Six-Year Outcomes in Subjects with Polypoidal Choroidal Vasculopathy in the EVEREST II Study.

INTRODUCTION: The EVEREST II study previously reported that intravitreally administered ranibizumab (IVR) combined with photodynamic therapy (PDT) achieved superior visual gain and polypoidal lesion closure compared to IVR alone in patients with polypoidal choroidal vasculopathy (PCV). This follow-up study reports the long-term outcomes 6 years after initiation of the EVEREST II study. METHODS: This is a non-interventional cohort study of 90 patients with PCV from 16 international trial sites who originally completed the EVEREST II study. The long-term outcomes were assessed during a recall visit at about 6 years from commencement of EVEREST II. RESULTS: The monotherapy and combination groups contained 41 and 49 participants, respectively. The change in best-corrected visual acuity (BCVA) from baseline to year 6 was not different between the monotherapy and combination groups; - 7.4 ± 23.0 versus - 6.1 ± 22.4 letters, respectively. The combination group had greater central subfield thickness (CST) reduction compared to the monotherapy group at year 6 (- 179.9 vs - 74.2 µm, p = 0.011). Fewer eyes had subretinal fluid (SRF)/intraretinal fluid (IRF) in the combination versus monotherapy group at year 6 (35.4% vs 57.5%, p = 0.032). Factors associated with BCVA at year 6 include BCVA (year 2), CST (year 2), presence of SRF/IRF at year 2, and number of anti-VEGF treatments (years 2-6). Factors associated with presence of SRF/IRF at year 6 include combination arm (OR 0.45, p = 0.033), BCVA (year 2) (OR 1.53, p = 0.046), and presence of SRF/IRF (year 2) (OR 2.59, p = 0.042). CONCLUSION: At 6 years following the EVEREST II study, one-third of participants still maintained good vision. As most participants continued to require treatment after exiting the initial trial, ongoing monitoring and re-treatment regardless of polypoidal lesion status are necessary in PCV. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01846273.

Multicentre, randomised clinical trial comparing intravitreal aflibercept monotherapy versus aflibercept combined with reduced-fluence photodynamic therapy (RF-PDT) for the treatment of polypoidal choroidal vasculopathy.

PURPOSE: To compare the efficacy and safety of intravitreal aflibercept (IVA) monotherapy versus aflibercept combined with reduced-fluence photodynamic therapy (RF-PDT) (IVA+RF-PDT) for the treatment of polypoidal choroidal vasculopathy (PCV). METHODS AND ANALYSIS: Multicentred, double-masked, randomised controlled trial to compare the two treatment modalities. The primary outcome of the study is to compare the 52-week visual outcome of IVA versus IVA+RF PDT. One hundred and sixty treatment-naïve patients with macular PCV confirmed on indocyanine green angiography will be recruited from three centres in Singapore. Eligible patients will be randomised (1:1 ratio) into one of the following groups: IVA monotherapy group-aflibercept monotherapy with sham photodynamic therapy (n=80); combination group-aflibercept with RF-PDT (n=80). Following baseline visit, all patients will be monitored at 4 weekly intervals during which disease activity will be assessed based on best-corrected visual acuity (BCVA), ophthalmic examination findings, optical coherence tomography (OCT) and angiography where indicated. Eyes that meet protocol-specified retreatment criteria will receive IVA and sham/RF-PDT according to their randomisation group. Primary endpoint will be assessed as change in BCVA at week 52 from baseline. Secondary endpoints will include anatomical changes based on OCT and dye angiography as well as safety assessment. Additionally, we will be collecting optical coherence tomography angiography data prospectively for exploratory analysis. ETHICS AND DISSEMINATION: This study will be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with the ICH E6 guidelines of Good Clinical Practice and the applicable regulatory requirements. Approval from the SingHealth Centralised Institutional Review Board has been sought prior to commencement of the study. TRIAL REGISTRATION NUMBER: NCT03941587.

Hints for Gentle Submacular Injection in Non-Human Primates Based on Intraoperative OCT Guidance.

