Intravitreal injection of a rationally designed AAV capsid library in non-human primate identifies variants with enhanced retinal transduction and neutralizing antibody evasion.

Adeno-associated virus (AAV) continues to be the gold standard vector for therapeutic gene delivery and has proven especially useful for treating ocular disease. Intravitreal injection (IVtI) is a promising delivery route because it increases accessibility of gene therapies to larger patient populations. However, data from clinical and non-human primate (NHP) studies utilizing currently available capsids indicate that anatomical barriers to AAV and pre-existing neutralizing antibodies can restrict gene expression to levels that are "sub-therapeutic" in a substantial proportion of patients. Here, we performed a combination of directed evolution in NHPs of an AAV2-based capsid library with simultaneous mutations across six surface-exposed variable regions and rational design to identify novel capsid variants with improved retinal transduction following IVtI. Following two rounds of screening in NHP, enriched variants were characterized in intravitreally injected mice and NHPs and shown to have increased transduction relative to AAV2. Lead capsid variant, P2-V1, demonstrated an increased ability to evade neutralizing antibodies in human vitreous samples relative to AAV2 and AAV2.7m8. Taken together, this study further contributed to our understanding of the selective pressures associated with retinal transduction via the vitreous and identified promising novel AAV capsid variants for clinical consideration.

Lifecycles of Individual Subretinal Drusenoid Deposits and Evolution of Outer Retinal Atrophy in Age-Related Macular Degeneration.

PURPOSE: To describe the progression and regression of individual subretinal drusenoid deposits (SDDs) and surrounding photoreceptors and retina in patients with age-related macular degeneration (AMD) over a 3.5-year period using multimodal imaging including adaptive optics scanning laser ophthalmoscopy (AOSLO). DESIGN: Longitudinal observational study. PARTICIPANTS: Four patients with intermediate AMD. METHODS: Six eyes of 4 patients with intermediate AMD each were imaged 4 times over 3.5 years. Five eyes of 3 patients showed only SDD and no drusen. Subretinal drusenoid deposit presence and progression were assessed by multimodal imaging and a 3-stage grading system based on spectral-domain (SD) OCT. Morphologic features and the fine structure of individual SDD lesions identified at baseline were examined by AOSLO at follow-up visits. Reflectivity of photoreceptors surrounding SDD were assessed with AOSLO and SD OCT. MAIN OUTCOME MEASURES: Morphologic features, fine structure, and size of individual SDD lesions by AOSLO; photoreceptor integrity surrounding SDD via AOSLO and SD OCT; and retinal layer thicknesses via SD OCT. RESULTS: Individual SDDs followed independent lifecycle trajectories, exhibiting growth, shrinkage, fusion, and disappearance. Alterations in shape, morphologic features, and internal structure were not obviously the result of the presence of invading phagocytes. Of 822 lesions across all stages examined at baseline, 566 (69%) grew, 123 (15%) shrank, 47 (6%) remained of similar size, 86 (11%) disappeared, and 5 (0.6%) reappeared after regression. A return of characteristic photoreceptor reflectivity in AOSLO (punctate) and in SD OCT (prominent ellipsoid zone) was observed after regression of some SDD in 5 eyes of 4 patients. All eyes exhibited thinning of photoreceptor layers, despite intact retinal pigment epithelium (RPE), to approximately 70% of baseline thicknesses, as well as poorly visible or undetectable outer retinal bands. CONCLUSIONS: Adaptive optics scanning laser ophthalmoscopy and SD OCT imaging of individual SDDs over 3.5 years revealed independent trajectories of progression and regression, believed to reflect the activities of local outer retinal cells. Restoration of some photoreceptor reflectivity and intact RPE after SDD regression should be seen in the larger context of outer retinal atrophy, previously suggested as a new form of advanced AMD, and herein replicated.

SubILM Injection of AAV for Gene Delivery to the Retina.

