PURPOSE: To report bilateral corneal endothelial cell density (ECD), as well as its correlation with subbasal nerve changes, in patients with unilateral herpes simplex keratitis (HSK). METHODS: Thirty-six eyes of 36 patients with corneal scarring caused by HSK, as well as their respective contralateral clinically unaffected eyes, were prospectively studied and compared with 26 eyes of 26 healthy volunteers. In vivo confocal microscopy and corneal sensation of the central cornea were performed bilaterally in all patients and in one random eye of controls. The ECD and subbasal corneal nerve density, including the lengths of total nerves, main trunks, and branches were evaluated and correlated to central corneal sensation. RESULTS: The ECD was significantly lower in eyes affected with HSK than in controls (2304 ± 578 vs. 2940 ± 370 cells/mm2, P < 0.0001). Surprisingly, lower ECD was also detected in contralateral clinically unaffected eyes (2548 ± 423), compared to controls (P = 0.02). Both affected and contralateral eyes showed decrease in total nerve length, compared to controls (10.0 ± 6.3 vs. 17.6 ± 6.3 vs. 21.9 ± 4.3 mm/mm2, respectively; P < 0.05 for all). The ECD correlated positively with total nerve length (r = 0.39, P = 0.0009) and with corneal sensation (r = 0.31, P = 0.009). CONCLUSIONS: In vivo confocal microscopy findings demonstrated alterations in corneal ECD in both affected and clinically unaffected contralateral eyes of patients with unilateral HSK. Moreover, the positive significant correlation between the ECD and the subbasal nerve density may suggest a potential link between corneal innervation and corneal endothelial cell homeostasis.

We observed that the third leading cause of blindness in the world, age-related macular degeneration (AMD), occurs at a very low documented frequency in a population-based cohort from Timor-Leste. Thus, we determined a complete catalog of the ancestry of the Timorese by analysis of whole exome chip data and haplogroup analysis of SNP genotypes determined by sequencing the Hypervariable I and II regions of the mitochondrial genome and 17 genotyped YSTR markers obtained from 535 individuals. We genotyped 20 previously reported AMD-associated SNPs in the Timorese to examine their allele frequencies compared to and between previously documented AMD cohorts of varying ethnicities. For those without AMD (average age > 55 years), genotype and allele frequencies were similar for most SNPs with a few exceptions. The major risk allele of HTRA1 rs11200638 (10q26) was at a significantly higher frequency in the Timorese, as well as 3 of the 5 protective CFH (1q32) SNPs (rs800292, rs2284664, and rs12066959). Additionally, the most commonly associated AMD-risk SNP, CFH rs1061170 (Y402H), was also seen at a much lower frequency in the Korean and Timorese populations than in the assessed Caucasian populations (C ~7 vs. ~40%, respectively). The difference in allele frequencies between the Timorese population and the other genotyped populations, along with the haplogroup analysis, also highlight the genetic diversity of the Timorese. Specifically, the most common ancestry groupings were Oceanic (Melanesian and Papuan) and Eastern Asian (specifically Han Chinese). The low prevalence of AMD in the Timorese population (2 of 535 randomly selected participants) may be due to the enrichment of protective alleles in this population at the 1q32 locus.

PURPOSE: To compare visual acuity outcomes, vision-related quality of life, and complications related to cataract surgery in eyes with and without glaucoma. DESIGN: Retrospective cohort study. METHODS: Cataract surgery outcomes in cases with and without glaucoma from the Veterans Affairs Ophthalmic Surgical Outcomes Data Project were compared. RESULTS: We identified 608 glaucoma cases and 4306 controls undergoing planned cataract surgery alone. After adjusting for age, pseudoexfoliation, small pupil, prior ocular surgery, and anterior chamber depth, we found that glaucoma cases were more likely to have posterior capsular tear with vitrectomy (odds ratio [OR] 1.8, P = .03) and sulcus intraocular lens placement (OR 1.65, P = .03) during cataract surgery. Glaucoma cases were more likely to have postoperative inflammation (OR 1.73, P < .0001), prolonged elevated intraocular pressure (OR 2.96, P = .0003), and additional surgery within 30 days (OR 1.92, P = .03). Mean best-corrected visual acuity (BCVA) and Visual Function Questionnaire (VFQ) scores significantly improved after cataract surgery in both groups (P < .0001), but there were larger improvements in BCVA (P = .01) and VFQ composite scores (P < .0001) in the nonglaucoma vs the glaucoma group. A total of 3621 nonglaucoma cases (94.1%) had postoperative BCVA 20/40 or better, compared to 466 glaucoma cases (89.6%) (P = .0003). CONCLUSIONS: Eyes with glaucoma are at increased risk for complications and have more modest visual outcomes after cataract surgery compared to eyes without glaucoma. Despite this, glaucoma patients still experience significant improvement in vision-related outcomes after cataract extraction. Further study is needed to explore potential factors that influence cataract surgery outcomes in glaucomatous eyes.

