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.

Chronic ocular small vessel disease: An overview of diabetic retinopathy and its relationship with cardiovascular health.

Diabetic retinopathy (DR) is a potentially blinding disease originating from small vessel damage in the retina in chronic hyperglycemic states. DR has a complex multi-pathway driven pathogenesis resulting in diabetic macular edema and retinal ischemia, the former being the most common cause of vision impairment in DR. Hypoxia induced cytokines stimulate vascular endothelial growth factor (VEGF) production and subsequent angiogenesis with resultant mechanical retinal damage over time. Anti-VEGF therapy is effective for the treatment of center-involving diabetic macular edema. There is evolving evidence showing the effectiveness of anti-VEGF as both adjuvant and monotherapy in the treatment of proliferative DR, however laser photocoagulation continues to remain the standard of care. DR in large cohort studies has been shown to be an independent risk factor for the development of cardiovascular disease and mortality. In addition, changes in retinal vascular caliber ratios may have implications for risk of macrovascular events with a gender discrepancy towards women.

Efficacy of Oral Dextrose versus Acetaminophen versus Placebo on Pain Relief during Retinopathy of Prematurity Eye Examinations: A Randomized, Double-Blind Controlled Clinical Trial.

Purpose: To assess the effect of oral dextrose versus acetaminophen versus placebo in pain relief in retinopathy of prematurity (ROP) examination. Methods: In this prospective randomized, double-blind controlled clinical trial study performed in the ophthalmology clinic of Shafa Hospital (referral hospital for eye disease), Kerman, Iran, 105 premature neonates with birth weight ≤2000 g and gestational age between 28 and 34 weeks were studied. Pain score measurement with Premature Infant Pain Profile-Revised (PIPP-R) during ROP examination in three intervention groups, acetaminophen group (15 mg/kg oral acetaminophen), dextrose group (one cc of oral dextrose 50%), and placebo group (one cc of distilled water), was done. Results: Out of 105 infants, 33 infants received acetaminophen drops, 35 infants received dextrose drops, and 37 infants received placebo. The mean pain score of the group receiving acetaminophen was 11.39, dextrose 12.17, and placebo 11.54. The acetaminophen group had a lower average PIPP-R score. This difference was not significant between the three groups (P = 0.38). Conclusions: Acetaminophen and dextrose in comparison with distilled water did not show a significant difference in reducing neonatal pain during ROP examinations. However, the PIPP-R score in the acetaminophen group was lower compared to the other groups.

Transscleral vs transpupillary diode laser photocoagulation for the treatment of zone II type 1 retinopathy of prematurity: Anatomical and refractive outcomes.

PURPOSE: To compare the anatomical and refractive outcomes of transscleral diode versus transpupillary laser photocoagulation for the treatment of zone II type 1 retinopathy of prematurity (ROP). METHODS: In this prospective comparative interventional case series, infants with type 1 ROP in zone II were assigned to either transpupillary or transscleral laser based on the surgeons' expertise area. The rate of regression, need for retreatment, and structural and biometric outcomes at month 6 were evaluated and compared between the two treatment groups. RESULTS: In total, 209 eyes were enrolled; 145 eyes of 77 infants and 64 eyes of 33 infants and were in transscleral and transpupillary groups, respectively. There was no significant difference in baseline characteristics between the groups. There was no significant difference in retreatment rates (1.6% vs. 3.4%; P = 0.669) and progression to stage 4 (1.6% vs. 2.8%; P = 0.999) between the transpupillary and transscleral groups, respectively. At month 6, the mean spherical equivalent was 0.31 ± 3.57 and 0.44 ± 2.85 diopters, and the axial length was 18.28 ± 6.22 and 18.36 ± 6.87 mm in the transpupillary and transscleral groups, respectively, without a significant difference between groups. There was no significant difference in the rate of myopia (43.8% vs. 33.8%; P = 0.169) and high myopia (4.7% vs. 4.8%; P = 0.965) in transpupillary and transscleral groups at month 6. CONCLUSION: The transpupillary and transscleral laser photocoagulation routes are both effective in the treatment of zone II type 1 ROP and show no significant differences in anatomical or refractive outcomes in relation to the route chosen.

Exacerbation of pigment epithelial detachment following aflibercept: A case of bevacizumab rescue.

