Bevacizumab in High-Risk Corneal Transplantation: A Pilot Multicenter Prospective Randomized Control Trial.

PURPOSE: To determine the efficacy of local (subconjunctival and topical) bevacizumab (Avastin) treatment in patients undergoing vascularized high-risk corneal transplantation. DESIGN: Pilot, prospective, randomized, double-blind, placebo-controlled clinical trial conducted at 5 clinical centers in the United States, India, and Brazil. PARTICIPANTS: Patients aged > 18 years undergoing high-risk penetrating keratoplasty, defined as corneal neovascularization (NV) in 1 or more quadrants ≥2 mm from the limbus or extension of corneal NV to the graft-host junction in a previously failed graft. METHODS: Patients were randomized to receive subconjunctival bevacizumab (2.5 mg/0.1 ml) or placebo at the time of surgery, followed by topical bevacizumab (10 mg/ml) or topical placebo, administered 4 times per day for 4 weeks. MAIN OUTCOME MEASURE: The 52-week endothelial immune rejection rate. RESULTS: Ninety-two patients were randomized to receive bevacizumab (n = 48) or control (n = 44). The 52-week endothelial rejection rate was 10% in the bevacizumab group and 19% in the control group (P = 0.20). Post hoc, extended follow-up at the lead study site showed an endothelial rejection rate of 3% in the bevacizumab group and 38% in the control group (P = 0.003). Treatment with bevacizumab was found to have a hazard ratio of 0.15 (95% confidence interval, 0.03-0.65, P = 0.01) in a post hoc Cox regression analysis. CONCLUSIONS: In patients undergoing vascularized high-risk corneal transplantation, there was no statistically significant difference in the rate of endothelial rejection at 1 year in the bevacizumab treatment group compared with the control group. This study may have been underpowered to detect a difference between treatment groups, and taken together, our data suggest that, in the current trial design, bevacizumab has a positive but not (yet) significant effect on endothelial rejection.

Symptoms of ocular surface disease in construction workers: comparative study with office workers.

BACKGROUND: To investigate and contrast the prevalence of dry eye symptoms in construction workers and office workers using the OSDI questionnaire. METHODS: A cross-sectional, observational study was conducted using the OSDI questionnaire to evaluate dry eye symptoms and associated risk factors. Sampled size calculation with a power of 80% and a 95% degree of confidence suggested the inclusion of 298 participants. RESULTS: We studied 304 subjects (149 construction workers and 155 office workers). More than half (55%) of the participants presented dry eye symptoms (OSDI > 12). The average OSDI score was 21.30 ± 22.20 points, being lower in the group of construction workers (12.45 ± 17.50) than in-office workers (28.51 ± 22.99) (p <  0.001). Considering participants who had moderate and severe symptoms (23 to 100 points in OSDI), office workers presented dry eye symptoms 4.15 times more frequently than construction workers (OR 4.15, 95% CI 2.52, 6.85). Women presented statistical evidence of higher OSDI scores than men (32.47 ± 23.72 vs. 14.87 ± 18.48, respectively). CONCLUSIONS: construction workers have four times less risk of presenting dry eye symptoms than people working in the average office space. This highlights the pernicious effects on the ocular surface of the office environment, which poses a significant risk for the development or worsening of dry eye symptoms.

A Clinical Trial Comparing the Safety and Efficacy of Topical Tacrolimus versus Methylprednisolone in Ocular Graft-versus-Host Disease.