Degeneration of photoreceptors is a primary cause of vision loss worldwide, making the underlying mechanisms surrounding photoreceptor cell death critical to developing new treatment strategies. Retinal detachment, characterized by the separation of photoreceptors from the underlying retinal pigment epithelium, is a sight-threatening event that can happen in a number of retinal diseases. The detached photoreceptors undergo apoptosis and programmed necrosis. Given that photoreceptors are nondividing cells, their loss leads to irreversible visual impairment even after successful retinal reattachment surgery. To better understand the underlying disease mechanisms, we analyzed innate immune system regulators in the vitreous of human patients with retinal detachment and correlated the results with findings in a mouse model of retinal detachment. We identified the alternative complement pathway as promoting early photoreceptor cell death during retinal detachment. Photoreceptors down-regulate membrane-bound inhibitors of complement, allowing for selective targeting by the alternative complement pathway. When photoreceptors in the detached retina were removed from the primary source of oxygen and nutrients (choroidal vascular bed), the retina became hypoxic, leading to an up-regulation of complement factor B, a key mediator of the alternative pathway. Inhibition of the alternative complement pathway in knockout mice or through pharmacological means ameliorated photoreceptor cell death during retinal detachment. Our current study begins to outline the mechanism by which the alternative complement pathway facilitates photoreceptor cell death in the damaged retina.

PURPOSE: To evaluate the efficacy of systemic infliximab for the induction of remission in patients with retinal vasculitis, inadequately responsive to other immunomodulatory therapy, based on fluorescein angiography grading for retinal vasculitis evaluation. METHODS: We analyzed 60 patients with retinal vasculitis, from the Massachusetts Eye Research and Surgery Institution in Cambridge, MA. Response to therapy was based on analysis of serial fluorescein angiography and fundus photography, including a baseline angiogram before initiation of infliximab. RESULTS: Sixty patients received infliximab therapy between July 2007 and July 2012 at Massachusetts Eye Research and Surgery Institution for a diagnosis of retinal vasculitis. All had previously showed a poor clinical response to other immunomodulatory regimens, or ceased therapy due to intolerable side effects. The initial dose of infliximab was 5 mg/kg in all patients and remained at this dose for the extent of treatment in 57 (95%) patients. At 6 months, 45 of 51 (88.23%) patients were maintaining remission with therapy, 5 (9.8%) were in partial remission, and 1 patient had failed. At 12 months, 39 of 39 (100%) patients were maintaining remission with therapy. CONCLUSION: Infliximab is effective for the treatment of recalcitrant noninfectious retinal vasculitis, refractory to conventional immunomodulatory therapy.

Inherited and age-related macular degenerations (AMDs) are important causes of vision loss. An early hallmark of these disorders is the formation of sub-retinal pigment epithelium (RPE) basal deposits. A role for the complement system in MDs was suggested by genetic association studies, but direct functional connections between alterations in the complement system and the pathogenesis of MD remain to be defined. We used primary RPE cells from a mouse model of inherited MD due to a p.R345W mutation in EGF-containing fibulin-like extracellular matrix protein 1 (EFEMP1) to investigate the role of the RPE in early MD pathogenesis. Efemp1(R345W) RPE cells recapitulate the basal deposit formation observed in vivo by producing sub-RPE deposits in vitro. The deposits share features with basal deposits, and their formation was mediated by EFEMP1(R345W) or complement component 3a (C3a), but not by complement component 5a (C5a). Increased activation of complement appears to occur in response to an abnormal extracellular matrix (ECM), generated by the mutant EFEMP1(R345W) protein and reduced ECM turnover due to inhibition of matrix metalloproteinase 2 by EFEMP1(R345W) and C3a. Increased production of C3a also stimulated the release of cytokines such as interleukin (IL)-6 and IL-1B, which appear to have a role in deposit formation, albeit downstream of C3a. These studies provide the first direct indication that complement components produced locally by the RPE are involved in the formation of basal deposits. Furthermore, these results suggest that C3a generated by RPE is a potential therapeutic target for the treatment of EFEMP1-associated MD as well as AMD.

