Archway Phase 3 Trial of the Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration 2-Year Results.

PURPOSE: To report 2-year results from the Archway clinical trial of the Port Delivery System with ranibizumab (PDS) for treatment of neovascular age-related macular degeneration (nAMD). DESIGN: Phase 3, randomized, multicenter, open-label, active-comparator-controlled trial. PARTICIPANTS: Patients with previously treated nAMD diagnosed within 9 months of screening and responsive to anti-vascular endothelial growth factor therapy. METHODS: Patients were randomized 3:2 to PDS with ranibizumab 100 mg/ml with fixed refill-exchanges every 24 weeks (PDS Q24W) or intravitreal ranibizumab 0.5 mg injections every 4 weeks (monthly ranibizumab). Patients were followed through 4 complete refill-exchange intervals (∼2 years). MAIN OUTCOME MEASURES: Change in best-corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study (ETDRS) letter score from baseline averaged over weeks 44 and 48, weeks 60 and 64, and weeks 88 and 92 (noninferiority margin, -3.9 ETDRS letters). RESULTS: The PDS Q24W was noninferior to monthly ranibizumab, with differences in adjusted mean change in BCVA score from baseline averaged over weeks 44/48, 60/64 and 88/92 of -0.2 (95% confidence interval [CI], -1.8 to +1.3), +0.4 (95% CI, -1.4 to +2.1) and -0.6 ETDRS letters (95% CI, -2.5 to +1.3), respectively. Anatomic outcomes were generally comparable between arms through week 96. Through each of 4 PDS refill-exchange intervals, 98.4%, 94.6%, 94.8%, and 94.7% of PDS Q24W patients assessed did not receive supplemental ranibizumab treatment. The PDS ocular safety profile was generally unchanged from primary analysis. Prespecified ocular adverse events of special interest (AESI) were reported in 59 (23.8%) PDS and 17 (10.2%) monthly ranibizumab patients. The most common AESI reported in both arms was cataract (PDS Q24W, 22 [8.9%]; monthly ranibizumab, 10 [6.0%]). Events in the PDS Q24W arm included (patient incidence) 10 (4.0%) conjunctival erosions, 6 (2.4%) conjunctival retractions, 4 (1.6%) endophthalmitis cases, and 4 (1.6%) implant dislocations. Serum ranibizumab sampling showed that the PDS continuously released ranibizumab over the 24-week refill-exchange interval and ranibizumab serum concentrations were within the range experienced with monthly ranibizumab. CONCLUSIONS: The PDS Q24W showed noninferior efficacy to monthly ranibizumab through approximately 2 years, with approximately 95% of PDS Q24W patients not receiving supplemental ranibizumab treatment in each refill-exchange interval. The AESIs were generally manageable, with learnings continually implemented to minimize PDS-related AEs. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Archway Randomized Phase 3 Trial of the Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration.

PURPOSE: To evaluate the safety and efficacy of the Port Delivery System with ranibizumab (PDS) for the treatment of neovascular age-related macular degeneration (nAMD). DESIGN: Phase 3, open-label, randomized, visual acuity assessor-masked noninferiority and equivalence trial. PARTICIPANTS: Patients with nAMD diagnosed within 9 months of screening previously treated with and responsive to anti-vascular endothelial growth factor therapy. METHODS: Patients were randomized 3:2 to treatment with the PDS with ranibizumab 100 mg/ml with fixed 24-week (Q24W) refill-exchanges (PDS Q24W) or intravitreal ranibizumab 0.5-mg injections every 4 weeks (monthly ranibizumab). MAIN OUTCOME MEASURES: Primary end point was change in best-corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study letter (letters) score from baseline averaged over weeks 36 and 40 (noninferiority margin,-4.5 letters; equivalence margin, ±4.5 letters). RESULTS: Archway enrolled 418 patients; 251 were randomized to and 248 received treatment with the PDS Q24W, and 167 were randomized to and received treatment with monthly ranibizumab. Baseline BCVA was 74.4 letters (PDS Q24W arm) and 75.5 letters (monthly ranibizumab arm; Snellen equivalent, 20/32). Adjusted mean change in BCVA score from baseline averaged over weeks 36 and 40 was +0.2 letters (standard error [SE], 0.5 letters) in the PDS Q24W arm and +0.5 letters (SE, 0.6 letters) in the monthly ranibizumab arm (difference, -0.3 letters; 95% confidence interval, -1.7 to 1.1 letters). PDS Q24W was both noninferior and equivalent to monthly ranibizumab. Of 246 PDS-treated patients assessed for supplemental ranibizumab treatment, 242 (98.4%) did not receive supplemental ranibizumab treatment before the first refill-exchange procedure, including 4 patients who discontinued treatment before the first refill-exchange procedure. Prespecified ocular adverse events of special interest were reported in 47 patients (19.0%) in the PDS Q24W arm and 10 patients (6.0%) in the monthly ranibizumab arm, which included, in the former arm, 4 (1.6%) endophthalmitis cases, 2 (0.8%) retinal detachments, 13 (5.2%) vitreous hemorrhages, 6 (2.4%) conjunctival erosions, and 5 (2.0%) conjunctival retractions. Most ocular adverse events in the PDS Q24W arm occurred within 1 month of implantation. CONCLUSIONS: Archway met its primary objective and PDS Q24W demonstrated noninferior and equivalent efficacy to monthly ranibizumab, with 98.4% of PDS-treated patients not receiving supplemental treatment in the first 24-week interval.

