Retinal vasproliferative tumor in a case of X-linked retinoschisis detachment.

PURPOSE: To describe the first published case of X-linked retinoschisis (XLRS) detachment with retinal vasoproliferative tumor (RVPT) and provide a literature review of the subject. OBSERVATIONS: The authors describe a case of a 17 year old male with X-linked retinoschisis who presented with a retinal detachment and a retinal vasoproliferative tumor. The patient was treated with pars plana vitrectomy, endolaser, subtenon's kenalog and anti-VEGF (vascular endothelial growth factor) intravitreal injections. He regained 20/60 vision with a flat macula and had significant resolution of the associated vasoproliferative leakage seen on fluorescein angiography. CONCLUSIONS AND IMPORTANCE: This case adds XLRS to the conditions associated with RVPT and gives support for treatment with laser photocoagulation and anti-VEGF therapy with bevacizumab to control the exudative process.

PROPHYLACTIC PREOPERATIVE LASER RETINOPEXY DOES NOT REDUCE THE OCCURRENCE OF RHEGMATOGENOUS RETINAL COMPLICATIONS IN MACULAR SURGERY.

PURPOSE: Knowledge on the utility of prophylactic 360° laser retinopexy before pars plana vitrectomy in the absence of peripheral retinal pathology is limited. This study compares the occurrence of rhegmatogenous events in the setting of small-gauge pars plana vitrectomy with and without prophylactic preoperative laser. METHODS: Our multicenter, retrospective case-control analysis reviewed patients who underwent epiretinal membrane removal or macular hole repair through 23- or 25-gauge pars plana vitrectomy: 205 controls who did not receive prophylactic laser and 176 cases who received preoperative prophylactic laser retinopexy anterior to the equator. Main outcome measures were the rate and characteristics of postoperative retinal tears and detachments. Patients with previous pars plana vitrectomy or significant retinal disease were excluded. RESULTS: Of those patients with prophylactic laser and those without, there was no significant difference in the number of retinal breaks (1.7% vs. 0.49%, respectively; P = 0.339) or retinal detachments (0% vs. 0.49%, respectively; P = 1.00). Of the lasered group, there was one sclerotomy-related retinal break and two non-sclerotomy-related retinal breaks. Of the nonlasered group, there was one non-sclerotomy-related retinal break and one sclerotomy-related retinal detachment. CONCLUSION: Preoperative prophylactic peripheral laser retinopexy does not seem to offer an added benefit in the prevention of intraoperative and postoperative rhegmatogenous events.

MULTIPLE EVANESCENT WHITE DOT SYNDROME WITH CENTRAL VISUAL LOSS.

PURPOSE: To report the clinical case of a 64-year-old man who developed several features of multiple evanescent white dot syndrome (MEWDS) but with central visual loss that persisted because of significant structural macular disease. METHODS: A case report was generated by a review of the clinical course and imaging investigations of one patient, along with review of the literature. RESULTS: A 64-year-old man noted decreased vision in the right eye for 2 weeks, associated with a central scotoma with shimmering, gauze effect of the vision. He had a good vision with normal ophthalmic examinations in the past. Ophthalmic examination revealed acuity of 20/400 with central scotoma and trace pupillary defect in the right eye, normal anterior segment, no evidence of intraocular inflammation, and fundus findings of unilateral MEWDS associated with a central zone of macular pigmentary atrophy. Autofluorescence imaging revealed reflectance changes of MEWDS as well as prominent central hypofluorescence and a zone of hyperfluorescence in inferior macula. Spectral-domain optical coherence tomography identified mild disruptions of outer retina in the regions of the MEWDS lesions and disorganization of the outer retina in the macular region overlying a shallow irregular retinal pigment epithelial detachment. The choroid demonstrated increased thickness compared with the fellow eye with suggestions of dilated outer vessels/pachyvessels. Fluorescein angiography and indocyanine green angiography revealed window defects and staining and hypocyanescence, respectively, of the central macular lesion. The MEWDS lesions resolved without evolution to chorioretinal scars, and the central vision and lesions did not benefit from a systemic steroid course or intravitreal anti-vascular endothelial growth factor therapy. CONCLUSION: This case illustrates an unusual presentation of MEWDS characterized by unilateral retinal disease presenting with symptoms and signs of profound central macular dysfunction. The clinical course did not evolve into other inflammatory retinal phenotypes, such as multifocal choroiditis or AZOOR (acute zonal occult outer retinopathy) that can sometimes develop MEWDS-like features or central disease. The central structural disease resembles some features of the pachychoroid clinical spectrum, which may have represented a superimposed diagnosis unrelated to the inflammatory phenotype.