Adeno-associated virus (AAV) has emerged as the vector of choice for delivering genes to the retina. Indeed, the first gene therapy to receive FDA approval in the United States is an AAV-based treatment for the inherited retinal disease, Leber congenital amaurosis-2. Voretigene neparvovec (Luxturna™) is delivered to patients via subretinal (SR) injection, an invasive surgical procedure that requires detachment of photoreceptors (PRs) from the retinal pigment epithelium (RPE). It has been reported that subretinal administration of vector under the cone-exclusive fovea leads to a loss of central retinal structure and visual acuity in some patients. Due to its technical difficulty and potential risks, alternatives to SR injection have been explored in primates. Intravitreally (Ivt) delivered AAV transduces inner retina and foveal cones, but with low efficiency. Novel AAV capsid variants identified via rational design or directed evolution have offered only incremental improvements, and have failed to promote pan-inner retinal transduction or significant outer retinal transduction beyond the fovea. Problems with retinal transduction by Ivt-delivered AAV include dilution in the vitreous, potential antibody-mediated neutralization of capsid in this nonimmune privileged space, and the presence of the inner limiting membrane (ILM), a basement membrane separating the vitreous from the neural retina. We have developed an alternative "subILM" injection method that overcomes all three hurdles. Specifically, vector is placed in a surgically induced, hydrodissected space between the ILM and neural retina. We have shown that subILM injection promotes more efficient retinal transduction by AAV than Ivt injection, and results in uniform and extensive transduction of retinal ganglion cells (RGCs) beneath the subILM bleb. We have also demonstrated transduction of Muller glia, ON bipolar cells, and photoreceptors by subILM injection. Our results confirm that the ILM is a major barrier to transduction by AAV in primate retina and that, when it is circumvented, the efficiency and depth to which AAV2 promotes transduction of multiple retinal cell classes is greatly enhanced. Here we describe in detail methods for vector preparation, vector dilution, and subILM injection as performed in macaque (Macaca sp.).

Somatic Gene Editing of GUCY2D by AAV-CRISPR/Cas9 Alters Retinal Structure and Function in Mouse and Macaque.

Mutations in GUCY2D, the gene encoding retinal guanylate cyclase-1 (retGC1), are the leading cause of autosomal dominant cone-rod dystrophy (CORD6). Significant progress toward clinical application of gene replacement therapy for Leber congenital amaurosis (LCA) due to recessive mutations in GUCY2D (LCA1) has been made, but a different approach is needed to treat CORD6 where gain of function mutations cause dysfunction and dystrophy. The CRISPR/Cas9 gene editing system efficiently disrupts genes at desired loci, enabling complete gene knockout or homology directed repair. Here, adeno-associated virus (AAV)-delivered CRISPR/Cas9 was used specifically to edit/disrupt this gene's early coding sequence in mouse and macaque photoreceptors in vivo, thereby knocking out retGC1 expression and demonstrably altering retinal function and structure. Neither preexisting nor induced Cas9-specific T-cell responses resulted in ocular inflammation in macaques, nor did it limit GUCY2D editing. The results show, for the first time, the ability to perform somatic gene editing in primates using AAV-CRISPR/Cas9 and demonstrate the viability this approach for treating inherited retinal diseases in general and CORD6 in particular.

DYNAMISM OF DOT SUBRETINAL DRUSENOID DEPOSITS IN AGE-RELATED MACULAR DEGENERATION DEMONSTRATED WITH ADAPTIVE OPTICS IMAGING.