PURPOSE: We describe a 61-year-old female patient with a retinal pigment epithelial detachment (PED) of the left eye in the setting of neovascular aged-macular degeneration (nAMD) with unanticipated responses to aflibercept and bevacizumab. OBSERVATIONS: A reduction of PED size from 423 µm to 309 µm and vision improvement (20/150- to 20/40) were observed after five consecutive monthly injections of bevacizumab. A switch to aflibercept for the following two consecutive months showed an unanticipated incremental decline in vision (20/80- at month 1, 20/150- at month 2), increased PED size (749 µm), and the development of subretinal fluid (SRF). After a switch back to bevacizumab, the subretinal fluid resolved. After nine consecutive monthly injections of bevacizumab, final vision in the left eye was 20/25, and final PED height was 84 µm. CONCLUSIONS: Different anti-VEGFs may induce varied and unpredictable responses among the most recalcitrant cases of nAMD. Unpredictably, PED size in our patient worsened with aflibercept treatment. IMPORTANCE: Treatment for nAMD with large PEDs has poor level 1 evidence for guidance, and customized treatment should be considered.

Bilateral anterior segment dysgenesis and persistent fetal vasculature associated with terminal 10q26 deletion.

Deletion of the 26q position on chromosome 10 results in a syndrome with well-documented systemic phenotypes. There are few reports of ophthalmic manifestations in terminal 10q26 deletion. We report a 4-week-old boy with terminal 10q26 deletion who had extensive ophthalmic abnormalities, including bilateral anterior segment dysgenesis and bilateral persistent fetal vasculature, with microphthalmia, microcornea, iris corectopia, congenital cataracts, and posterior embryotoxon.

Effect of pattern scanning laser on macular thickness in diabetic retinopathy.

PURPOSE: This study investigates the effect of pattern scanning laser (PASCAL) panretinal photocoagulation (PRP) on central macular thickness (CMT) and visual acuity (VA) in patients with proliferative diabetic retinopathy (PDR). METHODS: This retrospective non-randomized comparative case series included 262 eyes (163 with macular edema) of 177 patients with PDR. Treatment was PRP alone (137), PRP + anti-vascular endothelial growth factor (VEGF) (69), PRP + focal laser (28), or all three (89). CMT and central macular volume 3 and 6 mm from fovea were analyzed before and 1, 3, and 6 months after PRP. Spot number was plotted against CMT, and linear regression analysis was performed. RESULTS: For each treatment group and time point, there was a non-significant relationship between spot number and CMT. In eyes receiving all three treatment modalities, a significant negative relationship was found between spot number and 3-mm volume at 6 months (p = 0.04) and 6-mm volume at 1 month (p = 0.002) and 6 months (p = 0.011). There was no significant change in VA in any treatment group at the 6-month time point. CONCLUSION: PASCAL PRP ± focal laser or anti-VEGF was not associated with increased development of macular edema or change in VA. PASCAL PRP with focal laser and anti-VEGF may result in a decrease in macular edema.

The Vitreous Ecosystem in Diabetic Retinopathy: Insight into the Patho-Mechanisms of Disease.

Diabetic retinopathy is one of the leading causes of blindness in the world with the incidence of disease ever-increasing worldwide. The vitreous humor represents an extensive and complex interactive arena for cytokines in the diabetic eye. In recent decades, there has been significant progress in understanding this environment and its implications in disease pathophysiology. In this review, we investigate the vitreous ecosystem in diabetic retinopathy at the molecular level. Areas of concentration include: the current level of knowledge of growth factors, cytokine and chemokine mediators, and lipid-derived metabolites in the vitreous. We discuss the molecular patho-mechanisms of diabetic retinopathy based upon current vitreous research.

Peripheral Retinal Neovascularization in a Patient with Sarcoidosis and Cocaine-Associated Autoimmunity.

A 63-year-old African-American female with history of sarcoidosis (lymph node biopsy proven) and cocaine abuse for 8 years was referred to us because of new floater. Her ocular history was unremarkable except for vague complaints of visual disturbance during a hospital admission in 2016. On presentation, her visual acuity was 20/400 in the right eye and 20/30 in the left eye. Dilated fundus exam and multimodal imaging showed thick epiretinal membrane (ERM) superior to optic nerve head causing a lamellar macular hole and intra retinal edema in the right eye, a full thickness macular hole, and peripheral neovascularization in the left eye. Peripheral vasculitis was appreciated in both eyes and peripheral neovascularization in the left eye on fluorescein angiography. The patient underwent laser therapy, and the new vessels regressed in the left eye without any changes in systemic medications. Multiple factors may contribute to retinal vasculitis and neovascularization including sarcoidosis, cocaine abuse, and other undiagnosed systemic vasculitis, which makes this case a mystery.

