Wills Eye Hospital

BACKGROUND: Despite extensive knowledge regarding the diagnosis and management of keratoconus and ectatic corneal diseases, many controversies still exist. For that reason, there is a need for current guidelines for the diagnosis and management of these conditions. PURPOSE: This project aimed to reach consensus of ophthalmology experts from around the world regarding keratoconus and ectatic diseases, focusing on their definition, concepts, clinical management, and surgical treatments. METHODS: The Delphi method was followed with 3 questionnaire rounds and was complemented with a face-to-face meeting. Thirty-six panelists were involved and allocated to 1 of 3 panels: definition/diagnosis, nonsurgical management, or surgical treatment. The level of agreement considered for consensus was two thirds. RESULTS: Numerous agreements were generated in definitions, methods of diagnosing, and management of keratoconus and other ectatic diseases. Nonsurgical and surgical treatments for these conditions, including the use of corneal cross-linking and corneal transplantations, were presented in a stepwise approach. A flowchart describing a logical management sequence for keratoconus was created. CONCLUSIONS: This project resulted in definitions, statements, and recommendations for the diagnosis and management of keratoconus and other ectatic diseases. It also provides an insight into the current worldwide treatment of these conditions.

3D printing is a method of manufacturing in which materials, such as plastic or metal, are deposited onto one another in layers to produce a three dimensional object, such as a pair of eye glasses or other 3D objects. This process contrasts with traditional ink-based printers which produce a two dimensional object (ink on paper). To date, 3D printing has primarily been used in engineering to create engineering prototypes. However, recent advances in printing materials have now enabled 3D printers to make objects that are comparable with traditionally manufactured items. In contrast with conventional printers, 3D printing has the potential to enable mass customisation of goods on a large scale and has relevance in medicine including ophthalmology. 3D printing has already been proved viable in several medical applications including the manufacture of eyeglasses, custom prosthetic devices and dental implants. In this review, we discuss the potential for 3D printing to revolutionise manufacturing in the same way as the printing press revolutionised conventional printing. The applications and limitations of 3D printing are discussed; the production process is demonstrated by producing a set of eyeglass frames from 3D blueprints.

OBJECTIVE: To determine the rate of metastasis of uveal melanoma on the basis of tumor thickness in millimeters. METHODS: Retrospective medical record review. RESULTS: The mean (median) patient age was 58 (59) years. A total of 8033 eyes were examined. Of the 285 eyes with iris melanoma, the mean tumor thickness was 2.7 mm and metastasis occurred in 0.5%, 4%, and 7% at 3, 5, and 10 years, respectively. Of the 492 eyes with ciliary body melanoma, the mean tumor thickness was 6.6 mm and metastasis occurred in 12%, 19%, and 33% at 3, 5, and 10 years, respectively. Of the 7256 eyes with choroidal melanoma, the mean tumor thickness was 5.5 mm and metastasis occurred in 8%, 15%, and 25% at 3, 5, and 10 years, respectively. For all uveal melanoma, metastasis at 5, 10, and 20 years was 6%, 12%, and 20% for small melanoma (0-3.0 mm thickness), 14%, 26%, and 37% for medium melanoma (3.1-8.0 mm), and 35%, 49%, and 67% for large melanoma (>8.0 mm). More specifically, metastasis per millimeter increment at 10 years was 6% (0-1.0 mm thickness), 12% (1.1-2.0 mm), 12% (2.1-3.0 mm), 16% (3.1-4.0 mm), 27% (4.1-5.0 mm), 28% (5.1-6.0 mm), 29% (6.1-7.0 mm), 41% (7.1-8.0 mm), 50% (8.1-9.0 mm), 44% (9.1-10.0 mm), and 51% (>10.0 mm). Clinical factors predictive of metastasis by multivariate analysis included increasing patient age, ciliary body location, increasing tumor diameter, increasing tumor thickness, having a brown tumor, and the presence of subretinal fluid, intraocular hemorrhage, or extraocular extension. CONCLUSION: Increasing millimeter thickness of uveal melanoma is associated with increasing risk for metastasis.

