Retinal neurovascular alteration in type 2 diabetes with renal impairment in association with systemic arterial stiffness.

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.

Radiation Retinopathy and Benign Lymphoproliferative Orbital Tumor Presenting 47 Years Following Treatment of Hereditary Retinoblastoma.

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.

Novel Drug Delivery Methods and Approaches for the Treatment of Retinal Diseases.

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.

The Impact of Systemic Medications on Retinal Function.

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.

EIGHTY-TWO-YEAR-OLD MONOCULAR FEMALE WITH ACUTE DECREASED CENTRAL VISION.

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.

Fluorescein videoangiography data analysis protocol for mapping retinal vascular permeability in humans.

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.

Simultaneous Release of Aflibercept and Dexamethasone from an Ocular Drug Delivery System.

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.

Optimizing the protocol for retinal vascular permeability mapping from fluorescein videoangiography data.

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.

DEVELOPMENT OF CHOROIDAL NEOVASCULARIZATION AFTER TREATMENT WITH PHOTODYNAMIC THERAPY IN A 5-YEAR-OLD FEMALE WITH CHOROIDAL OSTEOMA.

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.

Compartmental and COMSOL Multiphysics 3D Modeling of Drug Diffusion to the Vitreous Following the Administration of a Sustained-Release Drug Delivery System.

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.

APPLICATION OF ADJUNCTIVE TOPICAL MITOMYCIN-C IN SCLEROSTOMY REVISION FOR REFRACTORY IDIOPATHIC UVEAL EFFUSION SYNDROME.

BACKGROUND/PURPOSE: To describe the use of topical mitomycin-C in sclerostomy revision for recalcitrant idiopathic uveal effusion syndrome. METHODS: A 50-year-old healthy man presented with painless, gradual vision loss in the right eye. He underwent multimodal retinal imaging with wide-field fundus photography, spectral domain optical coherence tomography, and B-scan and A-scan ultrasonography. He was found to have idiopathic (non-nanophthalmic) uveal effusion syndrome with choroidal and serous retinal detachments in the right eye and a peripheral choroidal detachment in the left eye. Central vision became threatened in the right eye. Medical treatment with oral corticosteroids and surgical treatment with choroidal drainage through sclerostomies and sclerostomy revision were administered. RESULTS: Initial treatment with systemic corticosteroids was ineffective. Subsequent choroidal drainage through sclerostomies only partially resolved the effusion. Later sclerostomy revision with application of topical mitomycin-C led to complete resolution with anatomical stability maintained after at least 42 months of follow-up. CONCLUSION: Successful use of topical mitomycin-C in sclerostomy revision has not previously been reported in idiopathic (non-nanophthalmic) uveal effusion syndrome. We propose that topical mitomycin-C may be considered as a potential therapeutic adjunct in the treatment of refractory idiopathic uveal effusion syndrome before further sclerostomy procedures are attempted in additional quadrants of the eye.

Automated quantitative OCTA measurements of uveal melanoma-treated eyes with and without radiation retinopathy after I-125 plaque therapy and of nonirradiated fellow eyes.

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.

Treatment Efficacy and Biocompatibility of a Biodegradable Aflibercept-Loaded Microsphere-Hydrogel Drug Delivery System.

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 µm2 for no treatment, (2) 8261 ± 709 µm2 for blank DDS, (3) 10,368 ± 885 µm2 for bolus, and (4) 10,306 ± 1212 µm2 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.

Safety and Biocompatibility of Aflibercept-Loaded Microsphere Thermo-Responsive Hydrogel Drug Delivery System in a Nonhuman Primate Model.

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.

Chloroquine and Hydroxychloroquine Retinal Toxicity Consideration in the Treatment of COVID-19.

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.

Advances in ocular drug delivery systems.

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.