Predictors of Outcome in Patients with Neovascular Age-Related Macular Degeneration Switched from Ranibizumab to 8-Weekly Aflibercept.

PURPOSE: The purpose of this study was to evaluate the outcomes over 12 months in patients with neovascular age-related macular degeneration (nAMD) with insufficient response to ranibizumab who were switched directly to 8-weekly fixed dosing of aflibercept without a loading phase. DESIGN: Retrospective interventional study. PARTICIPANTS: Consecutive patients with nAMD who were switched from pro re nata (PRN) intravitreal ranibizumab to 8-weekly fixed aflibercept because of persistent disease activity from November 1, 2013, to September 30, 2014, were included. METHODS: Demographic data, visual acuity (VA), and spectral-domain optical coherence tomography characteristics over time were evaluated to determine the prognostic indicators of final visual outcome at 12 months. MAIN OUTCOME MEASURES: The VA, central subfield thickness (CST), presence of macular fluid at month 12 compared with baseline, and the definition of prognostic indicators of final visual outcome at month 12. RESULTS: A total of 431 patients (447 eyes) were included in this study. There was no statistically significant difference in VA between baseline and month 12 (P = 0.79), whereas the CST significantly decreased at month 12 compared with baseline (P < 0.001). At the 12-month follow-up, 48.3% of eyes had no macular fluid compared with 8.5% at baseline. The mean number of injections at month 12 was 6.8±1.75. Poor prognostic indicators included increasing age, increasing CST, the presence of intraretinal fluid, pigment epithelial detachment, and subfoveal thickening. CONCLUSIONS: Patients who have not yet "responded" to PRN ranibizumab seem to exhibit retinal dehydration after switching to aflibercept, whereas there was no demonstration of VA benefit. Baseline features at the point of switching can independently predict outcomes.

Novel mutations and electrophysiologic findings in RGS9- and R9AP-associated retinal dysfunction (Bradyopsia).

PURPOSE: To examine the phenotypes of 8 patients with evidence of cone dysfunction and normal color vision (characteristic features of both oligocone trichromacy and bradyopsia), and subsequently to screen RGS9 and R9AP for disease-causing mutations. DESIGN: Retrospective case series. PARTICIPANTS: Eight affected individuals from 7 families. METHODS: Ophthalmologic examination, color vision testing, fundus photography, and detailed electrophysiologic assessment were undertaken. Blood samples were taken for DNA extraction from affected subjects and, where possible, unaffected relatives. Mutation screening of RGS9 and R9AP was performed. MAIN OUTCOME MEASURES: Detailed clinical, electrophysiologic, and molecular genetic findings. RESULTS: All 8 patients had normal ocular examination results, with visual acuity ranging from 6/12 to 6/18. Four subjects were found to harbor mutations in RGS9 or R9AP, with 3 of the identified sequence variants being novel. Three subjects, 2 Pakistani sisters and an Afghani female, had mutations in R9AP. A novel homozygous nonsense mutation, p.G205fs, was identified in the simplex case, and a second novel homozygous in-frame deletion, p.D32_Q34del, was found in the 2 sisters. The remaining patient, a British male, had a compound heterozygous mutation in RGS9 (p.R128X/p.W299R). The mutation p.R128X represents the first nonsense mutation reported in RGS9. The 4 mutation-positive subjects had concordant characteristic previously described electrophysiologic findings that were not present in the 4 individuals in whom mutations were not identified. Novel findings associated with these mutation-positive patients included that they all showed electroretinogram evidence of severe cone system dysfunction under photopic conditions but normal cone function to a red flash under scotopic conditions. Such findings seem unique for the disorder. CONCLUSIONS: This is the first report describing a nonsense mutation in RGS9. We have established novel electrophysiologic observations associated with RGS9 and R9AP mutations, including those relating to dark-adapted cone function and S-cone function. Patients with either RGS9/R9AP mutations (bradyopsia) or oligocone trichromacy have very similar clinical phenotypes, characterized by stationary cone dysfunction, mild photophobia, normal color vision, lack of nystagmus, and normal fundi. The distinctive electrophysiologic features associated with RGS9 and R9AP mutations enable directed genetic screening. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Macular perfusion determined by fundus fluorescein angiography at the 4-month time point in a prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (Bolt Study): Report 1.

