DILUTE POVIDONE-IODINE PROPHYLAXIS MAINTAINS SAFETY WHILE IMPROVING PATIENT COMFORT AFTER INTRAVITREAL INJECTIONS.

PURPOSE: To report the rates of postintravitreal injection (IVT) endophthalmitis with topical conjunctival application of various concentrations of povidone-iodine (PI), including no PI. METHODS: Retrospective chart review of patients receiving IVTs performed in a single practice between January 2011 and June 2016. Concentration of PI for all injections was recorded and cases of endophthalmitis identified and reviewed. RESULTS: A total of 35,060 IVTs in 1854 patients were included from the 5.5-year period. 29,281 injections were performed with standard 5% PI, 5,460 injections with diluted PI (3,731 with 2.5%, 1,673 with 1.25%, 56 with 0.625%), and 319 IVTs with no PI. Incidence of patient-reported PI sensitivity occurred in 15.9% of patients. Fourteen cases of endophthalmitis were identified: 12 in eyes that received 5% PI, one in an eye that received 1.25% PI, and one in an eye receiving no PI. The incidence of endophthalmitis was 0.04% for 5% PI, 0.02% for dilute PI, and 0.31% for no PI prophylaxis. All cases underwent prompt vitrectomy and had positive cultures for coagulase-negative Staphylococcus. CONCLUSION: Application of dilute PI solution to the conjunctiva at the time of IVT is an effective alternative to 5% PI for endophthalmitis prophylaxis in betadine-sensitive patients.

Variegated yet non-random rod and cone photoreceptor disease patterns in RPGR-ORF15-associated retinal degeneration.

Mutations in the ORF15 exon of the RPGR gene cause a common form of X-linked retinitis pigmentosa, which often results in severe loss of vision. In dogs and mice, gene augmentation therapy has been shown to arrest the progressive degeneration of rod and cone photoreceptors. However, the distribution of potentially treatable photoreceptors across the human retinas and the rate of degeneration are not known. Here, we have defined structural and functional features of the disease in 70 individuals with ORF15 mutations. We also correlated the features observed in patients with those of three Rpgr-mutant (Rpgr-ko, Rd9, and Rpgr-cko) mice. In patients, there was pronounced macular disease. Across the retina, rod and cone dysfunction showed a range of patterns and a spectrum of severity between individuals, but a high symmetry was observed between eyes of each individual. Genotype was not related to disease expression. In the Rpgr-ko mice, there were intra-retinal differences in rhodopsin and cone opsin trafficking. In Rd9 and Rpgr-cko mice, retinal degeneration showed inter-ocular symmetry. Longitudinal results in patients revealed localized rod and cone dysfunction with progression rates of 0.8 to 1.3 log per decade in sensitivity loss. Relatively retained rod and cone photoreceptors in mid- and far-peripheral temporal-inferior and nasal-inferior visual field regions should be good targets for future localized gene therapies in patients.

Long-term outcomes in eyes receiving fixed-interval dosing of anti-vascular endothelial growth factor agents for wet age-related macular degeneration.

PURPOSE: To report on long-term visual outcomes in patients receiving continuous fixed-interval dosing of anti-vascular endothelial growth factor (VEGF) treatment in neovascular age-related macular degeneration (AMD). DESIGN: Single-practice retrospective chart review. PARTICIPANTS: One hundred nine eyes with exudative AMD receiving continuous fixed-interval dosing (every 4-8 weeks) of anti-VEGF therapy (ranibizumab, bevacizumab, or aflibercept) for at least 5 years. Eyes were excluded if they averaged fewer than 6.5 injections per year. METHODS: Snellen visual acuity was recorded at baseline and all subsequent injections. Changes from baseline were calculated at yearly intervals. MAIN OUTCOME MEASURES: The primary outcome measure was mean change in letter score at 5, 6, and 7 years; secondary outcomes included the percentage of patients with 20/40 vision or better at 7 years and the mean change in letter score at each yearly time point based on baseline visual grouping (20/40 or better, 20/50-20/100, 20/200 or worse). RESULTS: Forty-four, 75, and 109 patients with 7, 6, and 5 years, respectively, of continuous treatment were identified. Mean change in letter score at year 5 was +14.0 letters (P = 3.9 × 10(-9)), +12.2 letters at 6 years (P = 1.5 × 10(-7)), and +12.1 letters at 7 years (P = 3.8 × 10(-5)). Driving vision (20/40 or better) was achieved in 43.2% of treated eyes. Subanalysis revealed that the greatest visual gains at 5 and 7 years were seen in those patients with baseline visual acuity worse than 20/200 (+24.5 and +25.5 letters), followed by those with 20/50 to 20/100 vision (+6.7 and +6.9 letters), and finally those with 20/20 to 20/40 (+3.7 and +3.4 letters). Patients received an average of 10.5 injections per year. CONCLUSIONS: Continuous fixed-interval dosing of anti-VEGF therapy in patients with exudative AMD results in favorable long-term preservation out to 7 years, with vision stabilizing or improving in 93.2% of eyes. Additionally, 43.2% of patients maintained driving vision in the treatment eye at 7 years compared with 10.1% at baseline. Our data suggest better outcomes with continuous therapy over published results with sporadic, as-needed therapy.