PURPOSE: To investigate the natural history of dot subretinal drusenoid deposits (SDD) in age-related macular degeneration, using high-resolution adaptive optics scanning laser ophthalmoscopy. METHODS: Six eyes of four patients with intermediate age-related macular degeneration were studied at baseline and 1 year later. Individual dot SDD within the central 30° retina were examined with adaptive optics scanning laser ophthalmoscopy and optical coherence tomography. RESULTS: A total of 269 solitary SDD were identified at baseline. Over 12.25 ± 1.18 months, all 35 Stage 1 SDD progressed to advanced stages. Eighteen (60%) Stage 2 lesions progressed to Stage 3 and 12 (40%) remained at Stage 2. Of 204 Stage 3 SDD, 12 (6.4%) disappeared and the rest remained. Twelve new SDD were identified, including 6 (50%) at Stage 1, 2 (16.7%) at Stage 2, and 4 (33.3%) at Stage 3. The mean percentage of the retina affected by dot SDD, measured by the adaptive optics scanning laser ophthalmoscopy, increased in 5/6 eyes (from 2.31% to 5.08% in the most changed eye) and decreased slightly in 1/6 eye (from 10.67% to 10.54%). Dynamism, the absolute value of the areas affected by new and regressed lesions, ranged from 0.7% to 9.3%. CONCLUSION: Adaptive optics scanning laser ophthalmoscopy reveals that dot SDD, like drusen, are dynamic.

Optimization of Retinal Gene Therapy for X-Linked Retinitis Pigmentosa Due to RPGR Mutations.

X-linked retinitis pigmentosa (XLRP) caused by mutations in the RPGR gene is an early onset and severe cause of blindness. Successful proof-of-concept studies in a canine model have recently shown that development of a corrective gene therapy for RPGR-XLRP may now be an attainable goal. In preparation for a future clinical trial, we have here optimized the therapeutic AAV vector construct by showing that GRK1 (rather than IRBP) is a more efficient promoter for targeting gene expression to both rods and cones in non-human primates. Two transgenes were used in RPGR mutant (XLPRA2) dogs under the control of the GRK1 promoter. First was the previously developed stabilized human RPGR (hRPGRstb). Second was a new full-length stabilized and codon-optimized human RPGR (hRPGRco). Long-term (>2 years) studies with an AAV2/5 vector carrying hRPGRstb under control of the GRK1 promoter showed rescue of rods and cones from degeneration and retention of vision. Shorter term (3 months) studies demonstrated comparable preservation of photoreceptors in canine eyes treated with an AAV2/5 vector carrying either transgene under the control of the GRK1 promoter. These results provide the critical molecular components (GRK1 promoter, hRPGRco transgene) to now construct a therapeutic viral vector optimized for RPGR-XLRP patients.

Novel Methodology for Creating Macaque Retinas with Sortable Photoreceptors and Ganglion Cells.

Purpose: The ability to generate macaque retinas with sortable cell populations would be of great benefit to both basic and translational studies of the primate retina. The purpose of our study was therefore to develop methods to achieve this goal by selectively labeling, in life, photoreceptors (PRs) and retinal ganglion cells (RGCs) with separate fluorescent markers. Methods: Labeling of macaque (Macaca fascicularis) PRs and RGCs was accomplished by subretinal delivery of AAV5-hGRK1-GFP, and retrograde transport of micro-ruby™ from the lateral geniculate nucleus, respectively. Retinas were anatomically separated into different regions. Dissociation conditions were optimized, and cells from each region underwent fluorescent activated cell sorting (FACS). Expression of retinal cell type- specific genes was assessed by quantitative real-time PCR to characterize isolated cell populations. Results: We show that macaque PRs and RGCs can be simultaneously labeled in-life and enriched populations isolated by FACS. Recovery from different retinal regions indicated efficient isolation/enrichment for PRs and RGCs, with the macula being particularly amendable to this technique. Conclusions: The methods and materials presented here allow for the identification of novel reagents designed to target RGCs and/or photoreceptors in a species that is phylogenetically and anatomically similar to human. These techniques will enable screening of intravitreally-delivered AAV capsid libraries for variants with increased tropism for PRs and/or RGCs and the evaluation of vector tropism and/or cellular promoter activity of gene therapy vectors in a clinically relevant species.

Patients' Adherence to Recommended Follow-up Eye Care After Diabetic Retinopathy Screening in a Publicly Funded County Clinic and Factors Associated With Follow-up Eye Care Use.

