Macular Degeneration: Green WR

Wong RW, Richa DC, Hahn P, Green WR, Dunaief JL. · F. M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, USA. · Retina. · Pubmed #18040235 No free full text.

Abstract: While it has been known for years that iron overload is associated with retinal degeneration in the context of ocular siderosis, intraocular hemorrhage, and the hereditary diseases aceruloplasminemia and pantothenate kinase associated neurodegeneration, recent evidence suggests that age-related macular degeneration (AMD) may also be exacerbated by retinal iron overload. In the retina, iron is necessary for normal cellular function. Iron overload, however, can cause retinal toxicity through the generation of oxygen free radicals. Histopathology of eyes with macular degeneration has shown elevated levels of iron in the retinal pigment epithelium, Bruch membrane, and within drusen, some of which was chelatable in vitro with deferoxamine. In this review, the authors summarize the evidence that iron overload may contribute to AMD pathogenesis. It is hoped that continued investigation of the role of iron and iron associated proteins in the retina will uncover clues to AMD pathogenesis and lead to new preventative or therapeutic options.

Green WR. · Departments of Ophthalmology and Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA. · Mol Vis. · Pubmed #10562651 links to  free full text

Abstract: Age-related macular degeneration is a diffuse condition involving the retinal pigment epithelium, the photoreceptor cell layer, and perhaps the choriocapillaris. The early morphologic change is the development of basal deposits of two distinct types. This phase is not ophthalmoscopically detectable but psychophysical testing may demonstrate reduced function. The process becomes detectable with the occurrence of secondary changes in the pigment epithelium, soft drusen formation, and choroidal neovascularization. A reparative response results in disciform scars. The various morphologic forms of age-related macular degeneration are interrelated.

Chan CC, Shen D, Zhou M, Ross RJ, Ding X, Zhang K, Green WR, Tuo J. · Immunopathology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA. · Trans Am Ophthalmol Soc. · Pubmed #18427598 links to  free full text

Abstract: PURPOSE: HtrA1 belongs to the high temperature requirement factor A family of serine proteases, which are involved in protein quality control and cell fate. A single-nucleotide polymorphism (SNP), rs11200638, in the promoter of HtrA1 at chromosome 10q26 is reported as a likely causal variant for age-related macular degeneration (AMD). The SNP is located in the regulatory region and increases production of HtrA1 protein. This study investigates HtrA1 expression and SNP genotypes in archived ocular slides with AMD. METHODS: Macular, nonretinal, and peripheral retinal cells were microdissected from archived slides from 57 eyes with AMD and 16 age-matched, non-AMD controls. HtrA1 rs11200638 SNP genotyping was performed using polymerase chain reaction (PCR) and restriction fragment length polymorphism analysis. HtrA1 transcripts were measured using real-time reverse transcriptase-PCR. HtrA1 protein expression was evaluated using avidin-biotin complex immunohistochemistry. RESULTS: HtrA1 (G/A) SNP was successfully genotyped in 52 AMD cases and 13 non-AMD subjects. The frequencies of the risk allele (A) were 55 of 104 (52.9%) and 8 of 26 (30.8%) in AMD and control groups, respectively. HtrA1 mRNA was detected in normal peripheral and macular retinas, higher in the periphery than maculae. HtrA1 mRNA was much higher in the macula and a lot lower in the periphery of the AMD eyes as compared to control eyes. HtrA1 protein was expressed in normal retinal vascular endothelia and retinal pigment epithelia. Intense immunoreaction against HtrA1 was found in AMD lesions, slightly more in wet than dry AMD lesions. CONCLUSION: This study successfully analyzes HtrA1 SNP and transcript expression in microdissected cells from archived paraffin fixed slides. Up-regulation of HtrA1 is detected in the macular lesions of AMD eyes. The data further suggest that rs11200638 in HtrA1 promoter is associated with AMD development.

Shen JK, Dong A, Hackett SF, Bell WR, Green WR, Campochiaro PA. · The Department of Ophthalmology, The Johns Hopkins University School of Medicine Maumenee, Baltimore, Maryland 21287-9277, USA. · Histol Histopathol. · Pubmed #17701910 No free full text.