Nonclinical Toxicology and Biocompatibility Program Supporting Clinical Development and Registration of the Port Delivery System With Ranibizumab for Neovascular Age-Related Macular Degeneration.

The Port Delivery System with ranibizumab (PDS) is an investigational drug delivery system designed to provide continuous intravitreal release of ranibizumab for extended durations. The PDS consists of a permanent, surgically placed, refillable intraocular implant; a customized formulation of ranibizumab; and ancillary devices to support surgery and refill procedures. A toxicology program was conducted to evaluate the ocular toxicology and biocompatibility of the PDS to support its clinical development program and product registrational activities. PDS safety studies included a 6-month chronic toxicology evaluation in minipigs as well as evaluation of nonfunctional surrogate implants (comprised of the same implant materials but without ranibizumab) in rabbits. Biocompatibility of the implant and ancillary devices was evaluated in both in vitro and in vivo studies. Implants and extracts from implants and ancillary devices were nongenotoxic, noncytotoxic, nonsensitizing, and nonirritating. Ocular findings were comparable between implanted and sham-operated eyes, and no systemic toxicity was observed. The results of this nonclinical toxicology program demonstrated that the PDS was biocompatible and that intravitreal delivery of ranibizumab via the PDS did not introduce any new toxicology-related safety concerns relative to intravitreal injections, supporting ongoing PDS clinical development and product registrational evaluation.

EVALUATION OF SURGICAL FACTORS AFFECTING VITREOUS HEMORRHAGE FOLLOWING PORT DELIVERY SYSTEM WITH RANIBIZUMAB IMPLANT INSERTION IN A MINIPIG MODEL.

PURPOSE: To develop an animal model of vitreous hemorrhage (VH) to explore the impact of surgical parameters on VH associated with insertion of the Port Delivery System with ranibizumab (PDS) implant. METHODS: Ninety eyes from 45 treatment-naive male Yucatan minipigs received PDS implant insertion or a sham procedure. The effect of prophylactic pars plana hemostasis, scleral incision length, scleral cauterization, surgical blade type/size, and viscoelastic usage on postsurgical VH was investigated. RESULTS: Postsurgical VH was detected in 60.0% (54/90) of implanted eyes. A systematic effect on VH was only detected for pars plana hemostasis before the pars plana incision. The percentage of eyes with VH was 96.6% (28/29) among eyes that did not receive prophylactic pars plana hemostasis and 42.4% (24/58) among eyes that did. There was no VH in eyes that received laser ablation of the pars plana using overlapping 1,000-ms spots; pars plana cautery or diathermy was less effective. The majority of all VH cases (83.3% [45/54]) were of mild to moderate severity (involving ≤25% of the fundus). CONCLUSION: In this minipig surgical model of VH, scleral dissection followed by pars plana laser ablation before pars plana incision most effectively mitigated VH secondary to PDS implant insertion.

The Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration: Results from the Randomized Phase 2 Ladder Clinical Trial.