PURPOSE: To evaluate the safety and efficacy of topical tacrolimus 0.05% versus topical methylprednisolone 0.5% in patients with ocular graft-versus-host disease (GVHD). DESIGN: Phase 1/2 prospective, randomized, double-masked clinical trial. PARTICIPANTS: Eighty eyes of 40 patients diagnosed with chronic ocular GVHD were enrolled. METHODS: Forty patients with ocular GVHD were randomized; 24 patients were treated with topical tacrolimus 0.05% and 16 patients were treated with topical methylprednisolone 0.5% twice daily for 10 weeks, in addition to continuing their baseline treatment regimen. MAIN OUTCOME MEASURES: Safety was evaluated based on occurrence of adverse events. Tolerability was assessed based on subject reports of discomfort after drop instillation. Intraocular pressure (IOP) was monitored. The main efficacy end points were corneal fluorescein staining (CFS), tear film break-up time (TBUT), Schirmer test results, and expression of the ocular surface inflammatory markers human leukocyte antigen-DR (HLA-DR) and intercellular adhesion molecule-1 (ICAM-1). Symptoms were evaluated using the Ocular Surface Disease Index (OSDI). RESULTS: After 10 weeks of treatment, no major adverse events occurred in either treatment group, and there was no significant difference in the composite tolerability scores between the 2 groups (P = 0.06). However, burning sensation was more pronounced with tacrolimus (P = 0.002). Topical tacrolimus was more effective than methylprednisolone in reducing the CFS score at week 10 (55% vs. 23% reduction, respectively; P = 0.01) and achieved significant improvement in TBUT when compared with baseline (P < 0.001). Reduction in OSDI score achieved statistical significance with tacrolimus (27% reduction; P = 0.02), but was marginal with methylprednisolone (32% reduction; P = 0.06). Expression of ICAM-1 by ocular surface epithelium decreased significantly in both groups (tacrolimus, P = 0.003; methylprednisolone, P = 0.008), whereas HLA-DR expression decreased significantly only in the tacrolimus group (P = 0.03). Schirmer test scores did not change significantly in either group during the study; IOP increased significantly with methylprednisolone at week 10 (P = 0.04). CONCLUSIONS: Topical tacrolimus 0.05% is safe, generally well tolerated, and effective for the treatment of ocular GVHD without the hypertensive effects of topical corticosteroids.

Prevalence of ocular hypertension and glaucoma in patients with chronic ocular graft-versus-host disease.

PURPOSE: To evaluate the prevalence of ocular hypertension (OHT) and glaucoma in patients with chronic ocular graft-versus-host disease (GVHD). METHODS: We performed a retrospective chart review of 218 patients diagnosed with chronic ocular GVHD. Ocular hypertension was defined as intraocular pressure (IOP) ≥ 24 mmHg in either eye without any glaucomatous optic disc changes. Glaucoma suspect was defined as optic disc changes with a cup-to-disc ratio ≥ 0.7 in either eye or asymmetry of ≥ 0.3 between the two eyes. Glaucoma was defined by glaucomatous optic disc changes plus glaucomatous visual field defects in two consecutive reliable visual field tests. The number of cases of ocular hypertension, glaucoma, and glaucoma suspects was evaluated. RESULTS: Thirty-three patients (15 %) were diagnosed with OHT, eight patients (3.6 %) with suspicion of glaucoma, and one patient (0.4 %) with glaucoma. OHT occurred within 6 months of developing ocular GVHD in 60 % of the cases and within the first year in 76 %. High IOP normalized in 67 % of patients when the dosage of topical or systemic corticosteroids was lowered, and 27 % of patients required anti-glaucoma therapy. CONCLUSIONS: Ocular hypertension is a common complication in patients with ocular GVHD, with a prevalence of 15 %. The rise in intraocular pressure is often transient and resolves with management of corticosteroids in most cases. However, clinicians should be aware that nearly one-third of the patients with OHT might require anti-glaucoma treatment. The prevalences of glaucoma and suspicion of glaucoma were not higher than in the general population.

Comparison of Two Questionnaires for Dry Eye Symptom Assessment: The Ocular Surface Disease Index and the Symptom Assessment in Dry Eye.

