Hydroxychloroquine retinopathy screening.

AIM: To compare current hydroxychloroquine retinopathy screening practices with the published 2002 American Academy of Ophthalmology (AAO) Preferred Practice Patterns (PPP). METHODS: A multiple-choice survey was distributed to 105 ophthalmologists to assess current screening practices and knowledge of patient risk factors. Results were compared with the PPP guidelines. A cost analysis of the PPP and survey paradigms was conducted. RESULTS: Sixty-seven (64%) of 105 surveys were completed. The majority (90%) of physicians screen for hydroxychloroquine retinopathy with either central automated threshold perimetry or Amsler grid as recommended by the PPP. Most survey respondents could not correctly identify the evidence-based risk factors. The majority screen more frequently than recommended: 87% screen high-risk patients and 94% screen low-risk patients more frequently than recommended in the PPP. The increased screening frequency of low-risk patients translates into an excess of $44 million in the first 5 years of therapy. If all patients were screened using exact PPP paradigm, savings could exceed $150 million every 10 years. CONCLUSIONS: Ophthalmologists currently screen for hydroxychloroquine retinopathy correctly; however, their lack of familiarity with evidence-based guidelines may result in excessive follow-up. Increasing awareness and implementation of the PPP could potentially reduce hydroxychloroquine retinopathy screening costs significantly.

Human retinal pigment epithelium proteome changes in early diabetes.

AIMS/HYPOTHESIS: Diabetic retinopathy is the most common complication of diabetes and a leading cause of blindness among working-age adults. Anatomical and functional changes occur in the retina and retinal pigment epithelium (RPE) prior to clinical symptoms of the disease. However, the molecular mechanisms responsible for these early changes, particularly in the RPE, remain unclear. To begin defining the molecular changes associated with pre-retinopathic diabetes, we conducted a comparative proteomics study of human donor RPE. METHODS: The RPE was dissected from diabetic human donor eyes with no clinically apparent diabetic retinopathy (n=6) and from eyes of age-matched control donors (n=17). Soluble proteins were separated based upon their mass and charge using two-dimensional (2-D) gel electrophoresis. Protein spots were visualised with a fluorescent dye and spot densities were compared between diabetic and control gels. Proteins from spots with significant disease-related changes in density were identified using mass spectrometry. RESULTS: Analysis of 325 spots on 2-D gels identified 31 spots that were either up- or downregulated relative to those from age-matched control donors. The protein identity of 18 spots was determined by mass spectrometry. A majority of altered proteins belonged to two major functional groups, metabolism and chaperones, while other affected categories included protein degradation, synthesis and transport, oxidoreductases, cytoskeletal structure and retinoid metabolism. CONCLUSIONS/INTERPRETATION: Changes identified in the RPE proteome of pre-retinopathic diabetic donor eyes compared with age-matched controls suggest specific cellular alterations that may contribute to diabetic retinopathy. Defining the pre-retinopathic changes affecting the RPE could provide important insight into the molecular events that lead to this disease.

Treatment of submacular hemorrhage with low-dose intravitreal tissue plasminogen activator injection and pneumatic displacement.

OBJECTIVE: To investigate the safety and efficacy of low-dose intravitreal tissue plasminogen activator (tPA) and an expansile gas bubble in displacing submacular hemorrhage in patients with age-related macular degeneration (ARMD). PATIENTS AND METHODS: We reviewed retrospectively the medical records of 14 consecutive patients with ARMD from 1 academic center who received low-dose intravitreal tPA (18-50 microg) and expansile gas (0.3-0.4 mL of perfluoropropane) for thrombolysis and displacement of submacular hemorrhage. After the procedure, patients maintained face-down positioning for 1 to 3 days. MAIN OUTCOME MEASURES: Displacement of blood from the fovea, early and final visual acuity, and toxicity of tPA. RESULTS: Submacular blood was completely displaced from the fovea in 10 (71%) of the 14 patients and partially displaced in 3 (21%). In 1 patient, no displacement occurred. Early (<2 months) postoperative visual acuity improved by 2 or more lines in 8 patients (57%). With a mean follow-up of 7.7 months, 2 (15%) of 13 patients maintained 2 or more lines of improvement and 69% (9 patients) maintained preoperative visual acuity. No clinical evidence of retinal toxicity was seen at this low-dose of tPA. CONCLUSIONS: Doses of intravitreal tPA ranging from 18 to 50 microg and an expansile gas bubble are safe and effective in displacing submacular hemorrhage in patients with ARMD. Final visual acuity was limited by the underlying presence of end-stage ARMD.