RaScaL: A Pilot Study to Assess the Efficacy, Durability, and Safety of a Single Intervention with Ranibizumab plus Peripheral Laser for Diabetic Macular Edema Associated with Peripheral Nonperfusion on Ultrawide-Field Fluorescein Angiography.

Background and Objectives: To determine the efficacy, durability, and safety of a single treatment with intravitreal ranibizumab plus peripheral scatter laser (RaScaL) in patients with diabetic macular edema associated with peripheral retinal nonperfusion on ultrawide-field fluorescein angiography (UWFA). Study Design: A 6-month, randomized, controlled, prospective phase I/II study of 30 treatment-naïve eyes of 22 patients (8 bilateral patients) with visual impairment secondary to diabetic macular edema associated with peripheral nonperfusion on UWFA. Patients were randomized to receive ranibizumab plus UWFA-guided peripheral scatter laser (n = 15) or triamcinolone acetonide plus macular laser (n = 15). Results: At 6 months, the RaScaL group patients had fewer recurrences warranting retreatment (33% vs. 80%, p < 0.003). Mean change in final visual acuity and central foveal thickness were not statistically significant between groups. Conclusion: This pilot study suggests the efficacy, safety and durability of the RaScaL treatment regimen in patients with diabetic macular edema associated with peripheral nonperfusion on UWFA. © 2014 S. Karger AG, Basel.

Spectral domain optical coherence tomography findings in CNGB3-associated achromatopsia and therapeutic implications.

We describe the spectral domain OCT findings in two siblings with CNGB3-associated achromatopsia. A 33-year-old female and her 31-year-old sibling were evaluated for mild nystagmus and decreased visual acuity which had been present since childhood. They were each evaluated with full field Ganzfeld electroretinography which demonstrated flat photopic responses and preserved rod function. Genetic testing performed at Carver lab at the University of Iowa confirmed a diagnosis of achromatopsia with identical mutations in the CNGB3 gene. Spectral domain optical coherence tomography was performed which revealed foveal changes in both siblings, with slight phenotypic variations in these genotypically identical siblings. OCT findings in achromatopsia emphasize the importance of early identification and treatment in this disorder.

Dexamethasone Sustained-Release Intracanalicular Insert for Control of Postoperative Inflammation After Pars Plana Vitrectomy.

PURPOSE: To evaluate the safety and efficacy of a dexamethasone sustained-release intracanalicular insert (DII) (Dextenza® Ocular Therapeutix, Inc., Bedford, MA) for control of inflammation and pain after pars plana vitrectomy (PPV) compared to standard topical steroid therapy. METHODS: Retrospective, case-matched comparison of consecutive patients undergoing PPV. Control patients were matched by diagnosis and procedure performed. The primary outcome was the proportion of patients with complete anterior chamber cell clearance (ACCC) at postoperative day 7. Secondary outcomes included proportion developing intraocular pressure (IOP) >25 mmHg, change in mean optical coherence tomography central foveal thickness (OCT CFT), and proportion developing cystoid macular edema (CME) on qualitative analysis of OCT. RESULTS: The DII group had a statistically significant higher rate of complete ACCC compared to the topical steroid group (65% versus 35%, respectively, with p=0.01). No eyes had IOP >25 mmHg in the DII, compared to 2 eyes in the topical steroid group (not statistically significant). Overall, mean OCT CFT decreased in both groups; one patient had CME in the DII group, as compared to three in the topical steroid group (not statistically significant). CONCLUSION: The dexamethasone intracanalicular insert provided excellent safety and efficacy in control of postoperative inflammation following PPV in this retrospective case-matched study.