BACKGROUND: Vitreomacular adhesion can lead to pathologic traction and macular hole. The standard treatment for severe, symptomatic vitreomacular adhesion is vitrectomy. Ocriplasmin is a recombinant protease with activity against fibronectin and laminin, components of the vitreoretinal interface. METHODS: We conducted two multicenter, randomized, double-blind, phase 3 clinical trials to compare a single intravitreal injection of ocriplasmin (125 μg) with a placebo injection in patients with symptomatic vitreomacular adhesion. The primary end point was resolution of vitreomacular adhesion at day 28. Secondary end points were total posterior vitreous detachment and nonsurgical closure of a macular hole at 28 days, avoidance of vitrectomy, and change in best-corrected visual acuity. RESULTS: Overall, 652 eyes were treated: 464 with ocriplasmin and 188 with placebo. Vitreomacular adhesion resolved in 26.5% of ocriplasmin-injected eyes and in 10.1% of placebo-injected eyes (P<0.001). Total posterior vitreous detachment was more prevalent among the eyes treated with ocriplasmin than among those injected with placebo (13.4% vs. 3.7%, P<0.001). Nonsurgical closure of macular holes was achieved in 40.6% of ocriplasmin-injected eyes, as compared with 10.6% of placebo-injected eyes (P<0.001). The best-corrected visual acuity was more likely to improve by a gain of at least three lines on the eye chart with ocriplasmin than with placebo. Ocular adverse events (e.g., vitreous floaters, photopsia, or injection-related eye pain--all self-reported--or conjunctival hemorrhage) occurred in 68.4% of ocriplasmin-injected eyes and in 53.5% of placebo-injected eyes (P<0.001), and the incidence of serious ocular adverse events was similar in the two groups (P=0.26). CONCLUSIONS: Intravitreal injection of the vitreolytic agent ocriplasmin resolved vitreomacular traction and closed macular holes in significantly more patients than did injection of placebo and was associated with a higher incidence of ocular adverse events, which were mainly transient. (Funded by ThromboGenics; ClinicalTrials.gov numbers, NCT00781859 and NCT00798317.).

PURPOSE: To update the 2008 International Classification of Corneal Dystrophies (IC3D) incorporating new clinical, histopathologic, and genetic information. METHODS: The IC3D reviewed worldwide peer-reviewed articles for new information on corneal dystrophies published between 2008 and 2014. Using this information, corneal dystrophy templates and anatomic classification were updated. New clinical, histopathologic, and confocal photographs were added. RESULTS: On the basis of revisiting the cellular origin of corneal dystrophy, a modified anatomic classification is proposed consisting of (1) epithelial and subepithelial dystrophies, (2) epithelial-stromal TGFBI dystrophies, (3) stromal dystrophies, and (4) endothelial dystrophies. Most of the dystrophy templates are updated. The entity "Epithelial recurrent erosion dystrophies" actually includes a number of potentially distinct epithelial dystrophies (Franceschetti corneal dystrophy, Dystrophia Smolandiensis, and Dystrophia Helsinglandica) but must be differentiated from dystrophies such as TGFBI-induced dystrophies, which are also often associated with recurrent epithelial erosions. The chromosome locus of Thiel-Behnke corneal dystrophy is only located on 5q31. The entity previously designated as a variant of Thiel-Behnke corneal dystrophy on chromosome 10q24 may represent a novel corneal dystrophy. Congenital hereditary endothelial dystrophy (CHED, formerly CHED2) is most likely only an autosomal recessive disorder. The so-called autosomal dominant inherited CHED (formerly CHED1) is insufficiently distinct to continue to be considered a unique corneal dystrophy. On review of almost all of the published cases, the description appeared most similar to a type of posterior polymorphous corneal dystrophy linked to the same chromosome 20 locus (PPCD1). Confocal microscopy also has emerged as a helpful tool to reveal in vivo features of several corneal dystrophies that previously required histopathologic examination to definitively diagnose. CONCLUSIONS: This revision of the IC3D classification includes an updated anatomic classification of corneal dystrophies more accurately classifying TGFBI dystrophies that affect multiple layers rather than are confined to one corneal layer. Typical histopathologic and confocal images have been added to the corneal dystrophy templates.