Abstract: Epidemiologic studies have suggested that elderly patients who consumed diets rich in antioxidants throughout their lives are less likely to be afflicted with age-related macular degeneration (AMD). This led to the Age-Related Eye Disease Study, which showed that supplements containing antioxidant vitamins and zinc reduce the risk of progression to severe stages of AMD. Despite these data that indirectly implicate oxidative damage in the pathogenesis of AMD, there has not been any direct demonstration of increased oxidative damage in the retinas of patients with AMD. In this study, we used biomarkers of oxidative damage in postmortem eyes from patients with AMD and comparably aged patients without AMD to directly assess for oxidative damage. Sections from 4 eyes with no pathologic features of AMD showed no immunofluorescent staining for markers of oxidative damage, while sections from 8 of 12 eyes with advanced geographic atrophy showed evidence of widespread oxidative damage in both posterior and anterior retina. Only 2 of 8 eyes with choroidal neovascularization and 2 of 16 eyes with diffuse drusen and no other signs of AMD showed evidence of oxidative damage. These data suggest that widespread oxidative damage occurs in the retina of some patients with AMD and is more likely to be seen in patients with advanced geographic atrophy. This does not rule out oxidative damage as a pathogenic mechanism in patients with CNV, but suggests that a subpopulation of patients with geographic atrophy may have a major deficiency in the oxidative defense system that puts the majority of cells in the retina at risk for oxidative damage.

Bojanowski CM, Shen D, Chew EY, Ning B, Csaky KG, Green WR, Chan CC, Tuo J. · Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892-1857, USA. · Environ Mol Mutagen. · Pubmed #16823865 links to  free full text

Abstract: Age-related macular degeneration (AMD) is the leading cause of visual impairment and blindness among the elderly in Western countries. Genetic factors, age, cigarette smoking, nutrition, and exposure to light have been identified as AMD risk factors. In this study, we investigated the association between ApoE C112R/R158C single nucleotide polymorphisms (which determine the E2, E3, and E4 isoforms) and age-related macular degeneration (AMD), and the mechanism underlying the association. Genomic DNA was extracted from 133 clinically screened controls, 94 volunteers with a younger mean age, 120 patients with advanced AMD, and 40 archived ocular AMD slides for single nucleotide polymorphism typing. The effects of recombinant ApoE isoforms on CCL2 (a chemokine), CX3CR1 (a chemokine receptor), and VEGF (a cytokine) expression in cultured human retinal pigment epithelium (RPE) cells were tested and serum cholesterol profiles of the clinically screened subjects were analyzed. ApoE112R (E4) distribution differed significantly between AMD patients and controls. ApoE112R allele frequency was 10.9% in the AMD group when compared with 16.5% in the younger controls and 18.8% in the clinically screened controls. The pathologically diagnosed archived AMD cases had the lowest allele frequency of 5%. No significant differences in ApoE158C (E2) distribution were observed among the groups. A meta-analysis of 8 cohorts including 4,289 subjects showed a strong association between AMD and 112R, but not 158C. In vitro studies found that recombinant ApoE suppresses CCL2 and VEGF expression in RPE cells. However, the E4 isoform showed more suppression than E3 in both cases. These results further confirm the association between ApoE112R and a decreased risk of AMD development. The underlying mechanisms may involve differential regulation of both CCL2 and VEGF by the ApoE isoforms.

Grossniklaus HE, Wilson DJ, Bressler SB, Bressler NM, Toth CA, Green WR, Miskala P. · Department of Ophthalmology, Emory University School of Medicine, 428 Emory Eye Center, 1365 Clifton Road, Atlanta, GA 30322, USA. · Am J Ophthalmol. · Pubmed #16386982 No free full text.

