity nor visual fields were changed. In subset analysis, DHA supplementation was beneficial in reducing rod ERG functional loss in patients aged P = .040) and preserving cone ERG function in patients ≥12 years ( P = .038). Conclusions Although DHA-supplemented patients had significantly elevated mean RBC-DHA levels, the rate of cone ERG functional loss was not significantly different between groups. Supplemental analyses provided evidence for a DHA benefit and a direction for subsequent investigations.

Mutations in the ABCA4(ABCR) gene cause autosomal recessive Stargardt disease (STGD). ABCR mutations were identified in patients with cone–rod dystrophy (CRD) and retinitis pigmentosa (RP) by direct sequencing of all 50 exons in 40 patients. Of 10 patients with RP, one contained twoABCR mutations suggesting a compound heterozygote. This patient had a characteristic fundus appearance with attenuated vessels, pale disks and bone-spicule pigmentation. Rod electroretinograms (ERGs) were non-detectable, cone ERGs were greatly reduced in amplitude and delayed in implicit time, and visual fields were constricted to 10° diameter. Eleven of 30 (37%) patients with CRD had mutations in ABCR. In general, these patients showed reduced but detectable rod ERG responses, reduced and delayed cone responses, and poor visual acuity. Rod photoresponses to high intensity flashes were of reduced maximum amplitude but showed normal values for the gain of phototransduction. Most CRD patients with mutations inABCR showed delayed recovery of sensitivity (dark adaptation) following exposure to bright light. Pupils were also significantly smaller in these patients compared to controls at 30 min following light exposure, consistent with a persistent ‘equivalent light’ background due to the accumulation of a tentatively identified ‘noisy’ photoproduct.

Importance X-linked retinitis pigmentosa is a severe inherited retinal degenerative disease with a frequency of 1 in 100 000 persons. Because no cure is available for this orphan disease and treatment options are limited, slowing of disease progression would be a meaningful outcome. Objective To determine whether high-dose docosahexaenoic acid (DHA), an ω-3 polyunsaturated fatty acid, slows progression of X-linked retinitis pigmentosa measured by cone electroretinography (ERG). Design, Setting, and Participants A 4-year, single-site, randomized, placebo-controlled, double-masked phase 2 clinical trial at a research center specializing in medical retina. Seventy-eight male patients diagnosed as having X-linked retinitis pigmentosa were randomized to DHA or placebo. Data were omitted for 2 patients with non–X-linked retinitis pigmentosa and 16 patients who were unable to follow protocol during the first year. The remaining participants were tested annually and composed a modified intent-to-treat cohort (DHA group, n = 33; placebo group, n = 27). Interventions All participants received a multivitamin and were randomly assigned to oral DHA (30 mg/kg/d) or placebo. Main Outcomes and Measures The primary outcome was the rate of loss of cone ERG function. Secondary outcomes were rod and maximal ERG amplitudes and cone ERG implicit times. Capsule counts and red blood cell DHA levels were assessed to monitor adherence. Results Average (6-month to 4-year) red blood cell DHA levels were 4-fold higher in the DHA group than in the placebo group ( P P = .30). No group differences were evident for change in rod ERG ( P = .27), maximal ERG ( P = .65), or cone implicit time (no change over 4 years). The rate of cone loss (ie, event rate) was markedly reduced compared with rates in previous studies. No severe treatment-emergent adverse events were found. Conclusions and Relevance Long-term DHA supplementation was not effective in slowing the loss of cone or rod ERG function associated with X-linked retinitis pigmentosa. Participant dropout and lower-than-expected disease event rate limited power to detect statistical significance. A larger sample size, longer trial, and attainment of a target blood DHA level (13%) would be desirable. While DHA supplementation at 30 mg/kg/d does not present serious adverse effects, routine monitoring of gastrointestinal tolerance is prudent. Trial Registration clinicaltrials.gov Identifier:NCT00100230

The recently developed MNREAD ACUITY CHARTSR have been suggested to be very useful tools for clinical examination and research in patients with low vision1. The MNREAD charts were designed to address limitations found with standard near optotype acuity tests. The design of many standard near acuity tests is not consistent with currently accepted acuity chart guidelines2, and it has been found that standard optotype acuities are poor predictors of reading performance3 and the ability to use low vision aids4. A potential advantage of the MNREAD charts is that they can be used to quantify reading speed across a range of sentence character sizes in patients with low vision. Previous studies have found that MNREAD measures of reading acuity, optimal character size and critical character size are very useful indices for characterizing reading abilities in patients with low vision1,5-6. However, the MNREAD charts are relatively new, and little is known about the test-retest reliability of MNREAD measures in patients with low vision.

Purpose To examine quantitatively characteristics of the peripapillary retinal nerve fiber layer (RNFL) in preterm children using Fourier-domain optical coherence tomography (FD-OCT). Design Prospective cross-sectional study. Methods A 3-mm high-resolution FD-OCT peripapillary RNFL circular scan centered on the optic disc was obtained from right eyes of 25 preterm children (10.6 ± 3.7 years old, 8 preterm and 17 with regressed retinopathy of prematurity with normal-appearing posterior poles) and 54 full-term controls (9.8 ± 3.2 years old). Images were analyzed using Spectralis FD-OCT software to obtain average thickness measurements for 6 sectors (temporal superior, temporal, temporal inferior, nasal inferior, nasal, nasal superior), and the global average. Results The RNFL global average for preterm children was 8% thinner than for full-term controls. In the preterm group, peripapillary RNFL thickness on the temporal side of the disc was 6% thicker than in full-term controls, while all other peripapillary RNFL sectors were 9% to 13% thinner. In the preterm group, temporal sector peripapillary RNFL thickness was correlated with gestational age (r = −0.47, P P = .008, 1-tailed), and with visual acuity (r = 0.42; P = .026, 1-tailed). Conclusions The significantly thinner RNFL global average for preterm children suggests that prematurity is associated with subclinical optic nerve hypoplasia. Significant correlations between temporal sector RNFL thickness and both the foveal thickness and visual acuity suggest that the peripapillary RNFL is related to abnormalities in macular development as a result of preterm birth.

