Thinning Of Outer Nuclear Layer Research Articles

LONGITUDINAL CHANGE OF OUTER NUCLEAR LAYER AFTER RETINAL PIGMENT EPITHELIAL TEAR SECONDARY TO AGE-RELATED MACULAR DEGENERATION.

To investigate longitudinal changes of outer nuclear layer (ONL) thickness in patients with retinal pigment epithelium tears secondary to neovascular age-related macular degeneration. This is an institutional retrospective interventional case series. Twenty-six eyes of 22 patients with retinal pigment epithelium tears identified between April 2009 and March 2015. The patients underwent intravitreal injection of anti-vascular endothelial growth factor agents as needed. Volume scans of optical coherence tomography at first diagnosis of tear (baseline) and after 12 months were analyzed. Outer nuclear layer was segmented, and average ONL thickness inside the tear area, at the border of the tear, and in areas outside the tear was measured. Change of ONL thickness. We also explored several factors for their association with ONL thinning including tear area, number of treatments, and the duration with persistent subretinal fluid. Thinning of ONL was found in all the investigated areas (P < 0.01, respectively). Among the investigated factors, larger tear area was associated with greater ONL thinning outside the tear area (standardized β = -0.37, P = 0.030), and younger age was associated with greater ONL thinning inside the tear area (standardized β = 0.37, P = 0.041). After an retinal pigment epithelium tear, thinning of ONL occurs in the area devoid of retinal pigment epithelium and also in adjacent areas. Few factors were predictive for the degree of ONL thinning. These results provide new insight in disease progression of this particular neovascular age-related macular degeneration subphenotype.

A splicing mutation in aryl hydrocarbon receptor associated with retinitis pigmentosa.

Retinitis pigmentosa (RP) refers to a group of retinal degenerative diseases, which often lead to vision loss. Although 70 genes have been identified in RP patients, the genetic cause of approximately 30% of RP cases remains unknown. We aimed to identify the cause of the disease in a cohort of RP families by whole exome sequencing. A rare homozygous splicing variant, c.1160 + 1G>A, which introduced skipping of exon 9 of the aryl hydrocarbon receptor (AHR), was identified in family RD-134. This variant is very rare in several exome databases and leads to skipping of exon 9 in the transcript. AHR is expressed in the human retina and is a ligand-activated transcription factor with multiple functions. Mutant AHR failed to promote 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD)-induced xenobiotic responsive element (XRE) luciferase activity. In parallel, mutation in AHR abolished activation of its downstream target gene, such as CYP1A1 and CYP1A2. To investigate the in vivo roles of Ahr in the retina, we generated a retina-specific conditional knockout mouse model of Ahr. Comparing with wild-type mouse, Ahr knockout mice exhibited reduced electroretinogram responses at 9 months of age. Retinal histology revealed retinal histology showed the degeneration of photoreceptors with a thinner outer nuclear layer. Thus, our data demonstrate that AHR is associated with RP.

A splicing mutation in aryl hydrocarbon receptor associated with retinitis pigmentosa

Retinitis pigmentosa (RP) refers to a group of retinal degenerative diseases, which often lead to vision loss. Although 70 genes have been identified in RP patients, the genetic cause of approximately 30% of RP cases remains unknown. We aimed to identify the cause of the disease in a cohort of RP families by whole exome sequencing. A rare homozygous splicing variant, c.1160 + 1G>A, which introduced skipping of exon 9 of the aryl hydrocarbon receptor (AHR), was identified in family RD-134. This variant is very rare in several exome databases and leads to skipping of exon 9 in the transcript. AHR is expressed in the human retina and is a ligand-activated transcription factor with multiple functions. Mutant AHR failed to promote 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD)-induced xenobiotic responsive element (XRE) luciferase activity. In parallel, mutation in AHR abolished activation of its downstream target gene, such as CYP1A1 and CYP1A2. To investigate the in vivo roles of Ahr in the retina, we generated a retina-specific conditional knockout mouse model of Ahr. Comparing with wild-type mouse, Ahr knockout mice exhibited reduced electroretinogram responses at 9 months of age. Retinal histology revealed retinal histology showed the degeneration of photoreceptors with a thinner outer nuclear layer. Thus, our data demonstrate that AHR is associated with RP.

