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Gene therapy of retinal diseases using recombinant adeno‐associated virus (rAAV) vector‐based delivery has shown clinical success, and clinical trials based on rAAV‐based optogenetic therapies are currently in progress. Recently, we have developed multi‐characteristic opsin (MCO), which has been shown to effectively re‐photosensitize photoreceptor‐degenerated retina in mice leading to vision restoration at ambient light environment. Here, we report the biodistribution of the rAAV2 carried MCO (vMCO‐I) in live samples and post‐mortem organs following intraocular delivery in wild‐type dogs. Immunohistochemistry showed that the intravitreal injection of vMCO‐I resulted in gene transduction in the inner nuclear layer (INL) but did not induce detectable inflammatory or immune reaction in the dog retina. Vector DNA analysis of live body wastes and body fluids such as saliva and nasal secretions using quantitative polymerase chain reaction (qPCR) showed no correlative increase of vector copy in nasal secretions or saliva, minimal increase of vector copy in urine in the low‐dose group 13 weeks after injection and in the faeces of the high‐dose group at 3–13 weeks after injection suggesting clearance of the virus vector via urine and faeces. Further analysis of vector DNA extracted from faeces using PCR showed no transgene after 3 weeks post‐injection. Intravitreal injection of vMCO‐I resulted in few sporadic off‐target presences of the vector in the mesenteric lymph node, liver, spleen and testis. This study showed that intravitreal rAAV2‐based delivery of MCO‐I for retinal gene therapy is safe.

PurposeTo determine if dietary administration of the dual ETA/ ETB receptor antagonist, macitentan, could protect retinal ganglion cells (RGCs) following endothelin-1 (ET-1) mediated vasoconstriction in Brown Norway rats.MethodsAdult male and female Brown Norway rats were either untreated or treated with macitentan (5 mg/kg body weight) once a day for 3 days followed by intravitreal injection of either 4 μl of 500 μM ET-1 (2 nmole/eye) or vehicle in one eye. Imaging of the retinal vasculature using fluorescein angiography was carried out at various time points, including, 5, 10, 15, 25 and 30 minutes. Following the imaging of the vasculature, rats were either treated with macitentan (5 mg/kg/body weight in dietary gels) or untreated (control gels without medication). Following treatments, rats were euthanized, retinal flat mounts were prepared, immunostained for RGC marker Brn3a, imaged and surviving RGCs were counted in a masked manner.ResultsVasoconstrictive effects following intravitreal ET-1 injection were greatly reduced in rats administered with macitentan in the diet prior to the ET-1 administration. ET-1 intravitreal injection produced a 31% loss of RGCs which was significantly reduced in macitentan-treated rats. Following ET-1 administration, GFAP immunostaining was increased in the ganglion cell layer as well as in the retrolaminar region, suggestive of astrocytic activation by ET-1 administration. RGC numbers in macitentan treated and ET-1 injected rats were similar to that observed in control retinas.ConclusionsET-1-mediated neurodegeneration could occur through both vascular and cellular mechanisms. The endothelin receptor antagonist, macitentan, has neuroprotective effects in retinas of Brown Norway rats that occurs through different mechanisms, including, enhancement of RGC survival and reduction ET-1 mediated vasoconstriction.

PURPOSE: Assess systemic vascular endothelial growth factor-A (VEGF) levels after treatment with intravitreous aflibercept, bevacizumab or ranibizumab. DESIGN: Comparative-effectiveness trial with participants randomly assigned to 2-mg aflibercept, 1.25-mg bevacizumab, or 0.3-mg ranibizumab following a retreatment algorithm. PARTICIPANTS: Participants with available plasma samples (N=436) METHODS: Plasma samples were collected before injections at baseline, 4-week, 52-week and 104-week visits. In a pre-planned secondary analysis, systemic free-VEGF levels from an ELISA immunoassay were compared across anti-VEGF agents and correlated with systemic side effects. MAIN OUTCOME MEASURES: Changes in the natural log (ln) of plasma VEGF levels. RESULTS: Baseline free-VEGF levels were similar across all 3 groups. At 4 weeks, mean ln(VEGF) changes were −0.30±0.61, −0.31±0.54, −0.02±0.44 pg/ml for the aflibercept, bevacizumab, and ranibizumab groups, respectively. The adjusted differences between treatment groups (adjusted CI; P-value) were −0.01 (−0.12, +0.10; P=0.89), −0.31 (−0.44, −0.18; P