The nervous system is complex not simply because of the enormous number of neurons it contains but by virtue of the specificity with which they are connected. Unraveling this specificity is the task of neuroanatomy. In this endeavor, neuroanatomists have traditionally exploited an impressive array of tools ranging from the Golgi method to electron microscopy. An ideal method for studying anatomy would label neurons that are interconnected, and, in addition, allow expression of foreign genes in these neurons. Fortuitously, nature has already partially developed such a method in the form of neurotropic viruses, which have evolved to deliver their genetic material between synaptically connected neurons while largely eluding glia and the immune system. While these characteristics make some of these viruses a threat to human health, simple modifications allow them to be used in controlled experimental settings, thus enabling neuroanatomists to trace multi-synaptic connections within and across brain regions. Wild-type neurotropic viruses, such as rabies and alpha-herpes virus, have already contributed greatly to our understanding of brain connectivity, and modern molecular techniques have enabled the construction of recombinant forms of these and other viruses. These newly engineered reagents are particularly useful, as they can target genetically defined populations of neurons, spread only one synapse to either inputs or outputs, and carry instructions by which the targeted neurons can be made to express exogenous proteins, such as calcium sensors or light-sensitive ion channels, that can be used to study neuronal function. In this review, we address these uniquely powerful features of the viruses already in the neuroanatomist's toolbox, as well as the aspects of their biology that currently limit their utility. Based on the latter, we consider strategies for improving viral tracing methods by reducing toxicity, improving control of transsynaptic spread, and extending the range of species that can be studied.

PURPOSE: To characterize the risk and risk factors for intraocular pressure (IOP) elevation in pediatric noninfectious uveitis. DESIGN: Multicenter retrospective cohort study. PARTICIPANTS: Nine hundred sixteen children (1593 eyes) younger than 18 years at presentation with noninfectious uveitis followed up between January 1978 and December 2007 at 5 academic uveitis centers in the United States. METHODS: Medical records review by trained, certified experts. MAIN OUTCOME MEASURES: Prevalence and incidence of IOP of 21 mmHg or more and 30 mmHg or more and incidence of a rise in IOP by 10 mmHg or more. To avoid underascertainment, outcomes were counted as present when IOP-lowering therapies were in use. RESULTS: Initially, 251 (15.8%) and 46 eyes (2.9%) had IOP ≥21 mmHg and ≥30 mmHg, respectively. Factors significantly associated with presenting IOP elevation included age of 6 to 12 years (versus other pediatric ages), prior cataract surgery, pars plana vitrectomy, duration of uveitis ≥6 months, contralateral IOP elevation, presenting visual acuity worse than 20/40, and topical corticosteroid use (in a dose-response relationship). The median follow-up was 1.25 years (interquartile range, 0.4-3.66). The estimated incidence of any observed IOP elevation to ≥21 mmHg, to ≥30 mmHg, and increase in IOP by ≥10 mmHg was 33.4%, 14.8%, and 24.4%, respectively, within 2 years. Factors associated with IOP elevation included pars plana vitrectomy, contralateral IOP elevation (adjusted hazard ratio [aHR], up to 9.54; P < 0.001), and the use of topical (aHR, up to 8.77 that followed a dose-response relationship; P < 0.001), periocular (aHR, up to 7.96; P < 0.001), and intraocular (aHR, up to 19.7; P < 0.001) corticosteroids. CONCLUSIONS: Intraocular pressure elevation affects a large minority of children with noninfectious uveitis. Statistically significant risk factors include IOP elevation or use of IOP-lowering treatment in the contralateral eye and local corticosteroid use that demonstrated a dose-and route of administration-dependent relationship. In contrast, use of immunosuppressive drug therapy did not increase such risk. Pediatric eyes with noninfectious uveitis should be followed up closely for IOP elevation, especially when strong risk factors such as the use of local corticosteroids and contralateral IOP elevation are present.

PURPOSE: Absorbable polyethylene glycol-based synthetic sealant (PEG sealant) polymerizes under xenon illumination and forms a clear, flexible, and firmly adherent hydrogel. The intraocular biocompatibility of PEG sealant and efficacy for closing retinal breaks were evaluated. METHODS: In an in vitro study, retinal detachment with a tear was created in porcine eyecups after vitreous gel removal. Polyethylene glycol-based synthetic sealant was applied to cover the tear and polymerized with a 40-second application of xenon light. Retinal adhesion strength was tested by forcefully squirting balanced salt solution (BSS) onto the retinal tear. Polyethylene glycol-based synthetic sealant was soaked in the BSS, incubated at 37°C, and the pH measured periodically over 72 hours. In an in vivo study, PEG sealant was injected into the vitreous cavity of the left eyes of rabbits. Ophthalmologic examinations were performed and bilateral ERGs were recorded simultaneously before and 28 days after injection. The eyes were enucleated for histological evaluation. RESULTS: Adhesion of PEG sealant to the retina was good in BSS. A forceful squirt of BSS onto the retinal tear covered with PEG sealant did not detach the retina; the retinal tear without PEG sealant detached immediately. The pH of the BSS containing PEG sealant was between 7.2 and 8.2. No inflammatory reaction was observed in the eyes throughout 28 days of follow-up. The ERGs recorded before and after injection showed typical patterns. Histological examinations did not reveal any abnormality or inflammation. CONCLUSIONS: Polyethylene glycol-based synthetic sealant appeared to effectively seal retinal breaks and was not toxic to the eye.