MIF Inhibitor ISO-1 Protects Photoreceptors and Reduces Gliosis in Experimental Retinal Detachment

Photoreceptor death and retinal gliosis underlie the majority of vision threatening retinal diseases including retinal detachment (RD). Although the underlying pathobiology of vision limiting processes in RD is not fully understood, inflammation is known to play a critical role. We conducted an iTRAQ proteomic screen of up- and down-regulated proteins in a murine model of RD to identify potential targetable candidates. Macrophage migration inhibitory factor (MIF) was identified and evaluated for neurotoxic and pro-gliotic effects during RD. Systemic administration of the MIF inhibitor ISO-1 significantly blocked photoreceptor apoptosis, outer nuclear layer (ONL) thinning, and retinal gliosis. ISO-1 and MIF knockout (MIFKO) had greater accumulation of Müller glia pERK expression in the detached retina, suggesting that Müller survival pathways might underlie the neuroprotective response. Our data show the feasibility of the MIF-inhibitor ISO-1 to block pathological damage responses in retinal detachment and provide a rationale to explore MIF inhibition as a potential therapeutic option for RD.

Optical coherence tomography identifies outer retina thinning in frontotemporal degeneration.

Whereas Alzheimer disease (AD) is associated with inner retina thinning visualized by spectral-domain optical coherence tomography (SD-OCT), we sought to determine if the retina has a distinguishing biomarker for frontotemporal degeneration (FTD). Using a cross-sectional design, we examined retinal structure in 38 consecutively enrolled patients with FTD and 44 controls using a standard SD-OCT protocol. Retinal layers were segmented with the Iowa Reference Algorithm. Subgroups of highly predictive molecular pathology (tauopathy, TAR DNA-binding protein 43, unknown) were determined by clinical criteria, genetic markers, and a CSF biomarker (total tau: β-amyloid) to exclude presumed AD. We excluded eyes with poor image quality or confounding diseases. SD-OCT measures of patients (n = 46 eyes) and controls (n = 69 eyes) were compared using a generalized linear model accounting for intereye correlation, and correlations between retinal layer thicknesses and Mini-Mental State Examination (MMSE) were evaluated. Adjusting for age, sex, and race, patients with FTD had a thinner outer retina than controls (132 vs 142 μm, p = 0.004). Patients with FTD also had a thinner outer nuclear layer (ONL) (88.5 vs 97.9 μm, p = 0.003) and ellipsoid zone (EZ) (14.5 vs 15.1 μm, p = 0.009) than controls, but had similar thicknesses for inner retinal layers. The outer retina thickness of patients correlated with MMSE (Spearman r = 0.44, p = 0.03). The highly predictive tauopathy subgroup (n = 31 eyes) also had a thinner ONL (88.7 vs 97.4 μm, p = 0.01) and EZ (14.4 vs 15.1 μm, p = 0.01) than controls. FTD is associated with outer retina thinning, and this thinning correlates with disease severity.

Subretinal Injection for Gene Therapy Does Not Cause Clinically Significant Outer Nuclear Layer Thinning in Normal Primate Foveae.

