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Purpose: To present a distinctive case of polypoidal choroidal vasculopathy (PCV) with an exceptionally elevated pigment epithelial detachment (PED)., Observations: We describe the case of a 48-year-old African-American woman who presented with a substantial lesion in the right eye. Fundus examination revealed an exceptionally elevated lesion extending in the inter-papilla-macular region with multiple dark pigmented spots. Indocyanine Green Angiography (ICGA) in the early phase displayed focal hyperfluorescent spots and a blockage of fluorescence within the lesion, particularly overlying the papillomacular bundle. In the late phase, hyperfluorescent spots within the lesion became evident, with a hyperfluorescent outline of the lesion indicating vascularization. Optical coherence tomography in the right eye disclosed an exceptionally elevated PED temporal to the optic nerve with an elevation of more than 2500 μm, along with subretinal fluid and trace intraretinal fluid., Conclusions and Importance: Multimodal imaging unveiled an atypical case of PCV featuring an exceptionally extensive polypoidal lesion overlying the papillomacular bundle with choroidal neovascularization. Given the presence of a highly conspicuous, elevated PED, it was felt that the risk of retinal pigment epithelium tear was high either with anti-VEGF therapy or even due to natural history. In this scenario, the initial treatment choice was photodynamic therapy rather than intravitreal anti-VEGF injection, which led to complete regression with excellent visual acuity., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: Diabetic retinopathy (DR) patients should be alert for subclinical macroangiopathy. We aimed to investigate the association between retinal neurovascular alteration and systemic arterial stiffness in type 2 diabetes mellitus (type 2 DM) patients with varying degrees of renal impairment., Methods: The study included 170 patients with confirmed diagnosis of type 2 DM aged ≥18 years old. Renal function was assessed by estimated glomerular filtration rate (eGFR). Arterial stiffness was measured by brachial-ankle pulse wave velocity (baPWV) and ankle brachial index (ABI). Retinal neurovascular parameters were derived from Optical Coherence Tomography (OCT)/OCT-Angiography, represented by vessel density (VD Central, Inner, Outer, Full), foveal avascular zone (FAZ area and FAZ perimeter) of the superficial capillary plexus, the average of macular ganglion cell-inner plexiform layer thickness (ave mGC-IPLt) and the average of retinal nerve fiber layer thickness (aveRNFLt). The association between variables among the groups (according to renal function, diabetic retinopathy (DR) severity, and arterial stiffness categories) were analyzed by regression analysis with multiple hypothesis testing commands., Results: Out of the 265 eyes, the mean DM duration and HbA1c were 6.21 ± 6.37 years and 8.44 ± 2.06% respectively. While the mean of eGFR, baPWV and ABI were 66.78 ± 32.80 ml/min/1.73m2, 15.49 ± 3.07 m/s, and 1.05 ± 0.12, respectively. Patients with more severe renal impairment demonstrated longer DM duration (p < 0.001), higher baPWV (p < 0.0001), and retinal vascular alteration. Proliverative DR group showed the lowest eGFR (p < 0.0001), highest baPWV (p < 0.0001), and retinal neurovascular changes. Significantly lower eGFR and retinal vascular alteration were found in the baPWV > 14 group. Some neurovascular parameters were significantly negatively correlated with baPWV; moreover, retinal neurovascular changes were also noted in the abnormal ABI group., Conclusions: The strong association between changes in the retinal neurovascular system, DR severity, renal impairment, and arterial stiffness in type 2 DM was confirmed. Patients with more severe renal impairment had higher levels of arterial stiffness, more severe DR and retinal neurovascular alteration. Retinal neurovascular changes seen in OCT/OCTA might mimic renal microvascular alteration and systemic arterial stiffness. Therefore, assessment of baPWV and OCT/OCTA should be integrated in DR screening to enhance cardiovascular risk stratification and prognosis as well as to provide clinically useful early identification of subclinical micro- and macrovascular alterations., (© 2024. The Author(s).)

Purpose: To better understand onset of radiation retinopathy and secondary orbital tumors in the setting of retinoblastoma treated with radiation and chemotherapy., Methods: Case report., Results: Here we present a 48-year-old female with a history of bilateral hereditary retinoblastoma status-post enucleation of the left eye and radiation therapy to the right eye, along with systemic chemotherapy. She underwent bladder leiomyosarcoma resection at age 24. In 2020, she presented with significantly delayed radiation retinopathy complicated by cystoid macular edema, and bevacizumab injections were initiated. An incidental benign lymphoproliferative tumor in the right lacrimal gland was found on B-scan ultrasound and was successfully excised., Conclusion: It is rare for radiation retinopathy to present with significant delay after local radiation treatment, with only 2 other cases found in the literature describing a similar late onset. In addition, there have been no other published cases of a secondary benign lymphoproliferative tumor in the setting of retinoblastoma treated with radiation and chemotherapy.

This review discusses emerging approaches to ocular drug delivery for retinal diseases. Intravitreal injections have proven to be an effective, safe, and commonly used drug delivery method. However, the optimal management of chronic retinal diseases requires frequent intravitreal injections over extended periods of time. Although this can be achieved in a clinical trial environment, it is difficult to replicate in routine clinical practice. In addition, frequent treatment increases the risk of complications, incurs more costs, and increases the treatment burden for patients and caregivers. Given the aging global population and diabetes pandemic, there is an urgent need for drug delivery methods that support more durable retinal therapy while maintaining the efficacy and safety of currently available intravitreal therapies. Several innovative drug delivery methods are currently being investigated. These include sustained-release implants and depots using prodrugs, microparticles, and hydrogels, surgically implanted reservoirs, gene therapy via submacular injections or suprachoroidal injections, as well as topical and systemic therapies., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2023 Asia-Pacific Academy of Ophthalmology. Published by Wolters Kluwer Health, Inc. on behalf of the Asia-Pacific Academy of Ophthalmology.)

