Purpose: Clinical manifestations of photoreceptor degeneration include gradual thinning of the outer nuclear layer (ONL) and progressive reduction of electroretinogram (ERG) amplitudes and vision loss. Although preclinical evaluations of treatment strategies greatly depend on rodent models, the courses of these changes in mice remain unclear. We thus sought to investigate the temporal correlations in changes of spatial vision, ERG response, and ONL thickness in mice with progressive photoreceptor degeneration. Methods: Adult wild-type (WT) mice and mice carrying rhodopsin deficiency (Rho-/-), a frequently used mouse model of human retinitis pigmentosa, were selected for investigation. Mouse spatial vision, including visual acuity (VA) and contrast sensitivity (CS), was determined using optomotor response (OMR) assays; ONL thickness was quantified by spectral-domain optical coherence tomography (SD-OCT), and ERG was performed to evaluate retinal functions. The mice were killed when they were 14 weeks old, and the cone photoreceptors in retinal sections were counted. Results: Spatial vision, ONL thickness, and ERG amplitudes remained stable in WT mice at all examined time points. While 6-week-old Rho-/- mice had VA, CS, as well as ERG responses similar to those of WT mice, progressive reductions in the spatial vision and retinal functions were recorded thereafter. Most tested 12-week-old Rho-/- mice had no visual-evoked OMR and ERG responses. Moreover, CS, but not VA, displayed a linear decline that was closely associated with ONL thinning, reduction of ERG amplitudes, and loss of cones. Conclusions: We presented a comprehensive study of the relation between the changes of spatial vision, retinal function, and ONL thickness in postnatal week (PW)6 to PW12 Rho-/- mice. CS is a more sensitive indicator of spatial vision compared to VA, although both are required as separate parameters for monitoring the visual changes in retina undergoing photoreceptor degeneration.

Collagen crosslinking provides the mechanical strength required for physiological maintenance of the extracellular matrix in most tissues in the human body, including the cornea. Aging and diabetes mellitus (DM) are processes that are both associated with increased collagen crosslinking that leads to increased corneal rigidity. By contrast, keratoconus (KC) is a corneal thinning disease associated with decreased mechanical stiffness leading to ectasia of the central cornea. Studies have suggested that crosslinking mediated by reactive advanced glycation end products during DM may protect the cornea from KC development. Parallel to this hypothesis, riboflavin-mediated photoreactive corneal crosslinking has been proposed as a therapeutic option to halt the progression of corneal thinning by inducing intra- and intermolecular crosslink formation within the collagen fibrils of the stroma, leading to stabilization of the disease. Here, we review the pathobiology of DM and KC in the context of corneal structure, the epidemiology behind the inverse correlation of DM and KC development, and the chemical mechanisms of lysyl oxidase-mediated crosslinking, advanced glycation end product-mediated crosslinking, and photoreactive riboflavin-mediated corneal crosslinking. The goal of this review is to define the biological and chemical pathways important in physiological and pathological processes related to collagen crosslinking in DM and KC.

The optic nerve conveys information about the outside world from the retina to multiple subcortical relay centers. Until recently, the optic nerve was widely believed to be incapable of re-growing if injured, with dire consequences for victims of traumatic, ischemic, or neurodegenerative diseases of this pathway. Over the past 10-20 years, research from our lab and others has made considerable progress in defining factors that normally suppress axon regeneration and the ability of retinal ganglion cells, the projection neurons of the retina, to survive after nerve injury. Here we describe research from our lab on the role of inflammation-derived growth factors, suppression of inter-cellular signals among diverse retinal cell types, and combinatorial therapies, along with related studies from other labs, that enable animals with optic nerve injury to regenerate damaged retinal axons back to the brain. These studies raise the possibility that vision might one day be restored to people with optic nerve damage.