Brolucizumab-related retinal vasculitis with exacerbation following ranibizumab retreatment: A clinicopathologic case study.

PURPOSE: To describe the clinical and pathologic characteristics of a case of retinal vasculitis and vitritis following brolucizumab administration and subsequent ranibizumab treatment. OBSERVATIONS: A 76-year old Caucasian woman experienced pain, decreased vision and floaters one week after receiving her third monthly intravitreal brolucizumab injection in the right eye for exudative age-related macular degeneration. Examination was significant for 0.5+ anterior chamber cells, vitritis, mild peripheral vascular sheathing, and decreased vision from 20/70 to 20/200. She was started on topical 1% prednisolone acetate with improvement in her examination. She was switched to ranibizumab one month after her last brolucizumab injection of the right eye. Three weeks after her ranibizumab injection, she noticed photophobia, pain and decreased vision. Examination revealed worsening uveitis, vitritis, vascular sheathing, and decreased vision to count fingers. Despite starting on 0.05% difluprednate drops every 2 hours and oral high-dose methylprednisolone, the patient did not have any significant improvement in her symptoms or examination. She underwent pars plana vitrectomy and vitreous biopsy with intravitreal triamcinolone injection to the right eye. Vitreous biopsy and culture ruled out infectious endophthalmitis, and further cytopathologic analysis revealed chronic inflammatory infiltrate. CONCLUSION AND IMPORTANCE: Treatment with brolucizumab can result in intraocular inflammation and retinal vasculitis likely due to a delayed hypersensitivity reaction to the drug, supported by cytopathologic analysis of a vitreous sample. We demonstrate a case where retreatment with an alternative anti-VEGF agent resulted in worsening vision and vasculitis.

Breaking the mold of orbital cellulitis.

A 52-year-old, immune-suppressed man presented with painful proptosis. Orbital imaging revealed enhancement of his right inferior rectus muscle and mild ethmoidal sinus disease. Sinus washings and turbinectomy demonstrated Curvularia. Despite aggressive intravenous antimicrobials, the patient remained febrile. Repeat imaging demonstrated a well-defined intramuscular abscess without contiguous orbital or paranasal involvement. Following surgical drainage, the patient improved. Cultures of the material expressed from the abscess confirmed a co-infection with Fusarium. Although rare, fungal abscess of the extraocular muscle should be considered in patients (particularly if immunosuppressed) with extraocular muscle enlargement resistant to conventional antimicrobial therapy. Prompt diagnosis and treatment could potentially prevent further serious morbidity or mortality.

Preclinical potency and safety studies of an AAV2-mediated gene therapy vector for the treatment of MERTK associated retinitis pigmentosa.

Abstract Proof of concept for MERTK gene replacement therapy has been demonstrated using different viral vectors in the Royal College of Surgeon (RCS) rat, a well characterized model of recessive retinitis pigmentosa that contains a mutation in the Mertk gene. MERTK plays a key role in renewal of photoreceptor outer segments (OS) by phagocytosis of shed OS tips. Mutations in MERTK cause impaired phagocytic activity and accumulation of OS debris in the interphotoreceptor space that ultimately leads to photoreceptor cell death. In the present study, we conducted a series of preclinical potency and GLP-compliant safety evaluations of an adeno-associated virus type 2 (AAV2) vector expressing human MERTK cDNA driven by the retinal pigment epithelium-specific, VMD2 promoter. We demonstrate the potency of the vector in RCS rats by improved electroretinogram (ERG) responses in treated eyes compared with contralateral untreated controls. Toxicology and biodistribution studies were performed in Sprague-Dawley (SD) rats injected with two different doses of AAV vectors and buffer control. Delivery of vector in SD rats did not result in a change in ERG amplitudes of rod and cone responses relative to balanced salt solution control-injected eyes, indicating that administration of AAV vector did not adversely affect normal retinal function. In vivo fundoscopic analysis and postmortem retinal morphology of the vector-injected eyes were normal compared with controls. Evaluation of blood smears showed the lack of transformed cells in the treated eyes. All injected eyes and day 1 blood samples were positive for vector genomes, and all peripheral tissues were negative. Our results demonstrate the potency and safety of the AAV2-VMD2-hMERTK vector in animal models tested. A GMP vector has been manufactured and is presently in clinical trial.