PURPOSE: To evaluate the safety and efficacy of the Port Delivery System with ranibizumab (PDS) for neovascular age-related macular degeneration (nAMD) treatment. DESIGN: Phase 2, multicenter, randomized, active treatment-controlled clinical trial. PARTICIPANTS: Patients diagnosed with nAMD within 9 months who had received 2 or more prior anti-vascular endothelial growth factor intravitreal injections and were responsive to treatment. METHODS: Patients were randomized 3:3:3:2 to receive the PDS filled with ranibizumab 10 mg/ml, 40 mg/ml, 100 mg/ml, or monthly intravitreal ranibizumab 0.5-mg injections. MAIN OUTCOME MEASURES: Time to first implant refill assessed when the last enrolled patient completed the month 9 visit (primary efficacy end point), improvement in best-corrected visual acuity (BCVA) and central foveal thickness (CFT), and safety. RESULTS: The primary analysis population was 220 patients, with 58, 62, 59, and 41 patients in the PDS 10-mg/ml, PDS 40-mg/ml, PDS 100-mg/ml, and monthly intravitreal ranibizumab 0.5-mg arms, respectively. Median time to first implant refill was 8.7, 13.0, and 15.0 months in the PDS 10-mg/ml, PDS 40-mg/ml, and PDS 100-mg/ml arms, respectively. At month 9, the adjusted mean BCVA change from baseline was ‒3.2 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, ‒0.5 ETDRS letters, +5.0 ETDRS letters, and +3.9 ETDRS letters in the PDS 10-mg/ml, PDS 40-mg/ml, PDS 100-mg/ml, and monthly intravitreal ranibizumab 0.5-mg arms, respectively. At month 9, the adjusted mean CFT change from baseline was similar in the PDS 100-mg/ml and monthly intravitreal ranibizumab 0.5-mg arms. The optimized PDS implant insertion and refill procedures were generally well tolerated. After surgical procedure optimization, postoperative vitreous hemorrhage rate was 4.5% (7/157; 1 event classified as serious). There was no evidence of implant clogging. CONCLUSIONS: In the phase 2 Ladder trial, the PDS was generally well tolerated and demonstrated a dose response across multiple end points in patients with nAMD. The PDS 100-mg/ml arm showed visual and anatomic outcomes comparable with monthly intravitreal ranibizumab 0.5-mg injections but with a reduced total number of ranibizumab treatments. The PDS has the potential to reduce treatment burden in nAMD while maintaining vision.

VISUALIZATION OF MACULAR PUCKER BY MULTICOLOR SCANNING LASER IMAGING.

PURPOSE: To compare the visualization of the epiretinal membrane (ERM) using multicolor imaging (MCI) (Heidelberg Engineering, Carlsbad, CA) and conventional white light flood color fundus photography (FP) (Topcon). METHODS: The paired images of patients with ERM who underwent same-day MCI and FP examinations were reviewed. Visibility of the ERM was graded using a scale (0: not visible, 1: barely visible, and 2: clearly visible) by masked readers, and surface folds were counted to quantify the membrane visibility for each method. Images from individual color channels in MCI (green, blue, and infrared) were also graded using the same method to further investigate MCI images. RESULTS: Forty-eight eyes of 42 patients were included. The average ERM visibility score was 1.8 ± 0.37 for MCI and 1.01 ± 0.63 for FP (P < 0.001). The number of the surface folds detected per quadrant was signifi8cantly higher in MCI than that in FP (6.79 ± 3.32 vs. 2.85 ± 2.81, P < 0.001). The ERM was graded with similar scores on the two modalities in 43.8% of the eyes; in 56.2%, the ERM was better visualized on MCI than that on FP. Conventional FP failed to detect ERM in 11.4% of eyes when the mean central retinal thickness was <413 microns. Analysis of laser color reflectance revealed that green reflectance provided better detection of surface folds (5.54 ± 2.12) compared to blue reflectance (4.2 ± 2.34) and infrared reflectance (1.2 ± 0.9). CONCLUSION: Multicolor scanning laser imaging provides superior ERM detection and delineation of surface folds than conventional FP, primarily due to the green channel present in the combination-pseudocolor image in MCI.

Genetic analysis of 10 pedigrees with inherited retinal degeneration by exome sequencing and phenotype-genotype association.

Our purpose was to identify causative mutations and characterize the phenotype associated with the genotype in 10 unrelated families with autosomal recessive retinal degeneration. Ophthalmic evaluation and DNA isolation were carried out in 10 pedigrees with inherited retinal degenerations (IRD). Exomes of probands from eight pedigrees were captured using Nimblegen V2/V3 or Agilent V5+UTR kits, and sequencing was performed on Illumina HiSeq. The DHDDS gene was screened for mutations in the remaining two pedigrees with Ashkenazi Jewish ancestry. Exome variants were filtered to detect candidate causal variants using exomeSuite software. Segregation and ethnicity-matched control sample analysis were performed by dideoxy sequencing. Retinal histology of a patient with DHDDS mutation was studied by microscopy. Genetic analysis identified six known mutations in ABCA4 (p.Gly1961Glu, p.Ala1773Val, c.5461-10T>C), RPE65 (p.Tyr249Cys, p.Gly484Asp), PDE6B (p.Lys706Ter) and DHDDS (p.Lys42Glu) and ten novel potentially pathogenic variants in CERKL (p.Met323Val fsX20), RPE65 (p.Phe252Ser, Thr454Leu fsX31), ARL6 (p.Arg121His), USH2A (p.Gly3142Ter, p.Cys3294Trp), PDE6B (p.Gln652Ter), and DHDDS (p.Thr206Ala) genes. Among these, variants/mutations in two separate genes were observed to segregate with IRD in two pedigrees. Retinal histopathology of a patient with a DHDDS mutation showed severe degeneration of retinal layers with relative preservation of the retinal pigment epithelium. Analysis of exome variants in ten pedigrees revealed nine novel potential disease-causing variants and nine previously reported homozygous or compound heterozygous mutations in the CERKL, ABCA4, RPE65, ARL6, USH2A, PDE6B, and DHDDS genes. Mutations that could be sufficient to cause pathology were observed in more than one gene in one pedigree.