: To determine the imaging approach for evaluating intraocular foreign bodies (IOFBs) by comparing the ability of different modalities [plain film x-ray, computed tomography (CT), magnetic resonsance imaging (MRI), convetional ultrasound, and ultrasound biomicroscopy] to detect and characterize IOFBs. : Systematic review of the literature. : CT is the most practical first step for evaluating patients with suspected IOFBs because it can detect a wide range of IOFB types at small limitis of detection. MRI and ultrasound are best reserved as adjunctive tests in most cases although these tests may provide important insights especially with wood, plastic, and glass IOFBs. Imaging characteristics of metal, wood, glass, plastic, stone, concrete, and graphite IOFBs are reviewed. : Understanding the limits of detection for each IOFB type and imaging modality as well as the characteristic features of different IOFBs is of paramount importance to optimizing the management of ocular trauma patients.

Under cone-mediated (photopic) conditions, an "instantaneous" flash of light, including both stimulus onset and offset, will simultaneously activate both "ON" and "OFF" bipolar cells, which either depolarize (ON) or hyperpolarize (OFF) in response and, respectively, produce positive-going and negative-going deflections in the electroretinogram (ERG). The stimulus-response (SR) relationship of the photopic ON response demonstrates logistic growth, like that manifested in the rod-mediated (scotopic) b-wave, which is driven by a single class of depolarizing bipolar cell. However, the photopic b-wave SR function is importantly shaped by OFF responses, leading to a "photopic hill." Furthermore, both on and off stimuli elicit activity in both ON and OFF bipolar cells. This has made it difficult to produce meaningful parameters for ready interpretation of the photopic b-wave SR relationship. Therefore, we evaluated whether the sum of sigmoidal SR functions, as descriptors of the depolarizing and hyperpolarizing components of the photopic flash ERG, could be used to elucidate and quantitate the mechanisms that produce the photopic hill. We used a novel fitting routine to optimize a sum of simple sigmoidal curves to SR data in five groups of subjects: Healthy adult, 10-week-old infant, congenital stationary night blindness (CSNB), X-linked juvenile retinoschisis (XJR), and preterm-born, both without and with a history of retinopathy of prematurity (ROP). Differences in ON and OFF amplitude, sensitivity, and implicit time among the groups were then compared using parameters extracted from these fits. We found that our modeling procedure enabled plausible derivations of ON and OFF pathway contributions to the ERG, and that the parameters produced appeared to have physiological relevance. In adult subjects, the ON and OFF amplitudes were similar in magnitude with respectively longer and shorter implicit times. Infant, CSNB, and XJR subjects showed significant ON pathway deficits. History of preterm-birth, without or with a diagnosis of ROP, did not much affect cone responses.

PRéCIS:: Neuroretinal rim minimum distance band (MDB) thickness is significantly lower in older subjects and African Americans compared with whites. It is similar in both sexes. PURPOSE: To evaluate the relationship between age, race, and sex with the neuroretinal rim using high-density spectral-domain optical coherence tomography optic nerve volume scans of normal eyes. METHODS: A total of 256 normal subjects underwent Spectralis spectral-domain optical coherence tomography optic nerve head volume scans. One eye was randomly selected and analyzed for each subject. Using custom-designed software, the neuroretinal rim MDB thickness was calculated from volume scans, and global and quadrant neuroretinal rim thickness values were determined. The MDB is a 3-dimensional neuroretinal rim band comprised of the shortest distance between the internal limiting membrane and the termination of the retinal pigment epithelium/Bruch's membrane complex. Multiple linear regression analysis was performed to determine the associations of age, race, and sex with neuroretinal rim MDB measurements. RESULTS: The population was 57% female and 69% white with a mean age of 58.4±15.3 years. The mean MDB thickness in the normal population was 278.4±47.5 µm. For this normal population, MDB thickness decreased by 0.84 µm annually (P<0.001). African Americans had thinner MDBs compared with whites (P=0.003). Males and females had similar MDB thickness values (P=0.349). CONCLUSION: Neuroretinal rim MDB thickness measurements decreased significantly with age. African Americans had thinner MDB neuroretinal rims than whites.