Abstract: PURPOSE: To compare the fundus photographic and fluorescein angiographic features with the histologic findings in eyes from patients enrolled in the Submacular Surgery Trials (SST). DESIGN: Clinical trials with clinicopathologic correlation. METHODS: Eyes that were obtained postmortem from patients who participated in the donor program were processed at the SST Pathology Center and examined histologically; the macular regions were reconstructed topographically with two-dimensional cartography. Fundus photographic and fluorescein angiographic features were correlated with the histopathologic and two-dimensional cartographic findings. RESULTS: The eyes from two patients each from the SST Group N and B Trials were studied. The study eye of one patient that had been assigned randomly to observation contained a subretinal fibrovascular scar that corresponded to a histologic growth pattern of a thick, collagenized subretinal component combined with a subretinal pigment epithelium (subRPE) fibrovascular component. The study eye of the other patient who was assigned randomly to observation showed angiographic occult without classic choroidal neovascularization (CNV) that corresponded to subRPE CNV. The study eye of one patient who was assigned randomly to surgery showed an angiographic surgical defect without CNV and histologic retinal pigment epithelium (RPE)/photoreceptor atrophy that was associated with a thin layer of subRPE CNV. The study eye of the other patient who was assigned randomly to surgery showed an angiographic surgical defect with classic CNV that corresponded to histologic RPE/photoreceptor atrophy that was associated with subRPE fibrovascular tissue and subretinal CNV. Both surgical eyes contained linear breaks in Bruch's membrane that included chevron-shaped breaks. CONCLUSION: Four SST study eyes that were examined postmortem contained CNV. The angiographic patterns and histologic features of the CNV support previous correlations of surgically excised CNV.

Green WR, Enger C. · No affiliation provided · Retina. · Pubmed #16049370 No free full text.

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Guyer DR, Green WR, de Bustros S, Fine SL. · No affiliation provided · Retina. · Pubmed #16049368 No free full text.

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Bressler SB, Silva JC, Bressler NM, Alexander J, Green WR. · No affiliation provided · Retina. · Pubmed #16049367 No free full text.

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Green WR, McDonnell PJ, Yeo JH. · No affiliation provided · Retina. · Pubmed #16049365 No free full text.

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Green WR, Gass JD. · No affiliation provided · Retina. · Pubmed #16049364 No free full text.

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Frangieh GT, Green WR, Engel HM. · No affiliation provided · Retina. · Pubmed #16049363 No free full text.

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Green WR, Key SN. · No affiliation provided · Retina. · Pubmed #16049362 No free full text.

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Bressler NM, Silva JC, Bressler SB, Fine SL, Green WR. · No affiliation provided · Retina. · Pubmed #16049360 No free full text.

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Grossniklaus HE, Miskala PH, Green WR, Bressler SB, Hawkins BS, Toth C, Wilson DJ, Bressler NM. · Montgomery Ophthalmic Pathology Labotratory, BT0428 Emory Eye Center, 1365 Clifton Road NE, Atlanta, GA 30322, USA. · Arch Ophthalmol. · Pubmed #16009831 No free full text.

Abstract: OBJECTIVES: To identify the histologic and ultrastructural features of surgically excised subfoveal choroidal neovascular lesions from patients enrolled in the Submacular Surgery Trials and to compare them with clinical data. METHODS: Surgically excised subfoveal choroidal neovascular lesions from patients enrolled in the Submacular Surgery Trials group N trial (lesion predominantly choroidal neovascularization [CNV] with evidence of classic CNV from age-related macular degeneration), group B trial (lesion predominantly hemorrhagic from age-related macular degeneration), and group H trial (idiopathic subfoveal CNV or subfoveal CNV from ocular histoplasmosis syndrome) between October 1, 1999, and September 1, 2001, were submitted to the pathology center. The lesion growth pattern (subretinal pigment epithelial [sub-RPE], subretinal, combined, or indeterminate) and the cellular and extracellular constituents were classified independently. Demographic, clinical, and fluorescein angiographic characteristics of patients, eyes, and lesions, respectively, were compared with the pathologic features. RESULTS: Of 269 patients assigned to surgery during the 24 months that pathologic specimens were collected, surgical specimens from study eyes of 199 were submitted to the pathology center. Of the 199 routine histologic specimens processed, 144 (72%) were classified as CNV, 51 (26%) as fibrocellular tissue, and 4 (2%) as hemorrhage. The median specimen size was smaller in group H (932 x 208 mum) than in groups N (1980 x 325 mum) and B (1800 x 395 mum). The CNV growth pattern was determined in 91 (46%) of 199 specimens. Of 159 group N and group B lesions, 76 (48%) had an indeterminate growth pattern, 28 (18%) had a sub-RPE growth pattern, and 33 (21%) had sub-RPE and subretinal growth patterns. Of 40 group H lesions, 32 (80%) had an indeterminate growth pattern, 7 (18%) had a subretinal growth pattern, and 1 (2%) had a combined sub-RPE and subretinal pattern. Based on electron microscopy, the most common cellular lesion components were RPE, macrophages, erythrocytes, fibrocytes, and vascular endothelium; the most common extracellular components were 24-nm collagen and fibrin. Basal laminar and linear deposits were found in 80% (40/50) and 16% (8/49) of group N specimens, 66% (43/65) and 5% (3/65) of group B specimens, and 8% (2/26) and 0% (0/26) of group H specimens, respectively. CONCLUSIONS: Most surgically excised subfoveal specimens had evidence of CNV or tissue associated with CNV. The constituents in CNV were consistent with granulation tissue proliferation. The presence of basal deposits in surgically excised specimens suggested a clinical diagnosis of age-related macular degeneration, even when blood was the predominant component of the lesion. Correlation of growth patterns above or below the RPE with fluorescein angiographic patterns of classic or occult CNV was limited because most specimens had insufficient material to determine these patterns.

