The Safety and Biological Activity of OTT166, a Novel Topical Selective Integrin Inhibitor for the Treatment of Diabetic Eye Disease: A Phase 1b Study.

BACKGROUND AND OBJECTIVES: To evaluate the safety, tolerability, and biological activity of a topical selective integrin inhibitor (OTT166) eyedrop administered BID for diabetic retinopathy (DR) and diabetic macular edema (DME). STUDY DESIGN/MATERIALS AND METHODS: A prospective, multicenter, randomized, double-masked Phase 1b study. Subjects with nonproliferative DR and DME with central subfield thickness (CST) &gt; 325 microns were randomized to OTT166 eyedrops (2.5% or 5%) BID for 28 days. Subjects were followed for an additional 28 days after treatment cessation. RESULTS: Forty-four subjects were enrolled. No drug-related serious adverse events (SAEs) and two drug-related adverse events (AEs) were reported. OTT166 was well-tolerated with no evidence of ocular toxicity. Best-corrected visual acuity (BCVA) remained stable. Mean central retinal thickness (CRT) overall was variable: +12.8/+1.8 microns at Day 28 (end of treatment) and -50.3/+5.5 microns at Day 56 (end of study) for the 2.5% and 5% groups, respectively. Median CRT overall demonstrated consistent reduction by end of study: -39.0/-16.5 microns for the 2.5% and 5% groups, respectively. Median responses were greater in the treatment-naïve group (-41.5/-26.0 microns for the 2.5% and 5% groups, respectively). Thirty-seven percent of 'responder' subjects exhibited a mean reduction in CRT of 46.6 microns on optical coherence tomography (OCT) at end of treatment (Day 28) which persisted to end of the study (Day 56) - mean reduction of 67.4 microns, suggesting a durable effect. CONCLUSION: OTT166 eyedrops were safe, well-tolerated, and demonstrated biological activity in 37% of responders. These results warrant further evaluation of OTT166 eyedrops. <b>[<i>Ophthalmic Surg Lasers Imaging Retina</i> 2022;53:553-560.]</b>.

Inherited Retinal Dystrophy in Southeastern United States: Characterization of South Carolina Patients and Comparative Literature Review.

Inherited retinal dystrophies (IRDs) are a group of rare diseases involving more than 340 genes and a variety of clinical phenotypes that lead to significant visual impairment. The aim of this study is to evaluate the rates and genetic characteristics of IRDs in the southeastern region of the United States (US). A retrospective chart review was performed on 325 patients with a clinical diagnosis of retinal dystrophy. Data including presenting symptoms, visual acuity, retinal exam findings, imaging findings, and genetic test results were compiled and compared to national and international IRD cohorts. The known ethnic groups included White (64%), African American or Black (30%), Hispanic (3%), and Asian (2%). The most prevalent dystrophies identified clinically were non-syndromic retinitis pigmentosa (29.8%), Stargardt disease (8.3%), Usher syndrome (8.3%), cone-rod dystrophy (8.0%), cone dystrophy (4.9%), and Leber congenital amaurosis (4.3%). Of the 101 patients (31.1%) with genetic testing, 54 (53.5%) had causative genetic variants identified. The most common pathogenic genetic variants were USH2A (n = 11), ABCA4 (n = 8), CLN3 (n = 7), and CEP290 (n = 3). Our study provides initial information characterizing IRDs within the diverse population of the southeastern US, which differs from national and international genetic and diagnostic trends with a relatively high proportion of retinitis pigmentosa in our African American or Black population and a relatively high frequency of USH2A pathogenic variants.

Iris melanoma presenting as childhood glaucoma.

PURPOSE: To describe the natural history and management of a rare case of iris melanoma in a pediatric patient. OBSERVATIONS: A Caucasian female presented with left pupillary abnormalities at age 7, progressive iris changes at age 9, and markedly elevated intraocular pressure with advanced optic nerve cupping at 11 years of age. She was found to have a pigmented lesion overlying her iris and invading her angle. Trans-corneal fine needle aspirate biopsy demonstrated malignant melanoma of the iris. The patient subsequently underwent Iodine-125 plaque brachytherapy for the tumor. CONCLUSIONS: and Importance: Early identification and treatment of iris melanoma may be associated with decreased risk of local progression and metastatic disease. Treatment of glaucoma in conjunction with uveal melanoma is complicated by tumor specific considerations, including treatment of the tumor and prevention of metastasis.

Detection of Minimally Visible Recurrent Retinoblastoma by Hand-held Spectral-Domain Optical Coherence Tomography.

