Role of the Choroid in Age-related Macular Degeneration: A Current Review.

Age-related macular degeneration (AMD) is a major cause of vision loss in the developed world and its pathogenesis is a topic of active research. To date, much study has been focused on the role of the retinal pigment epithelium (RPE) and Bruch's membrane (BrM) in AMD pathogenesis, but the role of the choroid has also been investigated. In this review, we focus on recent advancements in research in the role of the choroid in AMD, beginning with an exploration of the histopathologic, cellular and molecular changes that occur in the choroid in AMD and concluding by discussing new choroidal imaging techniques and patterns seen on fluorescein angiography, indocyanine green angiography, spectral-domain optical coherence tomography and optical coherence tomography angiography. Exploring these domains will lead to a better understanding of the factors at play beyond the outer retina in this important disease.

Oxidative Stress Induces an Interactive Decline in Wnt and Nrf2 Signaling in Degenerating Retinal Pigment Epithelium.

AIMS: Cells have evolved a highly sophisticated web of cytoprotective systems to neutralize unwanted oxidative stress, but are challenged by unique modern day stresses such as cigarette smoking and ingestion of a high-fat diet (HFD). Age-related disease, such as age-related macular degeneration (AMD), the most common cause of blindness among the elderly in Western societies, develops in part, when oxidative stress overwhelms cytoprotective systems to injure tissue. Since most studies focus on the protection by a single protective system, the aim of this study was to investigate the impact of more than one cytoprotective system against oxidative stress. RESULTS: Wingless (Wnt) and nuclear factor-erythroid 2-related factor 2 (Nrf2), two fundamental signaling systems that are vital to cell survival, decline after mice are exposed to chronic cigarette smoke and HFD, two established AMD risk factors, in a bidirectional feedback loop through phosphorylated glycogen synthase kinase 3 beta. Decreased Wnt and Nrf2 signaling leads to retinal pigment epithelial dysfunction and apoptosis, and a phenotype that is strikingly similar to geographic atrophy (GA), an advanced form of AMD with no effective treatment. INNOVATION: This study is the first to show that chronic oxidative stress from common modern day environmental exposures reduces two fundamental and vital cytoprotective networks in a bidirectional feedback loop, and their decline leads to advanced disease phenotype. CONCLUSION: Our data offer new insights into how combined modern oxidative stresses of cigarette smoking and HFD contribute to GA through an interactive decline in Wnt and Nrf2 signaling. Antioxid. Redox Signal. 29, 389-407.

The impact of oxidative stress and inflammation on RPE degeneration in non-neovascular AMD.

The retinal pigment epithelium (RPE) is a highly specialized, unique epithelial cell that interacts with photoreceptors on its apical side and with Bruch's membrane and the choriocapillaris on its basal side. Due to vital functions that keep photoreceptors healthy, the RPE is essential for maintaining vision. With aging and the accumulated effects of environmental stresses, the RPE can become dysfunctional and die. This degeneration plays a central role in age-related macular degeneration (AMD) pathobiology, the leading cause of blindness among the elderly in western societies. Oxidative stress and inflammation have both physiological and potentially pathological roles in RPE degeneration. Given the central role of the RPE, this review will focus on the impact of oxidative stress and inflammation on the RPE with AMD pathobiology. Physiological sources of oxidative stress as well as unique sources from photo-oxidative stress, the phagocytosis of photoreceptor outer segments, and modifiable factors such as cigarette smoking and high fat diet ingestion that can convert oxidative stress into a pathological role, and the negative impact of impairing the cytoprotective roles of mitochondrial dynamics and the Nrf2 signaling system on RPE health in AMD will be discussed. Likewise, the response by the innate immune system to an inciting trigger, and the potential role of local RPE production of inflammation, as well as a potential role for damage by inflammation with chronicity if the inciting trigger is not neutralized, will be debated.

STARGARDT DISEASE: Beyond Flecks and Atrophy.