Despite ever-growing adoption of subretinal (SRi) and intravitreal injections (IVTi) in ocular gene therapy trials, concerns regarding possible deleterious effects of the SRi on the outer retina are yet to be addressed. SRi offers several advantages over IVTi, such as a better photoreceptor transduction efficiency and a limited off-target exposure. We assessed structural changes in the outer retina in nonhuman primates following either SRi or IVTi of a gene therapeutic or control solution and compared both techniques in a noninferiority analysis. In a toxicology study, 22 cynomolgus monkeys underwent single intraocular injections with rAAV2/8 or vehicle; 18 animals received SRi, 4 animals received IVTi. Outer nuclear layer (ONL) thickness change on optical coherence tomography was used for a noninferiority analysis. Preservation of the physiological foveal bulge was used as a secondary outcome measure. The average ONL change from baseline after 2 weeks was -6.54 ± 5.16 (mean ± SD μm) and +1.50 ± 4.36 for SRi and IVTi groups accordingly. At 13 weeks, the SRi group maintained a difference of -6.54 ± 9.66 while IVTi group gained +1.00 ± 4.24. The ellipsoid zone line was transiently lost after SRi and completely recovered by 13 weeks in 77% of eyes. One SRi case resulted in subfoveal pigment accumulation and 39% ONL thinning. Despite limited ONL thinning following SRi, the observed effect was under the predefined clinical significance threshold. The SRi has proven not to be inferior to the IVTi in terms of ONL thickness loss and estimated loss of visual acuity.

Clinical characteristics of adult-onset foveomacular vitelliform dystrophy

Adult-onset foveomacular vitelliform dystrophy (AFVD) is characterized by gradually loss of vision, subretinal vitelliform macular lesions and retinal pigment epithelium (RPE) atrophy. The electrooculogram (EOG) is usually normal or reduce slightly. On optical coherence tomography (OCT), there are vitelliform substance which deposited between the photoreceptor layer and the RPE layer, and thinner outer nuclear layer above these deposits. OCT angiography can show the superficial and deep retinal capillaries plexus (DCP) above the yolk-like deposits, the choroidal capillary blood flow is reduced and the DCP blood flow is increased near macular. On indocyanine green angiography (ICG), there is choroidal neovascularization under vitelliform substance at early stage and fluorescence leakage in the corresponding retinal region at late stage. There is no effective treatment for AFVD at present, monogenic gene therapy is the most worth looking forward to. Understanding AFVD clinical manifestations, multi-mode imaging features and new advances in treatment can provide a reference for diagnosis and treatment options Key words: Vitelliform macular dystrophy/diagnosis; Disease attributes; Review

Multimodal Fundus Imaging of Sodium Iodate-Treated Mice Informs RPE Susceptibility and Origins of Increased Fundus Autofluorescence.

PurposeBy multimodal imaging, and the use of mouse and in vitro models, we have addressed changes in fundus autofluorescence (488 and 790 nm) and observed interactions between the photooxidative stress imposed by RPE bisretinoid lipofuscin and the oxidative impact of systemic sodium iodate (NaIO3).MethodsAbca4−/−, wild-type, and Rpe65rd12 mice were given systemic injections of NaIO3 (30 mg/kg). Analysis included noninvasive imaging of fundus autofluorescence (short-wavelength [SW-AF]; near-infrared excitation [NIR-AF]), quantitative fundus AF (qAF; 488 nm); light microscopy, RPE flat-mounts and measurements of outer nuclear layer (ONL) thickness. NaIO3 also was studied by using in vitro assays.ResultsIn SW-AF and NIR-AF images, fundus mottling was visible 3 and 7 days after NaIO3 injection with changes being more pronounced in Abca4−/− mice that are characterized by an abundance of RPE bisretinoid lipofuscin. In Abca4−/− mice, qAF was elevated 3 and 7 days after NaIO3 administration. In light micrographs and RPE flat-mounts stained to reveal tight junctions (ZO-1) and nuclei, the RPE monolayer was disorganized, and clumping and loss of RPE was visible. ONL thinning was most pronounced in Abca4−/− mice. Treatment of ARPE-19 cells with NaIO3 together with the photooxidation of the bisretinoid A2E by exposure to 430-nm light produced an additive effect whereby loss of cell viability was greater than with either perturbation alone.ConclusionsElevations in SW-AF intensity can occur due to photoreceptor cell dysfunction as induced secondarily by NaIO3. Photooxidative stress associated with RPE cell bisretinoid lipofuscin may confer increased susceptibility to the oxidant NaIO3.

