Thinning Of Outer Nuclear Layer Research Articles

Outer Nuclear Layer Thickness at the Fovea Determines Visual Outcomes in Resolved Central Serous Chorioretinopathy

To determine a correlation between foveal morphologic changes and visual outcomes in patients with resolved central serous chorioretinopathy (CSC). Observational case series. We measured the outer nuclear layer (ONL) thickness at the central fovea and evaluated the integrity of the photoreceptor inner and outer segment junction (IS/OS) using spectral-domain optical coherence tomography in 67 eyes (65 patients) with resolved CSC. The patients were divided into 2 groups: group A included 24 eyes (23 patients) with best-corrected visual acuity (BCVA) of less than 1.0, and group B included 43 eyes (42 patients) with BCVA of 1.0 or better. Group C was comprised of normal control eyes (10 volunteers). We also determined a correlation between the ONL thickness and BCVA. The average ONL thicknesses at the central fovea in groups A, B, and C were 74.6 microm, 103.2 microm, and 124.9 microm, respectively. The average ONL thickness at the central fovea in group A was significantly (P < .001) thinner than that in group B, and that in group B was significantly (P = .0014) thinner than that in group C. The ONL thickness was correlated with the BCVA (r(s) = 0.59; P < .001). Discontinuity of the IS/OS line was observed in 22 eyes (91.7%) in group A, in 9 eyes (20.9%) in group B, and in no eyes in group C, with the difference between groups A and B reaching significance (P < .001). The ONL thickness is positively correlated with the BCVA in resolved CSC. Discontinuity of the IS/OS line was prevalent in eyes with thinner ONL and lower BCVA.

G1961E mutant allele in the Stargardt disease gene ABCA4 causes bull's eye maculopathy

The aim of this study was to characterize the pathological and functional consequences of the G1961E mutant allele in the Stargardt disease gene ABCA4. Data from 15 patients were retrospectively reviewed and all the patients had at least one G1961E mutation. Comprehensive ophthalmic examination, full-field and pattern electroretinograms, and fundus autofluorescence (FAF) imaging were performed on all patients. Microperimetry, spectral-domain optical coherence tomography (OCT), and fluorescein angiography were performed in selected cases. Genetic screening was performed using the ABCR400 micro-array that currently detects 496 distinct ABCA4 variants. All patients had normal full-field scotopic and photopic electroretinograms (ERGs) and abnormal pattern electroretinograms (PERGs) performed on both eyes, and all the fundi had bull's eye maculopathy without retinal flecks on FAF. On OCT, 1 patient had disorganization of photoreceptor outer segment, 2 had outer nuclear layer (ONL) thinning likely due to photoreceptor atrophy proximal to the foveal center, and 3 had additional retinal pigment epithelium (RPE) atrophy. On microperimetry, 6 patients had eccentric superior fixation and amongst this group, 5 had an absolute scotoma in the foveal area. DNA analysis revealed that 3 patients were homozygous G1961E/G1961E and the rest were compound heterozygotes for G1961E and other ABCA4 mutations. The G1961E allele in either homozygosity or heterozygosity is associated with anatomical and functional pathologies limited to the parafoveal region and a trend to delayed onset of symptoms, relative to other manifestations of ABCA4 mutations. Our observations support the hypothesis that the G1961E allele contributes to localized macular changes rather than generalized retinal dysfunction, and is a cause of bull's eye maculopathy in either the homozygosity or heterozygosity state. In addition, genetic testing provides precise diagnosis of the underlying maculopathy, and current non-invasive imaging techniques could be used to detect photoreceptor damage at the earliest clinical onset of the disease.