Bioactive lysophospholipids generated by hepatic lipase degradation of lipoproteins lead to complement activation via the classical pathway.

PURPOSE: We determined bioactivity of lysophospholipids generated by degradation of the low-density (LDL), very low-density (VLDL), and high-density (HDL) lipoproteins with hepatic lipase (HL), cholesterol esterase (CE), and lipoprotein-associated phospholipase A2 (Lp-PLA2). METHODS: The LDL, VLDL, and HDL were treated with HL, CE, and Lp-PLA2 after immobilization on plates, and complement activation studies were performed with diluted human serum. Complement component 3 (C3) fixation, a marker for complement activation, was determined with a monoclonal anti-human C3d antibody. Enzymatic properties of HL and CE were assayed with triglyceride and phosphatidylcholine substrates for triglyceride hydrolase and phospholipase A activities. The ARPE-19 cells were used for viability studies. RESULTS: The HL degradation of human lipoproteins LDL, VLDL, or HDL results in the formation of modified lipoproteins that can activate the complement pathway. Complement activation is dose- and time-dependent upon HL and occurs via the classical pathway. Enzymatic studies suggest that the phospholipase A1 activity of HL generates complement-activating lysophospholipids. C-reactive protein (CRP), known to simultaneously interact with complement C1 and complement factor H (CFH), further enhances HL-induced complement activation. The lysophospholipids, 1-Palmitoyl-sn-glycero-3-phosphocholine and 1-Oleoyl-sn-glycero-3-phosphocholine, can be directly cytotoxic to ARPE-19 cells. CONCLUSIONS: The HL degradation of lipoproteins, known to accumulate in the outer retina and in drusen, can lead to the formation of bioactive lysophospholipids that can trigger complement activation and induce RPE cellular dysfunction. Given the known risk associations for age-related macular degeneration (AMD) with HL, CRP, and CFH, this study elucidates a possible damage pathway for age-related macular degeneration (AMD) in genetically predisposed individuals, that HL activity may lead to accumulation of lysophospholipids to initiate complement activation, with CFH dysregulation exacerbating the effects of this process.

Comparison of fundus autofluorescence between fundus camera and confocal scanning laser ophthalmoscope-based systems.

BACKGROUND AND OBJECTIVE: To compare fundus autofluorescence (FAF) imaging via fundus camera (FC) and confocal scanning laser ophthalmoscope (cSLO). PATIENTS AND METHODS: FAF images were obtained with a digital FC (530 to 580 nm excitation) and a cSLO (488 nm excitation). Two authors evaluated correlation of autofluorescence pattern, atrophic lesion size, and image quality between the two devices. RESULTS: In 120 eyes, the autofluorescence pattern correlated in 86% of lesions. By lesion subtype, correlation rates were 100% in hemorrhage, 97% in geographic atrophy, 82% in flecks, 75% in drusen, 70% in exudates, 67% in pigment epithelial detachment, 50% in fibrous scars, and 33% in macular hole. The mean lesion size in geographic atrophy was 4.57 ± 2.3 mm(2) via cSLO and 3.81 ± 1.94 mm(2) via FC (P < .0001). Image quality favored cSLO in 71 eyes. CONCLUSION: FAF images were highly correlated between the FC and cSLO. Differences between the two devices revealed contrasts. Multiple image capture and confocal optics yielded higher image contrast with the cSLO, although acquisition and exposure time was longer.

Unilateral retinopathy secondary to occult primary intraocular lymphoma.