Significant advances regarding understanding the etiology and treatment of retinopathy of prematurity have occurred in the 50 years since its discovery. Nevertheless, there is still a great deal to be learned. In spite of major technological advances in neonatal care, retinopathy of prematurity is a multi-factorial disease and probably cannot be completely prevented. Early intervention in the diagnosis and management of these infants has greatly improved their visual prognosis. Further studies may help pediatricians and neonatologists to understand and control associated risk factors. Ophthalmologists must continue to examine these patients early and follow them closely to control the associated treatable aspects of the disease, such as strabismus and amblyopia.

Objective: To determine whether the extent of retinal vessel development present on early screening examinations for retinopathy of prematurity has prognostic value? Design: The prospectively collected data from the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity were used to compare the development of acute retinopathy of prematurity and long-term structural and visual outcomes for eyes with differing extents of retinal vessel development. Patients: Study patients had eyes with the following vessel development. In zone I eyes, vessels extended from the disc less than twice the distance from the disc to the macula. In zone II eyes, vessels extended beyond zone I but not to the nasal ora serrata. Transitional eyes had vessels partly in zone I and partly in zone II. Results: The chance of developing threshold retinopathy of prematurity was inversely related to the early degree of vessel development: 54% for zone I eyes, 25% for transitional eyes, and 8% for zone II eyes. The presence of prominent iris vessels at 34 to 35 weeks of postmenstrual age was associated with increased risk for all three groups; zone I eyes almost always needed treatment (94%). The chance of having an unfavorable anatomic alteration of the posterior fundus, or poor vision at the ages of 1 year and 3½ years, was also inversely related to the degree of early vessel development. Vessel development was an independently important factor even when birth weight, gestational age, and race were considered. Conclusions: The degree of early retinal vessel development is a significant predictor of outcome from retinopathy of prematurity. Iris vessel dilatation is an important indication for greater vigilance in following up these infants.

Objectives: To compare grating visual acuity of eyes with varying severity of retinal residua of retinopathy of prematurity to grating vasual acuity of eyes that did not have acute-phase retinopaty of prematurity, showed no ocular abnormalities on follow-up, and were from patients who passed neurodevelopmental screening questions. Design: Monocular grating visual acuity was measured by means of the Teller acuity card procedure when children reached 1, 2, 3½, and 4½ years of age. Patients: A total of 1398 children with birth weights less than 1251 g whose acute-phase retinopathy of prematurity was documented as part of the Multicenter Cryotherapy for Retinopathy of Prematurity Study and who participated in follow-up visual acuity testing. Results: Eyes with no or mild residua of retinopathy of prematurity showed a mean visual acuity similar to that of the comparison group. Eyes in a subgroup with abnormally straightened temporal retinal vessels showed a mean visual acuity approximately 1 octave below that of the comparison group. Mean visual acuity scores from eyes with macular heterotopia ranged from 1 octave (at 1 year) to more than 2 octaves (at 4½ years) below the mean visual acuity of the comparison group. Mean visual acuity scores for the few eyes in the retinal fold or partial detachment group that had quantifiable visual acuity were well below the means for the comparison group. Conclusions: Acute-phase retinopathy of prematurity that regresses without retinal residua produces no deficit in grating visual acuity between 1 and 4½ years of age. In contrast, eyes with macular heterotopia show a visual acuity deficit, and the deficit is greater at older than at younger ages. Eyes with retinal fold or partial detachment that have measurable visual acuity show large visual acuity deficits at all ages.

• Four hundred eyes with moderate or severe proliferative diabetic retinopathy, initial good vision, and an average follow-up of 44.3 months were studied. Final visual acuity was 20/40 or better in 33% of these eyes, 20/50 to 5/200 in 32%, and 5/200 or worse in 35%. A poor visual prognosis was correlated with a traction detachment or relatively poor visual aculty at initial examination. No correlation was found between the length of follow-up and final visual prognosis. General guidelines are available for the management of these patients' conditions.

We controlled the development of epithelial edema of the cornea during closed vitreoretinal surgery even when the technique required continuous use of a contact lens by gentle debridement of only the shaggy, edematous superficial layer of wing cells, using an olive-tip irrigator. This technique may avoid the necessity of completely removing the epithelium and the attendant postoperative complications.

• Severe diabetic retinopathy with neovascular proliferation may produce severe vitreous hemorrhage that prevents laser therapy. Retinal ablation, if indicated, can be partly accomplished by cryopexy. In a small series of cases, cryotherapy to the retina was not apparently harmful and sometimes seemed beneficial. Blood absorption seemed more rapid and recurrent bleeding less frequent; however, vitreous hemorrhages in proliferative diabetic retinopathy are too variable in their natural history of absorption and recurrence to permit any definite conclusion as to the value of this method of retinal ablation. A national collaborative study with lengthy follow-ups will be necessary to determine whether chorioretinal scars produced by laser therapy and those produced by cryotherapy will afford similar protection from the forward course of proliferative diabetic retinopathy, vitreous hemorrhage and blindness. In the meantime, this report is intended to alert ophthalmologists that retinal cryoablation is a conservation alternative to "early" vitrectomy for vitreous hemorrhages from diabetic retinopathy.