Chan CC, Tuo J, Bojanowski CM, Csaky KG, Green WR. · National Eye Institute, National Institutes of Health, Bldg. 10, 10 Center Drive, Bethesda, MD 20895, USA. · Histol Histopathol. · Pubmed #15944936 links to  free full text

Abstract: There is a significant genetic component in age-related macular degeneration (AMD). CX3CR1, which encodes the fractalkine (chemokine, CX3CL1) receptor, has two single nucleotide polymorphisms (SNPs): V249I and T280M. These SNPs are correlated with other aged-related diseases such as atherosclerosis. We have reported an association of CX3CR1 SNP and AMD. In this study we examined CX3CR1 SNP frequencies and protein expression on archived sections of AMD and normal eyes. We microdissected non-retinal, peripheral retinal and macular cells from archived slides of eyes of AMD patients and normal subjects. CX3CR1 SNP typing was conducted by PCR and restriction fragment length polymorphism analysis. CX3CR1 transcripts from retinal cells were also measured using RT-PCR. CX3CR1 protein expression was evaluated using avidin-biotin complex immunohistochemistry. We successfully extracted DNA from 32/40 AMD cases and 2/2 normal eyes. Among the 32 AMD cases, 18 had neovascular AMD and 14 had non-neovascular AMD. The M280 allele was detected in 19/64 (32 cases x2) with a frequency of 29.7%, which was significantly higher as compared to the frequency in the normal population (11.2%). We detected CX3CR1 expression in the various retinal cells. CX3CR1 transcript and protein levels were diminished in the macular lesions. This study successfully analyzed CX3CR1 SNP and transcript expression in microdissected cells from archived paraffin fixed slides. Our data suggest that the M280 allele, a SNP resulting in aberrant CX3CR1 and CX3CL1 interaction, as well as lowered expression of macular CX3CR1, may contribute to the development of AMD.

Margalit E, Sunness JS, Green WR, Kelman SE, Schachat AP, Fiergang D, Allikmets R. · Wilmer Eye Institute, Baltimore, Maryland 21205, USA. · Arch Ophthalmol. · Pubmed #14609928 No free full text.

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Kim SY, Sadda S, Pearlman J, Humayun MS, de Juan E, Melia BM, Green WR. · The Wilmer Ophthalmological Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-9277, USA. · Retina. · Pubmed #12172115 No free full text.

