Yit C. Yang

Current concepts on primary open-angle glaucoma genetics: a contribution to disease pathophysiology and future treatment

Glaucoma is a common, complex, heterogenous disease and it constitutes the major cause of irreversible blindness worldwide. Primary open-angle glaucoma (POAG) is the most common type of glaucoma in all populations. Most of the molecular mechanisms leading to POAG development are still unknown. Gene mutations in various populations have been identified by genetic studies and a genetic basis for glaucoma pathogenesis has been established. Linkage analysis and association studies are genetic approaches in the investigation of the genetic basis of POAG. Genome-wide association studies (GWAS) are more powerful compared with linkage analysis in discovering genes of small effect that might contribute to the development of the disease. POAG links to at least 20 genetic loci, but only 2 genes identified in these loci, myocilin and optineurin, are considered as well-established glaucoma-causing genes, whereas the role of other loci, genes, and variants implicated in the development of POAG remains controversial. Gene mutations associated with POAG result in retinal ganglion cell death, which is the common outcome of pathogenetic mechanisms in glaucoma. In future, if the sensitivity and specificity of genotyping increases, it may be possible to screen individuals routinely for disease susceptibility. This review is an update on the latest progress of genetic studies associated with POAG. It emphasizes the correlation of recent achievements in genetics with glaucoma pathophysiology, glaucoma treatment perspectives, and the possibility of future prevention of irreversible visual loss caused by the disease.

Risk Factors and Incidence of Macular Edema after Cataract Surgery: A Database Study of 81984 Eyes

PURPOSE To define the incidence of pseudophakic macular edema (PME) after cataract surgery and to identify contributory risk factors. DESIGN Retrospective database study of electronic medical records (EMRs). PARTICIPANTS A total of 81984 eyes undergoing cataract surgery between December 2010 and December 2014 from 8 independent United Kingdom clinical sites. METHODS Structured clinical data mandated by the EMR were anonymized and extracted for each eye undergoing cataract surgery including: perioperative visual acuity, copathologic features, simultaneous surgical procedures, and the presence or absence of a specified list of intraoperative complications. Diabetic status with matched Early Treatment Diabetic Retinopathy Study (ETDRS) grading also was mandated by the EMR. Eyes receiving prophylactic nonsteroidal anti-inflammatory drugs were excluded. MAIN OUTCOME MEASURE Diagnosis of cystoid macular edema or new-onset macular edema in patients with diabetes, recorded by a healthcare professional within 90 days of surgery. RESULTS Baseline incidence of PME in eyes without operative complications, diabetes, or risk factors was 1.17%. Eyes in which PME developed were more likely to be male, older, and to demonstrate risk factors. The relative risk (RR) was increased in eyes with capsule rupture with or without vitreous loss (RR, 2.61; 95% confidence interval [CI], 1.57-4.34), a previous diagnosis of epiretinal membrane (RR, 5.60; 95% CI, 3.45-9.07), uveitis (RR, 2.88; 95% CI, 1.50-5.51), retinal vein occlusion (RR, 4.47; 95% CI, 2.56-5.92), or retinal detachment repair (RR, 3.93; 95% CI, 2.60-5.92). High myopia, age-related macular degeneration, or prostaglandin analog use were not shown to increase risk. Eyes with PME on average had poorer postoperative visual acuity, which persisted to the latest time point assessed, up to 24 weeks. Eyes from patients with diabetes, even in the absence of retinopathy, had an increased RR (RR, 1.80; 95% CI, 1.36-2.36) of new macular edema after surgery. The risk was higher in the presence of any diabetic retinopathy (DR; RR, 6.23; 95% CI, 5.12-7.58) and rose proportionately with increasing severity of DR. CONCLUSIONS Pseudophakic macular edema occurs commonly after phacoemulsification cataract surgery, even in the absence of complications and risk factors. This large retrospective study using structured EMR data quantified the RRs of PME and the risk with increasing ETDRS severity of DR. It highlights the need for prophylactic therapy, especially in those groups of eyes with the highest RRs.