PURPOSE: The purpose of the study is to report the clinical case of a 53-year-old woman whose presenting manifestation of primary intraocular lymphoma (PIOL) was unilateral retinal degeneration. METHOD: A case report was created with review of clinical, imaging, electrophysiologic, and pathological investigations. RESULTS: A 53-year-old woman with a distant history of ocular herpes simplex developed progressive central visual loss and intermittent photopsia over 4 years in her right eye. Ophthalmic examination revealed reduced visual acuity OD, central scotoma, and minimal ocular findings. Autofluorescence and infrared imaging revealed mild reflectance changes in the temporal macula, and spectral-domain optical coherence tomography identified mild disruptions of inner segment/outer segment junctions in the subfoveal region of the right eye. A mild window defect was seen on fluorescein angiography. Electrophysiology with multifocal electroretinogram (ERG) revealed evidence of unilateral macular dysfunction. Full-field ERGs revealed progressive global retinal dysfunction over 6 months, with unilateral decreases in amplitude and implicit time shifts, as seen in cases of autoimmune retinopathies. The eye eventually exhibited mild vitreous cellular infiltration on ophthalmoscopic examination, and vitrectomy diagnosed B cell non-Hodgkin's lymphoma. Further evaluation revealed no evidence of central nervous system or systemic disease, consistent with occult PIOL. CONCLUSIONS: This case illustrates an atypical presentation of PIOL characterized by unilateral retinal disease presenting with symptoms and signs of macular dysfunction. Clinical and ERG features evolved into an acute zonal occult outer retinopathy (AZOOR)-like phenotype. PIOL should be considered in atypical cases of AZOOR with vitreal reactions, and some cases of AZOOR may be related to B cell lymphocyte disorders.

Reticular pseudodrusen in early age-related macular degeneration are associated with choroidal thinning.

PURPOSE: To compare choroidal thickness (CT) measurements in early AMD between patients with and without reticular pseudodrusen (RPD) using spectral-domain optical coherence tomography (SD-OCT). METHODS: This cross-sectional study examined 84 age- and sex-matched AMD patients (40 RPD [63 eyes], 44 non-RPD [75 eyes]). Fundus photographs and scanning laser ophthalmoscopy images were graded to identify RPD and non-RPD groups by three retinal specialists (MO, SY, SB) who were masked to corresponding SD-OCTs. CT at the fovea and 2400 to 3000 µm superior and inferior to the fovea was measured on SD-OCT by a grader (AG) and reviewed by a retinal specialist (SB). Only images with a clear posterior choroidal margin were analyzed (six eyes excluded due to poor image quality), and enhanced depth imaging SD-OCT was used when available (20 of 138 eyes). Greatest retinal thickness (RT) on horizontal foveal SD-OCT was also recorded. RESULTS: Mean CTs in the superior, foveal, and inferior macula in RPD (191.3 µm ± 57.9 SD, 176.3 µm ± 60.5 SD, 179.7 µm ± 56.24 SD) were significantly less than that of non-RPD (228.0 µm ± 66.1 SD, 216.5 µm ± 70.3 SD, 224.4 µm ± 71.9 SD; P = 0.0010, P = 0.0005, P = 0.0001, respectively), as was greatest RT (P = 0.0301). CONCLUSIONS: CT was thinner throughout the macula in the RPD group as compared with the non-RPD group. The current analysis supports an association between RPD and a thinned choroidal layer and is consistent with a choroidal etiology of RPD. CT may be integral to understanding RPD, and may be helpful in stratifying AMD progression risk.

Polychromatic angiography for the assessment of VEGF-induced BRB dysfunction in the rabbit retina.

PURPOSE: To determine the utility of polychromatic angiography (PCA) in the assessment of VEGF-induced blood retinal barrier (BRB) dysfunction in rabbits. METHODS: Twenty-six eyes of 24 Dutch Belted rabbits were injected intravitreally with 1.25 µg (group A, n = 5), 10 µg (group C, n = 7), or 4 µg (group B, n = 6; group D, n = 4; and group E, n = 4) of VEGF on day 0. Groups D and E were also injected intravitreally with 1.25 µg and 12.5 µg bevacizumab, respectively, on day 2. On days 0, 2, 4, 7, 11, and 14, PCA was performed using a contrast agent mixture composed of fluorescein sodium, indocyanine green, PCM102, and PCM107 and imaged with a modified fundus camera. PCA scores were based on detected leaking fluorophores. RESULTS: On day 7, there was a statistically significant difference between PCA scores of group A (0.6 ± 0.89) and both groups B (2.67 ± 1.37, P = 0.0154) and C (3.33 ± 0.52, P = 0.00085). There was also a statistically significant difference between groups B and E (PCA score 0.75 ± 0.96, P = 0.032) on day 7. On day 11, there was statistically significant difference between group C (1.80 ± 1.1) and both groups A (0, P = 0.021) and B (0.33 ± 0.52, P = 0.037). CONCLUSIONS: A differential response to both increasing VEGF dose and administration of bevacizumab could be discerned using the PCA. PCA allowed stratification of VEGF-induced BRB dysfunction and inhibitory effects of bevacizumab therapy in the rabbit retina.