PURPOSE: To identify changes in the outer retina in areas without atrophy or flecks of Stargardt disease (STGD) using spectral-domain optical coherence tomography. METHODS: Twenty-three STGD patients and 26 control subjects were assessed for outer retina (from the outer border of Bruch membrane [BrM] to the inner border of the inner segment ellipsoid zone [EZ]), BrM-retinal pigment epithelium apex, the EZ thickness, and apical process interdigitation zone. RESULTS: Patients with STGD had increased BrM-EZ thickness in areas without apparent disease versus control subjects at 1,000, 1,500, 2,000, and 2,500 µm superior and 1,500 µm, 2,000 µm, and 2,500 µm inferior to the fovea (P < 0.05 to P < 0.001), greatest difference (3.4 µm) at 2,500 µm superiorly. The BrM-retinal pigment epithelium segment showed larger fractional contribution of 0.48 to 0.51 to the overall BrM-EZ thickness compared with 0.35 to 0.42 in control subjects. The thickness of EZ and the interspace between the retinal pigment epithelium apex and EZ were smaller in the STGD patients (P < 0.05 to P < 0.001). Patients with STGD displayed an interrupted interdigitation zone in 16 (84.2%) of 19 eyes versus 6 (23.1%) of 26 eyes of the control subjects (P < 0.001). The BrM-EZ segment of the outer retina of STGD patients lacked the typical normal trilaminar pattern. CONCLUSION: Subtle changes are present within the BrM-EZ segment of the outer retina of STGD patients in areas that are devoid of atrophy and flecks. These findings suggest that pathologic changes in STGD are more widespread than that seen by clinical examination.

Pentraxin 3 recruits complement factor H to protect against oxidative stress-induced complement and inflammasome overactivation.

The discovery that genetic abnormalities in complement factor H (FH) are associated with an increased risk for age-related macular degeneration (AMD), the most common cause of blindness among the elderly, raised hope of new treatments for this vision-threatening disease. Nonetheless, over a decade after the identification of this important association, how innate immunity contributes to AMD remains unresolved. Pentraxin 3 (PTX3), an essential component of the innate immunity system that plays a non-redundant role in controlling inflammation, regulates complement by interacting with complement components. Here, we show that PTX3 is induced by oxidative stress, a known cause of AMD, in the retinal pigmented epithelium (RPE). PTX3 deficiency in vitro and in vivo magnified complement activation induced by oxidative stress, leading to increased C3a, FB, and C3d, but not C5b-9 complex formation. Increased C3a levels, resulting from PTX3 deficiency, raised the levels of Il1b mRNA and secretion of activated interleukin (IL)-1ß by interacting with C3aR. Importantly, PTX3 deficiency augmented NLRP3 inflammasome activation, resulting in enhanced IL-1ß, but not IL-18, production by the RPE. Thus, in the presence of PTX3 deficiency, the complement and inflammasome pathways worked in concert to produce IL-1ß in sufficient abundance to, importantly, result in macrophages accumulating in the choroid. These results demonstrate that PTX3 acts as an essential brake for complement and inflammasome activation by regulating the abundance of FH in the RPE, and provide critical insights into the complex interplay between oxidative stress and innate immunity in the early stages of AMD development. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Comparison of the Pattern of Macular Ganglion Cell-Inner Plexiform Layer Defect Between Ischemic Optic Neuropathy and Open-Angle Glaucoma.

