Neonatal aphakia is associated with altered levels of dopamine metabolites in the non-human primate retina.

Neonatal aphakia is associated with retardation of the axial elongation of the neonatal eye. In contrast, form deprivation increases axial elongation, an effect that has been associated with decreased retinal dopamine metabolism. The present investigation was conducted to test the hypothesis that neonatal aphakia induces an effect on the levels of retinal dopamine opposite to form deprivation. Lensectomy and vitrectomy were performed on the right eyes of rhesus monkeys at approximately 1 week of age; their left eyes were unmanipulated. Axial length was measured by A-scan ultrasonography. Prior to surgery, mean axial length of the right and left eyes was identical. Following lens removal, both eyes continued to elongate, however the aphakic eyes elongated at a slower rate resulting in a significant shorter axial length compared to that of the unmanipulated eye. Removal of the crystalline lens had no effect on steady-state dopamine levels in either central or peripheral retina. However, levels of the dopamine metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid were significantly elevated in central retina, but not in the peripheral retina of aphakic eyes. Our results support the hypothesis that dopamine is a component of the retinal signaling pathways that are involved in the regulation of eye growth and emmetropization.

Retinopathy Associated With Ritonavir Treatment for HIV Infection: A Case Series Reappraisal in the COVID-19 Era.

Purpose: To report 3 cases of retinopathy secondary to ritonavir use in the treatment of HIV. Methods: A retrospective review of patient records was performed for data including ophthalmic examination findings, demographic and HIV clinical characteristics, and progression of maculopathy disease. The review identified 3 patients with a history of HIV treated with antiretroviral therapy including ritonavir who had been evaluated for bilateral vision loss in both eyes. Results: A fundus examination of each patient revealed characteristic macular atrophy, and optical coherence tomography demonstrated corresponding central outer retinal atrophy. Uveitis workup results were unremarkable. Given the characteristics of macular atrophy, history of ritonavir use, and the absence of intraocular inflammation, all 3 patients were diagnosed with bilateral ritonavir-associated retinopathy. Each patients' vision continued to deteriorate, even after the cessation of ritonavir. Conclusions: Ritonavir toxicity should be considered in the differential diagnosis of retinopathy among patients with an exposure history.

Visual Morbidity and Outcomes of Scleritis Associated with Intraocular Inflammation Compared to Isolated Scleritis.

PURPOSE: To compare visual outcomes, ocular complications and therapies for patients with scleritis-associated intraocular inflammation (SAI) and patients with isolated scleritis (IS). RESULTS: A total of 52 patients (36 with SAI and 16 with IS) were reviewed. Mean age (standard deviation) at presentation was 48.4 years old (± 15.4) in the SAI group and 53 years old (± 17.1) in the IS group (p = .37). Visual acuity was worse at presentation and last visit for patients with SAI compared to IS (p = .04). Patients in the SAI group developed greater posterior segment complications than in the IS group (p = .002). CONCLUSIONS: Scleritis with intraocular inflammation was associated with a higher rate of visual morbidity compared to isolated scleritis. More aggressive management strategies may be needed for patients who present with scleritis associated with inflammation.

Prevalence of visual impairment, ocular pathology, and ability to achieve a thorough examination in an eye clinic for patients with disabilities.