Seven new loci associated with age-related macular degeneration.

Age-related macular degeneration (AMD) is a common cause of blindness in older individuals. To accelerate the understanding of AMD biology and help design new therapies, we executed a collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry. We identified 19 loci associated at P < 5 × 10(-8). These loci show enrichment for genes involved in the regulation of complement activity, lipid metabolism, extracellular matrix remodeling and angiogenesis. Our results include seven loci with associations reaching P < 5 × 10(-8) for the first time, near the genes COL8A1-FILIP1L, IER3-DDR1, SLC16A8, TGFBR1, RAD51B, ADAMTS9 and B3GALTL. A genetic risk score combining SNP genotypes from all loci showed similar ability to distinguish cases and controls in all samples examined. Our findings provide new directions for biological, genetic and therapeutic studies of AMD.

Diabetic retinopathy: neuron protection as a therapeutic target.

Diabetic retinopathy (DR) has mainly been regarded as a microvascular disease that is caused by hyperglycaemia and characterized by retinal vascular leakage, macular oedema and preretinal neovascularisation. Increasing clinical evidence from electroretinographic, contrast sensitivity, perimetric, and colour vision studies suggest that neuronal changes may occur prior to clinically detectable microvasculopathy. Thus, there may be a primary neurodegenerative process which contributes to loss of vision in DR. Neuronal apoptosis in DR has been reported both in vivo and in vitro. Consequently, neuroprotection in DR may be a valuable therapeutic target. This review outlines the recent new concepts of neurodegeneration in the pathogenesis of DR, particularly emphasising its potential for new therapeutic approaches.

Heritability and genome-wide association study to assess genetic differences between advanced age-related macular degeneration subtypes.

PURPOSE: To investigate whether the 2 subtypes of advanced age-related macular degeneration (AMD), choroidal neovascularization (CNV), and geographic atrophy (GA) segregate separately in families and to identify which genetic variants are associated with these 2 subtypes. DESIGN: Sibling correlation study and genome-wide association study (GWAS). PARTICIPANTS: For the sibling correlation study, 209 sibling pairs with advanced AMD were included. For the GWAS, 2594 participants with advanced AMD subtypes and 4134 controls were included. Replication cohorts included 5383 advanced AMD participants and 15 240 controls. METHODS: Participants had the AMD grade assigned based on fundus photography, examination, or both. To determine heritability of advanced AMD subtypes, a sibling correlation study was performed. For the GWAS, genome-wide genotyping was conducted and 6 036 699 single nucleotide polymorphisms (SNPs) were imputed. Then, the SNPs were analyzed with a generalized linear model controlling for genotyping platform and genetic ancestry. The most significant associations were evaluated in independent cohorts. MAIN OUTCOME MEASURES: Concordance of advanced AMD subtypes in sibling pairs and associations between SNPs with GA and CNV advanced AMD subtypes. RESULTS: The difference between the observed and expected proportion of siblings concordant for the same subtype of advanced AMD was different to a statistically significant degree (P = 4.2 × 10(-5)), meaning that in siblings of probands with CNV or GA, the same advanced subtype is more likely to develop. In the analysis comparing participants with CNV to those with GA, a statistically significant association was observed at the ARMS2/HTRA1 locus (rs10490924; odds ratio [OR], 1.47; P = 4.3 × 10(-9)), which was confirmed in the replication samples (OR, 1.38; P = 7.4 × 10(-14) for combined discovery and replication analysis). CONCLUSIONS: Whether CNV versus GA develops in a patient with AMD is determined in part by genetic variation. In this large GWAS meta-analysis and replication analysis, the ARMS2/HTRA1 locus confers increased risk for both advanced AMD subtypes, but imparts greater risk for CNV than for GA. This locus explains a small proportion of the excess sibling correlation for advanced AMD subtype. Other loci were detected with suggestive associations that differ for advanced AMD subtypes and deserve follow-up in additional studies.