Quantitative Analysis of Retinal Structure Using Spectral-Domain Optical Coherence Tomography in RPGR-Associated Retinopathy

PurposeTo quantify retinal structure and progression using spectral-domain optical coherence tomography (SDOCT) in patients with retinitis pigmentosa (RP) associated with retinitis pigmentosa GTPase regulator gene (RPGR) mutations.DesignRetrospective observational case series.MethodsSetting: Moorfields Eye Hospital, London, United Kingdom. Subjects: Both eyes of 32 patients. SDOCT follow-up period of >1 year (3.1 ± 1.4 years). Main Outcome Measures: Ellipsoid zone (EZ) width (EZW) and outer nuclear layer (ONL) and inner retinal layer (IRL) thickness measurements. Progression rates, interocular symmetry, and association with age and genotype were investigated.ResultsSignificant differences were observed between baseline and final measurements of EZW and ONL thickness, but not for IRL thickness. Baseline and final EZWs were 2438 ± 1646 μm and 1901 ± 1423 μm for right eyes (P < .0001); 2420 ± 1758 μm and 1922 ± 1482 μm for left eyes (P < .0001). EZW constriction rates were 176.6 ± 130.1 μm/year and 173.1 ± 146.8 μm/year for right and left eyes. ONL thinning rates were 2.58 ± 2.85 μm/year and 2.52 ± 3.54 μm/year for right and left eyes. Interocular differences in EZW and ONL progression were not significant (P = .8609 and P = .6735, respectively). Strong correlations were found between EZW constriction rates of right and left eyes (rs = 0.627, P = .0002) and between EZW constriction and baseline EZW (rs = 0.714, P < .0001). There was moderate negative correlation between EZW constriction and age (rs = −0.532, P < .0001). Correlation between ONL thinning and age was not significant, as were differences between EZW and ONL progression rates with respect to genotype.ConclusionsThis study provides SDOCT progression rates for RPGR-associated RP. There is overall interocular symmetry with implications for future treatment trials where 1 eye could serve as a control.

Natural History of the Central Structural Abnormalities in Choroideremia: A Prospective Cross-Sectional Study

To describe in detail the central retinal structure of a large group of patients with choroideremia (CHM). A prospective, cross-sectional, descriptive study. Patients (n= 97, age 6-71 years) with CHM and subjects with normal vision (n= 44; ages 10-50 years) were included. Subjects were examined with spectral-domain optical coherence tomography (SD OCT) and near-infrared reflectance imaging. Visual acuity (VA) was measured during their encounter or obtained from recent ophthalmic examinations. Visual thresholds were measured in a subset of patients (n= 24) with automated static perimetry within the central regions (±15°) examined with SD OCT. Visual acuity and visual thresholds; total nuclear layer, inner nuclear layer (INL), and outer nuclear layer (ONL) thicknesses; and horizontal extent of the ONL and the photoreceptor outer segment (POS) interdigitation zone (IZ). Earliest abnormalities in regions with normally appearing retinal pigment epithelium (RPE) were the loss of the POS and ellipsoid zone associated with rod dysfunction. Transition zones (TZs) from relatively preserved retina to severe ONL thinning and inner retinal thickening moved centripetally with age. Most patients (88%) retained VAs better than 20/40 until their fifth decade of life. The VA decline coincided with migration of the TZ near the foveal center. There were outer retinal tubulations in degenerated, nonatrophic retina in the majority (69%) of patients. In general, RPE abnormalities paralleled photoreceptor degeneration, although there were regions with detectable but abnormally thin ONL co-localizing with severe RPE depigmentation and choroidal thinning. Abnormalities of the POS and rod dysfunction are the earliest central abnormalities observed in CHM. Foveal function is relatively preserved until the fifth decade of life. Migration of the TZs to the foveal center with foveal thinning and structural disorganization heralded central VA loss. The relationships established may help outline the eligibility criteria and outcome measures for clinical trials for CHM.