Treatment of Recurrent Primary Cutaneous Mucinous Carcinoma of the Eyelid with Modified Wide Local Excision.

Primary cutaneous mucinous carcinoma (PCMC) is a rare, low-grade malignant neoplasm of the sweat gland, whose history has been controversial regarding eccrine versus apocrine origin. This case report describes a 53-year-old male who presented to the University of Florida, Gainesville, ophthalmology clinic and was referred to the oculoplastics service with a painless, subcentimeter mass on the lateral right upper eyelid including the canthus, consistent with recurrent primary cutaneous mucinous carcinoma of the eyelid. Four years prior, the patient had undergone excisional biopsy of the lesion in a clinic, which revealed residual tumor, but the patient deferred further surgery at the time. The patient underwent surgical excision of the mass with reconstruction without operative complications and with negative surgical margins. PCMC is difficult to diagnose clinically due to its rarity and requires a histopathological examination for confirmation of the diagnosis. This report presents the first case in the literature of primary cutaneous mucinous carcinoma in a patient with human immunodeficiency virus (HIV). With this case report, we aim to raise awareness of primary cutaneous mucinous carcinoma as a potential part of the differential diagnosis for malignant eyelid lesions, including those present in patients with HIV.

Eicosanoid Profiles in the Vitreous Humor of Patients with Proliferative Diabetic Retinopathy.

Proliferative diabetic retinopathy is a potentially blinding sequela of uncontrolled diabetes that involves a complex interaction of pro-angiogenic and inflammatory pathways. In this study, we compared the levels of pro-angiogenic arachidonic acid-derived mediators in human vitreous humor obtained from eyes with high-risk proliferative diabetic retinopathy versus controls. The results indicated that lipoxygenase and cytochrome P450-derived eicosanoids were elevated (5-HETE, 12-HETE, 20-HETE, and 20-COOH-AA), and there appeared to be no differences in levels measured in eyes with tractional retinal detachments versus those without. These results provide further insight into the pathogenesis of this disease and for the development of future potential therapeutic agents that target arachidonic acid metabolites to treat diabetic retinopathy.

Endogenous Endophthalmitis: yield of the diagnostic evaluation.

BACKGROUND: Endogenous endophthalmitis is an infection of the eye secondary to sepsis, occurring in 0.04-0.5% of bacteremia or fungemia. Risk factors include intravenous drug abuse (IVDA), diabetes, indwelling catheters, and immune suppression. Many patients have known or suspected bacteremia or fungemia; however, culture yield is reported to be low (approximately 50%). The purpose of this study is to elucidate the yield of diagnostic evaluation including microbial cultures over a 6.5 year period at an academic center in the United States. METHODS: Retrospective chart review of patients with endogenous endophthalmitis at the University of Florida from June 2011 to February 2018. RESULTS: Included are 40 eyes of 35 patients. Endophthalmitis was secondary to an endogenous source in 23.5% of all endophthalmitis cases observed. Intraocular culture positivity was 28.6% overall but was 0% after initiation of systemic antibiotics. Most commonly identified organisms from the eye were coagulase-negative Staphylococcus and Candida. Blood culture positivity was 48.6%, most commonly Staphylococcus. IVDA was noted with increasing frequency as a risk factor. Diagnosis of endophthalmitis upon hospital admission was associated with a higher intraocular culture positivity (P = 0.040) and a shorter hospital stay (P = 0.035). Computed tomography (CT) and magnetic resonance imaging (MRI) were the highest yield imaging modalities; X-ray and non-ocular ultrasound were less diagnostically useful. Echocardiogram was positive by transesophageal route (TEE) in 22% and in 9% by transthoracic (TTE) testing. Following discharge from the hospital, 48.4% of patients failed to follow up with outpatient ophthalmology. CONCLUSIONS: Based on the results of this study, the interdisciplinary team should consider directed imaging, eye cultures prior to antimicrobial administration, thorough history for IVDA, and caution with premature discharge from the hospital.