Purpose: Delivery of Advanced Therapy Medicinal Products to the submacular space is increasingly evolving into a therapeutic modality. Cell replacement for age-related macular degeneration (AMD) and gene therapy for RPE65 are recent successful examples. Herein, a nonhuman primate (NHP) model was used to investigate surgical means to detach the macula. Methods: Sixteen eyes of 13 healthy macaques underwent a 25-gauge vitrectomy and subretinal injection of balanced salt solution monitored by microscope-integrated intraoperative optical coherence tomography (miOCT). The animals were followed with OCT and histology. Results: The miOCT monitoring allowed a more precise definition of surgical trauma ranging from an initial full-thickness foveal tear, or induction of a cystoid macular edema (CME), until no foveal defect was discernible, as the technique improved. However, as the subretinal fluid wave detached the fovea, the aforementioned lesions formed, whereas persistent retinal adhesion reproducibly proved to remain in the distal parafoveal semi-annulus. Measures to reduce foveal trauma during submacular fluid injection included reducing intraocular pressure, injection volume, and velocity, as well as the retinal location for bleb initiation, use of a vitreous tamponade, and a dual-bore subretinal cannula. Conclusions: A stable very low intraocular pressure and careful subretinal injection may avoid tangential macular stretching or mechanical CME formation, while vitreous tamponade may facilitate a more lamellar subretinal flow, all thereby reducing foveal trauma during submacular injection in NHP. Translational Relevance: These results can be relevant to any submacular surgery procedure used today, as they synergistically reduce the risk of compromising foveal integrity.

Premature Ocular Aging Features in Childhood Acute Lymphoblastic Leukemia Survivors.

Purpose: Childhood cancer survivors (CCS) demonstrate features of premature aging in a multitude of organ systems. The aim of this pilot study is to determine the presence of premature ocular aging features in CCS, specifically childhood acute lymphoblastic leukemia (ALL) survivors. Methods: This prospective case-control study was conducted over a period of 21 months, starting July 2015 till March 2017. A total of 59 childhood ALL survivors who attended the Paediatric Oncology Clinic of University Malaya Medical Centre (UMMC) and 48 age, race, and gender-matched controls went through a series of ocular examinations and tests. Inclusion criteria used to recruit survivors were age above 16 years, history of ALL in childhood, completion of treatment for ALL, and a remission period of at least 5 years. Patients with ocular disease and those who received hematopoietic stem cell transplantation were excluded. The parameters measured were visual acuity, amplitude of accommodation, pupil cycle time (PCT), and tear break-up time (TBUT). Results: Survivors of childhood ALL demonstrated significant differences in amplitude of accommodation, PCT, and TBUT compared to age-matched controls. Survivors had a lower median (interquartile range [IQR]) amplitude of accommodation compared to controls (11.0 D [9.0-13.0] vs. 12.0 D [10.5-15]; p = 0.045). Survivors also showed a longer median (IQR) PCT in comparison to controls (931.00 mseconds (857.00-1063.00) vs. 875.50 mseconds (825.75-966.00); p = 0.024). In addition, median (IQR) TBUT was worse in survivors in comparison to the control group (9 seconds [6-13] vs. 11 seconds [10-15]; p = 0.001). Conclusion: Survivors of childhood ALL demonstrate premature ocular aging features compared to age-matched controls. Thus, survivors may benefit from having ocular examinations as part of their routine late-effects screening to detect age-related ocular morbidities early in its course.

Clinical spectrum, treatment and outcomes of uveal melanoma in a tertiary centre.

INTRODUCTION: We aimed to describe the clinical characteristics, diagnostic challenges, treatment patterns and outcomes of uveal melanoma (UM) in a tertiary care centre. METHODS: This is a retrospective case series of 11 consecutive patients with UM who were managed in a tertiary referral centre between 2002 and 2017. Epidemiological, clinical, pathological and radiological characteristics were reviewed. Classification of choroidal melanoma as small, medium or large was based on the criteria established by the Collaborative Ocular Melanoma Study. RESULTS: Mean age at presentation was 42.9 (range 27‒67) years. In 7 (64%) patients, a definitive diagnosis of UM was made after a mean follow-up period of 6.4 (range 1‒17) months. There were one, six and four patients with small-, medium- and large-sized choroidal melanomas, respectively. Treatment was enucleation in 5 (45.5%) patients, plaque brachytherapy in 4 (36.4%) patients, transpupillary thermotherapy in 1 (9.1%) patient, and observation in 1 (9.1%) patient. Median follow-up was 29 months. Metastatic disease developed in 5 (45.5%) patients at the mean age of 46.6 (range 38‒56) years, with median overall survival of 20 months. Genetic mutations in three patients were monosomy 3 (n = 2), and gain of 3q and 8q (n = 1). CONCLUSION: Our study supports the finding that UM in Chinese and Asian Indian patients presents at a younger age than in Caucasians. Although it is rare, ophthalmologists should remain mindful of this life-threatening disease. We propose establishing a national and regional registry for ocular tumours with genetic information to characterise the disease spectrum in Southeast Asia.