Retinal Morphology and Sensitivity Are Primarily Impaired in Eyes with Neuromyelitis Optica Spectrum Disorder (NMOSD).

BackgroundPrevious studies of neuromyelitis optica spectrum disorder (NMOSD) using spectral domain optical coherence tomography (SD-OCT) showed that the outer nuclear layer (ONL) in eyes without a history of optic neuritis (ON) was thinner than that of healthy controls. It remains unclear whether the ONL thinning is caused by a direct attack on the retina by an autoantibody or a retrograde degeneration.ObjectiveTo determine the mechanisms involved in the retinal damage in eyes with NMOSD without ON.MethodsSD-OCT was used to determine the thicknesses of the different retinal layers of 21 eyes of 12 NMOSD patients without prior ON and 19 eyes of 10 healthy controls. Eyes with peripapillary retinal nerve fiber layer (RNFL) thinning were excluded to eliminate the confounding effects of retrograde degeneration. Microperimetry was used to determine the central retinal sensitivity. The data of the two groups were compared using generalized estimated equation models to account for inter-eye dependencies.ResultsThe ganglion cell plus inner plexiform layer and the inner nuclear layer plus outer plexiform layer thicknesses of the NMOSD eyes were not significantly different from that of the control eyes (P = 0.28, P = 0.78). However, the ONL and average macular thickness (AMT) in the NMOSD eyes were significantly thinner than that of the control eyes (P = 0.022, P = 0.036). The retinal sensitivity in the central 10°, 10° to 2°, and 2° sectors were significantly lower in the NMOSD eyes than in the control eyes (P = 0.013, P = 0.022, P = 0.002).ConclusionsThe ONL thinning, AMT thinning, and reduced retinal sensitivity in eyes with NMOSD without significant peripapillary RNFL thinning are most likely due to direct retinal pathology.

N-methyl-N-nitrosourea induces retinal degeneration in the rat via the inhibition of NF-κB activation.

Retinitis pigmentosa (RP) is a group of inherited neurodegenerative diseases characterized by the loss of photoreceptor cells through apoptosis. N-methyl-N-nitrosourea (MNU) is an alkylating toxicant that induces photoreceptor cell death resembling hereditary RP. This study aimed to investigate the role of nuclear factor κB (NF-κB) in MNU-induced photoreceptor degeneration. Adult rats received a single intraperitoneal injection of MNU (60mg/kg bodyweight). Hematoxylin and eosin staining demonstrated progressive outer nuclear layer (ONL) loss after MNU treatment. Transmission electron microscopy revealed nuclear pyknosis, chromatin margination in the photoreceptors, increased secondary lysosomes, and lobulated retinal-pigmented epithelial cells in MNU-treated rats. Numerous photoreceptor cells in the ONL showed positive TUNEL staining and apoptosis rate peaked at 24hours. Enhanced depth imaging spectral-domain optical coherence tomography showed ONL thinning and decreased choroid thickness. Electroretinograms showed decreased A wave amplitude that predominated in scotopic conditions. Western blot analysis showed that nuclear IκBα level increased, whereas nuclear NF-κB p65 decreased significantly in the retinas of MNU-treated rats. These findings indicate that MNU leads to selective photoreceptor degradation, and this is associated with the inhibition of NF-κB activation.

Expanded spectral domain-OCT findings in the early detection of hydroxychloroquine retinopathy and changes following drug cessation.