Purpose: To present a case of suspected sympathetic ophthalmia in an 82-year-old monocular woman., Methods: Case report., Results: Here, we present an 82-year-old woman, status postcataract extraction with lens subluxation followed by a complicated course ultimately requiring enucleation because of a blind and painful eye in 2020, who developed contralateral choroidal lesions 6 months postenucleation along with vitritis and anterior uveitis. The lesions were suspicious for an infectious versus autoimmune etiology. Thorough systemic work-up and multimodal imaging suggest an autoimmune case. The findings in this patient suggest early identified sympathetic ophthalmia with multifocal choroiditis. This patient responded well to treatment of the acute episode with systemic corticosteroids and ultimately required steroid-sparing immunosuppression., Conclusion: Sympathetic ophthalmia is a rare entity classically observed after intraocular surgery and trauma. It may mimic many infectious and noninfectious uveitis entities. In this patient, sympathetic is a primary concern given her history and age of presentation with consideration for other uveitic entities.

This study will provide a thorough review of systemic (and select intravitreal) medications, along with illicit drugs that are capable of causing various patterns of retinal toxicity. The diagnosis is established by taking a thorough medication and drug history, and then by pattern recognition of the clinical retinal changes and multimodal imaging features. Examples of all of these types of toxicity will be thoroughly reviewed, including agents that cause retinal pigment epithelial disruption (hydroxychloroquine, thioridazine, pentosan polysulfate sodium, dideoxyinosine), retinal vascular occlusion (quinine, oral contraceptives), cystoid macular edema/retinal edema (nicotinic acid, sulfa-containing medications, taxels, glitazones), crystalline deposition (tamoxifen, canthaxanthin, methoxyflurane), uveitis, miscellaneous, and subjective visual symptoms (digoxin, sildenafil). The impact of newer chemotherapeutics and immunotherapeutics (tyrosine kinase inhibitor, mitogen-activated protein kinase kinase, checkpoint, anaplastic lymphoma kinase, extracellular signal-regulated kinase inhibitors, and others), will also be thoroughly reviewed. The mechanism of action will be explored in detail when known. When applicable, preventive measures will be discussed, and treatment will be reviewed. Illicit drugs (cannabinoids, cocaine, heroin, methamphetamine, alkyl nitrite), will also be reviewed in terms of the potential impact on retinal function., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2023 Asia-Pacific Academy of Ophthalmology. Published by Wolters Kluwer Health, Inc. on behalf of the Asia-Pacific Academy of Ophthalmology.)

Fluorescein video angiographies (FVAs) are a diagnostic tool for eye diseases, such as diabetic retinopathy (DR). Currently, kinetic tracer model methods based on indicator-dilutions theory use FVAs to extract biomarkers (e.g., volumetric blood flow and retinal vascular permeability) via pixel mapping using two-step non-linear least square fitting. Prior to biomarker extraction, the FVAs must attain optimal quality. The objective of this research is to create a program to remove all frames experiencing signal drops (causes include blinking, squinting, and head movement). 15 FVAs (6 healthy control subjects, 6 diabetes mellitus no DR (DMnoDR) subjects, and 3 mild non-proliferative DR (NPDR) subjects) were analyzed for low quality frames. The average signal of each frame was analyzed as top, middle, and bottom thirds. The frame with maximum average signal up to the final frame of a created "Gold Standard" was compared with the raw AVI's frame with maximum average signal and subsequent frames. All frames before maximum average signal and any remaining frames were compared with the previous good-quality raw frame to determine if the frame of interest was of good quality. All remaining frames were subsequently re-evaluated and flagged if they had a local minimum prominence of 10% of the maximum average signal. The flagged frames', as well as former and subsequent frames', quality were subjectively determined. The AVI quality was subsequently tested via pre-DTKM processing and biomarker extraction via DTKM methods. Results displayed that the semi-automated frame removal process provides sufficient quality AVIs.

Purpose: To describe a patient with a choroidal osteoma treated with photodynamic therapy to prevent tumor growth in whom choroidal neovascularization (CNV) developed after being treated with photodynamic therapy., Methods: Case report., Results: A 5-year-old Hispanic woman presented with an asymptomatic choroidal osteoma, temporal to the macula of her right eye. According to the patient's mother, her medical, surgical, and family history was unremarkable. At examination, best-corrected visual acuity was 20/30 in both eyes. After 11 months of follow-up, signs of tumor growth toward the fovea without any signs of CNV was noted. Photodynamic therapy was performed to prevent invasion of the foveola. Two months thereafter, the patient developed CNV in the macula region in the right eye, decreasing visual acuity to 20/200. The patient was treated with four total intravitreal injections of 1.25 mg of bevacizumab over 24 weeks, which resulted in inactivation of the CNV and improved visual acuity to 20/20. Choroidal neovascularization had been never reported in her past history and her follow-up visits over 7 years. In addition, no evidence of recurrent neovascular activity or tumor growth was reported., Conclusion: Choroidal osteoma is a benign tumor that can result in vision-threatening complications, caused by tumor growth and tumor decalcification. Photodynamic therapy is an effective modality in inducing choroidal osteoma decalcification and stabilization; however, CNV due to reperfusion following photodynamic therapy can be seen in the retina.