Abstract: PURPOSE: To evaluate the extent of neural cell death in eyes with disciform age-related macular degeneration. METHODS: Six eyes with disciform degeneration at various stages and five age-matched control eyes were selected for morphometric analysis using digitized light microscopic images. Disciform scars were classified as subneurosensory retinal, subretinal pigment epithelial, or combined lesions. The nuclei of the ganglion cell, inner nuclear, and outer nuclear layers were counted in contiguous 100 microm segments spanning a distance from 1,500 microm nasal to 1,500 microm temporal to the fovea. RESULTS: The outer nuclear layer was most severely attenuated in eyes with disciform scars, demonstrating a 69.4% reduction in cell number relative to control eyes. A loss in retinal ganglion cells (by 7.3%) and an increase in inner nuclear layer cells (by 10%) were observed, but these changes were not significant. Photoreceptor loss was most pronounced when the disciform scar was not covered by the retinal pigment epithelium. CONCLUSION: The nuclei of the outer nuclear layer are significantly attenuated in eyes with disciform age-related macular degeneration, while the ganglion cell and inner nuclear layers are relatively preserved. These findings suggest that replacement of outer nuclear function, by either retinal transplantation or implantation of the intraocular retinal prosthesis, might be a feasible therapeutic option for patients with this condition.

Kim SY, Sadda S, Humayun MS, de Juan E, Melia BM, Green WR. · Wilmer Ophthalmological Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-9277, USA. · Retina. · Pubmed #12172114 No free full text.

Abstract: PURPOSE: To evaluate the extent of neural cell death in eyes with geographic atrophy (GA). METHODS: Ten eyes with GA and five age-matched control eyes were selected for morphometric analysis. The nuclei of the ganglion cell, inner nuclear, and outer nuclear layers were counted in contiguous 100-microm segments from 1,500 microm nasal to 1,500 microm temporal to the fovea. RESULTS: The outer nuclear layer was most severely attenuated in eyes with GA, demonstrating a 76.9% reduction relative to control eyes (P < 0.0001). A significant loss of ganglion cells (by 30.7%) was also observed (P = 0.0008). There was no significant difference in the inner nuclear layer cells (P = 0.30). Among the GA eyes, the nuclei in all three layers were significantly reduced in segments in which the retinal pigment epithelium was completely absent (P </= 0.0003). CONCLUSION: Although the nuclei of the outer nuclear layer in eyes with GA were markedly attenuated, the nuclei of the inner nuclear layer were relatively preserved. There was also a significant reduction in ganglion cells in GA eyes, but considerable numbers remained even in the areas of complete retinal pigment epithelium atrophy. This finding suggests that therapies aimed at replacing outer nuclear function (such as neural retinal and retinal pigment epithelium transplantation or implantation of the intraocular retinal prosthesis) may be feasible for restoring vision in these patients.

McLeod DS, Taomoto M, Otsuji T, Green WR, Sunness JS, Lutty GA. · Wilmer Ophthalmological Institute, Johns Hopkins Hospital, Baltimore, Maryland 21287-9115, USA. · Invest Ophthalmol Vis Sci. · Pubmed #12037009 links to  free full text

Abstract: PURPOSE: An image-analysis technique was developed to quantify changes in the retinal pigment epithelium (RPE) and choriocapillaris in eyes of deceased donors with age-related macular degeneration (AMD). METHODS: Both eyes of two donors with AMD and of one normal control donor were used to develop this technique. After removal of the anterior segments, the eyecups were hemisected through the macula, with the disc included in one half of the eyecup. The choroid with RPE cells was dissected from the sclera and incubated for alkaline phosphatase (APase) activity, and the pigment was partially bleached with H2O2. The APase-incubated choroid was flat embedded and sectioned after image and morphometric analyses. Quantitative computer-assisted morphometric analyses of the two AMD-affected eyes (cases 1 and 2) were compared with analysis of the normal eye of a 70-year-old control subject (case 3). RESULTS: The right eye in case 1 had geographic atrophy (GA) and demonstrated a large area in the posterior pole with very few RPE cells (90% loss of RPE), but the border of the area of RPE atrophy was not well defined. The density of choroidal blood vessels in this area was reduced 30% to 50%, compared with the same regions in the control eye. No area was completely devoid of choriocapillaris. Clinically undetected choroidal neovascularization (CNV) was observed in the right eye in case 1 in both the periphery and the macula and was generally associated with surviving RPE cells. The right eye in case 2 had GA (areolar RPE atrophy) and demonstrated a reduction in vascular density in the area from disc to macula that was even greater than that in the eye in case 1 (53% reduction in the submacular region). RPE atrophy between the disc and macula was almost complete. The border of the RPE defect was clearly delineated and coincided closely with the area of decreased choroidal vascular density. Surviving choriocapillaris in the area of RPE atrophy was significantly narrower than choriocapillaris in the control subject and in normal areas of the eyes with GA (P < 0.0001). CONCLUSIONS: In these eyes with GA, RPE atrophy was more severe than loss of choriocapillaris. Surviving choriocapillaris in areas with complete RPE loss was highly constricted. The association of surviving RPE cells with CNV suggests that RPE cells may furnish a stimulus for new vessel formation or stabilization.