PurposeTo report expanded SD-OCT findings of HCQ retinopathy that may assist the clinician in earlier diagnosis. To characterize structural changes of HCQ retinopathy with SD-OCT after drug cessation.MethodsSetting: Private practice and academic institution. Patient Population: Patients at New England Eye Center and Ophthalmic Consultants of Boston in Boston, MA diagnosed with HCQ retinopathy and followed after drug cessation. Retrospective clinical data review by the Boston Image Reading Center. Main Outcome Measures: SD-OCT findings suggestive of HCQ retinopathy before parafoveal ellipsoid disruption. Change in SD-OCT morphological appearance and retinal thickness of each of the nine subfields corresponding to the Early Treatment of Diabetic Retinopathy Study areas.ResultsThirty eyes with HCQ retinopathy were followed with SD-OCT after drug cessation. Findings before disruption of the parafoveal EZ included parafoveal outer nuclear layer (ONL) thinning, disruption of the parafoveal interdigitation zone, and reduced reflectivity of the parafoveal EZ. In early toxicity, 75 % developed progression after drug cessation, including disruption of the parafoveal EZ and retinal pigment epithelium and thinning of the ONL. Eyes with obvious toxicity had greater inferior outer ring thinning 12 months after drug cessation compared to early toxicity (p = 0.002, 95 % CI −2 to −8 μm). In obvious toxicity, the nasal inner subfield showed more thinning than the temporal inner subfield at 12 months after drug cessation (p = 0.018, 95 % CI −1 to −8 μm).ConclusionsOnce HCQ retinopathy is diagnosed and the medication is discontinued, structural retinal changes commonly occur.

Photodegradation of retinal bisretinoids in mouse models and implications for macular degeneration

Adducts of retinaldehyde (bisretinoids) form nonenzymatically in photoreceptor cells and accumulate in retinal pigment epithelial (RPE) cells as lipofuscin; these fluorophores are implicated in the pathogenesis of inherited and age-related macular degeneration (AMD). Here we demonstrate that bisretinoid photodegradation is ongoing in the eye. High-performance liquid chromatography (HPLC) analysis of eyes of dark-reared and cyclic light-reared wild-type mice, together with comparisons of pigmented versus albino mice, revealed a relationship between intraocular light and reduced levels of the bisretinoids A2E and A2-glycero-phosphoethanolamine (A2-GPE). Analysis of the bisretinoids A2E, A2-GPE, A2-dihydropyridine-phosphatidylethanolamine (A2-DHP-PE), and all-trans-retinal dimer-phosphatidylethanolamine (all-trans-retinal dimer-PE) also decreases in albino Abca4(-/-) mice reared in cyclic light compared with darkness. In albino Abca4(-/-) mice receiving a diet supplemented with the antioxidant vitamin E, higher levels of RPE bisretinoid were evidenced by HPLC analysis and quantitation of fundus autofluorescence; this effect is consistent with photooxidative processes known to precede bisretinoid degradation. Amelioration of outer nuclear layer thinning indicated that vitamin E treatment protected photoreceptor cells. Conversely, in-cage exposure to short-wavelength light resulted in reduced fundus autofluorescence, decreased HPLC-quantified A2E, outer nuclear layer thinning, and increased methylglyoxal (MG)-adducted protein. MG was also released upon bisretinoid photodegradation in cells. We suggest that the lower levels of these diretinal adducts in cyclic light-reared and albino mice reflect photodegradative loss of bisretinoid. These mechanisms may underlie associations among AMD risk, oxidative mechanisms, and lifetime light exposure.

Quantification of retinal layer thickness changes in acute macular neuroretinopathy

PurposeTo quantitatively evaluate retinal layer thickness changes in acute macular neuroretinopathy (AMN).MethodsAMN areas were identified using near-infrared reflectance (NIR) images. Intraretinal layer segmentation using Heidelberg software was performed. The inbuilt...