The somatotopic motor-neuron projections onto their cognate target muscles are essential for coordinated movement, but how that occurs for facial motor circuits, which have critical roles in respiratory and interactive behaviors, is poorly understood. We report extensive molecular heterogeneity in developing facial motor neurons in the mouse and identify markers of subnuclei and the motor pools innervating specific facial muscles. Facial subnuclei differentiate during migration to the ventral hindbrain, where neurons with progressively later birth dates-and evolutionarily more recent functions-settle in more-lateral positions. One subpopulation marker, ETV1, determines both positional and target muscle identity for neurons of the dorsolateral (DL) subnucleus. In Etv1 mutants, many markers of DL differentiation are lost, and individual motor pools project indifferently to their own and neighboring muscle targets. The resulting aberrant activation patterns are reminiscent of the facial synkinesis observed in humans after facial nerve injury.

For this "hot topic" session in uveitis we selected first and foremost an issue that puts our clinical work and research in "holding pattern." The issue is our method of evaluating the severity of uveitis. We posed the following questions to our esteemed panelists: 1.The relative significance of cells vs. flare in following uveitis patients 2.Cells/flare measurements 3.A glance into the future and the relevance of endpoints in clinical studies and their methodologies While there are different opinions in managing and monitoring uveitis patients, there seems to be an agreement on the high need of improving objective mode/s of reliably measuring both cells and flare and better understand their significance.

The purpose of this review was to identify areas of consensus and disagreement among experts for the definition of success following strabismus surgery using the Delphi process. Three rounds of electronic questionnaires were sent to a panel of 28 strabismus experts. Throughout the process, members of the panel were masked to one another's identities to minimize the possibility of influence among members. Prior to data collection, we defined consensus as an 85% agreement on the answer to each question. Questions for which there was no consensus were reworded, and the resultant new questions were used in each subsequent round of questioning. We arrived at consensus for 23 of the 36 questions (64%). Consensus was obtained for recommending unique criteria for the definition of success for certain specific strabismus conditions. In addition, it was considered important that stereopsis and the range of single binocular vision be included in the definition of success for certain types of strabismus.

PURPOSE: To review the roles of analytic and innovative thought in advancing knowledge, using past examples in ophthalmology, and to explore potential strategies to improve our understanding of age-related macular degeneration (AMD) and develop new therapies. DESIGN: Presented as the 2018 Charles L. Schepens, MD, Lecture at the American Academy of Ophthalmology Retina Subspecialty Day, Chicago, Illinois, on October 26, 2018. PARTICIPANTS: None. METHODS: Review of published literature and sources on creativity and innovation. MAIN OUTCOME MEASURES: Recommendations for future AMD research. RESULTS: Innovative solutions to problems often seem intuitively obvious in hindsight. Yet, some problems seem impossible to solve. In the 1990s, AMD was a significant unmet need, with only destructive therapies for neovascular disease. This changed with the development of 2 therapies: (1) verteporfin photodynamic therapy (PDT) and (2) anti-vascular endothelial growth factor (VEGF) therapies, which are now administered to millions of people annually around the world. Now, we are frustrated by the lack of therapies for early and intermediate AMD and geographic atrophy. Photodynamic therapy and anti-VEGF drug development occurred through a combination of analytic thought and creative disruption through innovation. To get past our current impasse in understanding and treating AMD, we need to harness both analysis and innovation. We have many important building blocks in place-information on genetics, clinical findings, imaging, and histology-and have identified key pathways and potential therapeutic targets. Perhaps we need additional investigation, analysis, and integration to improve our understanding through work on structure/function and genotype/phenotype correlations and development of imaging and systemic biomarkers. We likely also need an innovative disruption. This innovation might be the concept that there are subtypes of early and intermediate AMD characterized by specific clinical phenotypes, genotype, functional characteristics, and biomarkers that are dependent on particular pathways and treatable with a specific agent. We need to encourage innovation in each of us within our research and clinical community. CONCLUSIONS: Although we have accumulated extensive knowledge about AMD, we are currently at an impasse in the development of new treatments. We need to continue the analytic process, but at the same time encourage innovative disruption to develop successful AMD therapies.