Eculizumab for dense deposit disease and C3 glomerulonephritis.

BACKGROUND AND OBJECTIVES: The principle defect in dense deposit disease and C3 glomerulonephritis is hyperactivity of the alternative complement pathway. Eculizumab, a monoclonal antibody that binds to C5 to prevent formation of the membrane attack complex, may prove beneficial. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this open-label, proof of concept efficacy and safety study, six subjects with dense deposit disease or C3 glomerulonephritis were treated with eculizumab every other week for 1 year. All had proteinuria >1 g/d and/or AKI at enrollment. Subjects underwent biopsy before enrollment and repeat biopsy at the 1-year mark. RESULTS: The subjects included three patients with dense deposit disease (including one patient with recurrent dense deposit disease in allograft) and three patients with C3 glomerulonephritis (including two patients with recurrent C3 glomerulonephritis in allograft). Genetic and complement function testing revealed a mutation in CFH and MCP in one subject each, C3 nephritic factor in three subjects, and elevated levels of serum membrane attack complex in three subjects. After 12 months, two subjects showed significantly reduced serum creatinine, one subject achieved marked reduction in proteinuria, and one subject had stable laboratory parameters but histopathologic improvements. Elevated serum membrane attack complex levels normalized on therapy and paralleled improvements in creatinine and proteinuria. CONCLUSIONS: Clinical and histopathologic data suggest a response to eculizumab in some but not all subjects with dense deposit disease and C3 glomerulonephritis. Elevation of serum membrane attack complex before treatment may predict response. Additional research is needed to define the subgroup of dense deposit disease/C3 glomerulonephritis patients in whom eculizumab therapy can be considered.

RAGE binds C1q and enhances C1q-mediated phagocytosis.

RAGE, the multiligand receptor of the immunoglobulin superfamily of cell surface molecules, is implicated in innate and adaptive immunity. Complement component C1q serves roles in complement activation and antibody-independent opsonization. Using soluble forms of RAGE (sRAGE) and RAGE-expressing cells, we determined that RAGE is a native C1q globular domain receptor. Direct C1q-sRAGE interaction was demonstrated with surface plasmon resonance (SPR), with minimum K(d) 5.6 µM, and stronger binding affinity seen in ELISA-like experiments involving multivalent binding. Pull-down experiments suggested formation of a receptor complex of RAGE and Mac-1 to further enhance affinity for C1q. C1q induced U937 cell adhesion and phagocytosis was inhibited by antibodies to RAGE or Mac-1. These data link C1q and RAGE to the recruitment of leukocytes and phagocytosis of C1q-coated material.

Fundus autofluorescence imaging in a patient with rapidly developing scotoma.

PURPOSE: To evaluate the findings in a case of acute macular neuroretinopathy involving sudden development of scotomas accompanied by rapid focal increases in fundus autofluorescence. METHODS: The clinical presentation of the patient was documented by color fundus photographs, fundus autofluorescence, infrared imaging, and high-resolution spectral domain optical coherence tomography. The scotomas were assessed by Humphrey visual field 10-2 and MP-1 microperimetry. RESULTS: Visual field defects exhibited spatial correspondence with wedge-shaped lesions demonstrable in color fundus photographs and infrared imaging. It was notable that the lesions exhibited increased intensity on autofluorescence images obtained within 3 weeks of presentation. Optical coherence tomography revealed focal loss of photoreceptor inner segment/outer segment junctions in both eyes. CONCLUSION: This case was distinguished by the relative rapidity with which the lesions became hyperautofluorescent in fundus autofluorescence images. Given that the bisretinoids that are the source of autofluorescence form in photoreceptor cells and are transferred to retinal pigment epithelium secondarily, the rapid increase in autofluorescence is unlikely to only reflect retinal pigment epithelium status and is more likely to be indicative of photoreceptor cell dysfunctioning and loss of structural integrity.

Complement factor H 402H variant and reticular macular disease.