PURPOSE: To compare the pattern of macular ganglion cell plus inner plexiform layer (GCIPL) and peripapillary retinal nerve fiber layer (RNFL) thickness changes in moderate to severe primary open-angle glaucoma (POAG) with nonarteritic anterior ischemic optic neuropathy (NAION) using optical coherence tomography (OCT) auto-segmentation. METHODS: A total of 138 eyes (42 eyes with chronic unilateral NAION and their 42 unaffected fellow eyes, 32 eyes of 32 moderate to severe glaucoma patients, and 22 eyes of 22 healthy normal subjects) underwent neuro-ophthalmologic examinations and spectral-domain OCT in a cross-sectional study at a single academic institution. GCIPL and total retinal thicknesses were obtained from 20° by 20° cube scans of the macula centered around the fovea. The scanned region was divided into two concentric regions (inner and outer, with diameters of 3 and 6 mm, respectively) and eight sectors (four sectors in each of the inner and outer regions). Peripapillary RNFL thickness was also measured. RESULTS: Peripapillary RNFL, total macula, and GCIPL were significantly thinner in NAION and POAG eyes compared to unaffected fellow eyes of NAION and to age-matched healthy control eyes in all eight sectors (P < 0.001). There was no significant difference in peripapillary RNFL, total macula, and outer region GCIPL thicknesses between the affected eyes of the patients with NAION and glaucoma patients. However, the inner region GCIPL was significantly thinner in NAION eyes compared to POAG eyes after adjusting for age, sex, and mean deviation of the visual field (P = 0.001). Also, the GCIPL sector thicknesses were more strongly correlated with visual acuity than were the macular sectors in all patients (most sectors P ≤ 0.001). CONCLUSIONS: Patients with NAION show differences in the tissue damage with greater loss of parafoveal GCIPL tissue thickness compared to patients with POAG.

Biology of p62/sequestosome-1 in Age-Related Macular Degeneration (AMD).

p62/sequestosome-1 is a multidimensional protein that interacts with many signaling factors, and regulates a variety of cellular functions including inflammation, apoptosis, and autophagy. Our previous work has revealed in the retinal pigment epithelium (RPE) that p62 promotes autophagy and simultaneously enhances an Nrf2-mediated antioxidant response to protect against acute oxidative stress. Several recent studies demonstrated that p62 contributes to NFkB mediated inflammation and inflammasome activation under certain circumstances, raising the question of whether p62 protects against or contributes to tissue injury. Herein, we will review the general characteristics of p62, focusing on its pro- and anti-cell survival roles within different physiological/pathological contexts, and discuss the potential of p62 as a therapeutic target for AMD.

Lipoprotein(A) with An Intact Lysine Binding Site Protects the Retina From an Age-Related Macular Degeneration Phenotype in Mice (An American Ophthalmological Society Thesis).

PURPOSE: To test the hypothesis that the accumulation of oxidized phospholipids (OxPL) in the macula is toxic to the retina unless neutralized by a variety of mechanisms, including binding by lipoprotein(a) [Lp(a)], which is composed of apolipoprotein(a) [apo(a)] and apolipoprotein B-100 (apoB). METHODS: Human maculas and eyes from two Lp(a) transgenic murine models were subjected to morphologic, ultrastructural, and immunohistochemical analysis. "Wild-type Lp(a)" mice, which express human apoB-100 and apo(a) that contains oxidized phospholipid, and "mutant LBS(-) Lp(a)" mice with a defective apo(a) lysine binding site (LBS) for oxidized phospholipid binding, were fed a chow or high-fat diet for 2 to 12 months. Oxidized phospholipid-containing lipoproteins were detected by immunoreactivity to E06, a murine monoclonal antibody binding to the phosphocholine headgroup of oxidized, but not native, phospholipids. RESULTS: Oxidized phospholipids, apo(a), and apoB accumulate in maculas, including drusen, of age-related macular degeneration (AMD) samples and age-matched controls. Lp(a) mice fed a high-fat diet developed age-related changes. However, mutant LBS(-) Lp(a) mice fed a high-fat diet developed retinal pigment epithelial cell degeneration and drusen. These changes were associated with increased OxPL, decreased antioxidant defenses, increased complement, and decreased complement regulators. CONCLUSIONS: Human maculas accumulate Lp(a) and OxPL. Mutant LBS(-) Lp(a) mice, lacking the ability to bind E06-detectable oxidized phospholipid, develop AMD-like changes. The ability of Lp(a) to bind E06-detectable OxPL may play a protective role in AMD.