Failure of blood pressure (BP) to dip during sleep (nondipper pattern) is associated with cardiovascular disease and stroke. The prevalence and degree of nondipping and masked hypertension in patients with retinal vein occlusion (RVO), which is associated with stroke, has not been previously examined.We measured clinic and 24-hour ambulatory BPs in 22 patients with RVO and 20 control participants without known eye disease matched by age and sex. Mean BP dipping, defined as the ratio of difference in mean awake and sleep systolic BPs to mean awake systolic BP, and masked and nocturnal hypertension were compared between groups.Mean 24-hour ambulatory BP was 144/79 mmHg among those with RVO and 136/77 mmHg among controls. Patients with RVO had an almost 2-fold higher prevalence of nondipping pattern (80.8% [95% confidence interval, 52.8-94.1] vs. 50.4% [95% confidence interval, 26.1-74.5]; P = 0.008). Average sleep systolic BP dip in patients with RVO was 6.1% versus 11.9% in controls (P = 0.004). More patients with RVO had masked hypertension by ambulatory BPs than controls (71% vs. 50%), but this difference was not statistically significant.Our data suggest an association between RVO and nondipper BP pattern. Ambulatory BP monitoring may be useful in the evaluation of patients with RVO by identifying those who may benefit from more aggressive BP control.

Uveitis is estimated to account for 10% of all cases of blindness in the United States, including 30,000 new cases of legal blindness each year. Intraocular and oral corticosteroids are the effective mainstay treatment, but they carry the risk of serious long-term ocular and systemic morbidity. New noncorticosteroid therapies with a favorable side effect profile are necessary for the treatment of chronic uveitis, given the paucity of existing treatment choices. We have previously demonstrated that Nutlin-3, a small-molecule inhibitor of murine double minute 2 (MDM2) homolog, suppresses pathologic retinal angiogenesis through a p53-dependent mechanism, but the noncanonical p53-independent functions have not been adequately elucidated. Herein, we demonstrate an unanticipated function of MDM2 inhibition, where Nutlin-3 potently abrogates lipopolysaccharide-induced ocular inflammation. Furthermore, we identified a mechanism by which transcription and translation of NF-κB is mediated by MDM2, independent of p53, in ocular inflammation. Small-molecule MDM2 inhibition is a novel noncorticosteroid strategy for inhibiting ocular inflammation, which may potentially benefit patients with chronic uveitis.

Age-related macular degeneration (AMD) is the foremost cause of irreversible blindness in people over the age of 65 especially in developing countries. Therefore, an exploration of effective and alternative therapeutic interventions is an unmet medical need. It has been established that oxidative stress plays a key role in the pathogenesis of AMD, and hence, neutralizing oxidative stress is an effective therapeutic strategy for treatment of this serious disorder. Owing to autoregenerative properties, nanoceria has been widely used as a nonenzymatic antioxidant in the treatment of oxidative stress related disorders. Yet, its potential clinical implementation has been greatly hampered by its poor water solubility and lack of reliable tracking methodologies/processes and hence poor absorption, distribution, and targeted delivery. The water solubility and surface engineering of a drug with biocompatible motifs are fundamental to pharmaceutical products and precision medicine. Here, we report an engineered water-soluble, biocompatible, trackable nanoceria with enriched antioxidant activity to scavenge intracellular reactive oxygen species (ROS). Experimental studies with in vitro and in vivo models demonstrated that this antioxidant is autoregenerative and more active in inhibiting laser-induced choroidal neovascularization by decreasing ROS-induced pro-angiogenic vascular endothelial growth factor (VEGF) expression, cumulative oxidative damage, and recruitment of endothelial precursor cells without exhibiting any toxicity. This advanced formulation may offer a superior therapeutic effect to deal with oxidative stress induced pathogeneses, such as AMD.

Murine double minute-2 inhibitors offer a durable treatment for neovascular age-related macular degeneration by inducing apoptosis in pathologically proliferating cells, a similar effect as radiation therapy, but with potentially a more favorable side-effect profile since it does not induce DNA damage. Murine double minute-2 inhibitors may be complementary to current anti-VEGF treatments and potentially reduce the cumulative number of intravitreal injections.

A patient with systemic cytomegalovirus (CMV), including chorioretinitis, received localized and systemic ganciclovir, systemic cidofovir analog, and localized foscarnet. Mutations conferring ganciclovir and cidofovir resistance were detected in CMV from the aqueous fluid but not in CMV from plasma. Quantifying CMV from aqueous fluid was valuable for monitoring the clinical response and predicting resistance.