SPECTRAL-DOMAIN OPTICAL COHERENCE TOMOGRAPHY IMAGING OF THE DETACHED MACULA IN RHEGMATOGENOUS RETINAL DETACHMENT

To assess detached macula in rhegmatogenous retinal detachment by using spectral-domain optical coherence tomography. This retrospective study included 15 eyes of 15 patients with macula-off rhegmatogenous retinal detachment and 16 eyes of 16 patients with acute central serous chorioretinopathy. These patients were examined with a prototype spectral-domain optical coherence tomography system. Spectral-domain optical coherence tomography of eyes with rhegmatogenous retinal detachment revealed macular structural abnormalities, such as small cystoid cavities in the inner nuclear layer (2/15 eyes, 13%), cystoid and/or diffuse edema in the outer nuclear layer (10/15 eyes, 67%), undulations of the photoreceptor layer (7/15 eyes, 47%), and dropout of the photoreceptor inner and outer segment layers in the fovea (6/15 eyes, 40%); such changes were not seen in eyes with acute central serous chorioretinopathy. The dropout of foveal photoreceptor inner and outer segment layers was correlated with preoperative and postoperative visual acuities (rs = 0.78, P < 0.005 and rs = 0.63, P < 0.05, respectively), thickness of the outer nuclear layer at the fovea (rs = -0.69, P < 0.01), and height of the retinal detachment at the fovea (rs = 0.60, P < 0.05). Dropout of the foveal photoreceptor inner and outer segment layers seen on spectral-domain optical coherence tomography imaging may be involved in incomplete recovery of visual acuity after successful retinal reattachment surgery.

Cone-Rod Dependence in the Rat Retina: Variation with the Rate of Rod Damage

To assess the effect of accelerated rod damage on the integrity of cones in the rat retina. Rhodopsin-mutant P23H-3 and Sprague-Dawley (SD) rats were raised in scotopic ambient conditions (12 hours dark, 12 hours 5 lux) and then exposed to photopic conditions (12 hours dark, 12 hours 300 lux). Rods and cones were assessed for cell death, outer segment (OS) morphology, and electroretinogram (ERG) responses. Cones in the P23H-retina were affected rapidly by photopic exposure. Exposure for 2 days caused 50% reductions in LM- and S-cone OS length and cone ERG responses, associated with and preceded by reductions in rod OS length and ERG responses. Although 2 days' exposure increased the rate of rod death, outer nuclear layer thinning was minimal, and no evidence of cone death was detected. In the SD retina, the same photopic exposure had no measurable effects on death rates, OS length, or ERG responses in either rods or cones. Longer (7 days) photopic exposure reduced cone and rod OS length and ERG responses in SD, as well as P23H-3 retinas, but less severely than in the P23H-3 strain. Cones are damaged rapidly in the P23H-3 retina when rod damage is accelerated by raised ambient illumination. This close dependence of cone integrity on rod integrity contrasts with the life-long persistence of cone function in the scotopic reared P23H-3 rat. In humans suffering comparable photoreceptor dystrophies, the maintenance of steady, low ambient light may, by minimizing acute rod damage, optimize the function of surviving cones.

Topography of retinal damage in light-exposed albino rats

Previous studies have shown that retinal damage induced by damaging light exposure is more severe in superior retina than inferior retina when measured along the vertical meridian of eyes. However, the extent of retinal damage over all retinal regions is not clear. Albino rats were exposed to bright light (5000 lux for 6 h) and eyes removed 7 days later. Outer nuclear layer (ONL) thickness was measured along four different meridians; temporal-to-nasal (T–N), superior-to-inferior (S–I), superiotemporal-to-inferionasal (ST–IN), and superionasal-to-inferiotemporal (SN–IT). As reported previously, superior retina is more severely damaged than inferior retina along the S–I meridian. In addition, we found that the temporal retina is more severely damaged than nasal retina on the T–N meridian. Color-coded topographic maps clearly revealed that thinning of ONL was greatest at 1–1.5 mm superior and superiotemporal to the optic nerve head and that most damage was in the superiotemporal region of the fundus. For consistency in quantification of ONL thickness, using retinal sections cut along the S–I meridian is preferable to using those along the T–N meridian, since minor orientations to superior or inferior directions along the T–N meridian may cause greater variations in measured ONL thickness values in this experimental model.

Retinal Laminar Architecture in Human Retinitis Pigmentosa Caused byRhodopsinGene Mutations

