William F. Mieler

Revised Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy

BACKGROUND The American Academy of Ophthalmology recommendations for screening of chloroquine (CQ) and hydroxychloroquine (HCQ) retinopathy were published in 2002, but improved screening tools and new knowledge about the prevalence of toxicity have appeared in the ensuing years. No treatment exists as yet for this disorder, so it is imperative that patients and their physicians be aware of the best practices for minimizing toxic damage. RISK OF TOXICITY New data have shown that the risk of toxicity increases sharply toward 1% after 5 to 7 years of use, or a cumulative dose of 1000 g, of HCQ. The risk increases further with continued use of the drug. DOSAGE The prior recommendation emphasized dosing by weight. However, most patients are routinely given 400 mg of HCQ daily (or 250 mg CQ). This dose is now considered acceptable, except for individuals of short stature, for whom the dose should be determined on the basis of ideal body weight to avoid overdosage. SCREENING SCHEDULE A baseline examination is advised for patients starting these drugs to serve as a reference point and to rule out maculopathy, which might be a contraindication to their use. Annual screening should begin after 5 years (or sooner if there are unusual risk factors). SCREENING TESTS Newer objective tests, such as multifocal electroretinogram (mfERG), spectral domain optical coherence tomography (SD-OCT), and fundus autofluorescence (FAF), can be more sensitive than visual fields. It is now recommended that along with 10-2 automated fields, at least one of these procedures be used for routine screening where available. When fields are performed independently, even the most subtle 10-2 field changes should be taken seriously and are an indication for evaluation by objective testing. Because mfERG testing is an objective test that evaluates function, it may be used in place of visual fields. Amsler grid testing is no longer recommended. Fundus examinations are advised for documentation, but visible bulls-eye maculopathy is a late change, and the goal of screening is to recognize toxicity at an earlier stage. COUNSELING Patients should be aware of the risk of toxicity and the rationale for screening (to detect early changes and minimize visual loss, not necessarily to prevent it). The drugs should be stopped if possible when toxicity is recognized or strongly suspected, but this is a decision to be made in conjunction with patients and their medical physicians.

Voriconazole in the treatment of fungal eye infections: a review of current literature

Background: Voriconazole has an important role to play in the prophylaxis and management of fungal endophthalmitis and keratitis. New-generation triazoles, including voriconazole, posaconazole and ravuconazole, have been shown in laboratory studies and clinical experience to have very good safety profiles with few side effects. Fungal eye infections, while not common in temperate climates, have been notoriously difficult to diagnose and treat, and generally result in protracted therapy with poor final outcomes. Current treatment options are far from optimal. Aims: This paper will review studies and clinical case reports published in the ophthalmic literature that address the safety of these drugs in the eye, penetration and concentration in ocular tissues and media, and efficacy in treating common pathogens implicated in fungal keratitis and endophthalmitis. Conclusions: Over 40 clinical case reports of treatment with voriconazole suggest that it may be used safely and effectively against a broad range of fungal pathogens.

Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy (2016 Revision)

BACKGROUND The American Academy of Ophthalmology recommendations on screening for chloroquine (CQ) and hydroxychloroquine (HCQ) retinopathy are revised in light of new information about the prevalence of toxicity, risk factors, fundus distribution, and effectiveness of screening tools. PATTERN OF RETINOPATHY Although the locus of toxic damage is parafoveal in many eyes, Asian patients often show an extramacular pattern of damage. DOSE: We recommend a maximum daily HCQ use of ≤5.0 mg/kg real weight, which correlates better with risk than ideal weight. There are no similar demographic data for CQ, but dose comparisons in older literature suggest using ≤2.3 mg/kg real weight. RISK OF TOXICITY The risk of toxicity is dependent on daily dose and duration of use. At recommended doses, the risk of toxicity up to 5 years is under 1% and up to 10 years is under 2%, but it rises to almost 20% after 20 years. However, even after 20 years, a patient without toxicity has only a 4% risk of converting in the subsequent year. MAJOR RISK FACTORS High dose and long duration of use are the most significant risks. Other major factors are concomitant renal disease, or use of tamoxifen. SCREENING SCHEDULE A baseline fundus examination should be performed to rule out preexisting maculopathy. Begin annual screening after 5 years for patients on acceptable doses and without major risk factors. SCREENING TESTS The primary screening tests are automated visual fields plus spectral-domain optical coherence tomography (SD OCT). These should look beyond the central macula in Asian patients. The multifocal electroretinogram (mfERG) can provide objective corroboration for visual fields, and fundus autofluorescence (FAF) can show damage topographically. Modern screening should detect retinopathy before it is visible in the fundus. TOXICITY Retinopathy is not reversible, and there is no present therapy. Recognition at an early stage (before any RPE loss) is important to prevent central visual loss. However, questionable test results should be repeated or validated with additional procedures to avoid unnecessary cessation of valuable medication. COUNSELING Patients (and prescribing physicians) should be informed about risk of toxicity, proper dose levels, and the importance of regular annual screening.