OBJECTIVE: To determine the association of high-risk alleles in the complement factor H (CFH; Y402H, rs1061170) and age-related maculopathy susceptibility (ARMS2; A69S, rs10490924) genes with reticular macular disease (RMD), a major clinical subphenotype of age-related macular degeneration (AMD). METHODS: Using retinal images from the Columbia Macular Genetics Study, we identified 67 subject individuals with RMD. A comparison group of 64 subjects with AMD without RMD was matched by ethnicity, age, sex, and AMD clinical stage. RESULTS: In the RMD group, 53 of 67 subjects (79.1%) were female, the mean age was 83 years, and 47 of 67 (70.1%) had late AMD, with closely matched values in the non-RMD group. The frequencies of the CFH 402H allele were 39.6% in the RMD group (53 of 134 individuals) and 58.6% in the non-RMD group (75 of 128 individuals) (χ(2) = 8.8; P = .003; odds ratio, 0.46 [95% confidence interval, 0.28-0.76]). The corresponding frequencies of the risk allele for ARMS2 were 44.0% (40 of 128 individuals) and 31.3% (40 of 128 individuals), respectively (χ(2) = 4.0; P = .045; odds ratio, 1.73 [95% confidence interval, 1.04-2.90]). Homozygosity for 402H was particularly associated with the absence of RMD, occurring in 8 of 67 subjects (11.9%) with RMD vs 24 of 64 subjects (37.5%) without RMD (P < .001). Retinal macular disease also was associated with hypertension among male patients. CONCLUSIONS: The AMD-associated CFH 402H risk variant is significantly associated with the absence of RMD but enhanced risk for RMD is conferred by the ARMS2 69S AMD risk allele. These results are consistent with the hypothesis that 402H may confer a survival benefit against certain infections, some of which may cause RMD. CLINICAL RELEVANCE: Reticular macular disease may be genetically distinct from the rest of AMD.

Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration.

Despite significant progress in the identification of genetic loci for age-related macular degeneration (AMD), not all of the heritability has been explained. To identify variants which contribute to the remaining genetic susceptibility, we performed the largest meta-analysis of genome-wide association studies to date for advanced AMD. We imputed 6 036 699 single-nucleotide polymorphisms with the 1000 Genomes Project reference genotypes on 2594 cases and 4134 controls with follow-up replication of top signals in 5640 cases and 52 174 controls. We identified two new common susceptibility alleles, rs1999930 on 6q21-q22.3 near FRK/COL10A1 [odds ratio (OR) 0.87; P = 1.1 × 10(-8)] and rs4711751 on 6p12 near VEGFA (OR 1.15; P = 8.7 × 10(-9)). In addition to the two novel loci, 10 previously reported loci in ARMS2/HTRA1 (rs10490924), CFH (rs1061170, and rs1410996), CFB (rs641153), C3 (rs2230199), C2 (rs9332739), CFI (rs10033900), LIPC (rs10468017), TIMP3 (rs9621532) and CETP (rs3764261) were confirmed with genome-wide significant signals in this large study. Loci in the recently reported genes ABCA1 and COL8A1 were also detected with suggestive evidence of association with advanced AMD. The novel variants identified in this study suggest that angiogenesis (VEGFA) and extracellular collagen matrix (FRK/COL10A1) pathways contribute to the development of advanced AMD.

The ERCC6 gene and age-related macular degeneration.

BACKGROUND: Age-related macular degeneration (AMD) is the leading cause of irreversible visual loss in the developed countries and is caused by both environmental and genetic factors. A recent study (Tuo et al., PNAS) reported an association between AMD and a single nucleotide polymorphism (SNP) (rs3793784) in the ERCC6 (NM_000124) gene. The risk allele also increased ERCC6 expression. ERCC6 is involved in DNA repair and mutations in ERCC6 cause Cockayne syndrome (CS). Amongst others, photosensitivity and pigmentary retinopathy are hallmarks of CS. METHODOLOGY/PRINCIPAL FINDINGS: Separate and combined data from three large AMD case-control studies and a prospective population-based study (The Rotterdam Study) were used to analyse the genetic association between ERCC6 and AMD (2682 AMD cases and 3152 controls). We also measured ERCC6 mRNA levels in retinal pigment epithelium (RPE) cells of healthy and early AMD affected human donor eyes. Rs3793784 conferred a small increase in risk for late AMD in the Dutch population (The Rotterdam and AMRO-NL study), but this was not replicated in two non-European studies (AREDS, Columbia University). In addition, the AMRO-NL study revealed no significant association for 9 other variants spanning ERCC6. Finally, we determined that ERCC6 expression in the human RPE did not depend on rs3793784 genotype, but, interestingly, on AMD status: Early AMD-affected donor eyes had a 50% lower ERCC6 expression than healthy donor eyes (P = 0.018). CONCLUSIONS/SIGNIFICANCE: Our meta-analysis of four Caucasian cohorts does not replicate the reported association between SNPs in ERCC6 and AMD. Nevertheless, our findings on ERCC6 expression in the RPE suggest that ERCC6 may be functionally involved in AMD. Combining our data with those of the literature, we hypothesize that the AMD-related reduced transcriptional activity of ERCC6 may be caused by diverse, small and heterogeneous genetic and/or environmental determinants.

