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Retinal vessel changes and retinal whitening, distinctive features of malarial retinopathy, can be directly observed during routine eye examination in children with P. falciparum cerebral malaria. We investigated their clinical significance and underlying mechanisms through linked clinical, clinicopathological and image analysis studies. Orange vessels and severe foveal whitening (clinical examination, n = 817, OR, 95% CI: 2.90, 1.96–4.30; 3.4, 1.8–6.3, both p<0.001), and arteriolar involvement by intravascular filling defects (angiographic image analysis, n = 260, 2.81, 1.17–6.72, p<0.02) were strongly associated with death. Orange vessels had dense sequestration of late stage parasitised red cells (histopathology, n = 29; sensitivity 0.97, specificity 0.89) involving 360° of the lumen circumference, with altered protein expression in blood-retinal barrier cells and marked loss/disruption of pericytes. Retinal whitening was topographically associated with tissue response to hypoxia. Severe neurovascular sequestration is visible at the bedside, and is a marker of severe disease useful for diagnosis and management.

Background. Malarial retinopathy (MR) has diagnostic and prognostic value in children with Plasmodium falciparum cerebral malaria (CM). A clinicopathological correlation between observed retinal changes during life and the degree of sequestration of parasitized red blood cells was investigated in ocular and cerebral vessels at autopsy. Methods. In 18 Malawian children who died from clinically defined CM, we studied the intensity of sequestration and the maturity of sequestered parasites in the retina, in nonretinal ocular tissues, and in the brain. Results. Five children with clinically defined CM during life had other causes of death identified at autopsy, no MR, and scanty intracerebral sequestration. Thirteen children had MR and died from CM. MR severity correlated with percentage of microvessels parasitized in the retina, brain, and nonretinal tissues with some neuroectodermal components (all P < .01). In moderate/severe MR cases (n = 8), vascular congestion was more intense (p = 0.841; P < .001), sequestered parasites were more mature, and the quantity of extraerythrocytic hemozoin was higher, compared with mild MR cases (n = 5). Conclusions. These data provide a histopathological basis for the known correlation between degrees of retinopathy and cerebral dysfunction in CM. In addition to being a valuable tool for clinical diagnosis, retinal observations give important information about neurovascular pathophysiology in pediatric CM.

Background: Opticin is a recently discovered glycoprotein present predominantly in the vitreous humour. It is synthesised and secreted by the ciliary body epithelium (CBE) from the initiation of CBE development in the embryo, and production continues throughout life. Aim: To determine whether a variety of ciliary body tumours synthesise opticin to characterise further its role in ciliary body health and disease. Methods: Immunohistochemistry was used to determine the distribution of opticin in normal human CBE, and in hyperplastic and neoplastic CBE lesions. Results: Opticin was immunolocalised to the basal cell surface and basement membrane material of the non-pigmented CBE in nine donor eyes as well as four hyperplastic lesions of the CBE (Fuchs’s adenoma). By contrast, none of eight neoplastic lesions (two adenoma and six adenocarcinoma) of CBE stained for opticin. Conclusion: The present series supports the theory that opticin is produced by the non-pigmented CBE throughout adult life. Loss of opticin expression by this tissue is associated with and could contribute towards neoplastic transformation.

Previous research has indicated a role for serotonin (5-HT) in the anterior uvea of the eye. The purpose of this study was to examine whether mRNAs encoding particular 5-HT receptors are expressed in the ciliary body and iris of a number of human subjects. The presence of mRNA encoding 5-HT receptors in four human ciliary body samples was determined by reverse transcription-polymerase chain reaction experiments using a standard methodology. Positive signals for 5-HT(1A), 5-HT(2A), 5-HT(2B), 5-HT(2C) and 5-HT(7) receptor mRNAs were detected in the samples prepared from various human ciliary body samples. The detection of certain 5-HT receptor mRNAs in the human ciliary body supports the hypothesis that serotonin is involved in the control of aqueous dynamics and indicates that ligands acting on these 5-HT receptors may have potential use as intraocular pressure-lowering agents.

Purpose Up-regulation of pro-angiogenic cytokine expression occurring secondary to hypoxia in physiologic and pathophysiologic conditions is mediated by the family of transcription regulators know as hypoxia inducible factors (HIF). The present study was undertaken to investigate the expression of HIF occurring in human choroidal neovascularization (CNV) and the posterior segment of young and old eyes. Methods Surgically excised CNV from patients with either age-related macular degeneration (AMD; n = 9), punctuate inner choroidopathy (PIC; n  = 3) and young normal eyes were immunohistochemically probed with monoclonal antibodies against HIF−1α and −2α and compared to that for cell markers specific for vascular endothelial cells (CD34), macrophages (CD68), retinal pigment epithelial cells (RPE; panel cytokeratins/CK18) and VEGF. Following secondary antibody amplification, reactions were visualized with fast red chromogen. Results Cellular immunoreactivity of membranes for HIF−2α was strong in eight out of nine AMD specimens but it was only weakly positive for HIF−1α in five specimens. In contrast, two out of three PIC specimens were weakly positive for HIF−1α but demonstrated no staining for HIF−2α. Immunohistochemical analysis revealed areas within the CNV membranes that were predominantly immunopositive for CD68 and cytokeratin indicating the presence of RPE and/or macrophages and that these cells strongly co-localized with the presence of HIF and VEGF. No immunochemical co-localization was observed with HIF and the endothelial cell marker CD34 in any membranes studied. Normal globes also demonstrated HIF−2 positivity to be predominantly localized to the central RPE rather than peripheral RPE irrespective of age of donor. Conclusions The localization of HIF expression supports the concept that hypoxia is a major stimulus for the development of submacular wound healing and within this context CNV is but one component of this process.