To determine the underlying retinal micropathology in subclasses of autosomal dominant retinitis pigmentosa (ADRP) caused by rhodopsin (RHO) mutations. Patients with RHO-ADRP (n = 17, ages 6-73 years), representing class A (R135W and P347L) and class B (P23H, T58R, and G106R) functional phenotypes, were studied with optical coherence tomography (OCT), and colocalized visual thresholds were determined by dark- and light-adapted chromatic perimetry. Autofluorescence imaging was performed with near-infrared light. Retinal histology in hT17M-rhodopsin mice was compared with the human results. Class A patients had only cone-mediated vision. The outer nuclear layer (ONL) thinned with eccentricity and was not detectable within 3 to 4 mm of the fovea. Scotomatous extracentral retina showed loss of ONL, thickening of the inner retina, and demelanization of RPE. Class B patients had superior-inferior asymmetry in function and structure. The superior retina could have normal rod and cone vision, normal lamination (including ONL) and autofluorescence of the RPE melanin; laminopathy was found in the scotomas. With Fourier-domain-OCT, there was apparent inner nuclear layer (INL) thickening in regions with ONL thinning. Retinal regions without ONL had a thick hyporeflective layer that was continuous with the INL from neighboring regions with normal lamination. Transgenic mice had many of the laminar abnormalities found in patients. Retinal laminar abnormalities were present in both classes of RHO-ADRP and were related to the severity of colocalized vision loss. The results in human class B and the transgenic mice support the following disease sequence: ONL diminution with INL thickening; amalgamation of residual ONL with the thickened INL; and progressive retinal remodeling with eventual thinning.

SOD2 Knockdown Mouse Model of Early AMD

To test the hypothesis that oxidative injury to the retinal pigment epithelium (RPE) may lead to retinal damage similar to that associated with the early stages of age-related macular degeneration (AMD). A ribozyme that targets the protective enzyme manganese superoxide dismutase (MnSOD) was expressed in RPE-J cells, and adeno-associated virus (AAV) expressing the ribozyme gene was injected beneath the retinas of adult C57BL/6 mice. The RPE/choroid complex was examined for SOD2 protein levels and protein markers of oxidative damage using immunoblot analysis and LC MS/MS-identification of proteins and nitration sites. Lipids were extracted from retinal tissue and analyzed for the bis-retinoid compounds A2E and iso-A2E. The mice were analyzed by full-field electroretinography (ERG) for light response. Light and electron microscopy were used to measure cytological changes in the retinas. The treatment of RPE-J cells with Rz432 resulted in decreased MnSOD mRNA and protein as well as increased levels of superoxide anion and apoptotic cell death. When delivered by AAV, Rz432 reduced MnSOD protein and increased markers of oxidative damage, including nitrated and carboxyethylpyrrole-modified proteins in the RPE-choroid of mice. Ribozyme delivery caused a progressive loss of electroretinograph response, vacuolization, degeneration of the RPE, thickening of Bruch's membrane, and shortening and disorganization of the photoreceptor outer and inner segments. Progressive thinning of the photoreceptor outer nuclear layer resulted from apoptotic cell death. Similar to the eyes of patients with AMD, ribozyme-treated eyes exhibited increased autofluorescence and elevated levels of A2E and iso-A2E, major bis-retinoid pigments of lipofuscin. These results support the hypothesis that oxidative damage to the RPE may play a role in some of the key features of AMD.

Pathological and Electrophysiological Features of a Canine Cone–Rod Dystrophy in the Miniature Longhaired Dachshund

To characterize the electrophysiological and histopathological features of a retinal degenerative disease in a colony of miniature longhaired dachshunds known to have a form of progressive retinal atrophy (PRA). Serial electroretinograms were recorded from affected homozygous (n = 36) and heterozygous (n = 15) dogs. Morphologic investigations including immunohistochemistry and lectin histochemistry were performed on selected homozygous animals (n = 15). Clinical findings included loss of tapetal hyperreflectivity. The mode of inheritance was autosomal recessive. An early dramatic reduction of cone-specific ERG amplitude with a more modest reduction in rod b-wave amplitude was demonstrated. Progressively, rod specific responses diminished until there were no recordable responses to the ERG stimuli at 40 weeks of age. Morphologic changes confirmed early cone inner and outer segment loss. Other abnormalities included opsin mislocalization and outer nuclear layer thinning due to the subsequent loss of rod photoreceptors. A novel canine cone-rod dystrophy has been identified.

