VON HIPPEL–LINDAU DISEASE: Update on Pathogenesis and Systemic Aspects Purpose: To provide an update summarizing the biologic pathways governing von Hippel–Lindau (VHL) disease pathogenesis and to provide an overview of systemic manifestations as well as screening recommendations. Methods: A PubMed search of the English language literature was reviewed using the following search terms: von Hippel–Lindau, von Hippel–Lindau disease, and VHL. Of 6,696 publications, the most current and pertinent information related to the pathogenesis and systemic aspects of VHL disease were included in this review. Results: von Hippel–Lindau disease is one of the most frequently occurring multisystem familial cancer syndromes. The disease results from germline mutation in the VHL tumor suppressor gene on the short arm of chromosome 3. Mutation in the VHL gene affects multiple cellular processes including transcriptional regulation, extracellular matrix formation, apoptosis, and, in particular, the cellular adaptive response to hypoxia. As a result, there is widespread development of vascular tumors affecting the retina, brain, and spine, as well as a spectrum of benign and malignant tumors and/or cysts in visceral organs. Conclusion: The ophthalmologist plays a key role in VHL disease diagnosis, as retinal hemangioblastoma is frequently the first disease manifestation. Screening guidelines for individuals with known VHL disease, and those at risk of VHL disease, help to ensure early detection of potentially vision-threatening and life-threatening disease.

MANAGEMENT OF RETINAL HEMANGIOBLASTOMA IN VON HIPPEL–LINDAU DISEASE Purpose: To review the current state of diagnosis and management of retinal hemangioblastoma and retinal vascular proliferation arising from von Hippel–Lindau (VHL) disease. Methods: A review of the literature was performed. Consensus was reached among authors regarding current practice, with reference to published data where possible. Results: von Hippel–Lindau disease and its ocular manifestations are relatively rare, and there is limited evidence in the literature on which to base management. There was consensus on core principles, including 1) recognition and diagnosis of von Hippel–Lindau disease when present, with appropriate referral for care of this potentially lethal systemic condition; 2) regular ophthalmic evaluation for individuals with von Hippel–Lindau disease, to identify and offer timely treatment for new or active retinal hemangioblastomas; 3) ablative treatment of retinal hemangioblastomas that can be safely destroyed, to lower risk of vision loss; 4) observation or consideration of nonablative treatments for retinal hemangioblastomas that cannot be safely destroyed; and 5) observation of asymptomatic retinal vascular proliferation, with consideration of vitrectomy for lesions exerting effects on vision. Conclusion: Ocular outcomes can be gratifying in many cases with appropriate management. Improved understanding of the molecular basis for the disease creates an opportunity for rational design of better therapies.

OPHTHALMIC VASCULAR EVENTS AFTER INTRA‐ARTERIAL CHEMOTHERAPY FOR RETINOBLASTOMA: Real-World Comparison Between Primary and Secondary Treatments Purpose: To determine whether treatment order affects ophthalmic vascular event rates after intra‐arterial chemotherapy (IAC) for retinoblastoma. Methods: Patients who received IAC as primary or secondary treatment for retinoblastoma from January 2009 to January 2018 were included. All eyes were imaged with fundus photography and fluorescein angiography. Patient characteristics and vascular event rates were compared using t-test and Fisher's exact test. Results: There were 196 patients treated with 682 infusions of IAC, divided into primary (no previous therapy, 98 eyes of 98 patients, 328 infusions) and secondary (after other therapy, 105 eyes of 98 patients, 354 infusions) treatment. Overall, ophthalmic vascular events were found after 5% of infusions (17% eyes). A comparison of ophthalmic vascular events (primary vs. secondary IAC), with mean three infusions per eye (median 3, range 1–7), revealed no difference in overall percentage of eyes affected (18% vs. 15%, P = 0.57). Adverse vascular events per eye included retinal vasculature attenuation (1% vs. 0%, P = 0.99), peripheral retinal pruning (1% vs. 0%, P = 0.99), branch retinal artery occlusion (0% vs. 1%, P = 0.99), central retinal artery occlusion (0% vs. 1%, P = 0.99), macular ischemia (0% vs. 2%, P = 0.51), vitreous hemorrhage (2% vs. 3%, P = 0.92), subretinal hemorrhage (1% vs. 0%, P = 0.99), retinal pigment epithelium atrophy (6% vs. 3% P = 0.43), choroidal atrophy (4% vs. 2%, P = 0.92), optic disk pallor (1% vs. 0%, P = 0.99), and ophthalmic artery occlusion (9% vs. 6%, P = 0.35). Conclusion: Ophthalmic vascular events after IAC for retinoblastoma affect only 5% of eyes per infusion (17% of treated eyes). Vascular event risk per eye is similar when using IAC as primary or secondary treatment.

