Role of FAM18B in diabetic retinopathy.

PURPOSE: Genome-wide association studies have suggested an association between a previously uncharacterized gene, FAM18B, and diabetic retinopathy. This study explores the role of FAM18B in diabetic retinopathy. An improved understanding of FAM18B could yield important insights into the pathogenesis of this sight-threatening complication of diabetes mellitus. METHODS: Postmortem human eyes were examined with immunohistochemistry and immunofluorescence for the presence of FAM18B. Expression of FAM18B in primary human retinal microvascular endothelial cells (HRMECs) exposed to hyperglycemia, vascular endothelial growth factor (VEGF), or advanced glycation end products (AGEs) was determined with quantitative reverse-transcription PCR (qRT-PCR) and/or western blot. The role of FAM18B in regulating human retinal microvascular endothelial cell viability, migration, and endothelial tube formation was determined following RNAi-mediated knockdown of FAM18B. The presence of FAM18B was determined with qRT-PCR in CD34+/VEGFR2+ mononuclear cells isolated from a cohort of 17 diabetic subjects with and without diabetic retinopathy. RESULTS: Immunohistochemistry and immunofluorescence demonstrated the presence of FAM18B in the human retina with prominent vascular staining. Hyperglycemia, VEGF, and AGEs downregulated the expression of FAM18B in HRMECs. RNAi-mediated knockdown of FAM18B in HRMECs contributed to enhanced migration and tube formation as well as exacerbating the hyperglycemia-induced decrease in HRMEC viability. The enhanced migration, tube formation, and decrease in the viability of HRMECs as a result of FAM18B downregulation was reversed with pyrrolidine dithiocarbamate (PDTC), a specific nuclear factor-kappa B (NF-κB) inhibitor. CD34+/VEGFR2+ mononuclear cells from subjects with proliferative diabetic retinopathy demonstrated significantly reduced mRNA expression of FAM18B compared to diabetic subjects without retinopathy. CONCLUSIONS: FAM18B is expressed in the retina. Diabetic culture conditions decrease the expression of FAM18B in HRMECs. The downregulation of FAM18B by siRNA in HRMECs results in enhanced migration and tube formation, but also exacerbates the hyperglycemia-induced decrease in HRMEC viability. The pathogenic changes observed in HRMECs as a result of FAM18B downregulation were reversed with PDTC, a specific NF-κB inhibitor. This study is the first to demonstrate a potential role for FAM18B in the pathogenesis of diabetic retinopathy.

Ophthalmic evaluations in clinical studies of fingolimod (FTY720) in multiple sclerosis.

PURPOSE: To report outcomes of ophthalmic evaluations in clinical studies of patients receiving fingolimod (Gilenya; Novartis Pharma AG, Basel, Switzerland) for multiple sclerosis (MS). DESIGN: Analysis done on pooled safety data (N = 2615, all studies group) from 3 double-masked, randomized, parallel-group clinical trials (phase 2 core and extension >5 years, and phase 3 FREEDOMS and TRANSFORMS core and extension studies). PARTICIPANTS: Patients aged 18 to 55 years (18-60 years in phase 2 study) diagnosed with relapsing-remitting MS were included. Patients with diabetes mellitus or macular edema (ME) at screening were excluded. INTERVENTION: Participants received fingolimod (0.5/1.25 mg), placebo, or interferon beta for the respective study durations. Ophthalmic examination included detailed eye history (at screening), visual acuity (VA) assessment, dilated ophthalmoscopy, optical coherence tomography (OCT), and fluorescein angiography (FA). MAIN OUTCOME MEASURES: Extensive ophthalmic monitoring was performed for all patients. While being studied, patients with abnormal findings on dilated ophthalmoscopy and OCT compatible with ME were further studied by FA. All locally diagnosed ME cases were centrally reviewed by the retina specialist (M.A.Z.) on the Data and Safety Monitoring Board. RESULTS: Among 2615 patients assessed, 19 confirmed ME cases were observed in fingolimod-treated groups (0.5 mg: n = 4, 0.3%; 1.25 mg: n = 15, 1.2%). Most patients (n = 13, 68%) presented with blurred vision, decreased VA, or eye pain. Macular edema was diagnosed within 3 to 4 months of treatment initiation in most cases (n = 13, 68%); 2 patients had late onset (>12 months) ME. Of the 19 patients with ME, 5 (26%), all treated with fingolimod 1.25 mg, had a history of uveitis compared with 26 (1%) in the all studies group. In most cases (n = 16, 84%), ME resolved after discontinuing the study drug. Eleven patients required topical anti-inflammatory medications. No patient had further vision deterioration. CONCLUSIONS: Fingolimod 0.5 mg is associated with a low incidence of ME in MS studies. Patients with a history of uveitis may be at an increased risk of developing ME. An ophthalmic examination before initiating fingolimod therapy and regular follow-up eye examinations during fingolimod therapy are recommended.

Anatomical and Functional Outcomes of Relaxing Parafoveal Nasal Retinotomy for Refractory Macular Hole Repair.