Prolonged Rhodopsin Phosphorylation in Light-Induced Retinal Degeneration in Rat Models

The effects of various light-induced stresses on the retina were examined in the retinal degenerative rat model. Retinal morphology and electroretinograms (ERGs) were analyzed after application of light-induced stress of several intensities (650, 1300, 2500, or 5000 lux). For evaluation of rhodopsin (Rho) function, the kinetics of Rho regeneration and dephosphorylation were studied by spectrophotometric analysis and immunofluorescence labeling with antibodies specifically directed toward the phosphorylated residues (334)Ser and (338)Ser in the C terminus of Rho. Retinal cGMP concentration was determined by ELISA. Expression levels of neurotrophic factors (FGF2, brain-derived neurotrophic factor [BDNF], platelet-derived growth factor [PDGF], and ciliary neurotrophic factor [CNTF]) were evaluated quantitatively by RT-PCR. Light intensity-dependent deterioration of ERG responses and thinning of the retinal outer nuclear layer were observed in wild-type and Royal College of Surgeons (RCS) rat retinas. Under dark adaptation after light-induced stress, the kinetics of Rho regeneration were not different between wild-type and RCS rat retinas. Rho dephosphorylation at (334)Ser and (338)Ser was extremely delayed in RCS rat retinas compared with wild-type without light-induced stress, but Rho dephosphorylation at those sites became slower in both RCS and wild-type rat retinas. In terms of expression of neurotrophic factors, almost no significant changes were observed between the animals after light-induced stress. The present study indicates that light-induced stress causes intensity-dependent deterioration in retinal function and morphology in wild-type and RCS rat retinas. Disruption of the phototransduction cascade resulting from slower kinetics of Rho dephosphorylation appears to be involved in retinal degeneration.

Krypton laser photocoagulation induces retinal vascular remodeling rather than choroidal neovascularization

The purpose of this study is to analyze the retina and choroid response following krypton laser photocoagulation. Ninety-two C57BL6/Sev129 and 32 C57BL/6J, 5–6-week-old mice received one single krypton (630 nm) laser lesion: 50 μm, 0.05 s, 400 mW. On the following day, every day thereafter for 1 week and every 2–3 days for the following 3 weeks, serial sections throughout the lesion were systematically collected and studied. Immunohistology using specific markers or antibodies for glial fibrillary acidic protein (GFAP) (astrocytes, glia and Muller's cells), von Willebrand (vW) (vascular endothelial cells), TUNEL (cells undergoing caspase dependent apoptosis), PCNA (proliferating cell nuclear antigen) p36, CD4 and F4/80 (infiltrating inflammatory and T cells), DAPI (cell nuclei) and routine histology were carried out. Laser confocal microscopy was also performed on flat mounts. Temporal and spatial observations of the created photocoagulation lesions demonstrate that, after a few hours, activated glial cells within the retinal path of the laser beam express GFAP. After 48 h, GFAP-positive staining was also detected within the choroid lesion center. “Movement” of this GFAP-positive expression towards the lasered choroid was preceded by a well-demarcated and localized apoptosis of the retina outer nuclear layer cells within the laser beam path. Later, death of retinal outer nuclear cells and layer thinning at this site was followed by evagination of the inner nuclear retinal layer. Funneling of the entire inner nuclear and the thinned outer nuclear layers into the choroid lesion center was accompanied by “dragging” of the retinal capillaries. Thus, from days 10 to 14 after krypton laser photocoagulation onward, well-formed blood capillaries (of retinal origin) were observed within the lesion. Only a few of the vW-positive capillary endothelial cells stained also for PCNA p36. In the choroid, dilatation of the vascular bed occurred at the vicinity of the photocoagulation site and around it. Confocal microscopy demonstrates that the vessels throughout the path lesion are located within the neuroretina while in the choroid (after separation of the neural retina) only GFAP-positive but no lectin-positive cells can be seen. The involvement of infiltrating inflammatory cells in these remodeling and healing processes remained minimal throughout the study period. During the 4 weeks following krypton laser photocoagulation in the mouse eye, processes of wound healing and remodeling appear to be driven by cells (and vessels) originating from the retina.

Enhanced Shutoff of Phototransduction in Transgenic Mice Expressing Palmitoylation-deficient Rhodopsin*♦

Palmitoylation is a reversible, post-translational modification observed in a number of G-protein-coupled receptors. To gain a better understanding of its role in visual transduction, we produced transgenic knock-in mice that expressed a palmitoylation-deficient rhodopsin (Palm(-/-)). The mutant rhodopsin was expressed at wild-type levels and showed normal cellular localization to rod outer segments, indicating that neither rhodopsin stability nor its intracellular trafficking were compromised. But Palm(-/-) rods had briefer flash responses and reduced sensitivity to flashes and to steps of light. Upon exposure to light, rhodopsin became phosphorylated at a faster rate in mutant than in wild-type retinas. Since quench of rhodopsin begins with its phosphorylation, these results suggest that palmitoylation may modulate rod photoreceptor sensitivity by permitting rhodopsin to remain active for a longer period.