A 2-month-old male infant with bilateral familial retinoblastoma was treated with intravenous chemotherapy and focal adjuvant therapy. At 5 months of follow-up, fundus examination and ultrasonography disclosed no recurrence; however, hand-held spectral-domain optical coherence tomography (SD-OCT) demonstrated subclinical recurrence within a previous regression scar. Subsequent treatment led to flat scar. Hand-held SD-OCT can be a useful tool for detection of subclinical recurrent retinoblastoma. [J Pediatr Ophthalmol Strabismus. 2017;54:e6-e8.].

VARIABILITY IN FOVEAL AVASCULAR ZONE AND CAPILLARY DENSITY USING OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY MACHINES IN HEALTHY EYES.

PURPOSE: To evaluate the variability in foveal avascular zone (FAZ) and capillary density measurements on optical coherence tomography angiography using Optovue RTVue XR Avanti (OA) (Optovue) and Zeiss Cirrus HD-OCT 5000 (ZC) (Carl Zeiss Meditec). METHODS: In this prospective, comparative case series, parafoveal (3 × 3 mm) optical coherence tomography angiography scans were obtained on healthy volunteers using both the Avanti and Cirrus. The FAZ area and capillary density at the level of both the superficial and deep capillary plexus were measured automatically using the built-in ReVue software (Optovue) with the Avanti as well as manually using ImageJ (National Institutes of Health) with both machines. RESULTS: There were 50 eyes in 25 healthy volunteers included in the analysis. Mean subject age was 33 years and there were 14 women (56%). On optical coherence tomography, mean central macular thickness was significantly greater on OA (259.1 µm) than ZC (257.6 µm, P = 0.0228). On optical coherence tomography angiography, mean superficial and deep plexus FAZ measured 0.2855 mm and 0.3465 mm on Avanti automated (A-A), 0.2739 mm and 0.3637 mm on Avanti manual (A-M), and 0.2657 mm and 0.3993 mm on Cirrus manual (C-M), respectively. There were no statistically significant differences in superficial plexus FAZ measurements between the A-A and A-M (P = 0.4019) or A-A and C-M (P = 0.1336). The A-M measured significantly larger than C-M (P = 0.0396). Deep plexus FAZ measurements were similar on A-A and A-M (P = 0.6299), but both were significantly less compared with C-M (P < 0.0001 for A-A vs. C-M, P = 0.0184 for A-M vs. C-M). Mean superficial and deep plexus capillary densities were 53.6% and 59.3% on A-A, 48.1% and 47.7% on A-M, and 52.5% and 48.1% on C-M, respectively. Superficial plexus capillary density measurements were statistically similar on A-A and C-M (P = 0.0623), but both were significantly higher than A-M (P < 0.0001 for A-A vs. A-M, P < 0.0001 for A-M vs. C-M). However, deep plexus capillary density measurements on A-A were significantly higher than A-M (P < 0.0001) and C-M (P < 0.0001), but A-M and C-M measurements were similar (P = 0.5986). There was no significant difference in all parameters measured in both eyes of one subject using any of the three measuring techniques. CONCLUSION: While measurements taken with the same machine and technique are consistent and reliable between fellow eyes, significant variability exists in FAZ and capillary density measurements among different machines and techniques. Comparison of measurements across machines and techniques should be considered with caution.

IMAGE QUALITY AND ARTIFACTS ON OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY: Comparison of Pathologic and Paired Fellow Eyes in 65 Patients With Unilateral Choroidal Melanoma Treated With Plaque Radiotherapy.

PURPOSE: To study image quality and artifacts seen on optical coherence tomography angiography (OCTA). METHODS: Sixty-five consecutive patients with unilateral posterior uveal melanoma treated with plaque radiotherapy had OCTA during follow-up. Optical coherence tomography angiography was performed on both the affected and fellow eye. Signal strength and frequency of image artifacts on en face images were compared between affected and fellow eyes. RESULTS: A total of 130 eyes in 65 patients were analyzed, the mean age at time of OCTA was 55 years (median: 56, range: 12-81 years), and 39 (39/65, 60%) were female. Majority of tumors were located in the choroid (62/65, 95%) and extramacular (55/65, 85%). The mean distance to the foveola was 4 mm (median: 3, range: 0-18 mm) and optic nerve was 4 mm (median: 4, range: 0-16 mm). Optical coherence tomography angiography was performed at a mean 46 months after plaque radiotherapy. Most patients had a history of radiation maculopathy or papillopathy in the treated eye at the time of OCTA (46/65, 71%). Overall, 95 eyes (95/130, 73%) had at least one significant artifact on OCTA. The most common major artifacts were loss of focus (71/130, 55%), broad (>5 pixels width and >4 lines) blink lines (48/130, 37%), motion artifact (34/130, 26%), specular dot (33/130, 25%), and edge duplication (10/130, 8%). Statistically, eyes treated with plaque radiotherapy (affected vs. fellow eye) were more likely to have at least one major OCTA artifact (92 vs. 54%, P < 0.001) and, specifically, loss of focus was more frequent (78 vs. 31%, P < 0.001). Multivariate analysis found decreased visual acuity significantly associated with higher incidence of broad blink lines (P = 0.0166) and loss of signal (P < 0.0001), whereas male sex was associated with increased loss of signal (P = 0.0015), and distance to the foveola was related to edge duplication (P = 0.0119). CONCLUSION: Image artifacts on OCTA are commonly encountered and appear to be more frequent in eyes with pathology and poor visual acuity. Recognition of these artifacts might help improve image interpretation and decision making.