Evidence for contribution of tripartite hemolysin BL, phosphatidylcholine-preferring phospholipase C, and collagenase to virulence of Bacillus cereus endophthalmitis.

Bacillus cereus causes a highly fulminant endophthalmitis which usually results in blindness. We previously concluded that hemolysin BL (HBL), a tripartite necrotizing pore-forming toxin, is a probable endophthalmitis virulence factor because it is highly toxic to retinal tissue in vitro and in vivo. We also determined that B. cereus produces additional retinal toxins that might contribute to virulence. Here we fractionated crude B. cereus culture supernatant by anion-exchange chromatography and found that in vitro retinal toxicity was also associated with phosphatidylcholine-preferring phospholipase C (PC-PLC). The pure enzyme also caused retinal necrosis in vivo. We showed that phosphatidylinositol-specific PLC and sphingomyelinase were nontoxic and that two hemolysins, cereolysin O and a novel hemolysin designated hemolysin IV, were marginally toxic in vitro. The histopathology of experimental septic endophthalmitis in rabbits mimicked the pathology produced by pure HBL, and both HBL and PC-PLC were detected at toxic concentrations in infected vitreous fluid. Bacterial cells were first seen associated with the posterior margin of the lens and eventually were located throughout the lens cortex. Detection of collagenase in the vitreous humor suggested that infiltration was facilitated by the breakdown of the protective collagen lens capsule by that enzyme. This work supports our conclusion that HBL contributes to B. cereus virulence and implicates PC-PLC and collagenase as additional virulence factors.

Idiopathic reactive hyperplasia of the retinal pigment epithelium.

OBJECTIVES: To present and discuss 2 patients with acquired peripapillary pigmented lesions. METHODS: We reviewed the patients' clinical records and histopathologic findings. RESULTS: The first patient was diagnosed with a pigmented papillary lesion that was followed up for 38 years. The second patient was a child with neurofibromatosis type 1 who developed a pigmented peripapillary lesion following excision of an optic nerve glioma. Histologic findings in both cases demonstrated hyperplasia of the retinal pigment epithelium with associated findings. CONCLUSIONS: The lesions presented an idiopathic reactive hyperplasia of the retinal pigment epithelium. The clinical and histopathologic findings resemble findings reported with the combined hamartoma. We suggest that such lesions are reactive in nature, rather than hamartomatous.

Macular hole surgery using thrombin-activated fibrinogen and selective removal of the internal limiting membrane.

PURPOSE: To evaluate a tissue sealant (autologous cryoprecipitate activated with bovine thrombin) as an adjuvant in macular hole surgery. METHODS: Sixty-nine patients with stage 2, 3, or 4 full-thickness macular hole were enrolled consecutively in a prospective pilot study. Anatomic closure of the macular holes with a single operation was the primary outcome. Fifty-eight patients had pre- and postoperative standardized measurements including best refracted visual acuity, reading speed, and contrast sensitivity. Group A patients (45) had primary macular holes; Group B patients (13) had recurrent macular holes or macular holes with "other" retinal pathology. Surgical technique was standardized and membrane dissections were optional. RESULTS: The anatomic closure rate was 80% with a minimum of 6 months follow-up. Mean improvement in visual acuity for Group A (2.9+/-0.4 lines) was significantly better than for Group B (0.8+/-0.5 lines; P = 0.008). Eyes that underwent internal limiting membrane (ILM) dissections had an anatomic closure rate of 96% (23/24), compared with 71% (32/45) in "non-ILM" cases (P = 0.034). Adverse reactions included sterile hypopyon (10%), intraretinal hemorrhage (9%), pigmentary hyperplasia (3%), and retinal detachment (3%). CONCLUSION: Tissue sealants should be evaluated as an adjuvant in macular hole surgery in a randomized clinical trial. Inflammatory reactions may occur in some patients. Internal limiting membrane dissection may improve anatomic closure rates without adversely affecting the visual acuity.