Oxidized low-density-lipoprotein-induced injury in retinal pigment epithelium alters expression of the membrane complement regulatory factors CD46 and CD59 through exosomal and apoptotic bleb release.

Genetic and immunohistochemical studies have identified the alternative complement pathway as an important component of age-related macular degeneration (AMD). The objective of this chapter is to review the impact of complement regulators on complement activation in the macula as it relates to AMD. Our laboratory and other investigators have identified CD46 and CD59 as important retinal pigment epithelium (RPE) cell membrane complement regulators, which are decreased in AMD. Using oxidized low-density lipoproteins (oxLDLs), which are found in Bruch's membrane in AMD, we found that CD46 and CD59 were decreased in RPE cells in part, by their release in exosomes and apoptotic particles. The release of complement regulators could potentially impair complement regulation on RPE cells and contribute to lesion formation in the outer retina and Bruch's membrane during the development of AMD.

T cells and macrophages responding to oxidative damage cooperate in pathogenesis of a mouse model of age-related macular degeneration.

Age-related macular degeneration (AMD) is a major disease affecting central vision, but the pathogenic mechanisms are not fully understood. Using a mouse model, we examined the relationship of two factors implicated in AMD development: oxidative stress and the immune system. Carboxyethylpyrrole (CEP) is a lipid peroxidation product associated with AMD in humans and AMD-like pathology in mice. Previously, we demonstrated that CEP immunization leads to retinal infiltration of pro-inflammatory M1 macrophages before overt retinal degeneration. Here, we provide direct and indirect mechanisms for the effect of CEP on macrophages, and show for the first time that antigen-specific T cells play a leading role in AMD pathogenesis. In vitro, CEP directly induced M1 macrophage polarization and production of M1-related factors by retinal pigment epithelial (RPE) cells. In vivo, CEP eye injections in mice induced acute pro-inflammatory gene expression in the retina and human AMD eyes showed distinctively diffuse CEP immunolabeling within RPE cells. Importantly, interferon-gamma (IFN-γ) and interleukin-17 (IL-17)-producing CEP-specific T cells were identified ex vivo after CEP immunization and promoted M1 polarization in co-culture experiments. Finally, T cell immunosuppressive therapy inhibited CEP-mediated pathology. These data indicate that T cells and M1 macrophages activated by oxidative damage cooperate in AMD pathogenesis.

Oxidative stress induces mitochondrial dysfunction and a protective unfolded protein response in RPE cells.

How cells degenerate from oxidative stress in aging-related disease is incompletely understood. This study's intent was to identify key cytoprotective pathways activated by oxidative stress and determine the extent of their protection. Using an unbiased strategy with microarray analysis, we found that retinal pigmented epithelial (RPE) cells treated with cigarette smoke extract (CSE) had overrepresented genes involved in the antioxidant and unfolded protein response (UPR). Differentially expressed antioxidant genes were predominantly located in the cytoplasm, with no induction of genes that neutralize superoxide and H2O2 in the mitochondria, resulting in accumulation of superoxide and decreased ATP production. Simultaneously, CSE induced the UPR sensors IRE1α, p-PERK, and ATP6, including CHOP, which was cytoprotective because CHOP knockdown decreased cell viability. In mice given intravitreal CSE, the RPE had increased IRE1α and decreased ATP and developed epithelial-mesenchymal transition, as suggested by decreased LRAT abundance, altered ZO-1 immunolabeling, and dysmorphic cell shape. Mildly degenerated RPE from early age-related macular degeneration (AMD) samples had prominent IRE1α, but minimal mitochondrial TOM20 immunolabeling. Although oxidative stress is thought to induce an antioxidant response with cooperation between the mitochondria and the ER, herein we show that mitochondria become impaired sufficiently to induce epithelial-mesenchymal transition despite a protective UPR. With similar responses in early AMD samples, these results suggest that mitochondria are vulnerable to oxidative stress despite a protective UPR during the early phases of aging-related disease.