Defining response to anti-VEGF therapies in neovascular AMD

The introduction of anti-vascular endothelial growth factor (anti-VEGF) has made significant impact on the reduction of the visual loss due to neovascular age-related macular degeneration (n-AMD). There are significant inter-individual differences in response to an anti-VEGF agent, made more complex by the availability of multiple anti-VEGF agents with different molecular configurations. The response to anti-VEGF therapy have been found to be dependent on a variety of factors including patient’s age, lesion characteristics, lesion duration, baseline visual acuity (VA) and the presence of particular genotype risk alleles. Furthermore, a proportion of eyes with n-AMD show a decline in acuity or morphology, despite therapy or require very frequent re-treatment. There is currently no consensus as to how to classify optimal response, or lack of it, with these therapies. There is, in particular, confusion over terms such as ‘responder status’ after treatment for n-AMD, ‘tachyphylaxis’ and ‘recalcitrant’ n-AMD. This document aims to provide a consensus on definition/categorisation of the response of n-AMD to anti-VEGF therapies and on the time points at which response to treatment should be determined. Primary response is best determined at 1 month following the last initiation dose, while maintained treatment (secondary) response is determined any time after the 4th visit. In a particular eye, secondary responses do not mirror and cannot be predicted from that in the primary phase. Morphological and functional responses to anti-VEGF treatments, do not necessarily correlate, and may be dissociated in an individual eye. Furthermore, there is a ceiling effect that can negate the currently used functional metrics such as >5 letters improvement when the baseline VA is good (ETDRS>70 letters). It is therefore important to use a combination of both the parameters in determining the response.The following are proposed definitions: optimal (good) response is defined as when there is resolution of fluid (intraretinal fluid; IRF, subretinal fluid; SRF and retinal thickening), and/or improvement of >5 letters, subject to the ceiling effect of good starting VA. Poor response is defined as <25% reduction from the baseline in the central retinal thickness (CRT), with persistent or new IRF, SRF or minimal or change in VA (that is, change in VA of 0+4 letters). Non-response is defined as an increase in fluid (IRF, SRF and CRT), or increasing haemorrhage compared with the baseline and/or loss of >5 letters compared with the baseline or best corrected vision subsequently. Poor or non-response to anti-VEGF may be due to clinical factors including suboptimal dosing than that required by a particular patient, increased dosing intervals, treatment initiation when disease is already at an advanced or chronic stage), cellular mechanisms, lesion type, genetic variation and potential tachyphylaxis); non-clinical factors including poor access to clinics or delayed appointments may also result in poor treatment outcomes. In eyes classified as good responders, treatment should be continued with the same agent when disease activity is present or reactivation occurs following temporary dose holding. In eyes that show partial response, treatment may be continued, although re-evaluation with further imaging may be required to exclude confounding factors. Where there is persistent, unchanging accumulated fluid following three consecutive injections at monthly intervals, treatment may be withheld temporarily, but recommenced with the same or alternative anti-VEGF if the fluid subsequently increases (lesion considered active). Poor or non-response to anti-VEGF treatments requires re-evaluation of diagnosis and if necessary switch to alternative therapies including other anti-VEGF agents and/or with photodynamic therapy (PDT). Idiopathic polypoidal choroidopathy may require treatment with PDT monotherapy or combination with anti-VEGF. A committee comprised of retinal specialists with experience of managing patients with n-AMD similar to that which developed the Royal College of Ophthalmologists Guidelines to Ranibizumab was assembled. Individual aspects of the guidelines were proposed by the committee lead (WMA) based on relevant reference to published evidence base following a search of Medline and circulated to all committee members for discussion before approval or modification. Each draft was modified according to feedback from committee members until unanimous approval was obtained in the final draft. A system for categorising the range of responsiveness of n-AMD lesions to anti-VEGF therapy is proposed. The proposal is based primarily on morphological criteria but functional criteria have been included. Recommendations have been made on when to consider discontinuation of therapy either because of success or futility. These guidelines should help clinical decision-making and may prevent over and/or undertreatment with anti-VEGF therapy.