Human sclera: thickness and surface area.

PURPOSE: To assess the mean thickness and surface area of human sclera. METHODS: Fifty-five formalin-fixed eye bank eyes were hemisected from anterior to posterior. Cross-sectional slides were taken to include a millimeter scale ruler in each photograph. Slide photographs were projected and the scleral silhouette sketched. Mean scleral thickness measurements with standard deviation were obtained. Twenty-five human eye bank eyes were used to determine total scleral surface area by either a computerized tracing method (17 globes) or volumetric calculations (eight globes) using fluid displacement. RESULTS: Mean scleral thickness +/- SD was 0.53 +/- 0.14 mm at the corneoscleral limbus, significantly decreasing to 0.39 +/- 0.17 mm near the equator, and increasing to 0.9 to 1.0 mm near the optic nerve. The mean total scleral surface area by surface area computerized tracings was 16.3 +/- 1.8 cm2 and, by the volume displacement method, was 17.0 +/- 1.5 cm2. CONCLUSIONS: Scleral thickness and surface area measurements from cadaver eyes are important for ophthalmic surgeons and have implications for transscleral diffusion.

A system for classifying mechanical injuries of the eye (globe). The Ocular Trauma Classification Group.

PURPOSE: To develop a classification system for mechanical injuries of the eye. METHODS: The Ocular Trauma Classification Group, a committee of 13 ophthalmologists from seven separate institutions, was organized to discuss the standardization of ocular trauma classification. To develop the classification system, the group reviewed trauma classification systems in ophthalmology and general medicine and, in detail, reports on the characteristics and outcomes of eye trauma, then established a classification system based on standard terminology and features of eye injuries at initial examination that have demonstrated prognostic significance. RESULTS: This system classifies both open-globe and closed-globe injuries according to four separate variables: type of injury, based on the mechanism of injury; grade of injury, defined by visual acuity in the injured eye at initial examination; pupil, defined as the presence or absence of a relative afferent pupillary defect in the injured eye; and zone of injury, based on the anteroposterior extent of the injury. This system is designed to be used by ophthalmologists and nonophthalmologists who care for patients or conduct research on ocular injuries. An ocular injury is classified during the initial examination or at the time of the primary surgical intervention and does not require extraordinary testing. CONCLUSIONS: This classification system will categorize ocular injuries at the time of initial examination. It is designed to promote the use of standard terminology and assessment, with applications to clinical management and research stud ies regarding eye injuries.

Visual acuity in children with colobomatous defects.

Examining a child with a colobomatous defect can be challenging. The most important predictor of visual outcome is identification of normal foveal anatomy. The clinician should first evaluate the child for the associated systemic conditions. The next step is to identify the presence of normal foveal structures in the involved eye(s). If present, a trial of amblyopia treatment should be initiated. Anisometropic amblyopia is common and should be addressed. Retinal detachments are common and add uncertainty to predicting visual acuity.

A model for light toxicity of cultured human retinal pigment epithelium.

BACKGROUND: The effect of visible light on human retinal pigment epithelial (HRPE) cells has not been characterized under conditions that provide strict thermal control. METHODS: HRPE cells were isolated and grown to confluence. Cells were exposed to light in an incubator in which the cell temperature was controlled in response to a temperature sensor maintained in the tissue culture medium. Cells were exposed: (A) for 24, 36, and 48 h; and using a 24-h exposure followed by 24 h darkness; (B) at varying intensities of light using neutral density filters; (C) under a yellow filter; and (D) with a 12-h on-off cyclic light. RESULTS: (A) Light exposure of 36 and 48 h resulted in significant cytotoxicity, while the initial 24-h exposure did not induce subsequent cytotoxicity. (B) Light irradiance levels from 43 to 54 mW/cm2 were required to demonstrate cytotoxicity. (C) Use of a yellow filter did not eliminate the observed cytotoxicity. (D) Cyclic exposure did not result in significant cytotoxicity. CONCLUSION: This study establishes a model and basic parameters of light toxicity to HRPE cells in vitro using strict temperature control that may be used to evaluate photochemical injury to HRPE cells.