Retinal-detachment repair and vitreous-like-body reformation via a thermogelling polymer endotamponade.

Internal-tamponade agents are crucial surgical adjuncts in vitreoretinal surgery. Clinically used endotamponade agents act through buoyancy forces, yet can result in prolonged post-operative positioning, temporary loss of vision, raised intra-ocular pressure, cataract formation or the need for additional removal surgery. Here, we describe a thermogelling polymer that provides an internal tamponade effect through surface tension and swelling counter-forces. We tested the long-term biocompatibility of the polymer endotamponade in rabbit vitrectomy models, and its surgical efficacy and biocompatibility in a non-human primate retinal-detachment model. We also show that, while the thermogel biodegrades during the three months following surgery, it promotes the reformation of a vitreous-like body that mimics the biophysical properties of the natural vitreous. The thermogelling endotamponade might serve as a long-term vitreous substitute.

Optical Coherence Tomography in Patients With the Subretinal Implant Retina Implant Alpha IMS.

BACKGROUND AND OBJECTIVE: The aim of this study was to assess changes in retinal structure and thickness after subretinal implantation of the Retina Implant Alpha IMS (Retina Implant AG, Reutlingen, Germany). PATIENTS AND METHODS: Spectral-domain optical coherence tomography (SD-OCT) imaging was performed to assess the structure and thickness of the retina anterior to the microphotodiode array preoperatively, within 6 weeks and 6 months ± 1 month after implantation. Thickness measurements were performed using the distance tool of the built-in software. Three thickness measurements were performed in each of the four quadrants of the retina on the microchip within 6 weeks and 6 months ± 1 month after implantation. RESULTS: The mean ± standard deviation change in retinal thickness from within 6 weeks to 6 months ± 1 month after implantation in all four quadrants combined was 24 µm ± 68 µm. None of the tested variables (location, time, or their interaction) had a statistically significant effect on the mean retinal thickness (P = .961, P = .131, and P = .182, respectively; n = 19). CONCLUSION: The authors report on qualitative and quantitative findings in retinal structure in 27 patients after subretinal implantation of the Retina Implant Alpha IMS using OCT technology. No significant changes of retinal thickness could be observed in a period of 6 months after surgery. With more patients receiving subretinal implants and with advanced OCT technology, the data set will be extended to study possible changes in retinal structure in finer detail. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:993-999.].

Quantitative Analysis of En Face Spectral-Domain Optical Coherence Tomography Imaging in Polypoidal Choroidal Vasculopathy.

BACKGROUND AND OBJECTIVE: Spectral-domain optical coherence tomography (SD-OCT) imaging can be used to visualize polypoidal choroidal vasculopathy (PCV) lesions in the en face plane. Here, the authors describe a novel lesion quantification technique and compare PCV lesion area measurements and morphology before and after anti-vascular endothelial growth factor (VEGF) treatment. PATIENTS AND METHODS: Volumetric SD-OCT scans in eyes with PCV before and after induction anti-VEGF therapy were retrospectively analyzed. En face SD-OCT images were generated and a pixel intensity thresholding process was used to quantify total lesion area. RESULTS: Thirteen eyes with PCV were analyzed. En face SD-OCT PCV lesion area quantification showed good intergrader reliability (intraclass correlation coefficient = 0.944). Total PCV lesion area was significantly reduced after anti-VEGF therapy (2.22 mm2 vs. 2.73 mm2; P = .02). The overall geographic pattern of the branching vascular network was typically preserved. CONCLUSION: PCV lesion area analysis using en face SD-OCT is a reproducible tool that can quantify treatment related changes. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:126-133.].

Quantitative Changes in Pigment Epithelial Detachment Area and Volume Predict Retreatment in Polypoidal Choroidal Vasculopathy.