Clinical features of serous retinopathy observed with cobimetinib in patients with BRAF-mutated melanoma treated in the randomized coBRIM study.

BACKGROUND: Serous chorioretinopathy has been associated with MEK inhibitors, including cobimetinib. We describe the clinical features of serous retinopathy observed with cobimetinib in patients with BRAF V600-mutated melanoma treated in the Phase III coBRIM study. METHODS: In the coBRIM study, 493 patients were treated in two randomly assigned treatment groups: cobimetinib and vemurafenib (n = 247) or vemurafenib (n = 246). All patients underwent prospective ophthalmic examinations at screening, at regular intervals during the study, and whenever ocular symptoms developed. Patients with serous retinopathy were identified in the study database using a group of relevant and synonymous adverse event terms. RESULTS: Eighty-six serous retinopathy events were reported in 70 patients (79 events in 63 cobimetinib and vemurafenib-treated patients vs seven events in seven vemurafenib-treated patients). Most patients with serous retinopathy identified by ophthalmic examination had no symptoms or had mild symptoms, among them reduced visual acuity, blurred vision, dyschromatopsia, and photophobia. Serous retinopathy usually occurred early during cobimetinib and vemurafenib treatment; median time to onset was 1.0 month. Most events were managed by observation and continuation of cobimetinib without dose modification and resolved or were resolving by the data cutoff date (19 Sept 2014). CONCLUSIONS: Cobimetinib treatment was associated with serous retinopathy in patients with BRAF V600-mutated melanoma. Retinopathy was generally asymptomatic or mild. Periodic ophthalmologic evaluations at regular intervals and at the manifestation of any visual disturbance are recommended to facilitate early detection and resolution of serous retinopathy while patients are taking cobimetinib. Trial Registration Clinicaltrials.gov (NCT01689519). First received: September 18, 2012.

REAL-TIME FULL-DEPTH VISUALIZATION OF POSTERIOR OCULAR STRUCTURES: Comparison Between Full-Depth Imaging Spectral Domain Optical Coherence Tomography and Swept-Source Optical Coherence Tomography.

PURPOSE: To compare the real-time visualization of vitreoretino-choroidal structures using full-depth imaging (FDI) spectral domain optical coherence tomography (SD-OCT) and swept-source (SS)-OCT. METHODS: Foveal scans using both FDI SD-OCT (Heidelberg Spectralis) and SS-OCT (Topcon Deep Range Imaging-OCT-1) were obtained in 40 normal eyes, 40 eyes with macular pathologies, and 40 eyes with glaucoma. Full-depth imaging SD-OCT images were obtained by manually enhancing the vitreoretinal interface first and then the choroid while averaging each OCT B-scan 100 times. Swept-source-OCT images were obtained by averaging each B-scan 96 times. After masking and randomly mixing the original OCT images, two independent physicians graded visualization of the premacular bursa, interdigitation zone line, and chorioscleral boundary, and also sharpness of choroidal structures. RESULTS: A real-time full-depth image of vitreoretino-choroidal structures was successfully achieved with FDI SD-OCT in 118 cases (98.3%) and with SS-OCT in 45 cases (37.5%, P < 0.001). Full-depth imaging SD-OCT imaging was superior to SS-OCT imaging in visualizing the anterior border of the premacular bursa in 109 eyes (90.8%), with average grading of 1.63 ± 0.53 for the FDI SD-OCT and 0.39 ± 0.52 for the SS-OCT (P < 0.001). Swept-source-OCT was similar to FDI SD-OCT in visualizing the chorioscleral boundary in 108 eyes (90.0%), with average grading of 1.81 ± 0.39 for the SS-OCT and 1.78 ± 0.38 for the FDI-OCT (P = 0.566). The visualization of the interdigitation zone line was identical in the 2 imaging instruments (P = 1.000). The sharpness of the choroidal structures was greater with SS-OCT than with FDI-OCT (P < 0.001). CONCLUSION: Manual double-enhancing FDI technique using SD-OCT provided a good compromise between vitreous and retinochoroidal structures visualization in real time during scanning procedure. In contrast, SS-OCT imaged well details of choroidal sublayers. Appropriate OCT technology and software should be selected according to its application in clinical settings.