Purpose: Intravitreal injections of anti-vascular endothelial growth factors (anti-VEGF) are the current standard of care for patients with choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). There is a growing subset of patients that does not respond to anti-VEGF monotherapy treatment. Some patients, however, do respond to combination therapy of corticosteroids and anti-VEGF. This treatment requires monthly/bimonthly injections of anti-VEGF and semi-annual injections of corticosteroid. A drug delivery system (DDS) that simultaneously releases multiple drugs could benefit these patients by reducing the number of injections. The purpose of this study was to characterize the simultaneous release of aflibercept and dexamethasone from a biodegradable microparticle- and nanoparticle-hydrogel DDS., Methods: Dexamethasone-loaded nanoparticles and aflibercept-loaded microparticles were created using modified single- and double-emulsion techniques, respectively. Then, microparticles and nanoparticles were embedded into a thermoresponsive, biodegradable poly(ethylene glycol)-co-(L-lactic acid) diacrylate (PEG-PLLA-DA)-N-isopropylacrylamide (NIPAAm) hydrogel DDS. Drug release studies and characterization of DDS were conducted with varying doses of microparticles and nanoparticles., Results: The combination aflibercept-loaded microparticle- and dexamethasone-loaded nanoparticle- hydrogel (Combo-DDS) achieved a total release time of 224 days. Small decreases were seen in swelling ratio and equilibrium water content for Combo-DDS compared to monotherapy aflibercept-loaded microparticle-hydrogel DDS (AFL-DDS) and monotherapy dexamethasone-loaded nanoparticle-hydrogel DDS (DEX-DDS). Bioactivity of aflibercept was maintained in Combo-DDS compared to AFL-DDS., Conclusions: The Combo-DDS was able to extend and control the release of both aflibercept and dexamethasone simultaneously from a single DDS. This may eliminate the need for separate dosing regiments of anti-VEGF and corticosteroids for wet AMD patients.

An intact blood-retinal barrier is critical to maintaining the function of the retina. Many diseases of the eye have been directly associated with impairment in vascular permeability, and methods to measure vascular permeability could offer a window into early detection of disease; however, there exist no direct measures of vascular permeability that have be translated to the clinic. This work details a complete clinical workflow to quantify vascular permeability and volumetric blood flow from fluorescein videoangiography data, with validation through realistic simulations. For optimizing the protocol, this study carried on frame rate of fluorescein videoangiography to generate a high-resolution image while minimizing the error.

The purpose of this study was to examine antibiotic drug transport from a hydrogel drug delivery system (DDS) using a computational model and a 3D model of the eye. Hydrogel DDSs loaded with vancomycin (VAN) were synthesized and release behavior was characterized in vitro. Four different compartmental and four COMSOL models of the eye were developed to describe transport into the vitreous originating from a DDS placed topically, in the subconjunctiva, subretinally, and intravitreally. The concentration of the simulated DDS was assumed to be the initial concentration of the hydrogel DDS. The simulation was executed over 1500 and 100 h for the compartmental and COMSOL models, respectively. Based on the MATLAB model, topical, subconjunctival, subretinal and vitreous administration took most (~500 h to least (0 h) amount of time to reach peak concentrations in the vitreous, respectively. All routes successfully achieved therapeutic levels of drug (0.007 mg/mL) in the vitreous. These models predict the relative build-up of drug in the vitreous following DDS administration in four different points of origin in the eye. Our model may eventually be used to explore the minimum loading dose of drug required in our DDS leading to reduced drug use and waste.

Objectives: To determine if commercial OCTA measurements can provide quantitative biomarkers for detection of radiation retinopathy (RR) s/p I-125 plaque brachytherapy in patients with uveal melanoma., Methods: Retrospective review of 6 × 6 mm OCTA images of nonirradiated fellow eyes (group 1, 28 eyes), eyes without RR (group 2, 22 eyes), eyes with RR (group 3, 13 eyes). We used automated AngioVue AngioAnalytics OCTA software determinations of FAZ size, perimeter size, and 27 capillary density measurements (nine regions of each segmentation: full-thickness retina, superficial plexus, deep plexus)., Results: Average time since irradiation was 1.9 years in group 2, and 3.7 years in group 3. FAZ size was 1.2 mm in group 3 compared with 0.2 mm in group 1 and 0.3 mm in group 2 (both p < 0.001). Capillary density was statistically significantly reduced in group 3 compared with group 1 in all 27 regions. Group 2 had significantly decreased superficial plexus capillary density compared with group 1 in three regions. Group 3 had significantly reduced capillary density compared with group 2 in 6/27 (22%) regions. Linear regression showed a change in whole-scan density of -1.5 per year after irradiation in the full-thickness retina segmentation (p = 0.008)., Conclusion: Quantitative OCTA may aid in early detection of RR.

Purpose: To evaluate the in vivo treatment efficacy and biocompatibility of a biodegradable aflibercept-loaded microsphere-hydrogel drug delivery system (DDS) in a laser-induced choroidal neovascularization (CNV) rat model., Methods: Two weeks after CNV induction, animals were randomly assigned into four experimental groups: (1) no treatment, (2) single intravitreal (IVT) injection of blank DDS, (3) bimonthly bolus IVT aflibercept injections, and (4) single IVT injection of aflibercept-DDS. CNV lesion sizes were monitored longitudinally using fluorescence angiography and multi-Otsu thresholding for 6 months. For safety and biocompatibility assessment, an additional three non-CNV animals received a blank DDS injection. Electroretinogram, intraocular pressure, and clinical ophthalmoscopic examinations were performed., Results: The average lesion areas at week 0 (treatment intervention) were (1) 8693 ± 628 µm 2 for no treatment, (2) 8261 ± 709 µm 2 for blank DDS, (3) 10,368 ± 885 µm 2 for bolus, and (4) 10,306 ± 1212 µm 2 for aflibercept-DDS. For the nontreated groups, CNV lesion size increased by week 2 and remained increased throughout the study. The treated groups exhibited CNV size reduction after week 2 and remained for 6 months. At week 22, the average percent changes in CNV lesion area were +38.87% ± 7.08%, +34.19% ± 9.93%, -25.95% ± 3.51%, and -32.69% ± 5.40% for the above corresponding groups. No signs of chronic inflammation and other ocular abnormalities were found., Conclusions: The aflibercept-DDS was effective in treating CNV lesions for 6 months and is safe, well tolerated, and biocompatible., Translational Relevance: The proposed DDS is a promising system to reduce IVT injection frequency for anti-vascular endothelial growth factor treatment., Competing Interests: Disclosure: W. Liu, None; A.P. Tawakol, None; K.M. Rudeen, None; W.F. Mieler, None; J.J. Kang-Mieler, microsphere-thermoresponsive drug delivery system (P), (Copyright 2020 The Authors.)