Protective effects of NSP-116, a novel imidazolyl aniline derivative, against light-induced retinal damage in vitro and in vivo

In this study, we investigated the protective effects of NSP-116 [4-(4-acetylpiperazin-1-yl)-2-(1H-imidazol-1-yl) aniline], a novel imidazolyl aniline derivative, against light-induced photoreceptor cell damage. In an in vitro experiment, murine photoreceptor (661W) cells were damaged by exposure to light for 24h. Viability of 661W cells after light exposure was assessed by Hoechst 33342/Propidium iodide nuclear staining and a tetrazolium salt (WST-8) assay. Intracellular radical production in 661W cells was evaluated using the reactive oxygen species (ROS) sensitive probe 5-(and 6)-chloromethyl-2, 7-dichlorodihydrofluorescein diacetate acetyl ester (CM-H2DCFDA). NSP-116 significantly suppressed light-induced cell death and ROS production in 661W cells. In an in vivo mouse experiment, retinal damage was induced by exposure to white light at 8000lx for 3h after dark adaptation. Retinal damage was evaluated by recording the electroretinogram and measuring the outer nuclear layer (ONL) thickness at 5 days after light exposure. Single oral administration of NSP-116 before light exposure protected retinal function and ONL thinning after light exposure. Furthermore, the effect of NSP-116 on lipid peroxidation was evaluated using thiobarbituric acid reactive substance (TBARS) assay in porcine retina, and was found to decrease the production of TBARS. Electron spin resonance (ESR) measurements showed that NSP-116 exhibited radical scavenging activities against 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical, superoxide anion radical (∙O2−), and hydroxyl radical (∙OH). These findings suggest that NSP-116 has protective effects against light-induced photoreceptor degeneration in vitro and in vivo as a free radical scavenger, and it may be a novel therapeutic agent for retinal degenerative disorders, such as dry age-related macular degeneration (AMD).

Clinical features of acute macular neuroretinopathy

Objective To observe the clinical features of acute macular neuroretinopathy (AMN). Methods Six patients (11 eyes) with AMN were included in this study, with every 2-week follow-ups till six months. Among them, five had preceding dengue fever (83.3%), one had history of head trauma (16.7%). All patients received routine examination, fundus photography, infrared reflectance (IR) imaging, spectral-domain optical coherence tomography (SD-OCT) scanning and fluorescein fundus angiography (FFA) initially, and fundus photography, IR, SD-OCT during follow-up. Results Sudden onset of central/paracentral scotoma in one eye or both eyes was the main visual symptom. There were 1 eye with normal fundus, 2 eyes with wedge-shape lesions, 8 eyes with yellow-white or brown sheet lesion. IR imaging demonstrated localized areas of hypo-reflection in the macula. SD-OCT scanning through these areas revealed hyper-reflection in the photoreceptor layer and disruption of its normal reflective structures. Subsequent SD-OCT demonstrated that the hyper-reflection of the photoreceptor layer regressed gradually, followed by thinning of the outer nuclear layer. The external limiting membrane and ellipsoid zone became continuous; however, the interdigitation zone was not restored. There was no remarkable findings of the AMN lesions on FFA. The scotomas persisted in all 6 patients (11 eyes) by the last visit. Conclusions IR imaging demonstrated localized areas of hypo-reflection in the macula. SD-OCT revealed hyper-reflection in the photoreceptor layer in acute stage and the interdigitation zone was not restored in late stage. AMN has a relative poor prognosis with persistent scotomas through at least 6 months. Key words: Macula lutea/injuries; Retinal diseases/ diagnosis; Disease attributes

Protective Effects of Antiplacental Growth Factor Antibody Against Light-Induced Retinal Damage in Mice.