Background Conventional silicone oil provides suboptimal support of the inferior retina. In this study we evaluated the efficacy of Oxane HD in the management of complex retinal detachments involving lower quadrants of the retina. Methods A prospective, interventional, comparative study. Eighteen patients were recruited. Treatment outcomes were compared with a historical control group of 14 patients. Patients with grade C3 PVR or greater and inferior retinal breaks, recurrent inferior retinal detachments (with or without PVR) and giant retinal tears were included. In those patients who re-detached under heavy silicone oil ( n  = 4), retro-oil epiretinal membranes (ERMs) were obtained at the time of subsequent surgery to analyse the immunopathological response to oxane HD. Immunohistochemistry was used to detect glia, retinal pigment epithelium cells (RPE), macrophages, T lymphocytes, or neural elements in the tissue using well-characterised monoclonal antibodies. Results Retinal attachment of the posterior pole following removal of silicone oil was achieved in 66.6% of the treatment group ( n  = 12) and 64.3% of controls ( n  = 9) ( p  = 1.0). Post-operative PVR developed in five patients in the treatment group (27.8%) and five control patients (35.8%). Following removal of silicone oil, residual oil was observed in 27.8% of the treatment group and 7.1% of controls. Median visual acuity, 3 months following removal of silicone oil, was 2.0 (IQR 0.9–2.0) in the treatment group and 1.0 (IQR 0.6–1.8) in the control group. Complications in the treatment group included, hypotony ( n  = 3), uveitis ( n  = 2), glaucoma ( n  = 1). All ERMs analysed demonstrated microscopic appearances typical of PVR. The membranes were fibrocellular in nature, contained RPE and glial cells, and variable amounts of intracellular and extracellular pigment. In addition, all had a dense infiltrate of vacuolated (presumed oil-filled) macrophages. Conclusion We failed to observe an advantage following the use of Oxane HD in the treatment of inferior retinal detachments. Moreover, Oxane HD was difficult to remove and was associated with a higher incidence of complications.

BACKGROUND/AIMS Epiretinal and retrolental proliferation may occur during prolonged use of the novel tamponade agent perfluorohexyloctane (F6H8). This study aims to determine whether there is any histological evidence that F6H8has a role in the formation of these membranes. METHODS Eight epiretinal membranes and three opaque posterior lens capsules were excised from patients in whom F6H8 had been used as a long term retinal tamponade agent. The membranes and capsules were examined employing light microscopic methods, including immunohistochemistry. RESULTS The epiretinal membranes showed histological features typical of proliferative vitreoretinopathy (PVR) epiretinal membranes, but they also exhibited a dense macrophagic infiltration. In addition, three of the membranes contained multinucleated cells. Macrophages represented up to 30% of the cells present and appeared to contain large intracytoplasmic vacuoles. Similar cells were seen on the back of the posterior lens capsule in one specimen and all three capsules had posterior migration of lens epithelium. CONCLUSION The pathological findings are not simply those of PVR. The macrophage infiltration suggests that there may be a biological reaction to F6H8 which could reflect its surmised propensity to emulsify. Further investigations concerning the cellular response to this promising tamponade agent are warranted.

Up-regulation of pro-angiogenic cytokine expression occurring secondary to hypoxia in physiologic and pathophysiologic conditions is mediated by the family of transcription regulators know as hypoxia inducible factors (HIF). The present study was undertaken to investigate the expression of HIF occurring in human choroidal neovascularization (CNV) and the posterior segment of young and old eyes. Surgically excised CNV from patients with either age-related macular degeneration (AMD; n = 9), punctuate inner choroidopathy (PIC; n = 3) and young normal eyes were immunohistochemically probed with monoclonal antibodies against HIF-1alpha and -2alpha and compared to that for cell markers specific for vascular endothelial cells (CD34), macrophages (CD68), retinal pigment epithelial cells (RPE; panel cytokeratins/CK18) and VEGF. Following secondary antibody amplification, reactions were visualized with fast red chromogen. Cellular immunoreactivity of membranes for HIF-2alpha was strong in eight out of nine AMD specimens but it was only weakly positive for HIF-1alpha in five specimens. In contrast, two out of three PIC specimens were weakly positive for HIF-1alpha but demonstrated no staining for HIF-2alpha. Immunohistochemical analysis revealed areas within the CNV membranes that were predominantly immunopositive for CD68 and cytokeratin indicating the presence of RPE and/or macrophages and that these cells strongly co-localized with the presence of HIF and VEGF. No immunochemical co-localization was observed with HIF and the endothelial cell marker CD34 in any membranes studied. Normal globes also demonstrated HIF-2 positivity to be predominantly localized to the central RPE rather than peripheral RPE irrespective of age of donor. The localization of HIF expression supports the concept that hypoxia is a major stimulus for the development of submacular wound healing and within this context CNV is but one component of this process.