IMPORTANCE: The public health success of diabetic retinopathy (DR) screening programs depends on patients' adherence to the timetable of follow-up eye care recommended by the screening program. African Americans are among those at highest risk for DR and have one of the lowest rates of eye care use. OBJECTIVES: To assess the rate of adhering to recommended follow-up eye care in a DR screening program administered in a safety-net health care facility and to examine factors associated with follow-up eye care use. DESIGN, SETTING, AND PARTICIPANTS: Prospective follow-up study of persons with type 1 or type 2 diabetes. The setting was an internal medicine clinic of a publicly funded health system in Alabama, serving a population largely uninsured and African American, that had implemented a DR screening program using a nonmydriatic camera for ocular imaging and remote reading centers for evaluation of images. Patients with physician appointments between January 26 and July 24, 2012, were eligible for screening if they had a diagnosis of type 1 or type 2 diabetes and were 19 years or older. Data from the county health system's administrative database were obtained from January 26, 2012 (date of first enrollee), through May 1, 2015, to establish participants' eye care use in the ophthalmology clinic after screening. MAIN OUTCOMES AND MEASURES: Adherence to the recommended interval of follow-up eye appointments in the facility's ophthalmology service as determined by administrative records, as well as factors associated with adherence. RESULTS: Diabetic retinopathy screening was completed in 949 adults with diabetes, of whom 84.5% (802 of 949) were African American, 64.5% (612 of 949) were women, and 71.7% (680 of 949) lacked health insurance. Participants ranged in age from 21 to 95 years, and their mean (SD) age was 53.9 (10.4) years. The mean (SD) age at diabetes diagnosis was 44.3 (12.5) years, and the mean (SD) duration of diabetes was 9.6 (9.4) years. Across interval recommendation types, 29.9% (284 of 949) adhered to obtaining comprehensive follow-up eye care within the recommended time frame. Two years after a participant's screening date, 50.9% (483 of 949) had no record of having received eye care. Factors associated with adhering to interval appointments were having an advanced age (odds ratio, 1.02; 95% CI, 1.01-1.04) and knowing one's glycated hemoglobin level (odds ratio, 2.00; 95% CI, 1.34-2.97). Agreeing to assistance in making a follow-up eye care appointment was associated with nonadherence (odds ratio, 0.67; 95% CI, 0.45-0.99). CONCLUSIONS AND RELEVANCE: After a DR screening program in a public clinic largely serving an African American population, only one-third of participants adhered to interval recommendations for follow-up eye appointments, even though cost and accessibility were minimized as barriers to care. Our findings suggest that DR screening programs are not likely to meet their public health goals without incorporation of eye health education initiatives successfully promoting adherence to recommended comprehensive eye care for preventing vision loss.

Highly Efficient Delivery of Adeno-Associated Viral Vectors to the Primate Retina.

Adeno-associated virus (AAV) has emerged as the preferred vector for targeting gene expression to the retina. Subretinally injected AAV can efficiently transduce retinal pigment epithelium and photoreceptors in primate retina. Inner and middle primate retina can be transduced by intravitreally delivered AAV, but with low efficiency. This is due to dilution of vector, potential neutralization of capsid because it is not confined to the immune-privileged retinal compartment, and the presence of the inner limiting membrane (ILM), a barrier separating the vitreous from the neural retina. We here describe a novel "subILM" injection method that addresses all three issues. Specifically, vector is placed in a surgically induced, hydrodissected space between the ILM and neural retina. In an initial experiment, we injected viscoelastic (Healon(®)), a substance we confirmed was biocompatible with AAV, to create a subILM bleb and subsequently injected AAV2-GFP into the bleb after irrigation with basic salt solution. For later experiments, we used a Healon-AAV mixture to place single, subILM injections. In all cases, subILM delivery of AAV was well tolerated-no inflammation or gross structural changes were observed by ophthalmological examination or optical coherence tomography. In-life fluorescence imaging revealed profound transgene expression within the area of the subILM injection bleb that persisted for the study duration. Uniform and extensive transduction of retinal ganglion cells (RGCs) was achieved in the areas beneath the subILM bleb. Transduction of Müller glia, ON bipolar cells, and photoreceptors was also observed. Robust central labeling from green fluorescent protein-expressing RGCs confirmed their continued survival, and was observed in the lateral geniculate nucleus, the superior colliculus, and the pretectum. Our results confirm that the ILM is a major barrier to transduction by AAV in primate retina and that, when it is circumvented, the efficiency and depth to which AAV2 promotes transduction of multiple retinal cell classes are greatly enhanced.