Purpose To evaluate the information assessed with the LADARWave wavefront measurement device and correlate it with visual symptoms, refraction, and corneal topography in previously LASIK-treated eyes. Participants One hundred five eyes (58 patients) of individuals who underwent LASIK surgery were evaluated. Design Retrospective, noncomparative case series. Main outcome measures Complete ophthalmologic examination, corneal topography, and wavefront measurements were performed. Correlations were made between the examinations and symptoms. Methods Wavefront measurements were assessed with the LADARWave device. Manifest, cycloplegic refraction, and topographic data were compared with wavefront refraction and higher order aberrations. Visual symptoms were correlated to higher order aberrations in 3 different pupil sizes (5-mm, 7-mm, and scotopic pupil size). Pearson's correlation coefficient and generalized estimating equations were used for statistical analysis. Results In post-LASIK eyes, wavefront refraction components were poorly correlated to manifest and cycloplegic components. The comparison between manifest, cycloplegic, and wavefront refraction with total amount of higher order aberrations showed no strong correlation. The comparison between topography and manifest, cycloplegic, and wavefront refraction did not show strong correlation. Visual symptoms analysis showed correlation of double vision with total coma and with horizontal coma for the 5-mm and 7-mm pupil size; correlation between starburst and total coma for the 7-mm pupil size; and correlation of double vision with horizontal coma, glare with spherical aberrations and with total aberrations, and starburst with spherical aberrations for the scotopic pupil size. Scotopic pupil size had a positive association with starburst and a negative association with double vision. Conclusions The LADARWave wavefront measurement device is a valuable diagnostic tool in measuring refractive error with ocular aberrations in post-LASIK eyes. A strong correlation between visual symptoms and ocular aberrations, such as monocular diplopia with coma and starburst and glare with spherical aberration, suggest this device is valuable in diagnosing symptomatic LASIK-induced aberrations. Horizontal coma was correlated with double vision, whereas vertical coma was not.

An 11-year-old girl with a port-wine stain on both sides of her face (fi gure A, B) presented after reporting progressive diffi culty reading. Visual acuity in the right eye was 20/100 and in the left eye she could count fi ngers only. Fundus examination of the right eye showed an inferior retinal detachment with retinal pleats (fi gure C, arrow). A subretinal peripapillary lesion was also seen. Dilated examination of the left eye showed a bullous retinal detachment that could be seen through the pupil Lancet 2013; 382: 259

A healthy 12-year-old boy had a subcutaneous triamcinolone acetonide steroid injection at the site of a keloid on his left earlobe in November, 2008, at a plastic surgery clinic. Within 5 min, he developed left-sided facial numbness, diaphoresis, dizziness, hypaesthesia of the left side of the mouth and tongue, left upper lid ptosis, and nearly complete vision loss in his left eye. Several hours later his systemic symptoms had resolved, he had regained partial vision in his left eye, and his right eye was asymptomatic. On examination by a retina specialist he was noted to have a visual acuity of 20/400 as well as multiple white steroid emboli in the retinal arteries of his left eye (fi gure). He also had diff use retinal whitening in the macula and other regions of the retina consistent with a central retinal artery occlusion (fi gure). 3 days later, his visual acuity improved to 20/150. This case represents a vision-threatening and potentially fatal complication of subcutaneous auricular steroid injection. Subcutaneous injections of dermal fi llers and corticosteroids are done in many specialties such as dermatology, otolaryngology, plastic surgery, and ophthalmology. Corticosteroid injections in the face, including the orbit, eyelids, nose, oral cavity, and maxilla, have been reported to cause ocular embolic events such as anterior segment ischaemia, branch and central retinal artery occlusions, and ophthalmic artery occlusions. Due to diff use anastomoses in the facial arterial system, facial injections can cause retrograde embolisation of the ophthalmic or central retinal arteries. This may cause severe, irreversible vision loss. For all injections within the face, good practice is to aspirate before injection and to inject as slowly as possible in order to limit forces that could propel emboli. Patients with visual problems after steroid injection should have immediate ophthal mological evaluation to allow intervention that might improve visual acuity. In embolic central retinal artery occlusion, ocular massage and reduction of intraocular pressure (by anterior chamber paracentesis and intraocular pressure lowering drugs) might help to mobilise emboli and restore ocular blood fl ow, although evidence that this could help is scarce.