High-resolution ultrasonography of subretinal structure and assessment of retina degeneration in rat

The purpose of this work was to evaluate the ability of 80 MHz ultrasonography to differentiate intra-retinal layers and quantitatively assess photoreceptor dystrophy in small animal models. Four groups of 10 RCS rats each (five dystrophic and five controls) were explored at 25, 35, 45 and 55 days post-natal (PN). A series of retina cross-sections were obtained ex vivo from outside intact eyes using an 80 MHz three-dimensional ultrasound backscatter microscope (20-μm-axial resolution). Ultrasound features of normal retina were correlated to those of corresponding histology and thickness measurements of photoreceptor segment and nuclear layers were performed on all groups. To show the ability of 80 MHz ultrasonography to distinguish the retinal degeneration in vivo, one RCS rat was explored at 25 and 55 days post-natal. Ultrasound image of normal retina displayed four distinct layers marked by reflections at neurites/nuclei interfaces and permitted to differentiate the photoreceptor segment and nuclear layers. The backscatter level from the retina was shown to be related to the size, density and organization of the intra-layer structure. Ultrasound thickness measurements highly correlated with histologic measurements. A thinning ( p<0.05) of outer nuclear layer (ONL) was detected over time for controls and was thought to be assigned to retina maturation. Retinal degeneration started at PN35 and resulted in a more pronounced ONL thinning ( p<0.05) over time. ONL degeneration was accompanied by segment layer thickening ( p<0.05) at PN35 and thinning thereafter. These changes may indicate accumulation of outer segment debris at PN35 then progressive destruction. In vivo images of rat intra-retinal structure showed the ability of the method to distinguish the photoreceptor layer changes. Our results indicate that 80 MHz ultrasonography reveals intra-retinal layers and is sensitive to age and degenerative changes of photoreceptors. This technique has great potential to follow-up retinal dystrophy and therapeutic effects in vivo.

Depletion of taurine and glutamate from damaged photoreceptors in the retinas of dogs with primary glaucoma

To determine whether taurine and glutamate contents are reduced in damaged photoreceptors in dogs with primary glaucoma (PG) in a manner consistent with an ischemia-like release of both of these amino acids from damaged cells. Retinas from 6 dogs with PG and 3 control dogs. Serial, semithin sections of each canine retina were stained with toluidine blue to identify damaged photoreceptors or via immunogold techniques to quantify taurine and glutamate content in retinal cells. Regions with a thin outer nuclear layer and pathologic nuclear changes in photoreceptors were evident in retinas of dogs with PG. The density of immunostaining for taurine in damaged photoreceptors was significantly reduced to (mean +/- SEM) 37.5 +/- 2.6% of the density in adjacent undamaged photoreceptors. Photoreceptors with decreased taurine immunostaining also had decreased glutamate immunostaining, consistent with ischemia-like release of both of these amino acids from damaged cells. Immunostaining for glutamate, but not taurine, was increased in presumptive radial glial cells (i.e., Miller cells) in damaged regions, consistent with an ischemia-induced redistribution of amino acids in dogs with PG. Retinal damage in dogs with PG includes ischemia-like losses of taurine and glutamate from photoreceptors and accumulation of glutamate, but not taurine, in nearby Müller cells. These changes are consistent with glutamate release and depletion of intracellular taurine in damaged regions, perhaps contributing to progressive damage in these areas.

1056. PhiC31 Integrase for Long-Term Non-Viral Gene Therapy in Rat Retina

We have developed a lentiviral vector system that can transduce terminally differentiated retinal cells in vivo. Using this system, we designed experiments to evaluate the therapeutic potentials of gene therapy for retinal degenerations in the cyclic nucleotide-gated channel CNGA3-deficiet mice, an animal model for cone photoreceptor cell degeneration, and retinal degeneration slow (rds/rds) mice, an animal model for retinitis pigmentosa. Wild type human CNGA3 and mouse Peripherin cDNAs were transduced in cone and rod photoreceptor cell-specific manner by human red pigment gene and bovine rhodopsin gene promoters in CNGA3-deficient mice and rds/rds mice, respectively. Moreover the additional neuroprotective effects of human pigment epithelium-derived factor (hPEDF) driven by cytomegalovirus promoter were also assessed. In CNGA3-deficient mice, transduction of hCNGA3 and hPEDF reduced the speed of cone degeneration, although subacute thinning of outer nuclear layer (ONL) was observed in some samples. Electrophysiological analysis revealed that hCNGA3 reconstitution improved cone response and maximal response which is derived from rods and cones. These effects were prolonged by combinational transduction of hPEDF. In rds/rds mice, transduction of mPeripherin and hPEDF partially prevented thinning of ONL until eight months after the injection. Electrophysiologically we could detect improvement of rod response and maximal response, although the additional effects of hPEDF were not observed. We conclude that subretinal lentiviral vector delivery had significant rescue effects on these two retinal degeneration animal models.