Recent advances in pharmacological agents have led to successful treatment of a variety of retinal diseases such as neovascular age-related macular degeneration (AMD), diabetic macular oedema (DMO), and retinal vascular occlusions (RVO). These treatments often require repeated drug injections for an extended period of time. To reduce these repeated treatment burdens, minimally invasive drug delivery systems are needed. An ideal therapy should maintain effective levels of drug for the intended duration of treatment following a single application, recognising that a significant number of months of therapy may be required. There are numerous approaches under investigation to improve treatment options. This review will highlight the advantages and limitations of selected drug delivery systems of novel biomaterial implants and depots. The main emphasis will be placed on less invasive, longer acting, sustained release formulations for the treatment of retinal disorders.

Background: To demonstrate a technique for using optical coherence tomography angiography (OCTA) to simulate leakage in eyes with diabetic macular oedema and determine the sensitivity and positive predictive value of detecting leaking microvasculature on OCTA using fluorescein angiography (FA) as the comparative norm., Methods: 6×6 mm OCT angiograms were overlaid with the corresponding OCT thickness maps. Microvascular abnormalities on the OCT angiogram underlying areas of thickening on the OCT thickness map were assumed to be leaking. Two independent readers blindly read the OCTA overlay images then the FA images cropped to the same approximate region to delineate areas of leaking microvasculature. The results were compared to determine the sensitivity and positive predictive value of OCTA for detection of leaking vessels., Results: 28 eyes of 19 diabetic patients were included. Each eye demonstrated an average of seven leaking microvascular abnormalities on the OCTA images and 22 leaking abnormalities on the FA images. Sensitivity of leaking microvasculature detection by OCTA was 26.1% and positive predictive value was 68.4%. The correlation coefficient of the two readers' detection of leaking microvasculature was 0.605 for OCTA reads compared with 0.916 for FA., Conclusion: OCTA as a whole can be used to simulate leakage, but currently, sensitivity of the technique is low. Further understanding of the OCTA technology may yield novel means of detecting retinal pathology., Competing Interests: Competing interests: JIL is a consultant for Alcon, Genentech, pSivida, Ophtea, Quark and Kodiak and has previously consulted for Santen, Pfizer/Hospira, Regeneron, Lumenis, Alexion, AbbView and Alimera. She has grants supported by Allergan, Janssen, Ohr, Second Sight, Regeneron, Genentech and Clearside. The other authors do not have any personal financial interest in any related stocks or proprietary interest in any related companies., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

The proposed doses of chloroquine (CQ) and hydroxychloroquine (HCQ) for treatment of COVID-19 (1000 mg/day for 10 days, CQ; 800 mg first day then 400 mg/day for 5 days, HCQ) in many guidelines worldwide, are considerably higher than the maximum recommended daily safe doses of both agents (≤2.3 mg/kg/day, CQ; ≤5.0 mg/kg/day, HCQ) for development of retinal toxicity. Irreversible retinal damage can occur if the exposure to the safe doses is >5 years. It is not known whether exposure to high doses over a short period of time can also cause the damage. We recommend that before prescribing CQ or HCQ, history of ocular disease should be obtained to avoid the prescription if appropriate. If either agent is to be used, routine baseline ocular examination is not absolutely necessary. Patients who do not have ocular disease should also be informed about the potential risk of retinal toxicity. Both agents, however, have not yet been proven to be beneficial to COVID-19.

Purpose: To evaluate the safety and tolerability of a microsphere thermo-responsive hydrogel drug delivery system (DDS) loaded with aflibercept in a nonhuman primate model., Methods: A sterile 50 µL of aflibercept-loaded microsphere thermo-responsive hydrogel-DDS (aflibercept-DDS) was injected intravitreally into the right eye of 10 healthy rhesus macaques. A complete ophthalmic examination, intraocular pressure (IOP) measurement, fundus photography, spectral-domain optical coherence tomography (SD-OCT), and electroretinogram were performed monthly for 6 months. One macaque was euthanized monthly, and the enucleated eyes were submitted for measurement of bioactive aflibercept concentrations. Four eyes were submitted for histopathology., Results: Injected aflibercept-DDS was visualized in the vitreous until 6 months postinjection. No abnormalities were observed in the anterior segment, and IOP remained within normal range during the study period. A small number of cells were observed in the vitreous of some macaques, but otherwise the remainder of the posterior segment examination was normal. No significant changes in retinal architecture or function as assessed by SD-OCT and histology or full-field electroretinography, respectively, were observed. A mild, focal foreign body reaction around the injectate was observed with histology at 6 months postinjection. A mean of 2.1 ng/µL of aflibercept was measured in the vitreous., Conclusions: Intravitreally injected aflibercept-DDS achieved controlled, sustained release of aflibercept with no adverse effects for up to 6 months in the eyes of healthy rhesus macaques., Translational Relevance: Aflibercept-DDS may be a more effective method to deliver bioactive antivascular endothelial growth factor agents than current practice by reducing the frequency of intravitreal injections and providing controlled drug release., Competing Interests: Disclosure: S. Kim, None; J.J. Kang-Mieler, microsphere thermo-responsive drug delivery system (P); W. Liu, None; Z. Wang, None; G. Yiu, None; L.B.C. Teixeira, None; W.F. Mieler, None; S.M. Thomasy, None, (Copyright 2020 The Authors.)