PURPOSE: To report the demographics, types of visual/ocular pathology, and ability to achieve a comprehensive examination at a university-based outpatient clinic for individuals of all ages with disabilities. METHODS: The medical records for all patients with disabilities examined from January 2014 through December 2016 at our monthly clinic staffed by a pediatric ophthalmologist were reviewed retrospectively. Descriptive statistics were calculated for demographics, visual acuity, ocular diagnoses, nonocular diagnoses, refractive error, and achievable examination data. Ocular diagnoses were categorized as treatable or nontreatable and noted if newly diagnosed. RESULTS: A total of 178 patients with disabilities were examined at 281 visits; 119 patients (66.9%) were nonverbal. Of the 178, 140 patients (78.7%) had pathology or refractive error requiring glasses; 126 had pathology and 14 had no pathology. Of the 126 patients with pathology, 113 had treatable ocular diagnoses and 13 had only nontreatable diagnoses. Of the 113 with treatable conditions, 56 (49.6%) were newly diagnosed. Cycloplegic refraction was attained in 168 patients (94.4%); 85 had a significant refractive error, 66 of whom had another treatable ocular diagnosis. Lack of cooperation precluded slit-lamp examination in 1 patient, cycloplegic refraction in 3 (1.7%), dilated fundus examination in 4 (2.2%), and iCare or Goldmann intraocular pressure measurement in 28 (15.7%). CONCLUSIONS: Patients with disabilities in our cohort had a high prevalence of ocular pathology, which was often treatable and previously unrecognized. Refractive errors were common and frequently accompanied by other treatable conditions. A thorough ophthalmic examination was achievable in most individuals with disabilities.

Regionally Specific Economic Impact of Screening and Treating Retinopathy of Prematurity in Middle-Income Societies in the Philippines.

PURPOSE: To estimate the economic effects of implementing a universal screening and treatment program for retinopathy of prematurity (ROP) in the Philippines with the Economic Model for Retinopathy of Prematurity (EcROP). METHODS: The EcROP is a cost-effectiveness, cost-benefit, and cost-utility analysis. Fifty parents of legally blind individuals (aged 3 to 28 years) from three schools for the blind in the Philippines were interviewed to estimate the societal burden of raising a blind child. A decision tree analytic model, with deterministic and probabilistic sensitivity analysis, was used to calculate the incremental cost-effectiveness ratio (primary outcome) and the incremental monetary benefit (secondary outcome) for implementing an optimal national ROP program, compared to estimates of the current policy. Findings were extrapolated to estimate the national economic benefit of an ideal screening and treatment program. RESULTS: The incremental cost-effectiveness ratio for a national program over the current policy was strongly favorable to the ideal program for the Philippines and represents an opportunity for substantial societal cost savings. The per-child incremental, annual monetary benefit of a national program over the current policy was $2,627. Extrapolating to the population of children at risk in 1 year showed that the national annual net benefit estimate would be $64,320,692, which is favorable to the current policy. CONCLUSIONS: The EcROP demonstrates that implementing a national ROP screening and treatment program is cost-saving and cost-effective, and would substantially decrease childhood blindness in the Philippines. [J Pediatr Ophthalmol Strabismus. 2019;56(6):388-396.].

High susceptibility to experimental myopia in a mouse model with a retinal on pathway defect.

PURPOSE: Nob mice share the same mutation in the Nyx gene that is found in humans with complete congenital stationary night blindness (CSNB1). Nob mutant mice were studied to determine whether this defect resulted in myopia, as it does in humans. METHODS: Refractive development was measured in unmanipulated wild-type C57BL/6J (WT) and nob mice from 4 to 12 weeks of age by using an infrared photorefractor. The right eye was form deprived by means of a skull-mounted goggling apparatus at 4 weeks of age. Refractive errors were recorded every 2 weeks after goggling. The content of dopamine and the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were measured by HPLC with electrochemical detection (HPLC-ECD) in retinas of nob and WT mice under light- and dark-adapted conditions. RESULTS: The nob mice had greater hyperopic refractive errors than did the WT mice under normal visual conditions, until 12 weeks of age when both strains had similar refractions. At 6 weeks of age, refractions became less hyperopic in the nob mice but continued to become more hyperopic in the WT mice. After 2 weeks of form deprivation (6 weeks of age), the nob mice displayed a significant myopic shift (~4 D) in refractive error relative to the opposite and control eyes, whereas WT mice required 6 weeks of goggling to elicit a similar response. As expected with loss of ON pathway transmission, light exposure did not alter DOPAC levels in the nob mice. However, dopamine and DOPAC levels were significantly lower in the nob mice compared with WT. CONCLUSIONS: Under normal laboratory visual conditions, only minor differences in refractive development were observed between the nob and WT mice. The largest myopic shift in the nob mice resulted after form deprivation, suggesting that visual pathways dependent on nyctalopin and/or abnormally low dopaminergic activity play a role in regulating refractive development. These findings demonstrate an interaction of genetics and environment in refractive development.