PURPOSE: The aim of this study was to compare patient-reported symptoms of dry eye disease (DED) as assessed by the Ocular Surface Disease Index (OSDI), a 12-item symptom frequency-based questionnaire, and the Symptom Assessment iN Dry Eye (SANDE), a 2-item frequency- and severity-based visual analog scale. DESIGN: Clinic-based evaluation of a diagnostic test. PARTICIPANTS: A total of 114 patients with DED. METHODS: Patients were administered the OSDI and SANDE questionnaires at baseline and follow-up visits to evaluate DED-related symptoms. The correlations between both questionnaires' scores were evaluated using the Spearman coefficient, and their clinical differences were assessed using Bland-Altman analysis. MAIN OUTCOME MEASURES: Baseline and follow-up visit OSDI and SANDE dry eye symptom scores. RESULTS: At the baseline visit, the OSDI and SANDE questionnaire scores were significantly correlated (R = 0.64; P < 0.001). Moreover, a significant correlation was found between changes in the OSDI and SANDE scores from baseline to follow-up visits (R = 0.47; P < 0.001). A Bland-Altman analysis, after score normalization, revealed a difference (bias) of less than 2 centesimal units between the scores of the 2 questionnaires. CONCLUSIONS: Data collected from the SANDE questionnaire showed a significant correlation and negligible score differences with those from the OSDI, suggesting that the SANDE visual analog scale-based questionnaire has the potential to provide clinicians with a short, quick, and reliable measure for DED symptoms.

Vision-Related Quality of Life in Patients with Ocular Graft-versus-Host Disease.

PURPOSE: To assess the vision-related quality of life (QOL) in a cohort of patients with ocular graft-versus-host disease (GVHD). DESIGN: Prospective study. PARTICIPANTS: Eighty-four patients diagnosed with chronic ocular GVHD. METHODS: We assessed the vision-related QOL with the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25). The symptoms of ocular GVHD were assessed using the Ocular Surface Disease Index (OSDI) and Symptom Assessment in Dry Eye (SANDE) questionnaires. MAIN OUTCOME MEASURES: We assessed vision-related QOL with the NEI-VFQ-25 and compared the scores obtained from patients with ocular GVHD with those from a healthy population. In the ocular GVHD population, we also evaluated the associations between the NEI-VFQ-25 and the dry eye symptoms measured by the OSDI and SANDE questionnaires, age, duration of disease, best-corrected visual acuity (BCVA), corneal fluorescein staining (CFS), tear break-up time, and Schirmer test. RESULTS: The mean composite NEI-VFQ-25 score in patients with ocular GVHD was 76.5±17. Compared with healthy subjects, patients with ocular GVHD reported reduced scores on all NEI-VFQ-25 subscales (each P < 0.001) with the exception of color vision (P = 0.11). The NEI-VFQ-25 composite scores significantly correlated with OSDI (R = -0.81, P < 0.001), SANDE (R = -0.56, P < 0.001), CFS (R = -0.36, P = 0.001), and BCVA (R = -0.30, P = 0.004). CONCLUSIONS: Patients with ocular GVHD experience measurable impairment of vision-related QOL. This study highlights the impact of ocular GVHD on the vision-related QOL, and thus the importance of comprehensive diagnosis and treatment of this condition.

Effects of corneal nerve density on the response to treatment in dry eye disease.