Delayed Rod-Mediated Dark Adaptation Is a Functional Biomarker for Incident Early Age-Related Macular Degeneration.

PURPOSE: To examine whether slowed rod-mediated dark adaptation (DA) in adults with normal macular health at baseline is associated with the incidence of age-related macular degeneration (AMD) 3 years later. DESIGN: Prospective cohort. PARTICIPANTS: Adults aged ≥60 years were recruited from primary care ophthalmology clinics. Both eyes were required to be step 1 (normal) on the Age-Related Eye Disease Study 9-step AMD classification system based on color fundus photographs graded by experienced and masked evaluators. METHODS: Rod-mediated DA was assessed at baseline in 1 eye after a photobleach using a computerized dark adaptometer with targets centered at 5° on the inferior vertical meridian. Speed of DA was characterized by the rod-intercept value, with abnormal DA defined as rod-intercept ≥12.3 minutes. Demographic characteristics, best-corrected visual acuity, and smoking status were also assessed. Log-binomial regression was used to calculate unadjusted and adjusted risk ratios (RRs) and associated 95% confidence intervals (CIs) for the association between baseline DA and incident AMD. MAIN OUTCOME MEASURES: Presence of AMD at the 3-year follow-up visit for the eye tested for DA at baseline. RESULTS: Both baseline and follow-up visits were completed by 325 persons (mean age, 67.8 years). At baseline, 263 participants had normal DA with mean rod-intercept of 9.1 (standard deviation [SD], 1.5), and 62 participants had abnormal DA with mean rod-intercept of 15.1 (SD, 4.0). After adjustment for age and smoking, those with abnormal DA in the tested eye at baseline were approximately 2 times more likely to have AMD in that eye (RR, 1.92; 95% CI, 1.03-3.62) by the time of the follow-up visit, compared with those who had normal DA at baseline. CONCLUSIONS: Delayed rod-mediated DA in older adults with normal macular health is associated with incident early AMD 3 years later, and thus is a functional biomarker for early disease. The biological relevance of this test is high, because it assesses translocation of vitamin A derivatives across the retinal pigment epithelium and Bruch's membrane, 2 tissues with prominent age- and AMD-related pathology.

Feasibility and efficacy of diabetic retinopathy screening among youth with diabetes in a pediatric endocrinology clinic: a cross-sectional study.

BACKGROUND: We examined the feasibility and efficacy of using a non-mydriatic camera to screen for diabetic retinopathy (DR) among youth with type 1 or type 2 diabetes seen in a pediatric endocrinology clinic serving Alabama, the state that has the highest diabetes rate in the United States. METHODS: 236 youths with type 1 or type 2 diabetes were screened for DR using a non-mydriatic camera. Visual acuity was also assessed. A questionnaire asked parents about diabetes and eye care history. RESULTS: Mean duration since diabetes diagnosis was 5.5 years. 66 % reported receiving an eye examination within the previous year. 97.5 % had images that were gradable. DR was detected in 3.8 % of participants. 9.1 % were visually impaired. CONCLUSIONS: Use of a non-mydriatic fundus camera is feasible and efficacious for DR screening in youth with diabetes. DR screening at routine endocrinology visits may be beneficial in managing youth with diabetes and preventing irreversible vision loss, particularly for those in regions where diabetes rates are high.

Associations between abnormal rod-mediated dark adaptation and health and functioning in older adults with normal macular health.