PURPOSE: The purpose of this study was to assess macular perfusion with fundus fluorescein angiography at the 4-month time point in a prospective randomized, single-center 2-year trial comparing intravitreal bevacizumab and laser therapy in patients with diabetic macular edema. METHODS: All enrolled patients had standard Early Treatment of Diabetic Retinopathy Study 7-field fundus photographs and fundus fluorescein angiography at baseline and subsequently at 4-month intervals. Patients were excluded from the study if either the greatest linear dimension of the foveal avascular zone (FAZ) was >1,000 microm in diameter or there was severe perifoveal capillary loss (Early Treatment of Diabetic Retinopathy Study criteria) on fundus fluorescein angiography. The fundus fluorescein angiograms of the bevacizumab (n=42) and laser (n=38) groups were graded for greatest linear dimension of the FAZ, area of the FAZ, and perifoveal capillary loss by the Moorfields Reading Centre in a masked fashion. RESULTS: At baseline, the mean greatest linear dimension of the FAZ in the laser group was 685 +/- 262 microm and in the bevacizumab group was 737 +/- 262 microm. There was no significant difference at the 4-month time point (P 0.40) with the mean greatest linear dimension of the FAZ in the laser group recorded as 678 +/- 221 microm and in the bevacizumab group was 678 +/- 231 microm. At baseline, the median area of the FAZ in the laser group was 0.36 mm(2) (interquartile range, 0.21-0.46) and in the bevacizumab group was 0.33 mm(2) (interquartile range, 0.27-0.49). There was no significant difference at the 4-month time point (P=0.30) with the median area of the FAZ in the laser group recorded as 0.35 mm(2) (interquartile range, 0.20-0.52) and in the bevacizumab group was 0.34 mm(2) (interquartile range, 0.23-0.47). Similarly, there was no difference between the two treatment groups (P=0.64) when a comparison was made of the number of grades of change in perifoveal capillary loss observed in each patient. To date, no patients have been withdrawn from the study because of worsening macular ischemia. CONCLUSION: At 4 months, there was no evidence of worsening macular ischemia in either group.

Posterior hyaloid changes following intravitreal triamcinolone and macular laser for diffuse diabetic macular edema.

PURPOSE: To compare the effects of intravitreal triamcinolone and macular grid laser photocoagulation on the vitreomacular relationship in diffuse diabetic macular edema. METHODS: Review of optical coherence tomography images gathered in a prospective, interventional randomized clinical trial. SETTING: Institutional Practice. PROCEDURES: Seventy-seven optical coherence tomography images of 88 consecutive patients entered into a randomized clinical trial of the treatment of persistent diffuse diabetic macular edema were reviewed by two independent observers. All patients in the trial had diabetic macular edema following at least two macular grid laser treatments and were randomized to intravitreal injections of 4 mg triamcinolone or to further macular grid laser. Optical coherence tomography images were recorded at baseline, 4, 8, and 12 months and the patterns of vitreomacular relationship were classified into six categories. MAIN OUTCOME MEASURES: The patterns of vitreomacular relationship in the two groups were compared and correlated with the response to treatment. Outcome measures were defined as changes in best-corrected visual acuity Early Treatment Diabetic Retinopathy Study letters and central macular thickness on optical coherence tomography. RESULTS: Six eyes had peri-foveal vitreous detachment with or without traction in each group at baseline. At 12 months, the prevalence of peri-foveal vitreous detachment was significantly higher after intravitreal triamcinolone (n = 11) than macular grid laser (n = 8). These patients had poorer visual outcome (P = 0.01) and increased central macular thickness (P = 0.002). The development of complete posterior vitreous detachment was associated with significantly decreased central macular thickness (P = 0.001) but not better visual outcome (P = 0.72). CONCLUSION: These results suggest that posterior hyaloid changes may play a more influential role in the response to intravitreal triamcinolone than laser treatment for diffuse diabetic macular edema.