Ranibizumab in myopic choroidal neovascularization: the 12-month results from the REPAIR study

pathophysiology in LHON. In this study, we reported that ganglion cell analysis could precisely detect the loss of retinal ganglion cell in a time-dependent manner during early phase of LHON when RNFL thickness had not decreased yet. We also raise the possibility that there might be many more patients>60 years of age with visual loss owing to LHON than we have supposed previously. It may be worth investigating mtDNA point mutations regardless of age if a patient presents with unknown visual acuity loss with central scotoma.

Directional protein secretion by the retinal pigment epithelium: roles in retinal health and the development of age-related macular degeneration

The structural and functional integrity of the retinal pigment epithelium (RPE) is fundamental for maintaining the function of the neuroretina. These specialized cells form a polarized monolayer that acts as the retinal–blood barrier, separating two distinct environments with highly specialized functions: photoreceptors of the neuroretina at the apical side and Bruchs membrane/highly vascularized choriocapillaris at the basal side. The polarized nature of the RPE is essential for the health of these two regions, not only in nutrient and waste transport but also in the synthesis and directional secretion of proteins required in maintaining retinal homoeostasis and function. Although multiple malfunctions within the RPE cells have been associated with development of age‐related macular degeneration (AMD), the leading cause of legal blindness, clear causative processes have not yet been conclusively characterized at the molecular and cellular level. This article focuses on the involvement of directionally secreted RPE proteins in normal functioning of the retina and on the potential association of incorrect RPE protein secretion with development of AMD. Understanding the importance of RPE polarity and the correct secretion of essential structural and regulatory components emerge as critical factors for the development of novel therapeutic strategies targeting AMD.

Ranibizumab for the treatment of choroidal neovascularisation secondary to pathological myopia: interim analysis of the REPAIR study

AimsTo evaluate the efficacy and safety of intravitreal ranibizumab in patients with choroidal neovascularisation secondary to pathological myopia (myopic CNV). Data are from a pre-planned, 6-month interim analysis.MethodsPhase II, open-label, single arm, multicentre, 12-month study, recruiting patients (aged ≥18 years) with active primary or recurrent subfoveal or juxtafoveal myopic CNV, with a best-corrected visual acuity (BCVA) score of 24–78 Early Treatment Diabetic Retinopathy Study (ETDRS) letters in the study eye and a diagnosis of high myopia of at least −6 dioptres.Patients received 0.5 mg ranibizumab administered intravitreally to the study eye, followed by monthly injections given as needed (based on a predefined algorithm) for up to 11 months.ResultsAt 6 months, mean BCVA improved from baseline by 12.2 letters, as did central macular thickness (in this interim analysis defined as a measure of either central subfield macular thickness or centre point macular thickness) from baseline by 108 μm in the 48 study eyes of 48 patients. Fewer patients had centre-involving intraretinal oedema (13.0% vs 91.5%), intraretinal cysts (10.9% vs 57.4%), or subretinal fluid (13.0% vs 66.0%) at 6 months than at baseline. Patients received a mean of 1.9 retreatments, were satisfied with ranibizumab treatment, and well being was maintained. No new safety signals were identified.ConclusionsResults from the planned interim analysis support the role of ranibizumab in the treatment of myopic CNV, with excellent efficacy achieved with a low number of injections and few serious adverse events.

A randomized clinical trial comparing fixed vs pro-re-nata dosing of Ozurdex in refractory diabetic macular oedema (OZDRY study).