ObjectiveTo evaluate the 12-month efficacy and safety of intravitreal ranibizumab 0.5 mg and 2.0 mg administered monthly and on an as-needed (PRN) basis in treatment-naïve patients with subfoveal neovascular age-related macular degeneration (wet AMD).DesignA 24-month, phase III, randomized, multicenter, double-masked, dose-response study.ParticipantsPatients aged ≥50 years with subfoveal wet AMD.MethodsPatients (n = 1098) were randomized to receive ranibizumab 0.5 mg or 2.0 mg intravitreal injections administered monthly or on a PRN basis after 3 monthly loading doses.Main Outcome MeasuresThe primary efficacy end point was the mean change from baseline in best-corrected visual acuity (BCVA) at month 12. Key secondary end points included the mean number of ranibizumab injections, the mean change from baseline in central foveal thickness (CFT) over time, and the proportion of patients who gained ≥15 letters of BCVA. Unless otherwise specified, end point analyses were performed using the last-observation-carried-forward method to impute missing data.ResultsAt month 12, the mean change from baseline in BCVA for the 4 groups was +10.1 letters (0.5 mg monthly), +8.2 letters (0.5 mg PRN), +9.2 letters (2.0 mg monthly), and +8.6 letters (2.0 mg PRN). The proportion of patients who gained ≥15 letters from baseline at month 12 in the 4 groups was 34.5%, 30.2%, 36.1%, and 33.0%, respectively. The mean change from baseline in CFT at month 12 in the 4 groups was −172.0 μm, −161.2 μm, −163.3 μm, and −172.4 μm, respectively. The mean number of injections was 7.7 and 6.9 for the 0.5-mg PRN and 2.0-mg PRN groups, respectively. Ocular and systemic safety profiles were consistent with previous ranibizumab trials in AMD and comparable between groups.ConclusionsAt month 12, the ranibizumab 2.0 mg monthly group did not meet the prespecified superiority comparison and the ranibizumab 0.5 mg and 2.0 mg PRN groups did not meet the prespecified noninferiority (NI) comparison. However, all treatment groups demonstrated clinically meaningful visual improvement (+8.2 to +10.1 letters) and improved anatomic outcomes, with the PRN groups requiring approximately 4 fewer injections (6.9–7.7) than the monthly groups (11.2–11.3). No new safety events were observed despite a 4-fold dose escalation in the study. The pHase III, double-masked, multicenter, randomized, Active treatment-controlled study of the efficacy and safety of 0.5 mg and 2.0 mg Ranibizumab administered monthly or on an as-needed Basis (PRN) in patients with subfoveal neOvasculaR age-related macular degeneration (HARBOR) study confirmed that ranibizumab 0.5 mg dosed monthly provides optimum results in patients with wet AMD.Financial Disclosure(s)Proprietary or commercial disclosure may be found after the references. To evaluate the 12-month efficacy and safety of intravitreal ranibizumab 0.5 mg and 2.0 mg administered monthly and on an as-needed (PRN) basis in treatment-naïve patients with subfoveal neovascular age-related macular degeneration (wet AMD). A 24-month, phase III, randomized, multicenter, double-masked, dose-response study. Patients aged ≥50 years with subfoveal wet AMD. Patients (n = 1098) were randomized to receive ranibizumab 0.5 mg or 2.0 mg intravitreal injections administered monthly or on a PRN basis after 3 monthly loading doses. The primary efficacy end point was the mean change from baseline in best-corrected visual acuity (BCVA) at month 12. Key secondary end points included the mean number of ranibizumab injections, the mean change from baseline in central foveal thickness (CFT) over time, and the proportion of patients who gained ≥15 letters of BCVA. Unless otherwise specified, end point analyses were performed using the last-observation-carried-forward method to impute missing data. At month 12, the mean change from baseline in BCVA for the 4 groups was +10.1 letters (0.5 mg monthly), +8.2 letters (0.5 mg PRN), +9.2 letters (2.0 mg monthly), and +8.6 letters (2.0 mg PRN). The proportion of patients who gained ≥15 letters from baseline at month 12 in the 4 groups was 34.5%, 30.2%, 36.1%, and 33.0%, respectively. The mean change from baseline in CFT at month 12 in the 4 groups was −172.0 μm, −161.2 μm, −163.3 μm, and −172.4 μm, respectively. The mean number of injections was 7.7 and 6.9 for the 0.5-mg PRN and 2.0-mg PRN groups, respectively. Ocular and systemic safety profiles were consistent with previous ranibizumab trials in AMD and comparable between groups. At month 12, the ranibizumab 2.0 mg monthly group did not meet the prespecified superiority comparison and the ranibizumab 0.5 mg and 2.0 mg PRN groups did not meet the prespecified noninferiority (NI) comparison. However, all treatment groups demonstrated clinically meaningful visual improvement (+8.2 to +10.1 letters) and improved anatomic outcomes, with the PRN groups requiring approximately 4 fewer injections (6.9–7.7) than the monthly groups (11.2–11.3). No new safety events were observed despite a 4-fold dose escalation in the study. The pHase III, double-masked, multicenter, randomized, Active treatment-controlled study of the efficacy and safety of 0.5 mg and 2.0 mg Ranibizumab administered monthly or on an as-needed Basis (PRN) in patients with subfoveal neOvasculaR age-related macular degeneration (HARBOR) study confirmed that ranibizumab 0.5 mg dosed monthly provides optimum results in patients with wet AMD.

Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, and SMAD6. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates.

Objective: To compare the efficacy and safety of 1-mg and 4-mg doses of preservative-free intravitreal triamcinolone with standard care (grid photocoagulation in eyes without dense macular hemorrhage and deferral of photocoagulation until hemorrhage clears in eyes with dense macular hemorrhage) for eyes with vision loss associated with macular edema secondary to branch retinal vein occlusion (BRVO).

Two decades after the discovery of the first animal microRNA (miRNA), the number of miRNAs in animal genomes remains a vexing question. Here, we report findings from analyzing 1,323 short RNA sequencing samples (RNA-seq) from 13 different human tissue types. Using stringent thresholding criteria, we identified 3,707 statistically significant novel mature miRNAs at a false discovery rate of ≤ 0.05 arising from 3,494 novel precursors; 91.5% of these novel miRNAs were identified independently in 10 or more of the processed samples. Analysis of these novel miRNAs revealed tissue-specific dependencies and a commensurate low Jaccard similarity index in intertissue comparisons. Of these novel miRNAs, 1,657 (45%) were identified in 43 datasets that were generated by cross-linking followed by Argonaute immunoprecipitation and sequencing (Ago CLIP-seq) and represented 3 of the 13 tissues, indicating that these miRNAs are active in the RNA interference pathway. Moreover, experimental investigation through stem-loop PCR of a random collection of newly discovered miRNAs in 12 cell lines representing 5 tissues confirmed their presence and tissue dependence. Among the newly identified miRNAs are many novel miRNA clusters, new members of known miRNA clusters, previously unreported products from uncharacterized arms of miRNA precursors, and previously unrecognized paralogues of functionally important miRNA families (e.g., miR-15/107). Examination of the sequence conservation across vertebrate and invertebrate organisms showed 56.7% of the newly discovered miRNAs to be human-specific whereas the majority (94.4%) are primate lineage-specific. Our findings suggest that the repertoire of human miRNAs is far more extensive than currently represented by public repositories and that there is a significant number of lineage- and/or tissue-specific miRNAs that are uncharacterized.

Age-related macular degeneration, a deterioration of the central portion of the retina, is the chief cause of severe and irreversible loss of vision in developed countries.1,2 There is no effective treatment for most patients with age-related macular degeneration, and many patients therefore resort to experimental treatments. Physicians must know how to counsel their patients about the limitations and risks of these experimental therapies. Fortunately, several clinical trials sponsored by both the National Eye Institute and the private sector are evaluating novel prophylactic and therapeutic interventions. In addition, there is much exciting, ongoing basic research, some of which may lead . . .