Placental growth factor (PlGF) is part of the VEGF family and is known to be involved in angiogenesis, vasopermeability, and neuroprotection. Recently, PlGF has been reported as a novel therapeutic target for wet AMD. However, there are few reports about the effect of PlGF against dry AMD. Previously, we reported that PlGF has protective effects against retinal neuronal cell damage in vitro. Therefore, we investigated the effects of PlGF against photoreceptor degeneration. In this study, mice were exposed to white light at 8000 lx for 3 hours to induce retinal damage, which was evaluated by recording the electroretinogram amplitude and measuring the outer nuclear layer (ONL) thickness. The mice were injected intravitreally with PlGF before light exposure, PlGF after light exposure, or anti-PlGF antibody before light exposure. RPE-choroid-sclera flat mounts were immunostained with anti-ZO-1 antibody to evaluate the disruption of retinal pigmented epithelium (RPE) cell-cell junctional integrity after light exposure. Furthermore, the expression of VEGF receptor in the retina and RPE-choroid complex after light exposure was measured using Western blot analysis. Contrary to the expected outcome, PlGF treatment exacerbated the light-induced retinal functional damage and ONL thinning. In contrast, anti-PlGF treatment significantly improved the light-induced retinal degeneration. The disruption of RPE cell-cell junctional integrity after light exposure was suppressed by anti-PlGF treatment. Moreover, the VEGF receptor, which is involved in blood-retinal barrier breakdown, was up-regulated after light exposure. These findings suggest that anti-PlGF antibody has protective effects against light-induced retinal degeneration in the murine retina through inhibition of RPE breakdown after light exposure. Thus, anti-PlGF antibody may be useful therapeutic agents in dry AMD.

Conditional Induction of Oxidative Stress in RPE: A Mouse Model of Progressive Retinal Degeneration.

An appropriate animal model is essential to screening drugs or designing a treatment strategy for geographic atrophy. Since oxidative stress contributes to the pathological changes of the retinal pigment epithelium (RPE), we are reporting a new mouse AMD model of retinal degeneration by inducing mitochondrial oxidative stress in RPE. Sod2 the gene for manganese superoxide dismutase (MnSOD) was deleted in RPE layer using conditional knockout strategy. Fundus microscopy, SD-OCT and electroretinography were used to monitor retinal structure and function in living animals and microscopy was used to assess pathology post mortem. Tissue specific deletion of Sod2 caused elevated signs of oxidative stress, RPE dysfunction and showed some key features of AMD. Due to induction of oxidative stress, the conditional knockout mice show progressive reduction in ERG responses and thinning of outer nuclear layer (ONL) compared to non-induced littermates.

In-vivo mapping of drusen by fundus autofluorescence and spectral-domain optical coherence tomography imaging.

To determine fundus autofluorescence (FAF) signal variations and corresponding microstructural alterations on spectral-domain optical coherence tomography (SD-OCT) in areas of funduscopically visible drusen associated with age-related macular degeneration (AMD). Thirty eyes from 22 patients with geographic atrophy (GA) secondary to AMD (median age 74, range 64-87 years), who had undergone retinal imaging including color fundus photography (CFP), FAF and SD-OCT (Spectralis HRA+OCT; Heidelberg Engineering GmbH, Heidelberg, Germany) were retrospectively analyzed. In each eye, at least one druse (≥ 63 μm) in the perilesional zone of GA recorded on CFP was analyzed. Relative FAF intensities and alterations in SD-OCT bands at the site of each druse were evaluated. A total of 73 drusen were analyzed, which were associated with heterogeneous corresponding alterations on FAF and SD-OCT. The FAF signal was normal, increased, decreased or not evaluable in 32 (44 %), 27 (37 %), 12 (16 %), and 2 (3 %) drusen, respectively. Focal hyperreflectivity overlying drusen was most frequently spatially confined to increased FAF (present in 9 (33 %) of 27 drusen with increased FAF). Outer nuclear layer thinning and choroidal hyperreflectivity were associated with decreased FAF (present in 7 [58 %] of 12 and 6 [50 %] of 12 drusen with decreased FAF, respectively). The appearance of soft drusen on CFP does not allow for differentiation between preserved and markedly compromised outer retinal integrity, including incipient atrophy and focal neurosensory alterations of reflectivity overlying extracellular sub-retinal pigment epithelium (RPE) deposits. Multimodal imaging reveals a broad spectrum of microstructural changes, which may reflect different stages in the evolution of drusen.