Subfoveal choroidal neovascularization in punctate inner choroidopathy. Surgical management and pathologic findings.

PURPOSES: To evaluate submacular surgery for the management of subfoveal choroidal neovascularization in punctate inner choroidopathy, to describe the histopathology and ultrastructure of the excised subretinal tissue, and to propose a staging system that characterizes the development of choroidal neovascularization with associated subretinal fibrosis. METHODS: The authors reviewed the records of five patients (6 eyes) with punctate inner choroidopathy who underwent submacular surgery for subfoveal choroidal neovascularization. Surgical specimens were examined using light and transmission electron microscopy. RESULTS: Visual improvement was noted postoperatively in all six eyes, with follow-up ranging from 8 to 36 months (median, 14 months). Recurrences (6 in 4 eyes) were common. Five of the six recurrences required additional procedures: three were managed surgically, two with laser photocoagulation, and one with observation. "Bridging" of separate foci of choroidal neovascularization resulted in stellate or "dumbbell-shaped" areas of subretinal fibrosis in four of six eyes. Histopathologic evaluation of the excised tissue showed endothelial-lined vascular channels, retinal pigment epithelium, lymphocytes, plasma cells, fibrocytes, collagen fragments, and rarely, outer retinal elements. CONCLUSIONS: Subfoveal choroidal neovascularization in punctate inner choroidopathy may be managed with submacular surgery. Recurrences are common and may result in substantial loss of vision. Choroidal neovascular membranes with an accompanying fibrotic reaction are responsible for the stellate or dumbbell-shaped areas of subretinal fibrosis. No beneficial effect was demonstrated using corticosteroid treatment of the choroidal neovascularization.

Postoperative hypopyon after intravitreal bovine thrombin for macular hole surgery.

PURPOSE: We used intravitreal autologous fibrinogen with bovine thrombin for the surgical closure of macular holes in 60 cases. METHODS: Pars plana vitrectomy with separation of the posterior cortical vitreous was performed after air/fluid exchange. One to two drops each of autologous fibrinogen and bovine thrombin (20 to 80 U) were instilled in each patient. RESULTS: Five (8%) of 60 patients developed a hypopyon without unusual pain on the first postoperative day. Inflammation responded to frequent topical corticosteroids within 48 to 72 hours. CONCLUSION: Postvitrectomy hypopyon after the use of bovine thrombin may represent an immune reaction that must be differentiated from endophthalmitis. We recommend careful observation and frequent topical corticosteroids.

Misoprostol with cyclosporin A prolongs corneal allograft survival in an animal model.

Cyclosporin A (CSA) has been shown to prolong corneal allograft survival in a variety of animal models. Misoprostol is a prostaglandin E1 analogue with oral bioavailability and immunosuppressive properties. Misoprostol and CSA are synergistic immunosuppressants in vitro. In the present study, we evaluated the effect of adding misoprostol to a subtherapeutic dose of CSA in the orthotopic allogeneic rat penetrating keratoplasty model. Seventy inbred Lewis rats were recipients of orthotopic corneal allografts from Brown-Norway donors. Ten Lewis rats received orthotopic syngeneic grafts (Lew to Lew). Two separate experiments with 40 animals per trial were performed. In each trial, the rats were divided equally into four groups. Trial A: allogeneic control (A1), syngeneic control (A2), CSA at 10 mg/kg/d (A3), and CSA at 15 mg/kg/d (A4). Trial B: allogeneic control (B1), CSA alone at 7.5 mg/kg/d (B2), misoprostol alone at 1 mg/kg/d (B3), and CSA with misoprostol at 7.5 and 1 mg/kg/d, respectively (B4). Syngeneic control A2 as well as group A4 remained clear through postoperative day 22. The allogeneic control groups A1 and B1, plus treatment groups B2 and B3, rejected their grafts by postoperative day 12. Groups A3 and B4 demonstrated a delay in allograft rejection that continued to be statistically significant through the 12th postoperative day (p < 0.001). We conclude that the addition of systemic misoprostol to CSA can effectively prolong corneal allograft survival in the orthotopic allogeneic rat penetrating keratoplasty model.