Purpose: This work aimed to assess postoperative outcomes associated with relaxing parafoveal nasal retinotomy for refractory macular hole repair. Methods: This was a retrospective interventional study of patients with persistent or recurrent macular holes following 1 or more standard repair procedures with pars plana vitrectomy and internal limiting membrane peeling. Patients received an additional pars plana vitrectomy and relaxing parafoveal nasal retinotomy, followed by fluid-air and air-gas exchange. Key postoperative outcomes included the achievement of macular hole closure and changes in visual acuity from baseline. Results: Thirteen patients with refractory macular holes were included, with a median age of 65 years (range, 49-90 years). The aperture diameter of the 13 macular holes ranged from 180 to 799 µm (median, 538 µm). Vitrectomy and relaxing parafoveal nasal retinotomy were performed in all 13 eyes, and after a median follow-up of 12 months (range, 3-34 months), anatomical closure was achieved in 12 of 13 eyes (92.3%). Overall, visual acuity (mean ± SE) improved significantly from 1.20 ± 0.15 logMAR (approximate Snellen equivalent, 20/320) at baseline to 0.84 ± 0.11 logMAR (Snellen, ∼ 20/125) during postoperative follow-up (P < .05). Central and paracentral scotomas were observed in 8 of 11 eyes with postoperative Humphrey visual field 10-2 and/or 24-2 data available. Conclusions: Relaxing parafoveal nasal retinotomy may be an effective method to promote anatomical closure and improve vision outcomes in patients with recalcitrant macular holes.

Epidemiology of the association between anticoagulants and intraocular hemorrhage in patients with neovascular age-related macular degeneration.

PURPOSE: To determine the cumulative incidence and annual incidence of intraocular hemorrhage (subretinal hemorrhage or vitreous hemorrhage) in patients with neovascular age-related macular degeneration (AMD) and association with daily antiplatelet or anticoagulant (AP/AC) medication usage (aspirin, clopidogrel, and warfarin), age, gender, hypertension, diabetes mellitus, or bilateral neovascular AMD. METHODS: Retrospective cross-sectional study in a tertiary university setting. Data on 195 eyes of 195 patients without previous intraocular hemorrhage examined over 73 months were reviewed. RESULTS: Ninety-six of 195 patients (49.2%) were taking daily AP/ACs. Of patients taking daily AP/AC agents, 63.5% had hemorrhage compared with 29.2% of patients not taking (odds ratio = 4.21; 95% confidence interval = 1.42-8.46; P < 0.001). The overall annual incidence of intraocular hemorrhage was 0.14% per year. Among patients taking daily AP/AC, the cumulative incidence (61 of 96, 63.5%) and annual incidence (0.10%) of concurrent intraocular hemorrhage were significantly greater compared with patients not taking them (29 of 99, 29.2% and 0.04%, respectively; P < 0.0001). Fourteen of 18 patients (77%) taking more than 1 daily AP/AC had occurrence of intraocular hemorrhage. Antiplatelet or anticoagulant usage was an independent risk factor for the development of intraocular hemorrhage. The use of any agent resulted in a significantly increased risk of developing intraocular hemorrhage. Additionally, presence of bilateral neovascular AMD was a significant association in those taking daily AP/ACs, whereas age was a significant association in those not taking daily AP/AC agents. CONCLUSION: All three daily AP/AC types were significantly associated with an increased risk of the development intraocular hemorrhage in patients with neovascular AMD, whereas gender, hypertension, and diabetes were not. Age was not significantly associated with hemorrhage in patients taking daily AP/AC agents, whereas the presence of bilateral neovascular AMD was significantly associated with hemorrhage. These findings indicate that the AP/AC use may predispose patients with neovascular AMD to intraocular hemorrhage more so than age and duration of disease alone. While the risk that discontinuing these medicines would pose to the patients' health may be too great to justify, ensuring that an appropriate medication dosage is maintained should be a priority within this patient population.

Intravitreal triamcinolone with transpupillary therapy for subfoveal choroidal neovascularization in age related macular degeneration. A randomized controlled pilot study [ISRCTN74123635].

BACKGROUND: To assess the effect of intravitreal triamcinolone acetonide (iTA) as an adjunctive treatment to transpupillary therapy (TTT) for new subfoveal choroidal neovascular membranes (CNV) in age-related macular degeneration (AMD). METHODS: This prospective randomized controlled pilot study comprised 26 patients scheduled to receive TTT, due to either absent indications for photodynamic therapy or financial issues. Patients were assigned into; Group A (n = 14) received TTT alone and Group B (n = 12) received iTA (4 mg) followed by TTT within one week. Follow ups were at 2 weeks, and 1, 3 and 6 months for; best-corrected visual acuity (BCVA) by ETDRS chart at 4 meters, intraocular pressures (IOP), fluorescein angiography (FAG), and central foveal thickness by optical coherence tomography (OCT). RESULTS: All 26 patients completed 6 months of follow ups. The average age for both groups was 74 years. Occult CNV formed 64% and 41%; classis/predominately classic 21% and 16.6%; and minimally classic 15% and 42.4% of group A and B respectively. At baseline; the mean BCVA was 0.045 for group A and 0.04 for group B; mean CNV size was 6.15 disc diameter (DD) and 2.44 DD; mean OCT foveal thickness was 513 um and 411 um for group A and B respectively with no statistical differences (P = 0.8, 0.07, and 0.19). At six months the proportion of patients gained > or = 1 lines was 14% and 25% (P = 0.136) and stabilization was 86% and 66% (P = 0.336); the mean size of the CNV was 5.63 DD and 2.67 DD (P = 0.162); rate of CNV closure was 64% and 83% (P = 0.275); and the mean OCT central foveal thickness was 516.36 um and 453.67 um (P = 0.341), for group A and B respectively. CONCLUSION: The use of iTA as an adjunctive to TTT for new subfoveal CNV in AMD showed a tendency towards better functional results. However due to the small sample size of the study a statistically significant results could not be reached.