Formulation of a Peribulbar Block for Prolonged Postoperative Pain Management in Vitreoretinal Surgery: A Randomized Clinical Trial.

PURPOSE: To evaluate postoperative pain level using a supplemental peribulbar injection at the conclusion of retinal surgery. DESIGN: Prospective, parallel-assigned, single-masked, randomized clinical trial. PARTICIPANTS: Fifty-eight patients undergoing scleral buckle, vitrectomy, or combined surgery. METHODS: In a single academic institutional practice, 58 patients undergoing scleral buckle, vitrectomy, or combined surgery were enrolled. Exclusion criteria included those with a risk for glaucoma, a pre-existing chronic pain disorder, among others. Patients were assigned randomly to receive a postoperative peribulbar formulation of either bupivacaine, triamcinolone acetonide, and cefazolin (group A) or bupivacaine, balanced salt solution, and cefazolin (group B). The postoperative pain score and ocular motility were assessed by a masked observer on the first postoperative day. MAIN OUTCOME MEASURES: The primary outcome measure was the postoperative pain score. Secondary outcome measures included oral analgesic use, ocular motility, and intraocular pressure (IOP). RESULTS: The mean pain scores were 2.8±2.9 for group A and 3.8±2.6 for group B (P = 0.095). Pain was absent in 28% of group A patients versus 14% of group B patients (P = 0.11). Group A required less narcotic pain medication (hydroxycodone: group A, 0.7±3 mg vs. group B, 3±6 mg; P = 0.05; oxycodone: group A, 7±7 mg vs. 9±13 mg; P = 0.2) than group B. Motility was full in group B and limited in group A (P ≤ 0.001), with no differences in mean IOP measurements at any point after surgery. CONCLUSIONS: We did not demonstrate a statistically significant reduction in mean postoperative pain scores. However, patients in group A required less hydroxycodone use and had greater akinesia, suggesting prolonged neural blockade.

The Economic Model of Retinopathy of Prematurity (EcROP) Screening and Treatment: Mexico and the United States.

PURPOSE: To describe an economic (Ec) model for estimating the impact of screening and treatment for retinopathy of prematurity (ROP). DESIGN: EcROP is a cost-effectiveness, cost-utility, and cost-benefit analysis. METHODS: We surveyed caregivers of 52 children at schools for the blind or pediatric eye clinics in Atlanta, Georgia and 43 in Mexico City. A decision analytic model with sensitivity analysis determined the incremental cost-effectiveness (primary outcome) and incremental monetary benefit (secondary outcome) of an ideal (100% screening) national ROP program as compared to estimates of current practice. Direct costs included screening and treatment expenditures. Indirect costs estimated lost productivity of caretaker(s) and blind individuals as determined by face-to-face surveys. Utility and effectiveness were measured in quality-adjusted life years and benefit in US dollars. EcROP includes a sensitivity analysis to assesses the incremental cost-effectiveness and societal impact of ROP screening and treatment within a country or economic region. Estimates are based on evidence-based clinical data and region-specific economic data acquired from direct field survey. RESULTS: In both Mexico and the United States, an ideal national ROP screening and treatment program was highly cost-saving. The incremental net benefit of an ideal ROP program over current practice is $5556 per child ($206 574 333 annually) and $3628 per child ($205 906 959 annually) in Mexico and the United States, respectively. CONCLUSION: EcROP demonstrates that ROP screening and treatment is highly beneficial for quality of life, cost saving, and cost-effectiveness in the United States and Mexico. EcROP can be applied to any country or region to provide data for informed allocation of limited health care resources.