Prospective Comparison of Cirrus and Stratus Optical Coherence Tomography for Quantifying Retinal Thickness

PURPOSE To compare Cirrus Fourier-domain optical coherence tomography (OCT) with Stratus time-domain OCT for imaging retinal diseases and quantifying retinal thickness (RT) of all nine OCT zones, central macular thickness, and average macular thickness in eyes with and without macular edema. DESIGN Prospective comparison between two OCT systems. METHODS RT measurements were performed in 120 eyes of 60 patients suspected of having increased retina thickness using both Stratus and Cirrus OCT on the same day. Twenty-one eyes had both 512 x 128 and 200 x 200 Cirrus cube scans done. RESULTS Data from 101 eyes (53 patients) were analyzed; 46 eyes (45.5%) had macular edema on clinical examination (Group 1), whereas 55 eyes (54.4%) had no clinical evidence of macular edema (Group 2). There was modest correlation between all thickness measurements in 909 zones and each group (range of Pearson correlation, 0.51 to 0.89) and average value was significantly greater when measured with Cirrus OCT for all eyes (mean difference, 43.2 microm; P < .0001). There were few measurement differences between different resolution Cirrus cube scans. CONCLUSIONS Cirrus OCT measures RT approximately 43 microm greater than Stratus OCT, which is likely attributable to Cirrus OCT detection of the outer band of the retinal pigment epithelium vs Stratus OCT detection of the inner/outer segment photoreceptor junction. All zones showed a wide degree of variability in correlation. Both Cirrus cube scans provide similar data. Future studies comparing these systems might consider utilizing average macular thickness values, which reflect macular volume and may provide more consistent measurements.

A phase I study of intravitreal vascular endothelial growth factor trap-eye in patients with neovascular age-related macular degeneration.

PURPOSE To determine the safety, tolerability, maximum tolerated dose, and bioactivity of an intravitreal injection of vascular endothelial growth factor (VEGF) Trap-Eye, a fusion protein of binding domains from human VEGF receptors 1 and 2 with human immunoglobulin-G Fc that binds VEGF family members, in patients with neovascular age-related macular degeneration (AMD). DESIGN Dose-escalation, multicenter, interventional clinical trial. PARTICIPANTS Twenty-one patients (13 female, 8 male) with neovascular AMD (NVAMD) and lesions <or=12 disc areas in size and >or=50% active choroidal neovascularization (CNV) with best-corrected visual acuity (BCVA) <or=20/40 received a single intraocular injection of 0.05 mg (n = 3), 0.15 mg (n = 3), 0.5 mg (n = 3), 1 mg (n = 6), 2 mg (n = 3), or 4 mg (n = 3) of VEGF Trap-Eye. METHODS Safety assessments included eye examinations, vital signs, and laboratory tests. Measures of bioactivity included changes from baseline in BCVA, optical coherence tomography (OCT), and fluorescein angiography. The primary end point was 6 weeks and patients were followed up for 12 weeks. MAIN OUTCOME MEASURE Safety assessments. RESULTS There were no serious adverse events and no identifiable intraocular inflammation. The mean decrease in excess foveal thickness for all patients was 104.5 mum at 6 weeks, and the mean increase in visual acuity was 4.43 letters. In the 2 highest dose groups combined (2 and 4 mg), the mean increase in BCVA was 13.5 letters, with 3 of 6 patients demonstrating improvement of >or=3 lines and 3 patients requiring no adjunctive treatment of any type for 12 weeks. Some showed elimination of fluorescein leakage and reduction in area of CNV. CONCLUSIONS Intravitreal injection of up to 4 mg of VEGF Trap-Eye in patients with NVAMD was well tolerated with no evidence of ocular inflammation. Although the number of patients in each cohort was small, there was evidence of bioactivity, because several patients, especially those receiving 2 or 4 mg of VEGF Trap-Eye, showed substantial improvement in BCVA associated with reductions in foveal thickness. Phase III trials to investigate the efficacy of intraocular VEGF Trap-Eye in patients with NVAMD are under way.

Aqueous and Vitreous Concentrations Following Topical Administration of 1% Voriconazole in Humans

OBJECTIVE To determine the penetration of 1% voriconazole solution into the aqueous and vitreous following topical administration. METHODS A prospective nonrandomized study of 13 patients scheduled for pars plana vitrectomy surgery. Aqueous and vitreous samples were obtained and analyzed after topical administration of 1% voriconazole every 2 hours for 24 hours before surgery. Drug concentration quantitation was performed using high-performance liquid chromatography. RESULTS The mean (SD) sampling time after topical administration of the last voriconazole dose was 24 (14) minutes. The mean (SD) voriconazole concentrations in the aqueous and vitreous were 6.49 (3.04) microg/mL and 0.16 (0.08) microg/mL, respectively. Aqueous concentrations exceeded the minimum inhibitory concentration at which 90% of isolates are inhibited (MIC(90)) for a wide spectrum of fungi and mold, including Aspergillus, Fusarium, and Candida species. Vitreous concentrations of voriconazole exceeded the MIC(90) for Candida albicans. CONCLUSION Topically administered voriconazole achieves therapeutic concentrations in the aqueous of the noninflamed human eye for many fungi and molds and achieves therapeutic levels in the vitreous for Candida species. Topical voriconazole may be a useful agent for the management of fungal keratitis and for prophylaxis against the development of fungal endophthalmitis.