PURPOSE: To evaluate whether levels of corneal subbasal nerve fiber length (SNFL) in dry eye disease (DED) could prognosticate the level of improvement in signs and symptoms after treatment. DESIGN: Phase IV, double-masked, randomized clinical trial. PARTICIPANTS: Sixty patients with meibomian gland dysfunction-associated DED and 27 age-matched controls. METHODS: Patients with DED were randomized to receive topical artificial tears, loteprednol etabonate 0.5%, or loteprednol etabonate 0.5%/tobramycin 0.3% twice daily for 4 weeks. At baseline, in vivo confocal microscopy of central cornea was performed in both eyes. Patients with DED were divided into 2 subgroups: those with low baseline SNFL and those with near-normal baseline SNFL for this purpose (the cutoff point: the mean SNFL in controls minus 2 standard deviations). Clinical signs and symptoms at baseline and after 4 weeks of treatment were compared between the subgroups with low and near-normal SNFL for all therapeutic groups. MAIN OUTCOME MEASURES: Symptom questionnaires, corneal fluorescein staining (CFS), conjunctival staining with lissamine green, tear break-up time, Schirmer's test, and SNFL. RESULTS: In patients with DED, baseline SNFL (17.06±5.78 mm/mm(2)) was significantly lower than in controls (23.68±3.42 mm/mm(2), P = 0.001). In the artificial tear and loteprednol groups, although no significant improvement in any sign or symptom was noted in patients with low baseline SNFL (<16.84 mm/mm(2)), subjects with near-normal baseline SNFL (≥16.84 mm/mm(2)) showed significant improvement in both symptoms and CFS score (all P < 0.05). In the loteprednol/tobramycin group, no significant change was evident for any sign or symptom in either subgroup of low or near-normal baseline SNFL. CONCLUSIONS: Significant improvements in CFS and patient symptomatology after DED treatment were evident only in the subgroup with near-normal corneal SNFL. Consideration of SNFL may assist in explaining the variability of patients' response to DED therapy.

Outcomes of phacoemulsification in patients with chronic ocular graft-versus-host disease.

PURPOSE: The purpose of this study was to evaluate the outcomes of phacoemulsification in patients with ocular graft-versus-host disease (GVHD). METHODS: The occurrence of cataracts, cataract surgery, and its outcomes were analyzed in the medical records of 229 patients (458 eyes) with ocular GVHD. Outcome measures included pre- and postoperative corrected distance visual acuity (CDVA) and the rate of postoperative complications. RESULTS: Of the 458 eyes evaluated, 58 were pseudophakic; from the 400 phakic eyes, 238 (59 %) presented with cataracts and 62 (26 %) underwent cataract surgery. Analysis of postoperative complications and visual outcomes at 1 month was performed in 51 eyes in which detailed surgical and immediate postoperative records were available. Preoperatively, the mean CDVA was 0.67 ± 0.57 LogMAR (Snellen 20/93), improving postoperatively to 0.17 ± 0.18 (Snellen 20/29) at 1 month (P < 0.0001), and to 0.13 ± 0.14 (Snellen 20/26) by the final follow-up visit (P < 0.0001). Postoperative complications included corneal epithelial defects (8 %), filamentary keratitis (6 %), worsening of corneal epitheliopathy (16 %), posterior capsular opacification (18 %), and cystoid macular edema (4 %). A corrected distance visual acuity of 20/30 or better was achieved in 87 % of the eyes; suboptimal CDVA improvement was attributable to severe ocular surface disease, pre-existing advanced glaucoma, and prior macular surgery. CONCLUSIONS: Phacoemulsification in patients with chronic ocular GVHD is a safe and efficacious procedure resulting in significant visual improvement. Overall, postoperative adverse events responded well to timely management.

Suppression of Neovascularization by Topical and Subconjunctival Bevacizumab After High-Risk Corneal Transplantation.