PURPOSE: Delayed rod-mediated dark adaptation (DA) is characteristic of early age-related macular degeneration (AMD) and also can be observed in some older adults in normal macular health. We examine cross-sectional associations between rod-mediated DA and risk factors for AMD in older adults in normal macular health. METHODS: The sample consisted of adults aged ≥60 years old in normal macular health per grading of fundus photos using an established disease classification system. Rod-mediated DA was measured psychophysically following a photobleach using a computer-automated dark adaptometer with targets centered at 5° on the inferior vertical meridian. The speed of DA was characterized by the rod-intercept value, with abnormal DA defined as rod-intercept ≥ 12.3 minutes. We assessed several health and functional characteristics that the literature has suggested increase AMD risk (e.g., smoking, alcohol use, inflammatory markers, apolipoproteins, low luminance visual acuity, chronic medical conditions, body mass, family history). RESULTS: Among 381 participants (mean age, 68.5 years; SD, 5.5), 78% had normal and 22% had abnormal DA, with the prevalence of abnormal DA increasing with age. After age-adjustment, abnormal DA was associated with increased odds of elevated C-reactive protein (CRP), heavy use of or abstention from alcohol, high blood pressure, and drop in visual acuity under mesopic conditions. CONCLUSIONS: Despite having normal macular health according to accepted definitions of AMD presence, approximately one-quarter of older adults recruited from primary eye care clinics had abnormal DA, which was associated with known risk factors for AMD, including elevated CRP.

Myofibroblast and extracellular matrix origins in proliferative vitreoretinopathy.

BACKGROUND: To evaluate origins of the fibrocontractive cell populations and their relation to collagens I and II in proliferative vitreoretinopathy (PVR). METHODS: Human PVR membranes were evaluated by indirect immunofluorescence for GFAP, cytokeratin-18 (CK-18), α-smooth muscle actin (αSMA), collagens I and II. Collagen expression by porcine Müller and retinal pigment epithelial cells (RPE) was evaluated using RT-PCR of RNA harvested from freshly isolated primary and proliferating cultures. RESULTS: Collagen I was detected in all PVR samples and was widely distributed in the extracellular matrix. In contrast, collagen II was present in only two of the ten samples and was localized to thin, acellular bands near the border of the tissues. Using cell type-specific markers CK-18 and GFAP, RPE and glia were localized to the collagen I-rich matrices. Cells positive for GFAP and CK-18 can also co-express αSMA. Normal and proliferating RPE express collagen I, but Müller cells show no evidence of collagen I expression until they proliferate in culture. In contrast, normal RPE and Müller cells contain message for collagen II which is lost shortly after introduction into culture. CONCLUSIONS: Collagen I appears to be the predominate fibrillar collagen in human PVR membranes and collagen II a comparatively minor component. Müller cells and RPE are physically associated with the collagen I matrix and are capable of expressing this protein suggesting that they are the origin. It also appears that the majority of myofibroblasts in PVR membranes are derived from either RPE or Müller cells suggesting that they play a major role in membrane development.

Intraoperative retinal detachment prophylaxis in vitrectomy for retained cataract fragments.

PURPOSE: To assess the safety and efficacy of peripheral 360-degree laser retinopexy as prophylaxis against rhegmatogenous retinal detachment (RRD) in eyes having pars plana vitrectomy (PPV) for the removal of retained cataract fragments. SETTING: Private practice, Callahan Eye Foundation Hospital, University of Alabama at Birmingham, and Helen Keller Foundation for Research and Education, Birmingham, Alabama, USA. METHODS: This retrospective analysis comprised a consecutive series of patients who had PPV with 360-degree laser retinopexy for retained cataract fragment removal between January 1, 1995, and December 31, 2000. All laser treatments were applied with indirect ophthalmoscope delivery. RESULTS: In 78 eyes of 78 patients, the mean interval between cataract surgery and PPV with 360-degree laser retinopexy prophylaxis was 14 days. One (1.3%) of 78 eyes had postoperative RRD during a mean follow-up of 6 years. No laser-related complications occurred. CONCLUSIONS: The incidence of RRD after PPV with 360-degree laser retinopexy prophylaxis was 1.3%, a significant reduction from the average 8.2% RRD rate in the literature (P = .024). Although future prospective trials are indicated, the results suggest that 360-degree laser retinopexy prophylaxis could significantly reduce the incidence of this visually disabling complication.