Posterior segment manifestations of ocular trauma

&NA; Nonpenetrating or blunt ocular trauma, orbital trauma and systemic trauma may cause a variety of posterior segment abnormalities. Blunt ocular trauma may cause damage to the retina (commotio retinae), retinal pigment epithelium (retinal pigment epithelial edema), choroid (choroidal rupture) and optic nerve (optic nerve evulsion) alone or in combination. Traumatic macular holes and retinal detachment or dialysis may also occur after blunt ocular trauma. Trauma to the orbital tissues adjacent to the globe can cause concussive forces with damage to multiple structures within the eye (chorioretinitis sclopetaria). Systemic trauma may result in diffuse retinopathy (Purtschers retinopathy, shaken baby syndrome) or localized retinal abnormalities (whiplash retinopathy, fat embolism syndrome). Alterations in intravascular (Valsalva retinopathy) or intracranial pressure (Tersons syndrome) due to a variety of causes may result in preretinal or vitreous hemorrhage and associated visual loss. The purpose of this report is to review each of these entities of traumatic posterior segment abnormalities.

Rapid response of retinal pigment epithelial detachments to intravitreal aflibercept in neovascular age-related macular degeneration refractory to bevacizumab and ranibizumab

PurposeThe aim of this study is to report the short-term efficacy of aflibercept in the treatment of neovascular age-related macular degeneration (AMD) with associated retinal pigment epithelial detachment (PED) which is refractory or develops tachyphylaxis to bevacizumab and ranibizumab.MethodsThe method comprised a retrospective review of the medical records of patients with neovascular AMD and associated PEDs recently treated with aflibercept and previously treated with bevacizumab and ranibizumab.ResultsThree eyes of three female patients of ages 49, 55, and 65 years old with large serous PEDs and subretinal fluid (SRF) associated with occult choroidal neovascularization and neovascular AMD were treated with aflibercept after intravitreal bevacizumab and/or ranibizumab failed to resolve the lesions. All had complete resolution of SRF and complete or near-complete resolution of the PEDs after aflibercept injections over a 3-month period. Visual acuity improved in all three eyes.ConclusionIntravitreal aflibercept may be an effective treatment option for serous PED in neovascular AMD patients after bevacizumab and ranibizumab have previously failed. Larger studies with longer follow-up are required to determine the role of aflibercept in treatment of PED in neovascular AMD.

Longitudinal Study of New Eye Lesions in Children with Toxoplasmosis Who Were Not Treated During the First Year of Life

PURPOSE To determine the incidence of new chorioretinal lesions in children with toxoplasmosis diagnosed after, and therefore not treated during, their first year. DESIGN Prospective longitudinal cohort study. METHODS Thirty-eight children were evaluated in Chicago between 1981 and 2005 for new chorioretinal lesions. Thirty-eight children and mothers had serum IgG antibody to Toxoplasma gondii. RESULTS Twenty-eight of 38 children had one of the following: diagnosis with serum antibody to T. gondii indicative of chronic infection at age 24 months, central nervous system calcifications, hydrocephalus, illness compatible with congenital toxoplasmosis perinatally but not diagnosed at that time. Twenty-five returned for follow-up during 1981 to 2005. Their mean (range) age at last exam was 10.9 +/- 5.7 (range, 3.5 to 27.2) years and mean follow-up was 5.7 +/- 2.9 years. Eighteen (72%) children developed at least one new lesion. Thirteen (52%) had new central lesions, 11 (44%) had new peripheral lesions, and six (24%) had both. Thirteen (52%) had new lesions diagnosed at age > or =10 years. New lesions were found at more than one visit in four (22%), and bilateral new lesions developed in seven (39%) of 18 children who developed new lesions. Of 10 additional children with eye findings and serologic tests indicative of chronic infection, six returned for follow-up, four (67%) developing new lesions at > or =10 years of age. CONCLUSIONS More than 70% developed new chorioretinal lesions. New lesions were commonly diagnosed after the first decade of life.

Intravitreal injection technique and monitoring: updated guidelines of an expert panel.

Purpose: To review evidence and provide updated guidelines on intravitreal (IVT) injection technique and monitoring. Methods: A review of the published literature on IVT injection from 2004 to 2014 formed the basis for round table deliberations by an expert panel of ophthalmologists. Results: The dramatic increase in the number of IVT injections has been accompanied by a comparable increase in evidence surrounding IVT practice patterns and techniques. The expert panel identified a number of areas that have evolved since publication of the original IVT injection guidelines in 2004, the most notable of which were a lack of evidence to support the routine use of pre-, peri-, and postinjection antibiotics to reduce the risk of endophthalmitis, and the role of aerosolized droplets containing oral contaminants from the patient and/or providers as a potential source of infection. The panel emphasized the continued importance of applying povidone–iodine to and avoiding eyelid contact with the intended injection site and needle. Conclusion: Updated guidelines on IVT injection technique and monitoring are proposed based on a review of published literature and expert panel deliberations.