Predicting visual acuity in children with colobomas involving the optic nerve.

BACKGROUND: This study evaluates the relationship to visual acuity of four ophthalmoscopic features of colobomas involving the optic nerve. The goal was to identify those features that could predict potential visual acuity of children with these colobomas. METHODS: Fundus photographs of 23 eyes with colobomas involving the optic nerve met the entry criteria and were evaluated by two masked observers. The following features were evaluated: coloboma size, optic nerve color, foveal development, and subfoveal retinal pigment epithelial changes. Simple linear regression was used to identify the feature that most closely correlated with visual acuity. Refractive status was assessed by cycloplegic refraction. RESULTS: The only component that correlated with the development of good visual acuity was the degree of foveal involvement by the optic nerve coloboma (P = .002, R = 0.8). Significant refractive error and anisometropia were common in patients with colobomas involving the optic nerve. CONCLUSION: Central visual acuity in children born with colobomas involving the optic nerve correlates with the development of normal foveal anatomy, regardless of the size of the coloboma, the color of the optic nerve, or the presence of subfoveal pigmentary changes. Because refractive error is common, these children should receive an accurate refraction and amblyopia treatment.

Human scleral permeability. Effects of age, cryotherapy, transscleral diode laser, and surgical thinning.

PURPOSE: To determine the in vitro permeability of human sclera to compounds varying in molecular weight. To evaluate the effects of age, cryotherapy, transscleral diode laser, and surgical thinning on scleral permeability. METHODS: Scleral tissue from 97 human eye bank eyes was tested individually in a two-chamber Ussing apparatus with the following hydrophilic radiolabeled compounds on one side of the chamber: 5-fluorouracil, sucrose, dexamethasone, methotrexate, inulin, and three separate dextran polymers (MWt = 10,000, 40,000, and 70,000). Scleral hydration levels were obtained on 20 more scleral specimens. Additional groups of scleral specimens were treated with either a cryotherapy probe, a transscleral diode laser retinopexy probe, or partial thickness lamellar dissection, and specimens were mounted in the Ussing chambers for testing. Scleral tissue was digested to measure the amount of radioactivity present. Scleral sections were examined with electron microscopy. RESULTS: Scleral hydration was maintained during the perfusion. The mean scleral permeability (cm/second x 10(-6) +/- SD) was established for each of the above compounds. Age, cryotherapy, or diode laser treatment did not alter permeability or ultrastructure of the sclera. Surgical thinning significantly increased the scleral permeability to dexamethasone (P = 0.011) and methotrexate (P = 0.037). CONCLUSION: This study establishes baseline human scleral permeability to a series of hydrophilic compounds with various molecular weights. Age, cryotherapy, and diode laser treatment do not alter the permeability or ultrastructure of the sclera, whereas surgical thinning significantly increases permeability.

Rapamycin inhibits corneal allograft rejection and neovascularization.

OBJECTIVE: To investigate the immunosuppressive effect of rapamycin in prolonging allograft survival in the rat model of orthotopic allogeneic penetrating keratoplasty. DESIGN: Thirty inbred Lewis rats received corneal allografts from Brown Norway donors. Animals were divided into two rapamycin treatment groups and one allogeneic control group. RESULTS: By the second week after surgery, all of the control animals had experienced allograft failure due to allograft rejection. However, allografts in seven of 10 animals in the low-dose treatment group and allografts in seven of nine animals in the high-dose treatment group remained clear. In addition, corneal neovascularization was markedly reduced in the treated animals. CONCLUSIONS: The systemic administration of rapamycin prolongs corneal allograft survival and significantly inhibits the neovascular component of rejection in the rat model of orthotopic allogeneic penetrating keratoplasty.