Multimodal Imaging of Vitreoretinal Lymphoma.

PURPOSE: To assess the characteristics and prevalence of fundus abnormalities in vitreoretinal lymphoma (VRL) using multimodal imaging. METHODS: We retrospectively reviewed chart and imaging studies of patients diagnosed with VRL. RESULTS: All 10 VRL patients (14 eyes) included in the study showed vitreitis, hyperreflective lesions on near-infrared reflectance imaging, and hypoautofluorescent lesions on fundus autofluorescence. Other findings included hypofluorescent lesions on fluorescein angiography (79%), hypocyanescent lesions on indocyanine green angiography (77%), small retinal pigment epithelium detachments (PEDs) (71%) and large PEDs (36%) on optical coherence tomography (OCT). Outer retinal layer nodularity was identified on OCT in 93% of cases. Small PEDs corresponded to hyperreflective, hyperautofluorescent, hypofluorescent, hypocyanescent lesions. CONCLUSION: Multiple signs were present on multimodal imaging in VRL eyes. Lymphomatous infiltration created focal PEDs showing abnormal imaging signals. Outer retinal layer nodularity could represent an additional sign of infiltration. Multimodal imaging may guide physicians in the early diagnosis of VRL.

Impact on intraocular pressure after 20-mg decanted triamcinolone acetonide (kenalog) injection when using prophylactic antiglaucoma therapy.

PURPOSE: To analyze intraocular pressure (IOP) response after 20-mg decanted intravitreal triamcinolone acetonide followed by early prophylactic IOP-lowering therapy. METHODS: Overall, IOP results of 120 high-dose decanted intravitreal triamcinolone acetonide injections from 58 nonglaucomatous patients with macular edema, with antiglaucoma therapy prescribed from Week 1 regardless of baseline IOP were retrospectively reviewed. RESULTS: In cases of consistent compliance with IOP-lowering drugs (79.2%), IOP increased by 2 mmHg at 4 months (P = 0.300) and returned to baseline at 6 months. In cases of noncompliance (20.8%), IOP increased by 7 mmHg at 1 month (P < 0.001) and returned to baseline after starting treatment. Multivariate regression analysis showed that nonvitrectomized eyes and noncompliance with IOP-lowering drugs were independent predictors of increase in IOP greater than 21 mmHg (P = 0.0098 and P = 0.0019, respectively). Nonvitrectomized eyes had a 46% greater chance to experience increase in IOP compared with vitrectomized ones. Poor compliance with IOP-lowering drugs lead to a 45% greater likelihood of experiencing increase in IOP compared with compliant patients. Multiple injections were not associated with the increased risk for increase in IOP greater than 21 mmHg (P = 0.273). Of 120 cases, 2 eyes (1.7%) developed uncontrolled IOP and required glaucoma surgery by 4 months, with good final IOP outcome. CONCLUSION: Twenty milligram decanted intravitreal triamcinolone acetonide can be safely used to treat macular edema in nonglaucomatous patients; IOP elevation can be adequately controlled with prophylactic antiglaucoma drugs. Noncompliance with prophylactic therapy creates an early spike in IOP, and vitreous status can significantly impact increase in IOP. Compliance with IOP-lowering drugs should be stressed to patients receiving high-dose intravitreal triamcinolone acetonide especially in cases of nonvitrectomized eyes.

The spectrum of ocular alterations in patients with ß-thalassemia syndromes suggests a pathology similar to pseudoxanthoma elasticum.