Purpose: This article reports the presentation, management, and outcomes in patients suffering perforating ocular injuries., Methods: A retrospective review was conducted at a single ophthalmology Level 1 trauma center. Patients with evidence of traumatic ocular perforation, with surgical intervention attended by a single vitreoretinal surgeon (W.F.M.), were reviewed between 2009 and 2017., Results: Six eyes from 6 patients with perforating ocular injuries were studied. All patients were male, between ages 11 and 56 years. Perforation was the result of gunshots (3), other accidental injury (2), or surgical complication (1). Varying degrees of retinal detachments were seen in all 6 patients. Pars plana vitrectomy, with endolaser around posterior entry or exit wounds, was performed on average 21.7 ± 8.9 days from the time of injury (range, 0-58 days). In all cases with intraorbital foreign bodies, the foreign bodies were left in place. The most recent postoperative visual acuity ranged from 20/25 to counting fingers. Missile injuries tended to have poorer vision. All cases achieved full anatomic attachment at most recent follow-up. There have been no orbital complications related to retained intraorbital foreign bodies, including endophthalmitis, orbital infections, or mechanical strabismus., Conclusion: This study demonstrates successful anatomic outcomes of 6 cases of perforating ocular injuries. Visual outcomes were variable, though missile injuries demonstrated worse prognosis, whereas several nonmissile macula-involving cases achieved quite favorable results. Although traumatic perforating injuries generally have guarded visual prognoses, favorable results may be achieved in select scenarios., Competing Interests: Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: To investigate the efficacy of a poly(ethylene glycol) diacrylate and poly(N-isopropylacrylamide) based thermo-responsive hydrogel drug delivery system (DDS) to deliver prophylactic vancomycin (VAN) following ocular surgery., Methods: VAN was encapsulated in a hydrogel DDS and characterized in terms of initial burst, release kinetics, bioactivity, and cytotoxicity. Long-Evans rats received an intravitreal injection of Staphylococcus aureus to produce acute endophthalmitis in four experimental groups. One of four treatments were then applied: (1) bolus subconjunctival injection of VAN, (2) blank DDS, (3) saline treatment, and (4) subconjunctival injection of VAN DDS. Animals were scored for infection (0-3) at 12, 24, 48, and 72 hours, and eyes were harvested at 24 and 48 hours for histology., Results: Following a 36% initial burst, VAN release from the DDS continued at a steady rate for 2 weeks plateauing at 84% after 504 hours. Bioactivity was maintained for all release samples and cytotoxicity analysis for the DDS revealed cell viability >90%. Not until after 12 hours did any of the groups show evidence of infection; however, at 24 hours, animals that received the VAN DDS had significantly lower infection scores (0 ± 0) than those that received a bolus VAN injection, blank DDS, or saline (1.5 ±1.5, 2.3 ± 0.87, and 2.9 ± 0.25; respectively). At 48 and 72 hours, the VAN DDS and bolus VAN treatment groups performed comparably and showed significantly better infection scores than the control groups., Conclusions: This DDS appears to have promise as a vehicle for short term, prophylactic antibiotic delivery., Translational Relevance: This DDS may prevent the development of postoperative endophthalmitis.

Purpose: We report a case of otherwise healthy 48-year-old woman presenting with acute vision loss after injection of a soft tissue filler injection in the glabellar region with calcium hydroxylapatite microspheres (Radiesse®) with 9 months of follow-up., Observations: Fundus photographs and spectral domain optical coherence tomography (SD-OCT) were obtained at presentation, 4 months of follow-up, and 9 months of follow-up. Acutely, the retina was characterized by significant pallor and thickening but evolved into diffuse retinal fibrosis and atrophy. The patient was no light perception at presentation, and did not recover any visual function., Conclusions and Importance: Few case reports have described calcium hydroxylapatite filler injections leading to orbital and ocular complications. This is the first case report illustrating dense fibrotic and atrophic retinal changes on both fundus photography, fluorescein angiography, and SD-OCT. While various facial fillers have been reported to have serious ocular consequences, we illustrate the acute and subsequent sequelae of an ophthalmic artery occlusion from calcium hydroxylapatite microspheres (Radiesse®)., Competing Interests: Conflict of Interest: No authors have any proprietary interest in the subject matter of this manuscript.

Purpose: To report the ocular and adnexal injuries sustained by patients with Thomas A. Swift's electric rifles (TASER; TASER International, Scottsdale, AZ), review the literature, and discuss the management of this complex trauma., Design: Multicenter, retrospective case series and literature review., Participants: Seventeen eyes of 16 patients (5 eyes of 5 patients treated at 3 institutions, and 12 eyes of 11 previously reported cases)., Methods: The clinical data of 17 eyes were pooled. Spearman's correlation coefficient was used to assess the association between the extent of TASER injury and patient outcomes., Main Outcome Measures: Extent of TASER injury (zone of injury, penetrating vs. perforating) and association with patient outcomes (visual acuity [VA] and retinal detachment [RD])., Results: In our cohort, 4 patients were transported by law enforcement and 1 was transferred from a community hospital. Four patients were taken to the operating room for TASER removal and globe repair; 1 patient underwent removal in the emergency room. Of 17 pooled cases, 12 (71%) involved open-globe injury. Of these, there was a high rate of zone 3 injuries (100%; n = 12) and a high incidence of RD (73%; 8 of 11, eviscerated eye excluded). Among patients with closed-globe injury (n = 5), 1 patient demonstrated exudative RD and 1 patient demonstrated retinal dialysis with RD. Of 10 patients with RD, 1 (10%) achieved resolution with monitoring (exudative RD); 1 (10%) underwent cryopexy and pneumatic retinopexy; 3 (30%) underwent vitrectomy, and 5 (50%) with poor prognosis did not undergo vitreoretinal surgery. In the 3 patients who underwent vitrectomy, all 3 (100%) demonstrated redetachment resulting from proliferative vitreoretinopathy and required additional surgery. Visual acuity on presentation was significantly correlated with final VA (ρ = 0.783; P = 0.02). Men (94%) were more likely than women (6%) to sustain TASER trauma. Median age was 26 years. There was a 50% rate of loss to follow-up., Conclusions: Thomas A. Swift's electric rifle injuries to the eyes or ocular adnexa represent complex trauma. Zone 3 injuries are common. The visual prognosis is guarded, and eyes may require multiple surgeries to preserve vision. Patients are at high risk for loss to follow-up by way of incarceration., (Copyright © 2018 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: Current standard of care for neovascular eye diseases require repeated intravitreal bolus injections of anti-vascular endothelial growth factors (anti-VEGFs). The purpose of this study was to validate a degradable microsphere-thermoresponsive hydrogel drug delivery system (DDS) capable of releasing bioactive aflibercept in a controlled and extended manner for 6 months., Materials and Methods: The DDS was fabricated by suspending aflibercept-loaded poly(lactic-co-glycolic acid) microspheres within a biodegradable poly(ethylene glycol)-co-(l-lactic acid) diacrylate/N-isopropylacrylamide (PEG-PLLA-DA/NIPAAm) thermoresponsive hydrogel. Encapsulation efficiency of DDSs and in vitro release profiles were characterized by iodine-125 radiolabeled aflibercept. The degradation of hydrogel was determined by dry weight changes. The cytotoxicity from degraded DDS byproducts was investigated by quantifying cell viability using LIVE/DEAD® assay. In addition, dot blot and enzyme-linked immunosorbent assay were used to determine the bioactivity of released drug. Finally, morphology of microspheres and hydrogel were investigated by cryo-scanning electron microscopy before and after thermal transformation., Results: The microsphere-hydrogel DDS was capable of releasing bioactive aflibercept in a controlled and extended manner for 6 months. The amount and rate of aflibercept release can be controlled by both the cross-linker concentration and microspheres load amount. The initial burst (release within 24 h) was from 37.35 ± 4.92 to 74.56 ± 6.16 µg (2 and 3 mM hydrogel, each loaded with 10 and 20 mg/ml of microspheres, respectively), followed by controlled drug release of 0.07-0.15 µg/day. Higher PEG-PLLA-DA concentration (3 mM) degraded faster than the lower concentration (2 mM). No significant cytotoxicity from degraded DDS byproducts was found for all investigated time points. Bioactivity of released drug was maintained at therapeutic level over entire release period., Conclusions: The microsphere-hydrogel DDS is safe and can deliver bioactive aflibercept in a controlled manner. This may provide a significant advantage over current bolus injection therapies in the treatment of ocular neovascularization.