Purpose To elucidate the subclinical anatomy of retinopathy of prematurity (ROP) using spectral domain optical coherence tomography (SD OCT). Design Prospective, observational case series. Participants Three low-birth-weight, severely premature infants. Methods Clinical examination was performed using a portable slit lamp and indirect ophthalmoscope. Imaging was performed by using a handheld SD OCT device and Retcam (Clarity Medical Systems, Pleasanton, CA) or video-indirect recording. Spectral domain optical coherence tomography imaging was conducted without sedation at the bedside in the neonatal intensive care unit on 1 patient. The other 2 patients had an examination under anesthesia with SD OCT imaging in the operating room. Main Outcome Measures In vivo determination of vitreoretinal morphology, anatomy, and pathology by clinical examination, imaging, and SD OCT. Results Linear and volumetric imaging was achieved with the handheld system in infant eyes despite tunica vasculosa lentis and vitreous bands. Imaging was not possible in eyes with notable vitreous hemorrhage. Analysis of SD OCT images revealed preretinal structures (ranging from 409 to 2700 μm in width and 212 to 440 μm in height), retinoschisis, and retinal detachment in the posterior pole of patients with advanced ROP. Both the retinoschisis and the preretinal structures were not identified on conventional examination or imaging by expert pediatric ophthalmologists. The preretinal structures varied in location and size, and may represent preretinal fibrovascular proliferation. Some were found in close proximity to blood vessels, whereas others were near the optic nerve. Conclusions Handheld SD OCT imaging can be performed on the sedated or nonsedated neonate and provides valuable subclinical anatomic information. This novel imaging modality can reveal the location and extent of posterior ROP pathology not evident on standard examination. This could affect future clinical decision-making if studies validate a management strategy based on findings from this imaging technique. Financial Disclosure(s) Proprietary or commercial disclosure may be found after the references.

Vasculitic disorders are relatively rare. Their etiology and pathophysiology remain enigmatic, leading to confusing nomenclature and multiple classification schemes. Untreated vasculitis can be fatal. Early diagnosis is the key to successful treatment and better prognosis. However, early diagnosis can be difficult; vasculitic conditions usually present with non-specific symptoms for a long period before clinically overt manifestations occur. Ophthalmologists should be familiar with the ocular manifestations of the vasculitic disorders because they may not only be sight-threatening, but more importantly could be the presenting manifestations of active, potentially lethal systemic disease. This review summarizes clinical and ocular manifestations of systemic vasculitic disorders. Furthermore, it discusses general concepts in diagnosis and treatment of these diseases in an effort to provide a practical framework for the ophthalmologist evaluating patients with vasculitis.

A 56-year-old African-American man presented with 20/30 best-corrected visual acuity bilaterally. Fundoscopic examination, fundus photographs, and fl uorescein angiography showed signifi cant bilateral tortuosity of second and third order arterioles (fi gure). Other fi ndings in the left eye included an occluded superotemporal artery with arteriosclerosis and macular pigmentary changes. The tortuosity was believed to be most consistent with familial retinal arteriolar tortuosity (fRAT), a rare autosomal dominant disorder. However, the patient stated that he had no family history of ocular disease, and the only one of eight siblings accessible for examination did not demonstrate fRAT. Is olated tortuosity of the second and third order arterioles is pathognomonic for fRAT. Although a few associated systemic vascular abnormalities have been identifi ed, fRAT is considered to be an isolated retinal fi nding. Branch retinal artery occlusion has not been reported in fRAT, and this feature may be attributed to the patient’s other risk factors of cocaine use and signifi cant hypertension.

There are many neurological manifestations of vitamin B(12) deficiency. Optic neuropathy is a rare, but important, manifestation of vitamin B(12) deficiency that should be suspected in patients with risk factors for malnutrition. We present a case of a 68-year-old male who presented with bilateral decreased central vision for months and was found to have a low vitamin B(12) level. After a few months, his vision improved with parenteral vitamin B(12) supplementation. Vitamin B(12) optic neuropathy is a reversible, treatable cause of vision loss and may be a harbinger for other manifestations of the disease.

Goldmann-Favre syndrome (GFS) is one of the rarest inherited vitreoretinal dystrophies that manifests with hemeralopia, degenerative vitreous changes, peripheral and central retinoschisis, a liquefied vitreous cavity with preretinal band-shaped structures, macular oedema, cataract formation, and an abnormal electroretinogram (ERG).1–3 The term “clumped pigmentary retinal degeneration” (CPRD) describes a group of patients with decreased night and peripheral vision who have round and irregular clumps of pigment in the mid-peripheral fundus with little or no evidence of bone spicule formation.4 This pattern of pigmentation occurs in retinitis pigmentosa (RP) with preserved para-arteriolar retinal pigment epithelium (PPRPE),5 enhanced S-cone syndrome (ESCS), and GFS, and these disorders share common mutations in the NR2E3 gene, which is involved in retinal cell fate determination.6 We present clinical and molecular genetic studies of a family from the United Arab Emirates with a classic GFS phenotype and a mutation in the NR2E3 gene. Two affected siblings and two unaffected siblings from a consanguineous family in which there were nine unaffected siblings were examined. GFS was diagnosed according to previous clinical descriptions of the disease.1,2 Complete ocular examinations, fluorescein angiography (FA), ERG, and optical coherence tomography (OCT) were …