Neonatal aphakia retards ocular growth and alters scleral gene expression in rhesus monkeys.

PURPOSE: We hypothesize that remodeling of the scleral extracellular matrix, involving collagen and proteoglycan synthesis and turnover, is a key process involved in ocular growth. Decreased axial elongation is observed following neonatal removal of the crystalline lens in a rhesus monkey model of congenital cataract. We wanted to determine changes in gene expression in the operated and companion eye following lensectomy, especially for extracellular matrix in the sclera. METHODS: Between 4 and 7 days of age, infant monkeys underwent surgical removal of the lens from the right eye. Axial lengths of the operated and unmanipulated fellow eyes were measured and when interocular differences of >0.4 mm were achieved, monkeys were sacrificed and RNA was isolated from sclera. In order to determine changes in scleral gene expression in aphakic versus control eyes, we used Clontech's Atlas Gene Array (Human Cancer Array version 1.2) hybridized with total RNA from three monkeys. RESULTS: Atlas Gene Array analysis demonstrated differential expression of several genes in the operated versus the unmanipulated eye. Most notably, there was a statistically significant increase in expression of several extracellular matrix (ECM) genes including: aggrecan, decorin, biglycan, several collagens, and tenascin in the RNA from the sclera of the aphakic eyes when compared to the unmanipulated eyes. Genes for several matrix metalloproteinases (MMPs) showed no significant change following lens removal although there was a trend towards decreased expression. There were also statistically significant changes in the pattern of gene expression in the operated eye relative to the unmanipulated eye for cell adhesion, cell cycle, apoptosis, and cytoskeleton transcripts. CONCLUSIONS: Our results suggest that removal of the crystalline lens alters gene expression in the sclera with a prominent upregulation of ECM transcripts. These data support recent evidence that remodeling of the ECM composition of the sclera may be an important regulator of ocular growth.

Possible sources of neuroprotection following subretinal silicon chip implantation in RCS rats.

Current retinal prosthetics are designed to stimulate existing neural circuits in diseased retinas to create a visual signal. However, implantation of retinal prosthetics may create a neurotrophic environment that also leads to improvements in visual function. Possible sources of increased neuroprotective effects on the retina may arise from electrical activity generated by the prosthetic, mechanical injury due to surgical implantation, and/or presence of a chronic foreign body. This study evaluates these three neuroprotective sources by implanting Royal College of Surgeons (RCS) rats, a model of retinitis pigmentosa, with a subretinal implant at an early stage of photoreceptor degeneration. Treatment groups included rats implanted with active and inactive devices, as well as sham-operated. These groups were compared to unoperated controls. Evaluation of retinal function throughout an 18 week post-implantation period demonstrated transient functional improvements in eyes implanted with an inactive device at 6, 12 and 14 weeks post-implantation. However, the number of photoreceptors located directly over or around the implant or sham incision was significantly increased in eyes implanted with an active or inactive device or sham-operated. These results indicate that in the RCS rat localized neuroprotection of photoreceptors from mechanical injury or a chronic foreign body may provide similar results to subretinal electrical stimulation at the current output evaluated here.

Ocular measurements throughout the adult life span of rhesus monkeys.

PURPOSE: To examine the relationship of ocular components to refraction throughout the adult life span of the rhesus monkey (Macaca mulatta). METHODS: Cycloplegic retinoscopy, A-scan ultrasonography, slit lamp examination, indirect ophthalmoscopy, and keratometry were performed in a cross-sectional study of 111 monkeys, aged 5 to 31 years. Lens thickness and anterior and vitreous chamber depths were measured from the echograms. The intercorrelations of these variables were analyzed, as well as their association with age and sex. RESULTS: In monkeys aged 5 to 15 years, the mean refractive value of +1.5 D with an SD of 1.7 D was maintained near the previously established developmental asymptote of +2 D. In monkeys older than 15 years, there was greater interindividual variation (SD = 4.5 D), including extreme myopia and hyperopia. The cornea became steeper with age. The axial length of the eyes increased up to 12 years of age and began to shorten after 20 years. Changes also occurred in the other individual components that constitute eye length. These age-related changes were decreased vitreous chamber depth, decreased anterior chamber depth, and increased lens thickness. In general, males had longer eyes than females. The eyes of old monkeys were more likely to exhibit cataract and drusen, but age-related changes in focal atrophy of the retinal pigment epithelium did not achieve statistical significance. CONCLUSIONS: The components of the monkey eye change with age in a pattern similar to that reported in humans. Age-related changes in individual ocular components that could be detrimental to refraction appear to be compensated for by changes in other components.