Nrf2 signaling modulates cigarette smoke-induced complement activation in retinal pigmented epithelial cells.

Whereas cigarette smoking (CS) and dysregulated complement are thought to play central roles in age-related macular degeneration (AMD), their exact roles are unknown. The aim of this study was to determine if CS activates complement and if the antioxidant transcription factor Nrf2 modulates this response. In AMD specimens, Nrf2 immunolabeling was strong in the cytoplasm, with scattered nuclear labeling of macular retinal pigmented epithelial (RPE) cells that appeared normal, but was decreased and without nuclear labeling in dysmorphic cells overlying drusen, a hallmark AMD lesion. Cigarette smoke extract (CSE) induced Nrf2 nuclear translocation in RPE cells with increased antioxidant and complement gene expression. Whereas CFH protein was not altered by CSE, the cell membrane regulator proteins CD46, CD55, and CD59 were decreased, and C3a and C3b, but not iC3b, were increased compared to controls. C5b-9 was increased by CSE, but at sublytic levels, only after addition of normal human serum. Nrf2 knockdown enhanced the increase in C3a and C3b from CSE, but not iC3b, C5a, or C5b-9. CSE also increased IL-1b expression and secretion after C3a generation and was reduced by a C3aR antagonist. In contrast, the Nrf2 activator CDDO-Im restored complement gene expression in RPE cells exposed to CSE. We provide evidence of altered Nrf2 in human AMD and that CSE induces a proinflammatory environment specifically by generating C3a and C3b, and Nrf2 deficiency magnifies this specific complement response.

RhoA activity and post-ischemic inflammation in an experimental model of adult rodent anterior ischemic optic neuropathy.

Activation of inflammatory cells and the RhoA signaling pathway may contribute to optic nerve damage following non-arteritic anterior ischemic optic neuropathy (NAION). We induced an optic nerve infarct with a photothrombotic mechanism in a rat model of AION (rAION). Immunohistochemistry and Western blot were performed to detect activation of RhoA signaling and inflammation. The extent of Rho activity, inflammation, retinal ganglion cell (RGC) loss and extent of axon regeneration were determined at 8 and 14 days after infarct. Eight days after stroke, we observed significant inflammation and RhoA activity at the site of infarction as well as loss of cells in the RGC layer. RhoA activity had decreased and inflammation had decreased at day 14 compared with day 8; however, loss of RGCs was greater at 14 days than at 8 days. Stroked eyes showed minor axon regeneration around the optic nerve lesion site at both 8 and 14 days. These results demonstrate that inflammation and RhoA activation occur in rAION at the site of infarction.

Comparison of the diagnostic value of MR imaging and ophthalmoscopy for the staging of retinoblastoma.

PURPOSE: To compare the diagnostic value of magnetic resonance (MR) imaging and ophthalmoscopy for staging of retinoblastoma. METHODS: MR and ophthalmoscopic images of 36 patients who underwent enucleation were evaluated retrospectively following institutional review board approval. Histopathology being the standard of reference, the sensitivity and specificity of both diagnostic modalities were compared regarding growth pattern, iris neoangiogenesis, retinal detachment, vitreous seeds and optic nerve invasion. Data were analysed via McNemar's test. RESULTS: Both investigations showed no significant difference in accuracy for the detection of different tumour growth patterns (P = 0.80). Vitreous seeding detection was superior by ophthalmoscopy (P < 0.001). For prelaminar optic nerve invasion, MR imaging showed similar sensitivity as ophthalmoscopy but increased specificity of 40 % (CI 0.12-0.74) vs. 20 % (0.03-0.56). MR detected optic nerve involvement past the lamina cribrosa with a sensitivity of 80 % (0.28-0.99) and a specificity of 74 % (0.55-0.88). The absence of optic nerve enhancement excluded histopathological infiltration, but the presence of optic nerve enhancement included a high number of false positives (22-24 %). CONCLUSIONS: Ophthalmoscopy remains the method of choice for determining extent within the globe while MR imaging is useful for evaluating extraocular tumour extension. Thus, both have their own strengths and contribute uniquely to the staging of retinoblastoma. KEY POINTS: • Ophthalmoscopy: method of choice for determining extent of retinoblastoma within the globe. • MR imaging provides optimal evaluation of extrascleral and extraocular tumour extension. • Positive enhancement of the optic nerve on MRI does not necessarily indicate involvement.