Gene therapy for leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years.

OBJECTIVE: To determine the safety and efficacy of subretinal gene therapy in the RPE65 form of Leber congenital amaurosis using recombinant adeno-associated virus 2 (rAAV2) carrying the RPE65 gene. DESIGN: Open-label, dose-escalation phase I study of 15 patients (range, 11-30 years of age) evaluated after subretinal injection of the rAAV2- RPE65 vector into the worse-functioning eye. Five cohorts represented 4 dose levels and 2 different injection strategies. MAIN OUTCOME MEASURES: Primary outcomes were systemic and ocular safety. Secondary outcomes assayed visual function with dark-adapted full-field sensitivity testing and visual acuity with Early Treatment Diabetic Retinopathy Study charts. Further assays included immune responses to the vector, static visual fields, pupillometry, mobility performance, and optical coherence tomography. RESULTS: No systemic toxicity was detected; ocular adverse events were related to surgery. Visual function improved in all patients to different degrees; improvements were localized to treated areas. Cone and rod sensitivities increased significantly in the study eyes but not in the control eyes. Minor acuity improvements were recorded in many study and control eyes. Major acuity improvements occurred in study eyes with the lowest entry acuities and parafoveal fixation loci treated with subretinal injections. Other patients with better foveal structure lost retinal thickness and acuity after subfoveal injections. CONCLUSIONS: Gene therapy for Leber congenital amaurosis caused by RPE65 mutations is sufficiently safe and substantially efficacious in the extrafoveal retina. There is no benefit and some risk in treating the fovea. No evidence of age-dependent effects was found. Our results point to specific treatment strategies for subsequent phases. APPLICATION TO CLINICAL PRACTICE: Gene therapy for inherited retinal disease has the potential to become a future part of clinical practice. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00481546.

Intravitreal bevacizumab treatment of bilateral peripapillary choroidal neovascularization from optic nerve head drusen.

Choroidal neovascular membranes are a rare cause of decreased vision in children with optic nerve head drusen. We present a case of bilateral choroidal neovascular membranes associated with optic nerve head drusen in a 5-year-old boy who was successfully treated with a combination of focal laser photocoagulation and intravitreal bevacizumab.

Ab-externo AAV-mediated gene delivery to the suprachoroidal space using a 250 micron flexible microcatheter.

BACKGROUND: The current method of delivering gene replacement to the posterior segment of the eye involves a three-port pars plana vitrectomy followed by injection of the agent through a 37-gauge cannula, which is potentially wrought with retinal complications. In this paper we investigate the safety and efficacy of delivering adeno-associated viral (AAV) vector to the suprachoroidal space using an ab externo approach that utilizes an illuminated microcatheter. METHODS: 6 New Zealand White rabbits and 2 Dutch Belted rabbits were used to evaluate the ab externo delivery method. sc-AAV5-smCBA-hGFP vector was delivered into the suprachoroidal space using an illuminated iTrackTM 250A microcatheter. Six weeks after surgery, the rabbits were sacrificed and their eyes evaluated for AAV transfection using immunofluorescent antibody staining of GFP. RESULTS: Immunostaining of sectioned and whole-mounted eyes demonstrated robust transfection in all treated eyes, with no fluorescence in untreated control eyes. Transfection occurred diffusely and involved both the choroid and the retina. No apparent adverse effects caused by either the viral vector or the procedure itself could be seen either clinically or histologically. CONCLUSIONS: The ab externo method of delivery using a microcatheter was successful in safely and effectively delivering a gene therapy agent to the suprachoroidal space. This method presents a less invasive alternative to the current method of virally vectored gene delivery.

Subperiosteal orbital hemorrhage complicating cardiac surgery.

Subperiosteal orbital hemorrhage (SPOH) following cardiac surgery has not been previously reported. We present a patient who developed diplopia and right eye proptosis immediately after cardiac surgery for a mitral valve repair and coronary artery bypass graft. A computed tomography (CT) study demonstrated a right superior SPOH. The diplopia and proptosis resolved spontaneously within 4 weeks. Follow-up CT showed complete resolution of the SPOH.