INTRAVITREAL ANTI–VASCULAR ENDOTHELIAL GROWTH FACTOR FOR THE MANAGEMENT OF NEOVASCULARIZATION IN RETINOBLASTOMA AFTER INTRAVENOUS AND/OR INTRAARTERIAL CHEMOTHERAPY: Long-Term Outcomes in a Series of 35 Eyes Purpose: To report the use of anti–vascular endothelial growth factor in the management of retinoblastoma. Methods: Retrospective review of 35 eyes (33 patients) treated with at least one intravitreal anti–vascular endothelial growth factor (ranibizumab and/or aflibercept) for new iris (n = 26) and/or retinal neovascularization (n = 21) after intravenous chemotherapy and/or intraarterial chemotherapy. Results: Most eyes (n = 31/35, 89%) were Group D or E. Previous treatments were salvage intraarterial chemotherapy after intravenous chemotherapy (n = 21/35, 60%), first-line intraarterial chemotherapy (n = 7/35, 20%), and first-line intravenous chemotherapy (n = 7/35, 20%). Associated clinical features were retinal ischemia (94%), retinal detachment (51%), active tumor (34%), intravitreal hemorrhage (43%), and/or glaucoma (17%). Mean 1.6 anti–vascular endothelial growth factor injections/eye were given; 28 eyes received ranibizumab, 2 aflibercept, and 5 both agents. Eight eyes underwent complementary treatments of ischemic retina. Resolution of neovascularization was observed in 28 eyes (n = 28/35, 80%). Globe salvage was achieved in 51% (n = 18/35), including 25% of those with active tumor (n = 3/12). One eye became phthisic. Sixteen eyes were enucleated, nine for tumor relapse/progression. Five eyes had high-risk histopathologic risk factors and received adjuvant intravenous chemotherapy. All patients are alive with no extraocular extension nor metastases (mean follow-up 3.7 years, range 1.1–7.6). Conclusion: Intravitreal anti–vascular endothelial growth factor contributed to a globe salvage rate of 51% by providing conditions to continue conservative treatment.

OPTICAL COHERENCE TOMOGRAPHY BIOMARKERS TO DISTINGUISH DIABETIC MACULAR EDEMA FROM PSEUDOPHAKIC CYSTOID MACULAR EDEMA USING MACHINE LEARNING ALGORITHMS Purpose: In diabetic patients presenting with macular edema (ME) shortly after cataract surgery, identifying the underlying pathology can be challenging and influence management. Our aim was to develop a simple clinical classifier able to confirm a diabetic etiology using few spectral domain optical coherence tomography parameters. Methods: We analyzed spectral domain optical coherence tomography data of 153 patients with either pseudophakic cystoid ME (n = 57), diabetic ME (n = 86), or “mixed” (n = 10). We used advanced machine learning algorithms to develop a predictive classifier using the smallest number of parameters. Results: Most differentiating were the existence of hard exudates, hyperreflective foci, subretinal fluid, ME pattern, and the location of cysts within retinal layers. Using only 3 to 6 spectral domain optical coherence tomography parameters, we achieved a sensitivity of 94% to 98%, specificity of 94% to 95%, and an area under the curve of 0.937 to 0.987 (depending on the method) for confirming a diabetic etiology. A simple decision flowchart achieved a sensitivity of 96%, a specificity of 95%, and an area under the curve of 0.937. Conclusion: Confirming a diabetic etiology for edema in cases with uncertainty between diabetic cystoid ME and pseudophakic ME was possible using few spectral domain optical coherence tomography parameters with high accuracy. We propose a clinical decision flowchart for cases with uncertainty, which may support the decision for intravitreal injections rather than topical treatment.