Background: An ophthalmology consultation service is of significant benefit to patients in the hospital and is an instructive component of a residency education program. Ophthalmology consultations in a hospital present unique challenges to those seen in an outpatient clinic, for which the consulting ophthalmologist should be prepared. The purpose of this study was to profile the emergency room and inpatient ophthalmology consultations seen at an academic institution., Methods: A prospective study of 581 patients was conducted on inpatient and emergency room ophthalmology consultations at the University of Illinois at Chicago over twelve months. Characteristics such as the consulting service, type of and reason for consultation, subspecialty staffing service, diagnosis, and suitability for in-hospital evaluation were recorded., Results: Consultations were received from either inpatient wards (59.4%) or the Emergency Department (40.6%). The most common inpatient consulting services were internal medicine (22%), followed by neurosurgery (16%) and neurology (7%). All the consultations were categorized as acute (72.3%), chronic (6.0%), or screening (21.7%). Consultations categorized as screening included papilledema (31.0%), fungemia (20.6%), syndromic evaluation (19.8%), visual field evaluation (17.5%), and miscellaneous evaluation (11.1%). We classified the ophthalmic diagnoses into 63 unique diagnoses. Amongst the ophthalmic subspecialties, neuro-ophthalmologic diagnoses were the most common (32.0%), followed by retina (20.1%) and cornea (19.4%). Neuro-ophthalmology had the highest proportion of screening consultations (36.6%), while glaucoma had the least overall number of consultations (10.1%), and the least proportion of screening consultations (3.6%). A significant proportion of nonacute consultations (19.0%) was deemed to be more suitable for outpatient evaluation., Discussion: Consultation databases can be useful in preparing trainees for in-hospital clinical care. A wide range of ocular pathologies may present to the ophthalmology consultant, from acute trauma to screening for systemic syndromes. Some consultations may be more suitable for outpatient evaluation which may help optimize patient care.

Purpose: To characterize a biodegradable microsphere-hydrogel drug delivery system (DDS) for controlled and extended release of ranibizumab., Methods: The degradable microsphere-hydrogel DDSs were fabricated by suspending ranibizumab-loaded or blank poly(lactic- co- glycolic acid) microspheres within a poly(ethylene glycol)- co -(L-lactic-acid) diacrylate/N-isopropylacrylamide (PEG-PLLA-DA/NIPAAm) hydrogel. The thermal responsive behavior of various DDS formulations was characterized in terms of volume phase transition temperature (VPTT) and swelling ratios changes from 22°C to 42°C. The mechanical properties were characterized using rheological methods. Degradability of hydrogels were also examined via wet weight loss. Finally, Iodine-125 was used to radiolabel ranibizumab for characterization of encapsulation efficiency and in vitro release., Results: All DDS formulations investigated were injectable through a 28-gauge needle at room temperature. The VPTT increased with increase of cross-linker concentration. The swelling ratios decreased as temperature increased and were not influenced by presence of microspheres. Rheology data confirmed that increase of cross-linker concentration and microsphere loading made DDS stiffer. Increase of degradable cross-linker concentration facilitated hydrogel in vitro degradation. Controlled release of ranibizumab were achieved for investigated DDS formulations for 6 months; and increased degradable cross-linker concentration produced faster and more complete release., Conclusions: The biodegradable DDSs are suitable for sustained release of ranibizumab. Considering ease of injection, degradability and release of ranibizumab, DDS with 3 mM cross-linker concentration and less than 20 mg/mL microsphere loadings is more favorable for future application., Translational Relevance: The investigated DDS is promising for controlled and extended release of anti-VEGF therapeutics to achieve better treatment regimen in ocular neovascularizations.