OBJECTIVE: To identify the risk factors of conjunctival malignant melanoma that predict local tumor recurrence, orbital exenteration, distant metastasis, and tumor-related mortality. DESIGN: The clinical parameters of the patient, tumor, and treatment were analyzed in a nonrandomized fashion for their relation to 4 main outcome measures using Cox proportional hazards regression models. PARTICIPANTS: One hundred fifty consecutive patients. MAIN OUTCOME MEASURES: Local tumor recurrence, orbital exenteration, distant metastasis, and death from conjunctival melanoma. RESULTS: The Kaplan-Meier estimates of local tumor recurrence was 26% at 5 years, 51% at 10 years, and 65% at 15 years. The mean number of recurrences per patient was 1 (median, 0 recurrences). There was no recurrence in 98 patients (65%), 1 recurrence in 28 patients (19%), 2 recurrences in 11 patients (7%), 3 recurrences in 5 patients (3%), and 4 or more recurrences in 8 patients (5%). Using multivariate analysis, the factors correlated with local tumor recurrence were melanoma location (not touching the limbus) (P =.01) and pathological tumor margins (lateral margin involved) (P =.02). Multivariate analysis for features correlated with ultimate exenteration included initial visual acuity (20/40 OU or worse) (P<. 001), melanoma color red (P =.01), and melanoma location (not touching the limbus) (P =.02). Tumor metastasis was present in 16% of patients at 5 years, 26% of patients at 10 years, and 32% of patients at 15 years. Metastasis was first located in the regional lymph nodes in 17 cases, the brain in 4 cases, the liver in 3 cases, the lung in 2 cases, and was disseminated in 1 case. The risks for metastases using multivariate analysis included pathological tumor margins (lateral margin involved) (P =.002) and melanoma location (not touching limbus) (P =.04). Tumor-related death occurred in 7% patients at 5 years' follow-up and 13% at 8 years' follow-up. The risk factors for death using multivariate analysis included initial symptoms (lump) (P =.004) and pathologic findings (de novo melanoma without primary acquired melanosis) (P =.05). The technique of initial surgery was shown to be an important factor in preventing eventual tumor recurrence (P =.07), metastasis (P =.03), and death (P =.006) in the univariate analysis, but did not reach significance in the multivariate analysis. CONCLUSIONS: Conjunctival malignant melanoma is a potentially deadly tumor. In the present study, metastasis was detected in 26% of patients, and death occurred in 13% of patients at 10 years. Extralimbal melanoma and tumor involvement of the surgical margins were especially poor prognostic factors. Meticulous surgical planning using wide microsurgical excisional biopsy working with the "no touch" technique and supplemental alcohol corneal epitheliectomy and conjunctival cryotherapy is advised. Arch Ophthalmol. 2000;118:1497-1507

To our knowledge, there are no articles that describe the specific step-by-step details of the surgical removal of premalignant and malignant conjunctival tumors. We describe our current approach to the surgical management of squamous cell carcinoma (intraepithelial or invasive), localized melanoma, and primary acquired melanosis of the conjunctiva. The surgical method differs with limbal tumors, extralimbal tumors, and primary acquired melanosis. Limbal lesions are managed by localized alcohol corneal epitheliectomy, removal of the main mass by a partial lamellar scleroconjunctivectomy, and supplemental cryotherapy. Tumors located in the extralimbal conjunctiva are managed by alcohol application, wide circumferential surgical resection, and cryotherapy. Primary acquired melanosis is managed by alcohol epitheliectomy, removal of suspicious foci, quadrantic staging biopsies, and cryotherapy from the underside of the conjunctiva. In all cases, a "no touch" method is used and direct manipulation of the tumor is avoided to prevent tumor cell seeding into a new area. We have employed this technique on 109 patients with conjunctival squamous neoplasms and 137 patients with conjunctival melanoma, about 80 of which neoplasms were associated with primary acquired melanosis. Our observations suggest that well-planned initial surgical management using this technique decreases the chance of tumor recurrence for conjunctival melanoma and squamous cell carcinoma. We describe a detailed stepwise approach to the surgical management of conjunctival neoplasms. It requires meticulous clinical evaluation and complete removal of the tumor in one operation using a specific technique.

Cornelia de Lange syndrome (CdLS) is an archetypical genetic syndrome that is characterized by intellectual disability, well-defined facial features, upper limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in any one of seven genes, all of which have a structural or regulatory function in the cohesin complex. Although recent advances in next-generation sequencing have improved molecular diagnostics, marked heterogeneity exists in clinical and molecular diagnostic approaches and care practices worldwide. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria, both for classic CdLS and non-classic CdLS phenotypes, molecular investigations, long-term management and care planning.

Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale. Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. Design, Setting, and Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. Main Outcomes and Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68]). Conclusions and Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs.