Immunocytochemical characterisation of proteins secreted by retinal pigment epithelium in retinas of normal and Royal College of Surgeons dystrophic rats.

In a previous study, an antigen consisting of proteins secreted by retinal pigment epithelial (RPE) cells was injected into a sheep and the specificity of the resulting antiserum was shown by Western blotting and its effects on retinal development were determined in vitro and in vivo. In the present study, the distribution of these secreted proteins was determined by light microscopy immunocytochemistry in cultured neonatal rat RPE cells and retinas of normal and Royal College of Surgeons (RCS) dystrophic rats and cerebrum of normal adult rats. Immunolabelling for these RPE-secreted proteins was detected in cytoplasmic vesicles surrounding nuclei and within processes of cultured normal and transformed rat RPE. In retinas of late postnatal and adult rats, dense immunostaining was found in the cytoplasm of RPE cells and ganglion cell bodies. In addition to RPE and ganglion cells, scattered photoreceptors within the thin outer nuclear layer and small structures within the debris zone were also densely immunoreactive in retinas of 2-mo-old RCS dystrophic rats. The numbers of immunostained ganglion cells appeared to decrease in retinas of older RCS rats, although the immunoreactivity within the RPE appeared to increase in density. No other neuron within the retina, i.e. bipolar, amacrine or horizontal, was immunoreactive for RPE-secreted proteins. In the cerebral cortex of adult rats, immunoreactivity for RPE-secreted proteins was primarily detected within large perikarya of pyramidal neurons and smaller granule neurons. In conclusion, we report an immunocytochemical analysis of an antiserum raised against secreted proteins of rat RPE. This antiserum recognised proteins within secretory-like vesicles of cultured neonatal normal and transformed rat RPE and showed a specificity for RPE and ganglion cells in normal rat retinas, that appeared to be developmentally regulated, and neuron perikarya in adult rat cerebrum.

Ophthalmic pathology in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency caused by the G1528C mutation

Purpose. To define histopathologic features of a recently recognized chorioretinopathy associated with long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, a defect of mitochondrial fatty acid oxidation.Methods. Both eyes were obtained at autopsy from a child who died of LCHAD deficiency, caused by the G1528C mutation, at the age of 14 months. Routine histopathology and light microscopic immunohistochemistry were performed, with a panel of 12 antibodies to epithelial, mesenchymal, neuronal, and inflammatory cells, using the avidin-biotinylated peroxidase complex method.Results. The cells of the retinal pigment epithelium (RPE) were rarefied, flattened, and hypopigmented in the posterior pole. The RPE cells reacted normally with MAb Vim 34B to vimentin, and MAb CAM 5.2 and CY-90 for cytokeratin 8 and 18. Scattered among them were many pigment-laden macrophages, reactive with MAb PG-M1. A thin outer nuclear layer in the macular region suggested loss of photoreceptor cells. In routine stainings, patent choriocapillary vessels were sparse. However, a collapsed network of capillaries could be identified by MAb QBEND-10 to the CD34 epitope of vascular endothelial cells. In the peripheral fundus, the RPE and choriocapillaris were normal.Conclusions. The ophthalmopathologic findings corresponded to clinically defined stage 2 of the chorioretinopathy of LCHAD deficiency. Histopathologically, this chorioretinopathy can be classified as diffuse choroidal atrophy with loss of the choriocapillaris. The findings suggest a primary fault at the level of the RPE and choriocapillaris and a secondary macrophage response. Curr. Eye Res. 17: 551–559, 1998.These results were presented in part in the Joint Meeting of the Verboeff Society-European Ophthalmic Pathology Society, Houston, April 1996.