Evolution of fundus autofluorescence patterns over time in patients with chronic central serous chorioretinopathy.

PURPOSE: To determine the evolution of fundus autofluorescence (FAF) patterns in chronic central serous chorioretinopathy (CSCR) over time. METHODS: We retrospectively studied the changes in FAF patterns over time in 157 eyes of 112 patients with chronic CSCR using the Heidelberg Retina Angiography with a 488-nm excitation light and a 500-nm cutoff barrier filter. RESULTS: The mean duration of follow-up was 37.2 months. The most common baseline pattern was that of granular hypoautofluorescence (51.0%). The earliest change in chronic CSCR is diffuse hyperautofluorescence and it occurs approximately 4 months after the reported first episode. The most common change observed at this stage is a change within areas of hyperautofluorescence where hyper-reflective dots appeared or disappeared. Change in FAF patterns from areas of hyperautofluorescence to hypoautofluorescence was slow. Only 25% of eyes showed such a change in pattern by 36 months. It takes an average of 24 months for granular hypoautofluorescent pattern to develop confluent hypoautofluorescence. There were no predictive patterns for the development of confluent CSCR. CONCLUSION: Fundus autofluorescence (FAF) changes in CSCR evolve very gradually and so is not a good outcome measure for clinical trials.

Health-related quality of life, visual function and treatment satisfaction following intravitreal dexamethasone implant for diabetic macular edema.

PURPOSE: The aim of this study was to explore and describe quantitatively patient-reported outcome measures (PROMs), ie, health-related quality of life (QoL), visual function and treatment satisfaction, in patients with diabetic macular edema (DME) receiving two different regimens of Ozurdex (intravitreal dexamethasone implant). METHODS: In this multicenter, prospective study, 100 patients with center-involving refractory DME were randomized 1:1 to either five monthly fixed dosing or optical coherence tomography (OCT)-guided pro re nata (PRN) regimen of dexamethasone intravitreal implant therapy. The primary outcome was the difference between arms in change in PROMs and health-related QoL from baseline to 12 months, as measured by the Retinopathy-Dependent Quality of Life (RetDQoL) questionnaire, Visual Function Questionnaire-25 (VFQ-25) and Retinopathy Treatment Satisfaction Questionnaire (RetTSQ). RESULTS: There was no statistically significant difference in the RetDQoL score and VFQ-25 score at month 12 compared to those at baseline, whereas the total mean RetTSQ score increased significantly at the exit visit. The two treatment arms did not differ significantly regarding the change in PROMs and health-related QoL questionnaires. Logistic regression analysis showed that visual acuity (VA) of ≥55 letters, central foveal thickness <300 µm and macular volume <9.2 mm3 at the exit visit (month 12) predicted a higher change in RetTSQ. CONCLUSION: This study showed that there is a statistically significant improvement in treatment satisfaction, as measured by RetTSQ, in patients with DME treated with dexamethasone intravitreal implant, independent of the dose regimen, namely, fixed or PRN. However, it should be noted that the clinically meaningful change could not be assessed accurately, since no thresholds for clinically meaningful change currently exist for the RetTSQ. On the other hand, there was no significant change in health-related QoL, as measured using VFQ-25 and RetDQoL. Factors affecting the patients' treatment satisfaction were the final VA, the central foveal thickness and the macular volume.

Perspectives on reticular pseudodrusen in age-related macular degeneration.