ObjectiveTo compare the clinical effectiveness and safety of 5-monthly fixed dosing vs pro-re-nata (PRN) Ozurdex treatment in patients with refractory diabetic macular oedema (DMO).DesignProspective, multicentre, randomized active-controlled non-inferiority clinical trial.ParticipantsParticipants were 100 patients who attended Medical Retina Clinics for management of centre-involving refractory DMO.InterventionsParticipants were randomized 1 : 1 to either 5-monthly fixed dosing or optical coherence tomography (OCT)-guided PRN regimen of Ozurdex therapy for DMO. Data were collected on best-corrected visual acuity (BCVA), patient-reported outcome measures (PROM), macular thickness and morphology, diabetic retinopathy status, number of injections and adverse events from baseline for a period of 12 months.Main outcome measuresThe primary outcome was the difference between arms in change in BCVA from baseline to 12 months. The prespecified non-inferiority margin was five ETDRS letters. Key secondary outcomes included change in PROM scores, change in macular thickness, change in retinopathy and macular morphology, and safety profile.ResultsThe mean change in BCVA was +1.48 (SD 14.8) in the fixed arm vs −0.17 (SD 13.1) in the PRN arm, with adjusted effect estimate +0.97, 90% confidence interval (−4.01, +5.95), P=0.02 (per protocol analysis). The conclusions of the ITT analysis were primarily supportive, −0.34 (−5.49, 4.81) P=0.07, but sensitive to an alternative assumption on missing data, +0.28 (−4.72, 5.27) P=0.04.ConclusionsThe mean change in BCVA with 5-monthly fixed dosing of Ozurdex was non-inferior to OCT-guided PRN Ozurdex therapy for refractory DMO based on a per protocol analysis.

INTRAVITREAL CORTICOSTEROIDS IN DIABETIC MACULAR EDEMA: PHARMACOKINETIC CONSIDERATIONS.

Purpose: To review the relationship between kinetics, efficacy, and safety of several corticosteroid formulations for the treatment of diabetic macular edema. Methods: Reports of corticosteroid use for the treatment of diabetic macular edema were identified by a literature search, which focused on the pharmacokinetics, efficacy, and safety of these agents in preclinical animal models and clinical trials. Results: Available corticosteroids for diabetic macular edema treatment include intravitreal triamcinolone acetonide, dexamethasone, and fluocinolone acetonide. Because of differences in solubility and bioavailability, various delivery mechanisms are used. Bioerodible delivery systems achieve higher maximum concentrations than nonbioerodible formulations. There is a relationship between visual gains and drug persistence in the intravitreal compartment. Safety effects were more complex; level of intravitreal triamcinolone acetonide exposure is related to development of elevated intraocular pressure and cataract; this does not seem to be the case for dexamethasone, where two different doses showed similar mean intraocular pressure and incidence of cataract surgery. With fluocinolone acetonide, rates of intraocular pressure elevations requiring surgery seem to be dose related; rates of cataract extraction were similar regardless of dose. Conclusion: Available corticosteroids for diabetic macular edema exhibit different pharmacokinetic profiles that impact efficacy and adverse events and should be taken into account when developing individualized treatment plans.

Optical coherence tomography changes before the development of choroidal neovascularization in second eyes of patients with bilateral wet macular degeneration.

AimTo describe the frequency of neovascular age-related macular degeneration (nAMD) in second eyes of patients undergoing ranibizumab therapy in their first eye and to evaluate the patterns of optical coherence tomography (OCT) abnormalities in fellow eyes before nAMD.MethodPatients who developed choroidal neovascularization (CNV) in the second eye while on treatment for the first eye were identified. OCT scans of the second eyes, performed before the onset of CNV, were retrospectively examined and graded. Frequency of second eye involvement was estimated and patterns of progression of OCT abnormalities were described and classified.ResultsIn all, 65 out of 749 consecutive patients required ranibizumab in their second eye for treatment-naïve nAMD over a 2-year period. The mean interval from commencement of ranibizumab in first eye to conversion in second eye was 12 months (2–35.5 months). There were three patterns of CNV development: group A (12%, n=8) had no OCT abnormalities in the second eye just before developing CNV; group B (38%, n=25) had no abnormalities at baseline but developed OCT changes more than one visit before conversion and group C (50%, n=32) had OCT changes from baseline, which did not progress until just before conversion.ConclusionPatients with retinal pigment epithelial elevation without sub-retinal fluid on OCT in their fellow eyes have a high risk of progression to require therapy within a 2-year period. An anticipatory approach may be warranted, but a small group with completely normal OCT appearances can still develop lesions between visits.

Erratum: Defining response to anti-VEGF therapies in neovascular AMD

Correction to: Eye (2015) 29, 721–731; doi:10.1038/eye.2015.48; published online 17 April 2015 Since the online publication of the above article, the authors have noted that the name of the ninth author was published incorrectly. The correct name is SP Kelly. The authors have also noted that the conflict of interest statements were not complete.