Zhang K, Garibaldi DC, Li Y, Green WR, Zack DJ. · Department of Ophthalmology, Johns Hopkins University School of Medicine, 809 Maumenee, 600 N Wolfe St, Baltimore, MD 21287, USA. · Arch Ophthalmol. · Pubmed #11934323 links to  free full text

Abstract: OBJECTIVES: To identify the disease-causing mutation in a large family segregating dominantly inherited butterfly-shaped pattern dystrophy (BPD) and to describe the microscopic pathological changes observed in a member of this family. METHODS: Seventeen individuals at risk for dominantly inherited BPD in a family were examined and blood samples obtained. Linkage analysis and mutation screening of the human retinal degeneration slow (RDS)/peripherin locus were performed. Light and electron microscopic examinations were performed on 1 postmortem eye of 1 affected individual. RESULTS: Four individuals demonstrated macular degenerative changes with diminished visual acuity, and 3 others exhibited early signs of atrophy without visual deficits. Microscopic examination of the left eye of 1 patient revealed an area of total loss of the retinal pigment epithelium (RPE) and photoreceptor cell layer with intact choriocapillaris and lipofuscin-containing cells in the subretinal space. Outside the area of RPE atrophy, the RPE was greatly distended by lipofuscin. The disease locus in this family was mapped to 6p21.2, the region of the RDS/peripherin gene. Further analysis identified a G-->A change at nucleotide position 637 of RDS/peripherin, predicting a novel Cys213Tyr substitution in all affected members of the family. CONCLUSIONS: This study describes a new RDS/peripherin mutation for BPD and provides the first combined genetic-pathological study of this condition, to our knowledge. CLINICAL RELEVANCE: Accumulation of lipofuscin in RPE is a prominent feature of several retinal disorders, including age-related macular degeneration. Further elucidation of the cellular and molecular mechanism of BPD may provide insight into pathogenesis and lead to novel treatment approaches for this and other macular degenerations.

Ghazi NG, Jabbour NM, De La Cruz ZC, Green WR. · Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA. · Retina. · Pubmed #11642377 No free full text.

Abstract: BACKGROUND: Photodynamic therapy (PDT) is a relatively new modality that is currently under clinical and experimental evaluation for treatment of subfoveal choroidal neovascularization (CNV). The authors report the case of an 82-year-old woman who underwent verteporfin-mediated PDT for classic subfoveal CNV. Fluorescein angiography performed 2 weeks after treatment disclosed reduction of the initial area of neovascularization and leakage by approximately 60%. Three weeks after PDT, however, the area of leakage was almost the same size as that before treatment. The patient underwent submacular membranectomy almost 4 weeks after treatment. The authors describe the ultrastructural vascular changes after PDT and a clinicopathologic study of classic CNV. METHODS: The submacular membrane was studied by light and electron microscopy and immunohistochemical techniques. RESULTS: Ultrastructural examination of the peripheral vessels showed evidence of endothelial cell degeneration with platelet aggregation and thrombus formation. Occasional occluded vessels were surrounded by macrophages, a phenomenon previously reported to describe the process of resorption of such blood vessels. The vessels in the center of the membrane were unremarkable. CONCLUSION: Photodynamic therapy causes endothelial cell damage, thrombus formation, and vascular occlusion of classic CNV in age-related macular degeneration.

Del Priore LV, Kaplan HJ, Tezel TH, Hayashi N, Berger AS, Green WR. · Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, USA. · Am J Ophthalmol. · Pubmed #11292411 No free full text.