PURPOSE: To determine the prevalence and spectrum of ocular fundus abnormalities in patients with ß-thalassemia and to investigate risk factors for their development. DESIGN: Cross-sectional, observational study. PARTICIPANTS: A total of 255 patients with ß-thalassemia major (TM) and ß-thalassemia intermedia (TI) were consecutively recruited and investigated. METHODS: Patients underwent best correct visual acuity, indirect ophthalmoscopy, and fundus photography, including fundus autofluorescence (FAF) and near-infrared reflectance imaging using a confocal scanning laser ophthalmoscope (cSLO). Hematologic parameters were determined, including mean ferritin levels, aspartate amino transferase, alanine amino transferase, calcium, pre-transfusion hemoglobin, history of splenectomy, and liver iron concentration. Factors associated with the ocular phenotype were assessed using logistic regression. MAIN OUTCOME MEASURES: Ocular phenotype as determined by clinical examination and used multimodal imaging. RESULTS: A total of 153 patients (60.0%) affected by TM and 102 patients (40.0%) affected by TI participated, of whom 216 (84.7%) were receiving iron-chelating therapy. Ocular fundus abnormalities characteristic of pseudoxanthoma elasticum (PXE) were detected by cSLO in 70 of 255 patients (27.8%) and included peau d'orange (19.6%), angioid streaks (12.9%), pattern dystrophy-like changes (7.5%), and optic disc drusen (2.0%). Pseudoxanthoma elasticum-like changes were more frequent in patients with TI (P<0.001). Patients with PXE-like fundus changes were older than patients without these fundus changes (P<0.001). In both patients with TI and TM, age (P = 0.001) and splenectomy (P = 0.001) had the strongest association with presence of PXE-like fundus changes in multivariate analyses. A total of 43 of 255 patients (16.9%) showed increased retinal vascular tortuosity independently of the PXE-like fundus changes, which was associated with aspartate amino transferase (P = 0.036), hemoglobin (P = 0.008), and ferritin levels (P = 0.005). CONCLUSIONS: Pseudoxanthoma elasticum-like fundus changes are a frequent finding in patients with ß-thalassemia. In TI, these changes increase with duration or severity of the disease. This particular ocular phenotype suggests an ocular pathology similar to PXE. Retinal vascular tortuosity may be an additional disease manifestation independent of the PXE-like syndrome. Patients with long-standing disease requiring iron-chelating treatment and a history of splenectomy need regular ophthalmic checkups because they are at risk of developing PXE-like fundus changes and potentially of subsequent choroidal neovascularization.

Optical coherence tomography findings of the vitreoretinal interface in asymptomatic fellow eyes of patients with acute posterior vitreous detachment.

PURPOSE: To describe the vitreoretinal interface of the asymptomatic fellow eyes of patients with acute unilateral posterior vitreous detachment (PVD) based on biomicroscopic examination and spectral domain optical coherence tomography. METHODS: Sixty-five eyes of 65 consecutive patients with acute unilateral PVD were examined by slit-lamp, indirect ophthalmoscopy, and spectral domain optical coherence tomography. The state of PVD in different retinal locations and premacular pocket were assessed and graded using spectral domain optical coherence tomography. RESULTS: Nine eyes (13.85%) had no PVD, 15 (23.08%) had extrafoveal vitreous separation (Stage 1), 18 (27.69%) had partial foveal vitreous separation (Stage 2), 12 (18.46%) had complete foveal vitreous separation (Stage 3), and 11 (16.92%) had a complete PVD (Stage 4). The presence of a premacular pocket showed equal distribution in Stages 0, 1, and 2 (66.67, 80.00, and 77.78%, respectively) but was significantly less common in Stages 3 (P = 0.016) and 4 (P < 0.0001). Only certain posterior vitreous configurations were identified (P < 0.0001), suggesting an orderly progression of PVD evolution. CONCLUSION: Our spectral domain optical coherence tomography-based PVD staging system describes the evolution of PVDs. This can be used as a guide in predicting the occurrence and evolution of PVD in this population.

Multimodal imaging in deferoxamine retinopathy.

PURPOSE: To describe macular lesions in patients with deferoxamine (DFO) retinopathy, and to follow their clinical course using multimodal imaging. METHODS: The authors retrospectively reviewed charts and multimodal imaging of 20 patients with ß-thalassemia diagnosed with DFO retinopathy (40 eyes) after a minimum of 10 years of DFO treatment. Imaging included fundus photography, near-infrared reflectance and fundus autofluorescence imaging on confocal laser scanning ophthalmoscope, and spectral domain optical coherence tomography. RESULTS: Mean age of the 20 patients was 45 years, and mean duration of subcutaneous DFO therapy was 32 years (range, 20-52 years). Ten patients (50%) showed different types of pattern dystrophy-like fundus changes, including butterfly shaped-like (n = 3), fundus flavimaculatus-like (n = 3), fundus pulverulentus-like (n = 3), and vitelliform-like (n = 1) changes. Ten patients (50%) presented only minimal changes in the macula; these patients were significantly younger than patients presenting other patterns (P = 0.023). Confocal laser scanning ophthalmoscope and spectral domain optical coherence tomography showed that these abnormalities were more diverse and widespread than expected by ophthalmoscopy. Abnormal fundus autofluorescence and/or near-infrared reflectance signals corresponded to accumulation of material located within the outer retina or in the Bruch membrane-retinal pigment epithelium (RPE) complex on spectral domain optical coherence tomography. Follow-up examinations during a 40-month period revealed progressive development of RPE atrophy in areas of pattern dystrophy-like changes. CONCLUSION: DFO retinopathy included a variety of pattern dystrophy-like changes or minimal changes affecting the RPE-Bruch membrane-photoreceptor complex. Multimodal imaging demonstrated that fundus changes were more diverse and widespread than expected from ophthalmoscopy. Consistently with previous histologic description of DFO retinopathy, multimodal imaging confirmed that photoreceptor outer-derived retinoids, various fluorophores, and RPE displacement or clumping are involved in DFO retinopathy, finally leading to frank RPE atrophy in most cases of pattern dystrophy-like changes.