Dissecting Aortic Aneurysm 55 Years after Diagnosis of Iris Flocculi.

PURPOSE: The aim of this study is to report the clinical features, imaging studies, surgical removal, and pathology of congenital iris flocculi in a patient who developed a life-threatening dissecting aortic aneurysm after 55 years of follow-up. METHODS: Documentation with iris photography was performed from age 18 to 55 years, at which time anterior segment optical coherence tomography (OCT) was performed. At the time of subsequent cataract surgery, the iris flocculi were removed in each eye and submitted for light and electron microscopy. RESULTS: The size and shape of the iris flocculi waxed and waned over the years but caused no visual disturbance. Anterior segment OCT demonstrated clear, round cysts with thin lining and no solid component. At the age of 55, congestive heart failure from a dissecting aortic aneurysm was discovered and surgically repaired. Subsequent bilateral cataract surgery and cyst removal were performed, and the iris flocculi were studied with light and electron microscopy. CONCLUSIONS: Congenital iris flocculi cause little, if any, visual impairment in most cases. However, they are occasionally associated with dissecting aortic aneurysm due to a shared mutation in smooth muscle that affects both the iris and the aorta. Patients with iris flocculi should be monitored periodically for aortic abnormalities.

PARAFOVEAL CAPILLARY DENSITY AFTER PLAQUE RADIOTHERAPY FOR CHOROIDAL MELANOMA: Analysis of Eyes Without Radiation Maculopathy.

PURPOSE: To study the parafoveal capillary density using optical coherence tomography angiography (OCTA) in eyes treated with plaque radiotherapy. RESEARCH DESIGN: Retrospective comparative case series. PARTICIPANTS: Ten patients treated with plaque radiotherapy for choroidal melanoma without evident radiation maculopathy on ophthalmoscopy or optical coherence tomography were imaged with OCTA. MAIN OUTCOME MEASURE: Comparison of the parafoveal capillary density in the superficial and deep capillary plexuses in the irradiated versus fellow nonirradiated eye. RESULTS: Overall, mean patient age was 55 years (median: 57, range: 45-65 years), and majority were white (9/10, 90%) and female (9/10, 90%). No patient had diabetes mellitus, and 2 (2/10, 20%) had controlled systemic hypertension. The melanoma was located in the choroid in all patients (10/10, 100%), with 2 (2/10, 20%) in the macular region. The mean largest basal diameter was 11 mm (12, 6-16 mm), and mean thickness was 5 mm (5, 2-10 mm). Mean radiation dose to the tumor apex was 72 Gy (median: 70 Gy, range: 70-85 Gy). Mean foveolar radiation dose was 53 Gy (median: 35 Gy, range: 14-110 Gy). Mean follow-up duration after plaque radiotherapy was 17 months (median: 16 months, range: 5-39 months). There was no ophthalmoscopic evidence of radiation maculopathy throughout the follow-up in every case. Optical coherence tomography demonstrated normal foveal contour without edema or subretinal fluid in every case. On OCTA, there was no significant difference in signal strength (P = 0.1151), central macular thickness (P = 0.9316), and foveal avascular zone area in the superficial (P = 0.1595), and deep (P = 0.1534) capillary plexuses between the irradiated versus fellow eyes. However, there was a statistically significant decrease in capillary density in the parafoveal superficial (P = 0.0005) and deep (P = 0.0067) plexuses in the irradiated eye. In addition, mean logMAR visual acuity was 0.2 (0.1, 0.0-0.5) (Snellen equivalent 20/32) in the irradiated eye and 0.0 (0.0, range: 0.0-0.1) (Snellen equivalent 20/20) in the fellow eye (P = 0.0252). CONCLUSION: Optical coherence tomography angiography allows qualitative and quantitative analysis of parafoveal capillary density. After plaque radiotherapy for choroidal melanoma, in eyes with normal macular features on ophthalmoscopy and optical coherence tomography, there is a statistically significant decrease in parafoveal capillary density and logMAR visual acuity in irradiated eyes compared with fellow eyes. These subclinical ischemic findings represent the commencement of radiation maculopathy.

Esophageal adenocarcinoma and urothelial carcinoma orbital metastases masquerading as infection.