The use of anti-vascular endothelial growth factor (VEGF) therapy in ophthalmology has profoundly changed our management and treatment of conditions such as cystoid macular edema, diabetic macular edema, choroidal neovascularization, and other proliferative retinopathies. Although initially used for the treatment of choroidal neovascularization in neovascular age-related macular degeneration, their application has spread rapidly for other indications as their outcomes have often outperformed previously existing treatments. Retinal vein occlusion (RVO) continues to be one of the leading causes of vision loss secondary to macular edema, in addition to macular ischemia and neovascularization in more severe cases. Before the availability of anti-VEGF therapy, the use of macular grid laser and panretinal photocoagulation was the mainstay of treatment of macular edema and neovascularization, respectively, in patients with RVOs. Two landmarks studies established the guidelines of these treatments for nearly a quarter century. Since the availability of anti-VEGF agents, there has been a paradigm shift in the treatment of RVO. Most importantly, there has also been a significant improvement in visual outcomes in these patients. The goal of this article is to provide a review of the pertinent clinical studies that have investigated the use of anti-VEGF in patients with retinal vein occlusions., (Copyright 2017 Asia-Pacific Academy of Ophthalmology.)

Purpose: Demonstrate in vivo that controlled and extended release of a low dose of anti-vascular endothelial growth factor (anti-VEGF) from a microsphere-hydrogel drug delivery system (DDS) has a therapeutic effect in a laser-induced rat model of choroidal neovascularization (CNV)., Methods: Anti-VEGF (ranibizumab or aflibercept) was loaded into poly(lactic-co-glycolic acid) microspheres that were then suspended within an injectable poly(N-isopropylacrylamide)-based thermo-responsive hydrogel DDS.The DDS was shown previously to release bioactive anti-VEGF for ~200 days. CNV was induced using an Ar-green laser. The four experimental groups were as follows: (i) non-treated, (ii) drug-free DDS, (iii) anti-VEGF-loaded DDS, and (iv) bolus injection of anti-VEGF. CNV lesion areas were measured based on fluorescein angiograms and quantified using a multi-Otsu thresholding technique. Intraocular pressure (IOP) and dark-adapted electroretinogram (ERG) were also obtained pre- and post-treatment (1, 2, 4, 8, and 12 weeks)., Results: The anti-VEGF-loaded DDS group had significantly smaller (60%) CNV lesion areas than non-treated animals throughout the study. A small transient increase in IOP was seen immediately after injection; however, all IOP measurements at all time points were within the normal range. There were no significant changes in ERG maximal response compared to pre-treatment measurements for the drug-loaded DDS, which suggests no adverse effects on retinal cellular function., Conclusions: The current study demonstrates that the DDS can effectively decrease laser-induced CNV lesions in a murine model. Controlled and extended release from our DDS achieved greater treatment efficacy using an order of magnitude less drug than what is required with bolus administration. This suggests that our DDS may provide a significant advantage in the treatment of posterior segment eye diseases.

Introduction: The development of new therapies for treating various eye conditions has led to a demand for extended release delivery systems, which would lessen the need for frequent application while still achieving therapeutic drug levels in the target tissues. Areas covered: Following an overview of the different ocular drug delivery modalities, this article surveys the biomaterials used to develop sustained release drug delivery systems. Microspheres, nanospheres, liposomes, hydrogels, and composite systems are discussed in terms of their primary materials. The advantages and disadvantages of each drug delivery system are discussed for various applications. Recommendations for modifications and strategies for improvements to these basic systems are also discussed. Expert opinion: An ideal sustained release drug delivery system should be able to encapsulate and deliver the necessary drug to the target tissues at a therapeutic level without any detriment to the drug. Drug encapsulation should be as high as possible to minimize loss and unless it is specifically desired, the initial burst of drug release should be kept to a minimum. By modifying various biomaterials, it is possible to achieve sustained drug delivery to both the anterior and posterior segments of the eye.

Background: The American Academy of Ophthalmology recommendations on screening for chloroquine (CQ) and hydroxychloroquine (HCQ) retinopathy are revised in light of new information about the prevalence of toxicity, risk factors, fundus distribution, and effectiveness of screening tools., Pattern of Retinopathy: Although the locus of toxic damage is parafoveal in many eyes, Asian patients often show an extramacular pattern of damage. DOSE: We recommend a maximum daily HCQ use of ≤5.0 mg/kg real weight, which correlates better with risk than ideal weight. There are no similar demographic data for CQ, but dose comparisons in older literature suggest using ≤2.3 mg/kg real weight., Risk of Toxicity: The risk of toxicity is dependent on daily dose and duration of use. At recommended doses, the risk of toxicity up to 5 years is under 1% and up to 10 years is under 2%, but it rises to almost 20% after 20 years. However, even after 20 years, a patient without toxicity has only a 4% risk of converting in the subsequent year., Major Risk Factors: High dose and long duration of use are the most significant risks. Other major factors are concomitant renal disease, or use of tamoxifen., Screening Schedule: A baseline fundus examination should be performed to rule out preexisting maculopathy. Begin annual screening after 5 years for patients on acceptable doses and without major risk factors., Screening Tests: The primary screening tests are automated visual fields plus spectral-domain optical coherence tomography (SD OCT). These should look beyond the central macula in Asian patients. The multifocal electroretinogram (mfERG) can provide objective corroboration for visual fields, and fundus autofluorescence (FAF) can show damage topographically. Modern screening should detect retinopathy before it is visible in the fundus., Toxicity: Retinopathy is not reversible, and there is no present therapy. Recognition at an early stage (before any RPE loss) is important to prevent central visual loss. However, questionable test results should be repeated or validated with additional procedures to avoid unnecessary cessation of valuable medication., Counseling: Patients (and prescribing physicians) should be informed about risk of toxicity, proper dose levels, and the importance of regular annual screening., (Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Hydrogel as an ocular drug delivery platform holds great potential. Hydrogels are three-dimensional, hydrophilic, polymeric networks capable of absorbing large amounts of water or biological fluids. They have the ability to swell in an aqueous solvent system, holding solvents within a cross-linked gel system for potential sustained delivery. Through manipulation of permeation and diffusion characteristics, they can retain hydrophobic and hydrophilic agents, small molecules and macromolecules. In addition, hydrogel can be combined with nano- or microspheres to enhance delivery capacity. The aqueous environment of hydrogels can also protect cells and pharmacological agents. Depending on the specific structure, they can be nondegradable or degradable in their application., (© 2016 S. Karger AG, Basel.)