PURPOSE: To determine if changes in pigment epithelial detachment (PED) area and volume predict retreatment in polypoidal choroidal vasculopathy (PCV). DESIGN: Retrospective case-control study. METHODS: PCV patients on pro re nata (PRN) anti-vascular endothelial growth factor (VEGF) therapy with >1 year follow-up at an academic retina service were included. Monthly anti-VEGF injections were given until a dry macula was achieved, and treatment deferred. Retreatment indication was recurrence of intraretinal or subretinal fluid or new hemorrhage. PED area and volume changes between visits with a dry macula ("D") and immediate preceding visits ("D-1") were analyzed with an automated optical coherence tomography-based software. Univariate and multivariate analyses were conducted to determine associations between changes in PED parameters and retreatment need at immediate subsequent visits ("D+1"). RESULTS: Twenty-two PCV patients (mean age 69.6 years) were included. Of 46 visits D, 11 (23.9%) were followed by retreatment at D+1. An increase in PED area (>0.43 mm2) and volume (>0.0245 mm3) from D-1 to D was associated with 18.2 (95% CI, 3.7-125.6; P < .001) and 101.9 (95% CI, 9.5-14 308.0; P < .001) higher retreatment odds at D+1, respectively. These associations remained significant after multivariate analyses adjusting for baseline PED area or volume, greatest linear dimension, and type of anti-VEGF agent. CONCLUSION: In PCV on PRN anti-VEGF therapy, increases in PED area and volume at one visit, despite achievement of a dry macula, are associated with retreatment at the next visit. Retreatment criteria relying on intraretinal or subretinal fluid or new hemorrhages may be expanded to include PED changes. Studies are needed to determine if using PED parameters in treatment decisions reduces recurrences.

Optical coherence tomography patterns as predictors of visual outcome in dengue-related maculopathy.

PURPOSE: The purpose of this study was to characterize the presentations, long-term outcomes, and visual prognostic factors in dengue-related maculopathy of 41 patients with dengue fever and impaired vision from dengue-related maculopathy in a retrospective noninterventional and observational series. METHODS: The medical records of patients with dengue-related maculopathy diagnosed over 18 months between July 2004 and December 2005 at The Eye Institute, Tan Tock Seng Hospital and Communicable Disease Center, Singapore, were reviewed and followed up for 24 months. Visual acuity and symptoms (presence of scotoma on automated visual fields and Amsler grid) were correlated with optical coherence tomography evaluation. RESULTS: Mean age was 28.7 years and there were more men (53.7%). The most common visual complaints were blurring of vision (51.2%) and central scotoma (34.1%). Most patients recovered best-corrected visual acuity >20/40. Optical coherence tomography showed 3 patterns of maculopathy: 1) diffuse retinal thickening; 2) cystoid macular edema; and 3) foveolitis. The visual outcome was independent of the extent of edema, but scotomata persisted longest in patients with foveolitis and shortest with those with diffuse retinal thickening. CONCLUSION: Dengue-associated ocular inflammation is an emerging ophthalmic condition and often involves the posterior segment. Prognosis is variable. Patients usually regain good vision but may retain persistent scotomata even at 2 years despite clinical resolution of the disease. Optical coherence tomography patterns in dengue maculopathy are useful for characterization, monitoring, and prognostication of the visual defect.

Spectral domain optical coherence tomography imaging of retinal diseases in Singapore.

In this retrospective case series, the authors reviewed cases of patients with macular disorders whose eyes had been imaged using spectral domain optical coherence tomography (SD-OCT) (Cirrus HD-OCT; Carl Zeiss Meditec, Inc., Dublin, CA). SD-OCT images were obtained from patients with a variety of ocular conditions attending a tertiary retinal clinic in Singapore from August 2007 to December 2007, according to standardized protocols. Images of 428 eyes from 301 patients were reviewed. Ocular diagnoses included diabetic macular edema, exudative age-related macular degeneration, central serous chorioretinopathy, cystoid macular edema, retinal vein and artery occlusions, infective chorioretinitis, and others. The authors present four cases of particular interest to illustrate how SD-OCT was useful in complementing the clinician's assessment of macular disease.

Recurrent Enterococcus faecalis endophthalmitis after phacoemulsification.

We present the first reported case of late recurrence of postoperative Enterococcus faecalis endophthalmitis after cataract surgery in a 45-year-old diabetic man. Culture-positive E faecalis endophthalmitis was diagnosed 2 days after uneventful phacoemulsification. Early vitrectomy with intravitreal and subconjunctival vancomycin and amikacin and topical vancomycin resulted in apparently complete clinical resolution after 4 months and a best corrected visual acuity of 20/25. Recurrent endophthalmitis with hypopyon occurred 7 months postoperatively and resolved with intravitreal vancomycin and topical prednisolone acetate 1%. However, the patient had a similar relapse at 9 months that resulted in deterioration of visual acuity to no light perception despite a repeat vitrectomy, intraocular lens explantation, capsular bag removal, and intravitreal antibiotics. The late recurrences could have been the result of persistent sequestration of the organism in the capsular bag.