Orbital metastases can masquerade as other orbital processes. We present two cases of orbital metastases, the first being the first reported adenocarcinoma of the esophagus presenting as an orbital metastasis prior to the primary being known, and the other as the first urothelial carcinoma to present as orbital cellulitis. The first patient presented with left upper eyelid pain. CT scan identified a superolateral subperiosteal fluid collection without concomitant sinus disease, which was drained in the operating room. Two weeks later repeat CT scan showed recurrent orbital subperiosteal fluid. It was drained and a biopsy showed necrotic adenocarcinoma. The second case presented with a painless right proptosis, decreased vision, and globally decreased ocular motility 3 days after bladder resection for urothelial carcinoma. CT scan demonstrated pan sinusitis with a soft tissue mass in the apex of the right orbit with extension through the superior orbital fissure. After no improvement on antibiotics endoscopic drainage was performed. Pathology revealed metastatic urothelial carcinoma within the orbital fat.

Lower limits of intraocular pressure in glaucoma clinical trials.

PURPOSE: To determine the association of the lower limit of intraocular pressure (IOP) specified in the inclusion criteria to baseline and active treatment visit IOPs for monotherapy treatments. METHODS: A review of clinical trial articles evaluating currently used topical glaucoma medicines. Articles were published between January 1995 and December 2011. RESULTS: This study included 37 monotherapy treatment arms from 15 studies. There were 18 prostaglandin analogs, 8 ß-blockers, 8 carbonic anhydrase inhibitors, 2 α-agonists, and 1 unoprostone. For all studies included generally there was a stepwise increase in the baseline 8 AM and diurnal IOP of approximately 1 mm Hg for each 1 mm Hg increase in entry criteria. This was true for all treatment arms together, with or without a PM entry criterion (P<0.0001). However, the inclusion of an afternoon entry criterion time point did not seem to affect average IOP at baseline for the 8 AM and diurnal IOP. The treated reductions from baseline were not statistically different based on morning or afternoon entry criteria for either the 8 AM or diurnal IOPs (P≥0.07). CONCLUSIONS: Progressively higher 8 AM entry criteria IOPs at untreated baseline may influence, depending on design, in a linear manner the 8 AM and diurnal baseline IOPs of glaucoma studies at baseline. However, this effect was not observed in the treated reductions from baseline. Further, the addition of an afternoon entry criterion time point does not seem to change baseline 8 AM and diurnal IOPs.

Orbital cellulitis complicated by central retinal artery occlusion.

The authors present a case of a 16-year-old boy who sought treatment in Storm Eye Institute for orbital cellulitis complicated by central retinal artery occlusion. He was examined for severe signs of orbital cellulitis, including decreased vision and an afferent pupillary defect. Intravenous antibiotics failed to provide timely improvement, and the patient was surgically managed with endoscopic orbital decompression. An ocular examination under anesthesia revealed retinal ischemia in the affected eye, and fluorescein angiography confirmed the diagnosis of central retinal artery occlusion. The patient's vision improved slightly following resolution of the infection. Central retinal artery occlusion is a rare complication of orbital cellulitis in adults and has yet to be reported in the pediatric population.

Predictive value of the efficacy of glaucoma medications in animal models: preclinical to regulatory studies.

To gain regulatory approval for a new medicine, a pharmaceutical company must take the new product through a series of clinical trials (Phases I-III). Animal models are important in the new drug-development process because they allow for the testing of the efficacy and safety of potential new medicines in a cost-efficient manner that avoids the risk of serious adverse events to humans. Unfortunately, there is no perfect animal treatment model for glaucoma. Animal studies hopefully predict the results of clinical studies, but with estimating efficacy, the limited size and duration of these studies, as well as the animal model selection, might restrict the ability to accurately predict future results. There is little information which compares various available animal models and how well these preclinical studies predict the efficacy of a new product in clinical trials. The purpose of this review article is to analyse animal model studies evaluating potential glaucoma products and determine parameters associated with commercial availability. We discuss how animal models provide some success in predicting commercial launch of a new glaucoma medicine, especially the hypertensive and monkey models, but highlight that caution must be used in interpreting individual models or studies.

Cystoid macular edema secondary to fluconazole toxicity.

Fluconazole is an antifungal commonly used to treat Coccidioides immitis, but this medication has a number of side effects including fatigue, rash, headache, dizziness, nausea, vomiting, diarrhea, and elevated liver enzymes. We are unaware of any cases of retinal toxicity related to fluconazole. In this case we present a 76 year old woman with longstanding Coccidioides treated with high dose fluconazole. She becomes symptomatic with fluconazole toxicity and subsequently develops bilateral cystoid macular edema. As her dose of fluconazole is decreased and she is transitioned to voriconazole the edema resolves and her visual acuity improves. This patient's clinical course illustrates retinal toxicity may present with high and prolonged doses of fluconazole.