Endophthalmitis is characterized by marked inflammation of intraocular fluids and tissues. Infective endophthalmitis may be categorized by the cause of the infection, which helps predict the underlying etiology and most likely causative organisms. The major category remains acute-onset postoperative endophthalmitis. Infective endophthalmitis is a clinical diagnosis but is confirmed by evaluation of intraocular fluid specimens. The Endophthalmitis Vitrectomy Study offered important guidelines for the initial management of endophthalmitis, and these guidelines remain relevant to this day. Prompt initiation of empiric broad-spectrum antimicrobial therapy is important in achieving best outcomes., (© 2016 S. Karger AG, Basel.)

The Endophthalmitis Vitrectomy Study (EVS) provided ophthalmologists with evidence-based management strategies to deal with endophthalmitis for the first time. However, since the completion of the EVS, numerous unresolved issues remain. The use of oral antibiotics has important implications for the ophthalmologist, particularly in the prophylaxis and/or management of postoperative, posttraumatic, or bleb-associated bacterial endophthalmitis. One can reasonably conclude that significant intraocular penetration of an antibiotic after oral administration may be a property unique to the newer-generation fluoroquinolones. Prophylactic use of mupirocin nasal ointment resulted in significant reduction of conjunctival flora with or without preoperative topical 5% povidone-iodine preparation. Ocular fungal infections have traditionally been very difficult to treat due to limited therapeutic options both systemically and intravitreally. Because of its broad spectrum of coverage, low MIC90 levels for the organisms of concern, good tolerability, and excellent bioavailability, voriconazole through various routes of administration may be useful to the ophthalmologist in the primary treatment of or as an adjunct to the current management of ocular fungal infections., (© 2016 S. Karger AG, Basel.)

Background: There has been a recent evolution in the management of uveal melanoma in regard to prognostic evaluation and treatment modalities. This study aims to evaluate the epidemiological trends of uveal melanoma since 1973 by using the Surveillance, Epidemiology, and End Results (SEER) Registry., Methods: A total of 7043 uveal melanoma cases from the SEER database were retrospectively analysed, spanning 1973 to 2009. The main outcome measures were disease specific and overall patient survival., Results: The mean patient age at diagnosis was 61.4 years, which has increased over the last 37 years. The mean follow-up interval was 85.9 months. The proportion of tumours demonstrating spindle cell histology has decreased. Spindle cell tumours yielded superior disease-specific survival to epithelioid and mixed tumours. The median age at diagnosis of spindle cell tumours (60 years) was significantly younger than epithelioid tumours (65 years) and mixed tumours (64 years old; p < 0.0001). In a Cox proportional hazards regression analysis, tumour histology, T stage and age at diagnosis were associated with disease-specific survival. The prevalence of cutaneous melanoma was increased in patients with uveal melanoma, but the lifetime prevalence of other primary cancers was not appreciably increased., Conclusions: The SEER data set demonstrates epidemiological trends in patient age at diagnosis and tumour histology over the last 37 years. Several patient and tumour characteristics are predictors of disease-specific survival. These findings have implications for disease surveillance and prognostic counselling., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Purpose: To report bilateral hemorrhagic retinopathy in an adult female subject after lumbar spinal surgery and seizure., Case Report: A 38-year-old woman presented with bilateral blurry vision and spots in the visual field. The patient had lumbar spondylosis surgery that was complicated by a dural tear with persistent cerebrospinal fluid leak. Visual symptoms started immediately after witnessed seizure-like activity. At presentation, visual acuity was 20/100 and 20/25 in the right and left eye, respectively. Dilated fundus examination demonstrated bilateral hemorrhagic retinopathy with subhyaloid, intraretinal, and subretinal involvement. At 4-month follow-up, visual acuity improved to 20/60 and 20/20 in the right and left eye, respectively. Dilated fundus examination and fundus photography showed resolution of retinal hemorrhages in both eyes., Conclusions: The first case of bilateral hemorrhagic retinopathy after lumbar spondylosis surgery and witnessed seizure in an adult was reported. Ophthalmic examination may be warranted after episodes of seizure in adults.

Purpose: To report outer retinal disruption and uveal effusion after gemcitabine and docetaxel combination therapy., Case Report: A 78-year-old woman presented with blurry vision after two cycles of gemcitabine and docetaxel combination chemotherapy for stage IV sarcoma. At presentation, visual acuity was finger counting and 20/25 in the right and left eyes, respectively. Slit-lamp examination and B-scan ultrasonography revealed severe uveal effusion in the right eye and choroidal folds in the left eye. Spectral domain optical coherence tomography showed disruption of photoreceptor inner segment ellipsoid band in the right eye. The patient was monitored weekly with ophthalmic examination and B-scan ultrasonography, while continuing with gemcitabine monotherapy. At 8 weeks follow-up, uveal effusion improved considerably and visual acuity was 20/40 and 20/20 in the right and left eyes, respectively., Conclusions: Uveal effusion and outer retinal disruption were reported after gemcitabine and docetaxel chemotherapy. Early detection and close ophthalmic monitoring may allow concurrent cancer treatment and prevention of possible chemotherapy-induced ocular side effects.

Several medications are associated with retinal vascular toxicity. These include intraocular aminoglycosides, oral contraceptives, interferon alpha, several other agents, and talc, which occurs as a vehicle in some oral medications that may be abused intravenously. As a group, these entities represent a small but clinically relevant category of retinal toxicity from medications. Some of the manifestations (e.g., retinal vascular occlusion) are nonspecific, but others are more specific, including clinically visible talc emboli in retinal vessels. Toxicity may be asymptomatic or may cause irreversible visual loss. By maintaining a high index of suspicion, the correct diagnosis can usually be made.