BACKGROUND: Chemoreduction is a method of reducing tumor volume to allow for more focused, less damaging therapeutic measures. OBJECTIVE: To determine whether chemoreduction could be used to decrease the size of retinoblastoma so that enucleation or external beam radiotherapy could be avoided and more conservative modalities employed. METHODS: A prospective pilot study was performed to assess the effectiveness of a 2-month chemoreduction regimen of vincristine sulfate, etoposide, and carboplatin in patients with retinoblastoma. The study included 20 patients with 54 tumors in 31 eyes. RESULTS: At the initial examination, the mean tumor base was 12 mm and the thickness, 7 mm. Vitreous seeds were present in 14 eyes (45%). A secondary retinal detachment was present in 24 eyes (77%) and, when present, involved a mean of 71% of the retina. In 11 eyes (36%) the retina was totally detached with serous subretinal fluid. After 2 months of chemoreduction, all 54 tumors showed regression in size, and 48 (89%) showed evidence of calcification. The mean tumor base was 8 mm and the thickness, 4 mm. Overall, there was a mean 35% decrease in base and 49% decrease in thickness of the tumor at the end of the treatment period. A complete response was found in 25 tumors (46%) and a partial response in 29 (54%). The subretinal fluid had resolved completely in 50% of the cases (12/24 eyes), and, in the 11 eyes with total retinal detachment, the subretinal fluid had completely resolved, leaving flat retina, in 6 eyes (54%). The vitreous seeds demonstrated some degree of regression in all cases, and in 5 eyes there was 90% to 100% calcification of the seeds. Short-term systemic toxic effects were mild (transient bone marrow suppression). Enucleation was avoided in all cases; external beam radiotherapy was necessary in 9 eyes because of diffuse vitreous seeds. The remaining 22 eyes were treated with local methods after chemoreduction. CONCLUSION: Tumor shrinkage with chemoreduction may allow treatment with less invasive measures, such as cryotherapy, laser photocoagulation, thermotherapy, or plaque radiotherapy, thereby avoiding enucleation and external beam radiotherapy.

Color Doppler imaging is a recent advance in ultrasonography that allows simultaneous two-dimensional imaging of structure and blood flow to be performed. Doppler information is superimposed in color over a conventional gray-scale ultrasound image. Using this technique, we examined 40 normal eyes. The central retinal artery, posterior ciliary arteries, ophthalmic artery, and central retinal vein could be located in all patients. Using the color image as a guide, Doppler spectral analysis allows quantitative assessment of blood flow velocity in these vessels. Color Doppler imaging is a new modality for the study of ocular and orbital hemodynamics.

PURPOSE: To analyze the foveal avascular zone (FAZ) in normal eyes using optical coherence tomography angiography. METHODS: Prospective noncomparative case series. The parafoveal region of 70 eyes from 67 healthy subjects was imaged using optical coherence tomography angiography to visualize the superficial and deep capillary plexuses and correlated with standard macular volume scans using spectral domain optical coherence tomography to determine foveal morphology. RESULTS: In all 70 eyes imaged, 2 vascular plexuses could be detected within the retina: a superficial plexus within the ganglion cell layer and a deep plexus within the inner nuclear layer. A measurable FAZ was visualized in both plexuses in all imaged eyes. The FAZ area was variable in the study population with a mean of 0.266 mm² ± 0.097 mm² in the superficial plexus (range: 0.071 mm²-0.527 mm²) and a mean of 0.495 mm² ± 0.227 mm² in the deep plexus (range: 0.160 mm²-0.795 mm²). The FAZ area was significantly larger in the deep plexus (P < 0.0001) compared with superficial plexus. The FAZ area in both plexuses correlated inversely with central macular thickness and central macular volume (P < 0.0001). No significant correlation was found between superficial plexus FAZ area and age (P = 0.55) or sex (P = 0.34). In the same manner, no significant correlation was found between deep plexus FAZ area and age (P = 0.13) or sex (P = 0.13). CONCLUSION: Optical coherence tomography angiography provides a noninvasive method to visualize and measure the superficial and deep plexus FAZ in a normal population. The FAZ can vary in size and shape, with the FAZ area significantly larger in the deep compared with the superficial plexus. Both superficial and deep FAZ area correlate inversely with foveal thickness and volume.