Drusen have been considered the clinical hallmark of age-related macular degeneration (AMD). Reticular pseudodrusen (RPD), although first described about 25 years ago, have only been recently recognized as an additional clinical phenotype of AMD with distinct characteristics on multimodal imaging and significant impact on visual function. Eyes with RPD are at greater risk of progression to advanced AMD when compared with eyes with drusen only. RPD can also occur in the absence of drusen. Unlike features external to the retinal pigment epithelium that have received most attention in AMD, evidence suggests that RPD are associated with changes internal to the RPE. Therefore, new avenues regarding the pathogenesis of AMD are highlighted by these recent observations. We summarize the current knowledge regarding the histology, imaging, and functional changes in eyes with RPD in AMD and offer concepts of future research for the AMD community to discuss.

Caregiver Burden in Patients Receiving Ranibizumab Therapy for Neovascular Age Related Macular Degeneration.

PURPOSE: To assess the caregiver burden and factors determining the burden in patients receiving ranibizumab therapy for neovascular AMD (nAMD). METHODS: This is a cross-sectional questionnaire survey of 250 matched patient caregiver dyads across three large ophthalmic treatment centres in United Kingdom. The primary outcome was the subjective caregiver burden measured using caregiver reaction assessment scale (CRA). Objective caregiver burden was determined by the caregiver tasks and level of care provided. The factors that may predict the caregiver burden such as the patient's visual acuity of the better eye and vision related quality of life, demographics, satisfaction and support provided by the healthcare and the health status of the dyads were also collected and assessed in a hierarchical regression model. RESULTS: The mean CRA score was 3.2±0.5, similar to the score reported by caregivers for atrial fibrillation who require regular hospital appointments for monitoring their thromboprophylaxis. Caregiver tasks including accompanying for hospital appointments for eye treatment and patient's visual acuity in the better eye were the biggest contributors to the caregiver burden hierarchical model explaining 18% and 11% of the variance respectively. CONCLUSION: Ranibizumab therapy for nAMD is associated with significant caregiver burden. Both disease impact and treatment frequency contributed to the overall burden.

Injection frequency and response to bevacizumab monotherapy for diabetic macular oedema (BOLT Report 5).

AIMS: To explore the parameters that influence injection frequency in patients treated with intravitreal bevacizumab (ivB) for diabetic macular oedema. Injection frequency was considered as a surrogate marker of persistent or recurrent oedema. METHODS: A post hoc analysis of the patients randomised to the ivB arm of a prospective, randomised controlled trial (A prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (BOLT study)) was done to assess the factors that may determine the injection frequency at 12 and 24 months. The injection response patterns were classified based on the specific time point at which the macula was first defined as 'dry'. RESULTS: Eyes with better baseline visual acuity less frequently had persistent oedema and had fewer recurrences in the second year. All eyes with baseline subretinal detachment showed persistent macular oedema at 24 months. None of the other factors assessed influenced injection frequency or response in the first or second year. CONCLUSIONS: Good long-term response is predicted by resolution of macular oedema by 4 months. However, approximately 20% of patients with persistent oedema at 12 months achieved a dry macula and 50% gained more than 15 letters at 24 months with sustained treatment, suggesting that oedema at 4 or 12 months should not be used as a stopping criterion for treatment.

Pegaptanib sodium for neovascular age-related macular degeneration: clinical experience in the UK.

The pathogenesis of age-related macular degeneration (AMD) is unclear, but it can take either a neovascular/exudative/wet form, characterized by choroidal neovascularization (CNV), or a dry form. No treatments are available for the dry form, but there are a number of pharmacological interventions that inhibit vascular endothelial growth factor (VEGF), which is central to the pathogenesis of CNV and neovascular AMD. Available anti-VEGF agents either target all active VEGF isoforms (eg, ranibizumab), or take a more selective approach and inhibit only VEGF(165) (eg, pegaptantib sodium). Current guidance on their use is equivocal and restrictive at best, resulting in associated difficulties in securing adequate, timely funding for treatment. The Moorfields Eye Hospital undertook an audit of 70 patients receiving intravitreal (ITV) pegaptanib sodium on a pro re nata (prn) dosing schedule. Despite initial funding delays, the audit recorded superior treatment outcomes compared with those reported in the VISION trials at 12 weeks: 88% of audit patients maintained stable vision, 29% gained vision and 6% experienced severe vision loss compared with 70%, >/=6% and

New algorithm for assessing patient suitability for macular translocation surgery.