Macular choroidal volume variations in highly myopic eyes with myopic traction maculopathy and choroidal neovascularization.

PURPOSE: To compare the choroidal volume (CV) between emmetropic and highly myopic eyes, and to assess if the presence of myopic fundus abnormalities, myopic traction maculopathy, or choroidal neovascularization affects the CV. METHODS: We retrospectively reviewed imaging studies of 98 eyes of 98 patients who underwent CV measurement on optical coherence tomography. We included 31 emmetropic eyes (Group 1), 36 highly myopic eyes without vitreoretinal or choroidal pathologies (Group 2), 21 highly myopic eyes with traction maculopathy (Group 3), and 10 highly myopic eyes with history of choroidal neovascularization (Group 3). Eyes with chorioretinal atrophy were excluded. Regression analysis was performed to evaluate the correlation between CV and multiple variables. RESULTS: Choroidal volume was lower in Group 2 than in Group 1 (P < 0.001), and in Groups 3 and 4 than in Group 2 (P < 0.001 and P = 0.002, respectively). Age (P = 0.002), axial length (P < 0.001), sex (P = 0.047), staphyloma (P < 0.001), and myopic group (P = 0.05) were independent predictors for the final CV (R = 0.645). In highly myopic eyes, CV decreased by 0.32 mm for every 10 years and by 0.49 mm per millimeter of axial length. CONCLUSION: Choroidal thinning is present in highly myopic eyes compared with emmetropic eyes, and is related to age, axial length, sex, and staphyloma. However, myopic eyes with coexisting myopic traction maculopathy or history of choroidal neovascularization have more severe thinning, likely leading to insufficient metabolic supplementation for the macula.

Influence of scanning density on macular choroidal volume measurement using spectral-domain optical coherence tomography.

BACKGROUND: To evaluate the impact of scanning density on macular choroidal volume measurement using spectral-domain optical coherence tomography (SD-OCT). METHODS: Thirty eyes of normal subjects underwent consecutive raster choroidal scanning protocols using SD-OCT in enhanced-depth imaging mode. Manual choroidal segmentation was performed using the built-in automated retinal segmentation software to obtain five analyses with different inter-scan distances, including inter-scan distances of 30 µm, 60 µm, 120 µm, 240 µm, and 480 µm. The built-in software of the device automatically generated the choroidal thickness and volume map in the similar manner as for the retinal volume map, using the standardized Early Treatment Diabetic Retinopathy Study (ETDRS) grid. For each raster scan, mean absolute difference and relative difference of mean foveal choroidal thickness (FCT), foveal choroidal volume (FCV) and total macular choroidal volume (TCV) in comparison to "true value" (i.e., 30-µm inter-scan distance) were calculated. RESULTS: The maximum relative differences were 10% and 16% for TCV and FCV respectively. For mean FCT, the maximum absolute difference was 31 µm, and maximum relative difference was 12.7%. No statistically significant differences were found in measurements of mean foveal choroidal thickness (p = 0.912) and volume (p = 0.944), as well as macular choroidal volume (p = 0.912), with varying inter-scan distance. CONCLUSIONS: Our study shows that approximately 16 scans over the macula with a inter-scan distance of 480 µm is sufficient to provide a clinically relevant and reliable choroidal thickness/volume map. This information could be useful in the design of choroidal scanning protocols for future clinical trials.

Correlation of spectral domain optical coherence tomography characteristics with visual acuity in eyes with subfoveal scarring after treatment for wet age-related macular degeneration.