IMPORTANCE: Intra-arterial chemotherapy has emerged as a treatment for intraocular retinoblastoma and has been quickly adopted by centers worldwide. OBJECTIVE: To conduct a systematic review and attempt a meta-analysis to summarize the reported outcomes of intra-arterial chemotherapy. EVIDENCE REVIEW: In January 2015, we performed comprehensive searches in Medline, Embase, Cochrane, and Web of Science from inception through January 2015, including any peer-reviewed English-language publication that described outcomes related to toxicity or efficacy in at least 4 patients. FINDINGS: From a total of 208 identified publications, 28 met inclusion criteria. Twelve reports with discernable nonduplicative information were included, reporting 655 patients, 757 eyes, and 2350 catheterizations. All were single-arm case series, and 67% (8 of 12) were retrospective. Across all studies, globe salvage was achieved for 502 (66%) of all eyes. Most common reported toxicities were chorioretinal atrophy and vascular occlusions. There were at least 13 reports of children with metastases. After publication, 7 additional children had metastases. The 4 different classification systems used challenged the comparison of disease severity at presentation. Visual outcome was not addressed in most studies. Meta-analyses were not possible because no study had a comparative group. Assessment of risk of bias was not possible because no validated tool for single-arm studies was available. CONCLUSIONS AND RELEVANCE: Intra-arterial chemotherapy is a promising new treatment associated with high rates of globe salvage. However, the literature is limited by the predominance of retrospective case series, absence of comparison groups, short median follow-up, heterogeneous definitions and tumor classifications, and frequent duplicate reporting. Metastases have been observed, and long-term follow-up is needed. Until the results of clinical, prospective studies are available, it is recommended that intra-arterial chemotherapy be offered selectively among other options, with fully informed discussion about all possible risks, benefits, and uncertainties.

PURPOSE: The Argus II Retinal Prosthesis System (Second Sight Medical Products, Inc, Sylmar, CA) was developed to restore some vision to patients blind as a result of retinitis pigmentosa (RP) or outer retinal degeneration. A clinical trial was initiated in 2006 to study the long-term safety and efficacy of the Argus II System in patients with bare or no light perception resulting from end-stage RP. DESIGN: Prospective, multicenter, single-arm clinical trial. Within-patient controls included the nonimplanted fellow eye and patients' native residual vision compared with their vision with the Argus II. PARTICIPANTS: Thirty participants in 10 centers in the United States and Europe. METHODS: The worse-seeing eye of blind patients was implanted with the Argus II. Patients wore glasses mounted with a small camera and a video processor that converted images into stimulation patterns sent to the electrode array on the retina. MAIN OUTCOME MEASURES: The primary outcome measures were safety (the number, seriousness, and relatedness of adverse events) and visual function, as measured by 3 computer-based, objective tests. Secondary measures included functional vision performance on objectively scored real-world tasks. RESULTS: Twenty-four of 30 patients remained implanted with functioning Argus II Systems at 5 years after implantation. Only 1 additional serious adverse event was experienced after the 3-year time point. Patients performed significantly better with the Argus II on than off on all visual function tests and functional vision tasks. CONCLUSIONS: The 5-year results of the Argus II trial support the long-term safety profile and benefit of the Argus II System for patients blind as a result of RP. The Argus II is the first and only retinal implant to have market approval in the European Economic Area, the United States, and Canada.

Retinoblastoma clinical observations revealed the role of tumor suppressor genes in human cancer, Knudson's 'two-hit' model of cancer induction. We now demonstrate that loss of both RB1 tumor suppressor gene alleles initiates quiescent RB1(-/-) retinomas with low level genomic instability and high expression of the senescence-associated proteins p16(INK4a) and p130. Although retinomas can remain unchanged throughout life, highly proliferative, clonal and aneuploid retinoblastomas commonly emerge, exhibiting altered gene copy number and expression of oncogenes (MYCN, E2F3, DEK, KIF14 and MDM4) and tumor suppressor genes (CDH11, p75(NTR)) and reduced expression of p16(INK4a) and p130. We suggest that RB1 inactivation in developing retina induces genomic instability, but senescence can block transformation at the stage of retinoma. However, stable retinoma is rarely clinically observed because progressive genomic instability commonly leads to highly proliferative retinoblastoma.