Abstract: PURPOSE: To report the histopathology after retinal pigment epithelial cell transplantation and subfoveal membranectomy in age-related macular degeneration. METHODS: An 85-year-old white woman with bilateral choroidal neovascularization underwent subfoveal membranectomy combined with transplantation of a sheet of human adult retinal pigment epithelium (retinal pigment epithelium) under the foveal center in the right eye. The patient was immunosuppressed postoperatively with prednisone, cyclosporine, and azathioprine. The patient died from congestive heart failure 114 days after surgery. RESULTS: A patch of hyperpigmentation was visible at the transplant site under the foveola after surgery. Mound-like clusters of individual round, large densely pigmented cells were present in the subretinal space and outer retina in this area. There was loss of the photoreceptor outer segments and native retinal pigment epithelium in the center of the transplant bed, with disruption of the outer nuclear layer predominantly over regions of multilayered pigmented cells. Cystic spaces were present in the inner and outer retina. A residual intra-Bruchs membrane component of the original choroidal neovascular complex was present under the transplant site. CONCLUSIONS: The transplant site contained clusters of round, pigmented cells that did not form a uniform monolayer in most areas. The morphology at the transplant site is consistent with the lack of visual improvement seen after surgery in this patient.

Dubovy SR, Hairston RJ, Schatz H, Schachat AP, Bressler NM, Finkelstein D, Green WR. · Wilmer Ophthalmological Institute, and Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA. · Retina. · Pubmed #11131418 No free full text.

Abstract: PURPOSE: The authors describe the clinicopathologic features of three patients with adult onset foveomacular pigment epithelial dystrophy (AOFPED). METHODS: The eyes of three patients were studied ophthalmoscopically and by fluorescein angiography, and obtained postmortem and studied by light and electron microscopy. RESULTS: Histopathologic study of the three patient's eyes disclosed central loss of the retinal pigment epithelium and photoreceptor cell layer with a moderate number of pigment-containing macrophages present in the subretinal space and outer retina. To either side, the retinal pigment epithelium was distended with much lipofuscin. Basal laminar and basal linear deposits were present throughout the central area. No discontinuities of Bruch membrane were present. CONCLUSION: The findings in the eyes of three patients with AOFPED included marked aging changes that are similar to those seen in age-related macular degeneration. Pigmented cells with lipofuscin in the subretinal space account for the vitelliform appearance.

del Cerro M, Humayun MS, Sadda SR, Cao J, Hayashi N, Green WR, del Cerro C, de Juan E. · Department of Ophthalmology, University of Rochester School of Medicine, New York, USA. · Invest Ophthalmol Vis Sci. · Pubmed #10967076 links to  free full text

Abstract: PURPOSE: To describe the histologic findings of the transplanted eye of a 94-year-old man with neovascular age-related macular degeneration, who 3 years earlier underwent subretinal transplantation of both a fetal neural retinal sheet and a retinal microaggregrate suspension. METHODS: Serial sections of the posterior segment of the eye and the transplanted areas were processed and studied by routine histologic techniques, including both light and transmission electron microscopy (TEM). Transplanted areas were also examined for the presence of glial, neuronal, and photoreceptor cell markers by standard immunohistochemical methods. RESULTS: After transplantation in this patient, there was no visual improvement. Light microscopic examination disclosed survival of the transplanted cells in the subretinal space with no evidence of inflammation or rejection. The neural retinal sheet transplant developed a layered configuration. The retinal pigment epithelium (RPE) was absent over much of the posterior pole, including the area of transplantation. TEM examination and immunohistochemical analysis disclosed the presence of neuronal and glial cells within the transplant. A few transplant neuronal cell processes overlying a focus of residual RPE cells were positive for S-antigen, but well-developed photoreceptor outer segments were not present. CONCLUSIONS: Long-term survival of transplanted neural retinal tissue can be achieved in human patients without immunosuppression. The lack of photoreceptor development in this patient may be the result of absent or dysfunctional RPE. Nonetheless, the long-term survival of grafted tissue in the human subretinal space in the absence of immunosuppressive treatment is promising for future efforts in the field of neural retinal transplantation.