PURPOSE: Correlating spectral domain optical coherence tomography characteristics with final best-corrected visual acuity (BCVA) in eyes with subfoveal scarring after treatment for wet age-related macular degeneration. METHODS: Seventy-nine eyes from 64 subjects, who developed subfoveal scarring after treatment of wet age-related macular degeneration, were retrospectively studied. Spectral domain optical coherence tomography characteristics were analyzed, including percentage disruption of inner segment/outer segment junction and external limiting membrane, central macular thickness, subfoveal scar thickness, subretinal scar area, and proximity of retina with intact outer structures to the fovea. A multivariate stepwise regression analysis was performed with the final BCVA logarithm of minimum angle of resolution as a response and the above-identified spectral domain optical coherence tomography variables as predictors. RESULTS: There was no correlation between the final BCVA and any of the demographic data, treatment modality received, and central macular thickness. The final BCVA was significantly correlated with the percentage of inner segment/outer segment disruption (P = 0.011), external limiting membrane disruption (P = 0.005), and scar area on spectral domain optical coherence tomography (P = 0.018). Multivariate analysis showed that the baseline BCVA and distance between the fovea and nearest retina with intact outer structures are the most predictive of the final BCVA (R(2) = 0.52). CONCLUSION: Baseline BCVA and integrity of outer retinal structures are good predictors of the final BCVA of wet age-related macular degeneration patients developing scarring after treatment.

Safety and efficacy of oral fluorescein angiography in detecting macular edema in comparison with spectral-domain optical coherence tomography.

PURPOSE: To evaluate the safety of oral fluorescein angiography (FA) and to compare its efficacy in detection of macular edema (ME) with spectral-domain optical coherence tomography (SD-OCT). METHODS: Results of imaging studies for 1,928 eyes of 1,019 patients who had simultaneously undergone both oral FA and SD-OCT by a confocal laser ophthalmoscope were reviewed. Sensitivity in detecting ME, discrepancy rate, and "kappa" agreement were determined for both the techniques and with eyes stratified by disease diagnosis. RESULTS: No allergic reactions occurred after oral FA. Mild gastric discomfort was noted in <1% of the patients; 1,840 eyes (95.4%) showed concordance between the two techniques, and kappa agreement was 90.3%. For ME, oral FA showed an overall sensitivity of 0.97 and SD-OCT of 0.91. Equivalent sensitivity was found in cases of wet age-related macular degeneration (0.99). Oral FA was more sensitive than SD-OCT in cases of retinovascular diseases. The SD-OCT showed higher sensitivity in cases of macular holes. Detection of ME by SD-OCT was significantly higher in cases of intense leakage on oral FA (P < 0.001). CONCLUSION: Oral FA proved to be a safe and an adequate technique to evaluate ME. It is more sensitive than SD-OCT in detection of ME in cases of retinovascular diseases but can fail to detect ME in cases of macular holes. A noninvasive examination with simultaneous oral FA and SD-OCT may be considered to obtain a comprehensive evaluation of the presence of ME from different pathologies.

Choroidal abnormalities detected by near-infrared reflectance imaging as a new diagnostic criterion for neurofibromatosis 1.

OBJECTIVE: To investigate in a large sample of consecutive patients with neurofibromatosis type 1 (NF1) the possibility of including the presence of choroidal abnormalities detected by near-infrared reflectance (NIR) as a new diagnostic criterion for NF1. DESIGN: Cross-sectional evaluation of a diagnostic test. PARTICIPANTS AND CONTROLS: Ninety-five consecutive adult and pediatric patients (190 eyes) with NF1, diagnosed based on the National Institutes of Health (NIH) criteria. Controls included 100 healthy age- and gender-matched control subjects. METHODS: Confocal scanning laser ophthalmoscopy was performed for each subject, investigating the presence and the number of choroidal abnormalities. MAIN OUTCOME MEASURES: Sensitivity, specificity, and diagnostic accuracy for the different cutoff values of the criterion choroidal nodules detected by NIR compared with the NIH criteria. RESULTS: Choroidal nodules detected by NIR imaging were present in 79 (82%) of 95 of the NF1 patients, including 15 (71%) of the 21 NF1 pediatric patients. Similar abnormalities were present in 7 (7%) of 100 healthy subjects, including 2 (8%) of the 25 healthy pediatric subjects. The highest accuracy was obtained at the cutoff value of 1.5 choroidal nodules detected by NIR imagery. Sensitivity and specificity of the examination at the optimal cutoff point were 83% and 96%, respectively. Diagnostic accuracy was 90% in the overall population and 83% in the pediatric population. Both of these values were in line with the most common NIH diagnostic criteria. CONCLUSIONS: Choroidal abnormalities appearing as bright patchy nodules detected by NIR imaging frequently occurred in NF1 patients. The present study shows that NIR examination to detect choroidal involvement should be considered as a new diagnostic criterion for NF1.