Acute posterior multifocal placoid pigment epitheliopathy and thalamic infarction.

OBJECTIVES: To report a patient with acute posterior multifocal placoid pigment epitheliopathy (APMPPE) who developed a thalamic infarction and to discuss this unusual presentation. DESIGN: Interventional case report and literature review. METHODS: A 23-year-old man with APMPPE presented with acute confusion and memory loss. He underwent complete ophthalmologic and neurologic examination, with neuroimaging including magnetic resonance angiography (MRA). MAIN OUTCOME MEASURES: Clinical course and angiographic findings. RESULTS: Magnetic resonance imaging (MRI) showed a left posteromedial thalamic infarction, with a corresponding filling defect of the left posterior communicating artery demonstrated by MRA. The patient underwent further treatment with intravenous corticosteroids followed by continued oral therapy with taper over several weeks. CONCLUSION: Although the association of APMPPE and cerebral vasculitis has been described, this patient is unique due to the subtle clinical presentation and anatomic location. This case emphasizes the importance of appropriate counseling of patients with APMPPE, as well as prompt recognition of clinical symptoms to enable timely intervention and treatment.

Epidemiology of blinding trauma in the United States Eye Injury Registry.

PURPOSE: To analyze the epidemiology and clinical characteristics of serious eye injuries leading to legal blindness. METHODS: Analysis of information on 11,320 eyes in the United States Eye Injury Registry (USEIR) database. Legal blindness in this study was defined as visual acuity of worse than 20/200. RESULTS: No less than 27% of eyes with serious injury had < 20/200 final vision, although the rate varied greatly with injury type. Several risk factors were found to statistically significantly increase the chance of eye trauma resulting in blindness: age over 60 years, injury by assault, sustained on street/highway, or occurring during fall or by gunshot. Trauma to the left eye carried a statistically significantly poor prognosis as did two injury types, rupture and perforating. Involvement of the posterior segment was another factor indicating poor outcome; in particular, vitreous hemorrhage, retinal detachment, choroidal rupture, and endophthalmitis were found to increase the risk of blindness. Conversely, young age, contusion and intraocular foreign body injuries, among others, signaled a better than average chance of good outcome. Overall, 60.5% of injured eyes showed visual improvement after treatment. CONCLUSIONS: This large study identified multiple risk factors whose presence significantly increases the chance of the injured eye becoming "legally blind." Continued efforts to improve treatment and develop/implement prevention measures based on risk analysis should reduce the incidence of blinding trauma.

Birmingham Eye Trauma Terminology (BETT): terminology and classification of mechanical eye injuries.

Lacking a standardized terminology of eye injury types, it is impossible to fulfill a very basic requirement in medicine: that all communications be unambiguous. Accurate interpretation of published research results, which plays an absolutely crucial role in determining how an individual patient with an eye injury is treated, becomes difficult. This article presents an internationally standardized system that finally allows accurate description of eye injuries of all types.

Epidemiology and socioeconomics.

Ophthalmologists should be responsible for a systemic collection of standardized data on the occurrence of eye injuries. Such a database is the key for designing prophylactic measures to successfully prevent ocular trauma. The USEIR model, whether reporting takes place over the Internet [www.USEIRonline.org www.WEIRonline.org (worldwide)] or on paper, has proved to be an efficient epidemiological tool. Use of this model in different countries has allowed making unbiased comparisons between regions or countries, highlighting injury patterns that may be different in different geographical areas, and pinpointing areas where prophylaxis (through legislation and public campaigns) appears most effective. Participation of all ophthalmologists who evaluate/treat patients with serious eye trauma is strongly encouraged.