PERIPAPILLARY NEUROVASCULAR COUPLING IN THE EARLY STAGES OF DIABETIC RETINOPATHY Purpose: To study radial peripapillary capillary (RPC) density in the early stages of diabetic retinopathy (DR), using optical coherence tomography angiography. Methods: A cross-sectional evaluation of RPCs was performed using optical coherence tomography angiography (Avanti RTVue-XR 100, Optovue Inc, Fremont, CA). Annular RPC density was the primary outcome. Global density and retinal nerve fiber layer thickness were secondary outcomes. Diabetic eyes were divided into three groups: no DR, mild nonproliferative DR (mild NPDR), and moderate NPDR. Multilevel mixed-effects univariate and multivariate linear regression models were used. Results: We included 155 eyes (n = 42 control; n = 27 no DR; n = 28 mild NPDR; and n = 58 moderate NPDR) from 86 subjects (mean [SD] age 63.39 [10.70] years; 46.45% male). When compared with controls, a significant decrease in annular RPC density was found in all groups of diabetic eyes on multivariate analysis (no DR: β = −2.95, P < 0.001; mild NPDR: β = −1.76, P = 0.017; and moderate NPDR: β = −2.82, P < 0.001). We also detected a significant decrease in retinal nerve fiber layer thickness in diabetic eyes (even in the no DR group). Furthermore, in diabetic eyes, annular RPC density and retinal nerve fiber layer thickness correlated significantly (R = 0.4874, P < 0.001). Conclusion: Peripapillary neurovascular changes occur early in the course of DR. Their significance in the progression of DR warrants further research.

GENETIC RISK FACTORS IN ACUTE CENTRAL SEROUS CHORIORETINOPATHY Purpose: To investigate genetic associations in white patients with acute central serous chorioretinopathy (aCSC) and to assess genetic differences between aCSC and chronic CSC (cCSC). Methods: A total of 135 aCSC patients, 272 cCSC patients, and 1,385 control individuals were included. Eight single nucleotide polymorphisms were genotyped for ARMS2 (rs10490924), CFH (rs800292, rs1061170, rs1065489, rs1329428, rs2284664, rs3753394), and NR3C2 (rs2070951). Also, C4B gene copy numbers were analyzed. Results: Three single nucleotide polymorphisms in the CFH gene were significantly associated with aCSC: rs800292 (P = 0.003, odds ratio = 1.53 [95% confidence interval = 1.15–2.03]), rs1061170 (P = 0.002, odds ratio = 0.64 [95% confidence interval = 0.48–0.86]), and rs1329428 (P = 5.87 × 10−6, odds ratio = 1.83 [95% confidence interval = 1.40–2.38]). A significant difference was found in the distribution of C4B gene copy numbers in aCSC patients compared with controls (P = 0.0042). No differences could be found among the selected variants between aCSC and cCSC patients. Conclusion: Three variants in the CFH gene and copy number variations in C4B were found to be significantly associated with the risk of aCSC development. Despite the differences in clinical presentation, acute and chronic CSC may share a similar genetic predisposition based on our present analysis. Other genetic and/or nongenetic risk factors may be more influential in the differentiation toward an acute or a chronic phenotype of CSC.