Operational challenges in delivery of a charity care program for diabetic retinopathy screening in an urban setting.

INTRODUCTION: The University of Chicago Medicine (UCM) partners with Chicago Family Health Center (Chicago Family) in the Diabetic Retinopathy Screening Program (DRP), a charity care program to screen uninsured and underinsured patients with diabetes for diabetic retinopathy, which is a leading cause of preventable vision loss in the US. The DRP faced operational challenges throughout its pilot year: a high number of ungradable retinal images, slow turnaround time for reading retinal images and sending results, incomplete referrals, and a high rate of no-shows for diagnostic appointments. APPROACH: Chicago Family recalled patients with ungradable images for repeat imaging, and regular training was provided to staff taking the images. Weekly e-mails were sent to the physician champion reminding him to read images, and image software was installed on his laptop. Patients received reminder cards and preappointment and postappointment phone call reminders, and appointment information was shared with referring physicians. The UCM clinic was double-booked, so patients were seen within four weeks of referral. Discussions were held with UCM/Chicago Family teams to stress the influence of timely referrals on no-show rate; reminders were sent to referring physicians for referrals. RESULTS: Complete referrals were received within five days; the overall number of ungradable images decreased; image report turnaround time continued to be a challenge because of difficulties related to physician availability and technology; show rates began to increase. CONCLUSIONS: The methods of this intervention will translate well to other programs that provide care for similar patient populations in urban areas.

Short-term intraocular pressure trends after intravitreal injection of bevacizumab (avastin).

PURPOSE: To report the changes in intraocular pressure (IOP) after intravitreal injection of bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA). DESIGN: Retrospective chart review. METHODS: After the charts of 29 patients who underwent 51 consecutive intravitreal injections of bevacizumab were reviewed, analysis of the short-term effect of bevacizumab injections on IOP was performed. RESULTS: Mean baseline IOP ± SD was 15.1 ± 2.35 mm Hg (range, 10-22 mm Hg). Mean postinjection IOP ± SD was 20.1 ± 4.70 mm Hg (range, 16-31 mm Hg). Mean change in IOP from baseline to ≈30 minutes after bevacizumab injection was 5.0 mm Hg (P = 0.0027). Mean IOP ± SD at the first follow-up visit, which occurred ≈25 days (range, 5-43 days) after injection, was 14.7 ± 2.93 mm Hg (range, 10-20 mm Hg). CONCLUSIONS: Intravitreal injection of bevacizumab seems to be safe from an IOP standpoint in the short term. IOP monitoring immediately after injection may not be necessary.

Risks of intravitreous injection: a comprehensive review.

PURPOSE: To evaluate the prevalence of the most common serious adverse events associated with intravitreous (IVT) injection. METHODS: A systematic search of the literature via PubMed from 1966 to March 1, 2004, was conducted to identify studies evaluating the safety of IVT injection. Data submitted in New Drug Applications to the U.S. Food and Drug Administration for drugs administered into the vitreous were included where available. Serious adverse events reported in each study were recorded, and risk per eye and risk per injection were calculated for the following serious adverse events: endophthalmitis, retinal detachment, iritis/uveitis, intraocular hemorrhage, ocular hypertension, cataract, and hypotony. Rare complications also were noted. RESULTS: Data from 14,866 IVT injections in 4,382 eyes were analyzed. There were 38 cases of endophthalmitis (including those reported as pseudoendophthalmitis) for a prevalence of 0.3% per injection and 0.9% per eye. Excluding cases reported specifically as pseudoendophthalmitis, the prevalence of endophthalmitis was 0.2% per injection and 0.5% per eye. Retinal detachment, iritis/uveitis, ocular hypertension, cataract, intraocular hemorrhage, and hypotony were generally associated with IVT injection of specific compounds and were infrequently attributed by the investigators to the injection procedure itself. Retinal vascular occlusions were described rarely in patients after IVT injection, and it was unclear in most cases whether these represented true injection-related complications or chance associations. CONCLUSION: The risk of serious adverse events reported after IVT injection is low. Nevertheless, careful attention to injection technique and appropriate postinjection monitoring are essential because uncommon injection-related complications may be associated with permanent vision loss.