Decreased membrane complement regulators in the retinal pigmented epithelium contributes to age-related macular degeneration.

Dysregulated complement is thought to play a central role in age-related macular degeneration (AMD) pathogenesis, but the specific mechanisms have yet to be determined. In maculae of AMD specimens, we found that the complement regulatory protein, CD59, was increased in regions of uninvolved retinal pigmented epithelium (RPE) of early AMD, but decreased in the RPE overlying drusen and in geographic atrophy, an advanced form of AMD. While CD46 immunostaining was basolaterally distributed in the RPE of unaffected controls, it was decreased in diseased areas of early AMD samples. Since oxidized low-density lipoproteins (oxLDL) collect in drusen of AMD and are a known complement trigger, we treated ARPE-19 cells with oxLDL and found that cellular CD46 and CD59 proteins were decreased by 2.9- and nine-fold (p < 0.01), respectively. OxLDLs increased complement factor B mRNA and Bb protein, but not factor D, I or H. OxLDLs increased C3b, but not C3a, C5 or C5b-9. C5b-9 was increased by 27% (p < 0.01) when the medium was supplemented with human serum, which was sufficient to induce poly(ADP-ribose) polymerase cleavage, a marker of apoptosis. The decreased levels of CD46 and CD59 were in part explained by their release in exosomal and apoptotic membranous particles. In addition, CD59 was partially degraded through activation of IRE1α. Collectively, these results suggest that a combination of impaired complement regulators results in inadequately controlled complement by the RPE in AMD that induces RPE damage.

High-resolution MR imaging of the orbit in patients with retinoblastoma.

Retinoblastoma is the most common intraocular childhood malignancy, with a prevalence of one in 18,000 children younger than 5 years old in the United States. In 80% of patients, retinoblastoma is diagnosed before the age of three, and in 95% of patients, retinoblastoma is diagnosed before the age of five. Although reports exist of retinoblastoma in adults, onset beyond 6 years of age is rare. Broadly, retinoblastoma may be classified into two groups: sporadic and heritable. In either case, the origin of the tumor is a biallelic mutation in primitive neuroepithelial cells. Although their details vary, several staging schemes are used to describe the extent of retinoblastoma according to the following four general criteria: intraocular location, extraocular (extraorbital) location, central nervous system disease, and systemic metastases. In the past decade, substantial changes have taken place in terms of staging and monitoring treatment in patients with retinoblastoma. Diagnosis and treatment of retinoblastoma involve a multidisciplinary approach, for which imaging is a vital component. Increasing awareness and concerns about the effects of radiation in patients with retinoblastoma have led to a shift away from external-beam radiation therapy and toward chemotherapy and locoregional treatment, as well as the establishment of magnetic resonance imaging as the most important imaging modality for diagnosis, staging, and treatment monitoring.

Notch signaling promotes growth and invasion in uveal melanoma.