CLINICAL CHARACTERIZATION OF STARGARDT DISEASE PATIENTS WITH THE p.N1868I ABCA4 MUTATION Purpose: To investigate the Stargardt disease phenotype associated with an unusually common and “extremely hypomorphic” ABCA4 variant, p.N1868I. Methods: The charts of 27 patients with p.N1868I on one allele and a severe/deleterious mutation on the other allele were reviewed. Subjective age of onset, best-corrected visual acuity, and stage of disease were recorded for all 27 patients, 18 of whom had multiple visits. When available, fundus photography, spectral domain optical coherence tomography, fundus autofluorescence, full-field electroretinograms, Goldmann visual fields, and fluorescein angiography were included. Five families with multiple affected members were analyzed. Results: The median age at symptom onset was 41.5 years, and 3 p.N1868I patients had not developed visual symptoms as of the most recent eye examination. Median best-corrected visual acuity in the better-seeing eye at baseline was 20/25−2, and the median duration from symptom onset to legal blindness was 25 years. The five families described in this study demonstrated clinically significant intrafamilial variability, and affected family members who did not share the p.N1868I variant had relatively more severe phenotypes. Conclusion: This study demonstrates the consistency of foveal sparing, the variation in age at onset, the intrafamilial variability, and the prognosis with regard to visual acuity in p.N1868I-associated Stargardt disease.

FIVE-YEAR FUNCTIONAL OUTCOMES AFTER EPIRETINAL MEMBRANE SURGERY: A Prospective, Controlled Study Purpose: To evaluate 5-year functional outcomes involving the inner retina after epiretinal membrane (ERM) surgery. Methods: The study eye (SE) and fellow eye (FE) of 20 patients undergoing ERM surgery were examined preoperatively and at 3, 12, 24, 36, 48, and 60 months postoperatively. Retinal nerve fiber layer and ganglion cell–inner plexiform layer (GC-IPL) thicknesses were analyzed using spectral domain optical coherence tomography. Humphrey visual field mean deviation, pattern SD, and qualitative changes were assessed and compared over time. Results: Mean GC-IPL thickness in SEs was less than that of FEs at all time points with progressive thinning in SEs after ERM surgery. There was significant thinning of the superotemporal GC-IPL in SEs as compared to FEs at 3 months and 60 months (P < 0.05). Humphrey visual field mean deviation was greater in SEs as compared to FEs but statistically significant only at 0, 12, and 24 months (P < 0.05). Pattern SD increased from baseline in SEs but remained near baseline in FEs. Conclusion: Surgical eyes after ERM surgery demonstrated progressive thinning of the GC-IPL and transient worsening trends in Humphrey visual field mean deviation and pattern SD as compared to controls after ERM surgery.

INNER MACULAR CHANGES AFTER VITRECTOMY WITH INTERNAL LIMITING MEMBRANE PEELING FOR RHEGMATOGENOUS RETINAL DETACHMENT: Similarity With Alport Syndrome Purpose: The internal limiting membrane (ILM), the innermost basement membrane of the retina, is peeled occasionally during vitreous surgery. This study aimed to investigate the effect of ILM loss on the retina. Methods: We used optical coherence tomography to retrospectively evaluate retinal changes in 26 eyes (11 ILM-peeled and 15 ILM-unpeeled eyes) of 26 patients after vitrectomy for retinal detachment. In addition, we studied six eyes of three patients with Alport syndrome, in which ILM is genetically impaired. Results: We observed significant inner retinal displacement of the foveal pit toward the optic disk with inner retinal thickening in the nasal area (fellow, 191.9 ± 24.3 μm vs. affected, 210.3 ± 31.4 μm; P = 0.048), inner retinal thinning in the temporal area (fellow, 174.3 ± 18.3 μm vs. affected, 142.2 ± 23.6 μm; P < 0.001), foveal thickening (ILM-unpeeled, 217.0 ± 39.4 μm vs. ILM-peeled, 302.0 ± 86.2 μm; P = 0.006), inner retinal dimples predominantly in the temporal area, and deviation between the foveal pit and foveal bulge. Eyes with Alport syndrome exhibited similar findings. Conclusion: Internal limiting membrane loss seems to cause characteristic inner retinal changes of the macula in both congenital and acquired conditions.