Transduction of photoreceptors with equine infectious anemia virus lentiviral vectors: safety and biodistribution of StarGen for Stargardt disease.

PURPOSE: StarGen is an equine infectious anemia virus (EIAV)-based lentiviral vector that expresses the photoreceptor-specific adenosine triphosphate (ATP)-binding cassette transporter (ABCA4) protein that is mutated in Stargardt disease (STGD1), a juvenile macular dystrophy. EIAV vectors are able to efficiently transduce rod and cone photoreceptors in addition to retinal pigment epithelium in the adult macaque and rabbit retina following subretinal delivery. The safety and biodistribution of StarGen following subretinal delivery in macaques and rabbits was assessed. METHODS: Regular ophthalmic examinations, IOP measurements, ERG responses, and histopathology were carried out in both species to compare control and vector-treated eyes. Tissue and fluid samples were obtained to evaluate the persistence, biodistribution, and shedding of the vector following subretinal delivery. RESULTS: Ophthalmic examinations revealed a slightly higher level of inflammation in StarGen compared with control treated eyes in both species. However, inflammation was transient and no overt toxicity was observed in StarGen treated eyes and there were no abnormal clinical findings. There was no StarGen-associated rise in IOP or abnormal ERG response in either rabbits or macaques. Histopathologic examination of the eyes did not reveal any detrimental changes resulting from subretinal administration of StarGen. Although antibodies to StarGen vector components were detected in rabbit but not macaque serum, this immunologic response did not result in any long-term toxicity. Biodistribution analysis demonstrated that the StarGen vector was restricted to the ocular compartment. CONCLUSIONS: In summary, these studies demonstrate StarGen to be well tolerated and localized following subretinal administration.

Nicotinic acetylcholine receptor subunits in rhesus monkey retina.

PURPOSE: The purpose of this study was to detect and establish the cellular localizations of nicotinic acetylcholine receptor (nAChR) subunits in Rhesus monkey retina. METHODS: Retinas were dissected from the eyes of monkeys killed after unrelated experiments. RNA was extracted and analyzed by RT-PCR, using primers designed against human sequences of alpha3-alpha7, alpha9, and beta2-beta4 nAChR subunits. The RT-PCR products were separated by gel electrophoresis and sequenced. Frozen sections of postmortem fixed monkey eyes were immunolabeled with well-characterized and specific monoclonal antibodies against the alpha3, alpha4, alpha6, alpha7, beta2, or beta4 nAChR subunits and visualized with fluorescence labeling. RESULTS: Products of the predicted size for the alpha3-alpha7, alpha9, and beta2-beta4 nAChR subunits were detected by RT-PCR in Rhesus monkey retina. Homology between transcripts from monkey retina and human nucleotide sequences ranged from 93 to 99%. Immunohistochemical studies demonstrated that neurons in various cell layers of monkey retina expressed alpha3, alpha4, alpha7, or beta2 nAChR subunits and cells with the morphology of microglia were immunoreactive for the alpha6 or beta4 nAChR subunits. CONCLUSIONS: nAChR subunits are expressed in the monkey retina and localize to diverse retinal neurons as well as putative microglia. Besides mediating visual processing, retinal nAChRs may influence refractive development and ocular pathologies such as neovascularization.