PURPOSE: To determine whether uveal melanoma, the most common primary intraocular malignancy in adults, requires Notch activity for growth and metastasis. EXPERIMENTAL DESIGN: Expression of Notch pathway members was characterized in primary tumor samples and in cell lines, along with the effects of Notch inhibition or activation on tumor growth and invasion. RESULTS: Notch receptors, ligands, and targets were expressed in all five cell lines examined and in 30 primary uveal melanoma samples. Interestingly, the three lines with high levels of baseline pathway activity (OCM1, OCM3, and OCM8) had their growth reduced by pharmacologic Notch blockade using the γ-secretase inhibitor (GSI) MRK003. In contrast, two uveal melanoma lines (Mel285 and Mel290) with very low expression of Notch targets were insensitive to the GSI. Constitutively active forms of Notch1 and Notch2 promoted growth of uveal melanoma cultures and were able to rescue the inhibitory effects of GSI. MRK003 treatment also inhibited anchorage-independent clonogenic growth and cell invasion and reduced phosphorylation levels of STAT3 and extracellular signal-regulated kinase (Erk)1/2. Suppression of canonical Notch activity using short hairpin RNA targeting Notch2 or CBF1 was also able to reduce tumor growth and invasion. Finally, intraocular xenograft growth was significantly decreased by GSI treatment. CONCLUSION: Our findings suggest that Notch plays an important role in inducing proliferation and invasion in uveal melanoma and that inhibiting this pathway may be effective in preventing tumor growth and metastasis.

Optical coherence tomography for retinal metastasis with unknown primary tumor.

The authors describe the optical coherence tomography (OCT) findings and the therapeutic approach of a patient with metastatic neoplastic disease of the retina. A patient with a history of brain cancer of undetermined origin underwent imaging and surgery to investigate a suspected metastatic retinal lesion of the right eye. Retinal thinning with cordon-like hyperreflective structures was seen on OCT. Neoplastic cells consistent with small cell carcinoma were identified in the vitreous sample. Those cells were thought to be similar to the previous biopsied cerebellar tumor specimen. OCT imaging, along with vitrectomy and retinal biopsy, may be useful in the evaluation of patients with suspected metastatic lesions of the retina.

Lipids, lipoproteins, and age-related macular degeneration.

Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly. While excellent treatment has emerged for neovascular disease, treatment for early AMD is lacking due to an incomplete understanding of the early molecular events. A prominent age-related change is the accumulation of neutral lipid in normal Bruch's membrane (BrM) throughout adulthood and also disease-related BrM accumulations called basal deposits and drusen. AMD lesion formation has thus been conceptualized as sharing mechanisms with atherosclerotic plaque formation, where low-density lipoprotein (LDL) retention within the arterial wall initiates a cascade of pathologic events. However, we do not yet understand how lipoproteins contribute to AMD. This paper explores how systemic and local production of lipoproteins might contribute to the pathogenesis of AMD.

Intraorbital meningiomas: a pathologic review using current World Health Organization criteria.

CONTEXT: Meningiomas represent approximately 4% of all intraorbital tumors and can arise from the optic nerve or extend into the orbit from adjacent structures. OBJECTIVE: To examine a cohort of intraorbital meningiomas and use the current World Health Organization (WHO) scheme to assess the effect of changes to the classification of tumors at this site. DESIGN: The histopathology and clinical findings of intraorbital meningiomas resected between 1968 and 2008 at our institution were reviewed according to the WHO 2007 classification scheme. RESULTS: A total of 51 intraorbital meningiomas were reviewed. The mean age at presentation was 45 years, but 5 tumors arose in children. Two patients were known to have neurofibromatosis type 2, and 1 had inherited retinoblastoma. Orbital meningiomas were more frequently encountered in women (30 cases) than in men (21 cases). In 21 patients, the tumor was associated with the optic nerve. The most common (25 of 51 tumors; 49%) histopathologic subtype was meningothelial. Most (47 of 51; 92%) of the tumors were WHO grade I. Four tumors (8%) were WHO grade II, with 4 or more mitotic figures per 10 high-power fields, brain invasion, chordoid histology, or a combination of these features. CONCLUSIONS: Intraorbital meningiomas were most frequently of the meningothelial or transitional subtypes and were WHO grade I. One relatively common intracranial subtype, fibrous meningioma, was not encountered. The percentage of WHO grade II tumors in the orbit (8%) is similar to that reported for intracranial tumors using the current grading scheme.