Purpose: To assess the effectiveness of topical and subconjunctival bevacizumab in suppressing vascularization in graft and host bed after high-risk corneal transplantation. Design: Secondary analysis of prospective, randomized, double-blind, placebo-controlled multicentric clinical trial. Participants: The study includes patients aged > 18 years who underwent high-risk penetrating keratoplasty, which was defined as corneal vascularization in ≥ 1 quadrants of the corneal graft and host bed, excluding the limbus. Methods: Patients were randomized to treatment and control groups. The patients in the treatment group received subconjunctival injection of bevacizumab (2.5 mg/0.1 ml) on the day of the procedure, followed by topical bevacizumab (10 mg/ml) 4 times per day for 4 weeks. The patients in control group received injection of vehicle (0.9% sodium chloride) on the day of procedure, followed by topical vehicle (carboxymethylcellulose sodium 1%) 4 times a day for 4 weeks. Main Outcome Measures: Vessel and invasion area of vessels in the corneal graft and host beds. Results: This study included 56 eyes of 56 patients who underwent high-risk corneal transplantation, with equal numbers in the bevacizumab and vehicle (control) treatment groups. The mean age of patients who received bevacizumab was 61.2 ± 15.9 years, and the mean age of those treated with vehicle was 60.0 ± 16.1 years. The vessel area at baseline was comparable in the bevacizumab (16.72% ± 3.19%) and control groups (15.48% ± 3.12%; P = 0.72). Similarly, the invasion areas were also similar in the treatment (35.60% ± 2.47%) and control (34.23% ± 2.64%; P = 0.9) groups at baseline. The reduction in vessel area was significantly higher in the bevacizumab-treated group (83.7%) over a period of 52 weeks compared with the control group (61.5%; P < 0.0001). In the bevacizumab-treated group, invasion area was reduced by 75.8% as compared with 46.5% in the control group. The vessel area was similar at 52 weeks postprocedure in cases of first (3.54% ± 1.21%) and repeat (3.80% ± 0.40%) corneal transplantation in patients who received bevacizumab treatment. In the vehicle-treated patients, the vessel area was significantly higher in repeat (9.76% ± 0.32%) compared with first (8.06% ± 1.02%; P < 0.0001) penetrating keratoplasty. In the bevacizumab treatment group, invasion areas at week 52 were comparable in first (11.70% ± 3.38%) and repeat (11.64% ± 1.74%) procedures, whereas invasion area was significantly higher in repeat (27.87% ± 2.57%) as compared with first (24.11% ± 2.17%) penetrating keratoplasty in vehicle-treated patients. Conclusions: In patients undergoing vascularized high-risk corneal transplantation, bevacizumab is efficacious in reducing vascularization of corneal graft and host bed, thereby reducing the risk of corneal graft rejection in vascularized host beds. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Applications of Infrared Thermography in Ophthalmology.

Body temperature is one of the key vital signs for determining a disease's severity, as it reflects the thermal energy generated by an individual's metabolism. Since the first study on the relationship between body temperature and diseases by Carl Reinhold August Wunderlich at the end of the 19th century, various forms of thermometers have been developed to measure body temperature. Traditionally, methods for measuring temperature can be invasive, semi-invasive, and non-invasive. In recent years, great technological advances have reduced the cost of thermographic cameras, which allowed extending their use. Thermal cameras capture the infrared radiation of the electromagnetic spectrum and process the images to represent the temperature of the object under study through a range of colors, where each color and its hue indicate a previously established temperature. Currently, cameras have a sensitivity that allows them to detect changes in temperature as small as 0.01 °C. Along with its use in other areas of medicine, thermography has been used at the ocular level for more than 50 years. In healthy subjects, the literature reports that the average corneal temperature ranges from 32.9 to 36 °C. One of the possible sources of variability in normal values is age, and other possible sources of variation are gender and external temperature. In addition to the evaluation of healthy subjects, thermography has been used to evaluate its usefulness in various eye diseases, such as Graves' orbitopathy, and tear duct obstruction for orbital diseases. The ocular surface is the most studied area. Ocular surface temperature is influenced by multiple conditions, one of the most studied being dry eye; other diseases studied include allergic conjunctivitis and pterygium as well as systemic diseases such as carotid artery stenosis. Among the corneal diseases studied are keratoconus, infectious keratitis, corneal graft rejection, the use of scleral or soft contact lenses, and the response to refractive or cataract surgery. Other diseases where thermographic features have been reported are glaucoma, diabetic retinopathy, age-related macular degeneration, retinal vascular occlusions, intraocular tumors as well as scleritis, and other inflammatory eye diseases.