Surgical outcomes after massive subretinal hemorrhage secondary to age-related macular degeneration.

PURPOSE: Massive subretinal hemorrhage (SRH), defined as a thick submacular bleed that extends past the equator in at least two quadrants, is a rare sequela of age-related macular degeneration. This report describes outcomes after surgical intervention for massive SRH. METHODS: The study design is a retrospective interventional case series. Records of consecutive patients who underwent surgical intervention for massive SRH were reviewed. Outcomes included change from baseline in postoperative acuity at Months 1, 3, 6, 9, and 12 and postoperative complications. RESULTS: Fifteen consecutive eyes of 13 patients who underwent surgery for massive SRH were included. Procedures performed on initial surgery included subretinal instillation of 25 µg/0.1 mL tissue plasminogen activator (15 of 15), gas tamponade (12 of 15), oil tamponade (3 of 15), 180° or greater retinotomy (4 of 15), and/or cataract extraction (2 of 15). Patients were followed for a median of 20 months (range, 3-66 months). The median visual acuity at baseline and postoperative Month 1 was hand motions but improved to counting fingers at postoperative Months 3 (P = 0.04), 6 (P = 0.04), 9 (P = 0.04), and 12 (P = 0.10). Of the 15 eyes, 9 required at least 1 additional procedure for an indication of hyphema and/or vitreous hemorrhage (n = 6), retinal detachment (n = 2), glaucoma (n = 1), cataract (n = 1), and aphakia (n = 1). At the time of the onset of SRH, 5 of 13 patients were anticoagulated with warfarin (4 patients) or clopidogrel (1 patient), and 1 was diagnosed with a coagulopathy, factor XI deficiency. CONCLUSION: Massive SRH related to age-related macular degeneration has a grave prognosis. Risk factors may include anticoagulation and coagulopathy. Limitations of the study include its retrospective nature, small sample size, imprecision in acuity measurements below 20/400, and lack of a control group. In this series, surgical intervention was associated with a modest improvement in median visual acuity up to 1 year postoperatively.

Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC).

Advanced age-related macular degeneration (AMD) is the leading cause of late onset blindness. We present results of a genome-wide association study of 979 advanced AMD cases and 1,709 controls using the Affymetrix 6.0 platform with replication in seven additional cohorts (totaling 5,789 unrelated cases and 4,234 unrelated controls). We also present a comprehensive analysis of copy-number variations and polymorphisms for AMD. Our discovery data implicated the association between AMD and a variant in the hepatic lipase gene (LIPC) in the high-density lipoprotein cholesterol (HDL) pathway (discovery P = 4.53e-05 for rs493258). Our LIPC association was strongest for a functional promoter variant, rs10468017, (P = 1.34e-08), that influences LIPC expression and serum HDL levels with a protective effect of the minor T allele (HDL increasing) for advanced wet and dry AMD. The association we found with LIPC was corroborated by the Michigan/Penn/Mayo genome-wide association study; the locus near the tissue inhibitor of metalloproteinase 3 was corroborated by our replication cohort for rs9621532 with P = 3.71e-09. We observed weaker associations with other HDL loci (ABCA1, P = 9.73e-04; cholesterylester transfer protein, P = 1.41e-03; FADS1-3, P = 2.69e-02). Based on a lack of consistent association between HDL increasing alleles and AMD risk, the LIPC association may not be the result of an effect on HDL levels, but it could represent a pleiotropic effect of the same functional component. Results implicate different biologic pathways than previously reported and provide new avenues for prevention and treatment of AMD.