PURPOSE: We propose a case selection algorithm to assess suitability for macular translocation for subfoveal neovascular membrane (CNV) secondary to age-related macular degeneration. The algorithm is based on preoperative assessment of residual foveal function, as assessed by a slit-lamp fixation task and duration of visual loss, in patients with poor acuity. We validate our slit-lamp fixation task against an objective analysis (Nidek MP-1 Microperimetry) and proceed to examine surgical outcomes as selected by the algorithm. METHODS: A prospective series of 27 consecutive patients with CNV underwent translocation at Moorfields Eye Hospital, London between May 2003 and May 2006. RESULTS: Validation of the slit-lamp fixation task revealed 100% concordance in classification of fixation between the slit-lamp task and the microperimeter. At an average follow up of 12.2 months, the mean Early Treatment of Diabetic Retinopathy Study distance acuity improved from logMAR 0.88 to 0.68 (P < 0.03). Sixty-six per cent of patients achieved an acuity of < or =logMAR 0.8 (6/30), 22% an acuity of < or =logMAR 0.3 (6/12) and 33% gained three lines of acuity. The mean MN Read reading acuity improved from logMAR 1.23 to 0.91 (P < 0.01). Forty-four per cent of patients achieved an acuity of > or =logMAR 0.7 (N10), 15% an acuity of > or =logMAR 0.4 (N5) and 44% gained three lines of acuity. DISCUSSION: We have demonstrated a simple case selection algorithm that is based on residual foveal function and suggests good outcomes. The strongest indicators of foveal function are fixation characteristics and duration of visual loss. In contrast to previous studies, our algorithm suggests good outcomes independently of preoperative visual acuity and CNV characteristics.

Vitreous and aqueous concentrations of proangiogenic, antiangiogenic factors and other cytokines in diabetic retinopathy patients with macular edema: Implications for structural differences in macular profiles.

The aim of the study was to determine anatomical and growth factor profiles in patients with clinically significant macular oedema (CSMO) undergoing pars plana vitrectomy (PPV). Twenty patients with moderate nonproliferative diabetic retinopathy (NPDR) with persistent CSMO underwent PPV. Patients had baseline and postoperative clinical assessment including Ocular Coherence Tomography (OCT). Baseline vitreous and aqueous and serial postoperative aqueous samples were analysed for vascular endothelial growth factor-A (VEGF-A), pigment epithelium derived Factor (PEDF) and other factors (pg/ml) including hepatocyte growth factor, MMP 9, soluble flt-1 Receptor, and TGF beta1 by ELISA. Vitreous from patients with full thickness macular holes (8) and proliferative diabetic retinopathy (22) were collected for comparison as controls. Vitreous VEGF-A concentration in the NPDR group was 957 pg/ml compared to 239 pg/ml in the macula hole (FTMH) control (p < 0.0001) and 596 pg/ml compared to PDR (p = 0.006). The median diabetic vitreous PEDF concentration was 1.36 microg/ml (FTMH 2.6 microg/ml p = 0.05). In NPDR, it was higher (1.59 microg/ml) than PDR (1.27 microg/ml) p = 0.02. There were changes to the HGF, soluble flt-1 Receptor and TGF b1 concentrations in the NPDR compared to either PDR or the normal state. In CSMO, two OCT profiles were identified: dome-shaped macular elevation (Group 1) (n = 4) and diffuse-low elevation profile (Group 2) (n = 16) which also showed differences in the postoperative median aqueous VEGF concentrations despite macular volume decreasing for both. The results suggest that there is an up-regulation of VEGF in the vitreous of the diabetic eye with a reciprocal decrease in PEDF. The structural and molecular differences between the two OCT macular profiles may explain the varying response to PPV in patients with diffuse CSMO.