Utility of wound cultures in the management of open globe injuries: a 5-year retrospective review.

BACKGROUND: Endophthalmitis after open globe injury can be devastating to vision recovery. As treatment of endophthalmitis is often empiric, some surgeons may obtain cultures at presentation of trauma in anticipation of later infection. This study examines the usefulness of wound cultures obtained during globe repair. RESULTS: Institutional Review Board approval was obtained. Medical records were retrospectively reviewed, with 168 open globes included. Cultures of the wound site had been taken in all cases included in this study. Wound cultures were positive in 63% of cases but were not used for clinical decision-making for any patient in this study. Two patients had evidence of endophthalmitis at presentation, with results of vitreous culture matching those from the wound. No patient later developed endophthalmitis after open globe repair. CONCLUSIONS: Despite a high rate of wound contamination, few cases of endophthalmitis (1.2%) were seen in this series. In no case did the results of wound culture impact choice of antibiotic prophylaxis or treatment. Cultures obtained at the time of open globe repair were not cost effective in the subsequent management of the injury.

Exercise band-induced lens dislocations: A case series.

PURPOSE: We report three cases of lens dislocation due to ocular trauma from a recoiling exercise band. OBSERVATIONS: Three patients had closed globe injury resulting in lens dislocation. All had previously undergone intraocular surgeries; two patients were within three weeks of pars plana vitrectomy for retinal detachment repair. Findings included vision loss, hyphema, and increased intraocular pressure refractory to medical management. The retina remained attached post-traumatically in all cases. Lens removal or repositioning resulted in improved vision. CONCLUSIONS AND IMPORTANCE: A recoiling exercise band can cause lens dislocation, hyphema, and ocular hypertension that may require surgical intervention. Our report emphasizes the importance of patient counseling in the perioperative period for the prevention of traumatic complications.

Dosimetric dependence of ocular structures on eye size and shape for external radiation fields of electrons, photons, and neutrons.

The dosimetric dependence of ocular structures on eye size and shape was investigated within the standard ICRP Publication 116 irradiation geometries. A realistic transport geometry was constructed by inserting a scalable and deformable stylised eye model developed in our previous study within the head of the ICRP Publication 110 adult male reference computational phantom. Beam irradiations of external electrons, photons, and neutrons on this phantom were simulated using the Monte Carlo radiation transport code PHITS in the geometries of AP, RLAT, PA and ROT. Absorbed doses in ocular structures such as ciliary body, retina, and optic nerves were computed as well as that in lens. A clear dosimetric dependence of ocular structures on eye size and shape was observed for external electrons while only a small dependence was seen for external photons and neutrons. Difference of the tendency was attributed to their depth-dose distributions where spread dose distributions were created by photons and neutrons while more concentrated distributions were created by external electrons.

Surgical management of diabetic tractional retinal detachments.

Tractional retinal detachment is an end-stage form of diabetic retinopathy that occurs when contractile forces in the vitreous and neovascular tissue lead to the detachment of the neurosensory retina. We review the literature related to the management of this disease. Preoperative planning includes appropriate patient selection, diagnostic and prognostic imaging, and medical optimization with reduction of systemic risk factors. Use of antivascular endothelial growth factor for preoperative treatment has had significant benefits for tractional retinal detachment repair in improving surgical efficiency and outcomes. Advances in microsurgical instrumentation are discussed, with attention to small-gauge vitrectomy with improved flow dynamics, viewing strategies, and lighting allowing bimanual surgery. Special emphasis is placed on bimanual surgical technique, choice of tamponade, and the avoidance of iatrogenic damage. Complications and special considerations are further explored. Based on our compilation of relevant literature, we propose a surgical algorithm for the management of these complex patients.

Multiloculated Ciliary Body Cysts and Lenticular Coloboma: A Rare Phenotypic Variation Associated With Persistent Fetal Vasculature.

A case of a 4 year-old boy with persistent fetal vasculature, lenticular coloboma, and a benign, multiloculated ciliary body mass is reviewed. The presence of ciliary body cysts in association with persistent fetal vasculature is sparsely reported. Its presence in a child can cause a diagnostic dilemma and lead to amblyopia. [J Pediatr Ophthalmol Strabismus. 2018;55:e39-e41.].