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Murine cytomegalovirus retinitis during retrovirus-induced immunodeficiency (MAIDS) in mice: interleukin-2 immunotherapy correlates with increased intraocular levels of perforin mRNA.

Mice with a retrovirus-induced immunosuppression (MAIDS) are susceptible to experimental murine cytomegalovirus (MCMV) retinitis, but can be rendered resistant to retinitis by systemic interleukin-2 (IL-2) immunotherapy. Experiments were performed to explore the mechanism by which IL-2 treatment during MAIDS might restore resistance to MCMV retinitis. Whereas 80% of untreated MAIDS mice were susceptible to MCMV retinitis, none (0%) of IL-2-treated MAIDS mice developed necrotizing retinitis. In comparison, 100% of both untreated and IL-2-treated perforin knockout mice (PKO mice) were susceptible to MCMV retinitis, and severity of retinitis and amounts of infectious intraocular MCMV in IL-2-treated PKO mice were equivalent to that in untreated PKO mice. A competitive quantitative RT-PCR assay was used to measure the levels of perforin mRNA within MCMV-infected eyes of immunologically normal mice, untreated MAIDS mice, and IL-2-treated MAIDS mice. Although the level of perforin mRNA within MCMV-infected eyes of untreated MAIDS mice susceptible to retinitis was significantly reduced when compared to the high level found within MCMV-infected eyes of normal mice resistant to retinitis, systemic treatment of MAIDS mice with IL-2 increased perforin mRNA within MCMV-infected eyes to levels found in normal mice. The ability of IL-2 treatment to increase intraocular levels of perforin mRNA diminished with the progression of MAIDS. Our findings support the hypothesis that systemic IL-2 immunotherapy during MAIDS provides protection against MCMV retinitis by upregulation of perforin-mediated cytotoxicity used by cytotoxic lymphocytes to kill virus-infected cells.

Animals↗

Late ocular manifestations in neonatal herpes simplex infection.

Five patients who had had neonatal herpes simplex virus infection were re-examined at ages that varied from 6 to 9 years. In all of them the diagnosis had been supported by virus isolation and antibody titration, and herpes virus type 2, the genital strain, had been the causative agent. Only 1 of the patients was mentally retarded. Three of the patients had manifest squint, and only 1 patient had normal visual acuity in both eyes. The fundus changes varied from atrophy of the retinal pigment epithelium in 3 patients to atrophy of the optic disc in 2 eyes and extreme tortuosity of the retinal arterioles and veins in 1 patient. One patient developed bilateral retinitis with exudation into the vitreous at the age of 5 years. Fluorescein angiography of this patient showed peripheral vascular closure and preretinal neovascularisation, with leakage in both eyes. This may have been due to chronic retinal vasculitis; haemorrhagic infarction may have induced the damage to retinal tissues. Laser photocogulation resulted in slight improvement of the visual acuity, clearing of the vitreous, and decrease of the fluorescein leakage.

Child↗

Interleukin-2 immunotherapy and AIDS-related cytomegalovirus retinitis.

Cytokines are small proteins produced by T lymphocytes that mediate immune responses. Those produced by the CD4+ Th1 subset induce cell-mediated immunity, whereas those produced by the CD4+ Th2 subset are more efficient at stimulating immunoglobulin production. The goal of cytokine immunotherapy is prevention or reduction of disease progression through stimulation of cell-mediated immunity (i.e., immune reconstitution) by administration of an exogenous Th1 cytokine such as interleukin-2 (IL-2). Cytokine immunotherapy has its origins in cancer immunobiology where IL-2 has been used successfully to manage several human cancers (metastatic melanoma, acute myelogenous leukemia, and metastatic renal cell carcinoma). More recent work has demonstrated cytokine immunotherapy to be effective at improving immune responses in patients with HIV-1 disease. To explore cytokine immunotherapy for sight-threatening AIDS-related human cytomegalovirus (HCMV) retinitis, we developed a mouse model of experimental murine cytomegalovirus (MCMV) retinitis that employs mice with MAIDS, a retrovirus-induced immunodeficiency syndrome. Systemic cytokine immunotherapy with IL-2, but not with interleukin-12 (IL-12), provides absolute protection against MAIDS-related MCMV retinitis by stimulation of the perforin-mediated pathway of cytotoxicity used by natural killer cells and cytotoxic CD8+ T cells to kill virus-infected cells. Our findings warrant additional studies on the use of cytokine immunotherapy for management of HCMV retinitis (and possibly other opportunistic infections) during HIV-1-induced immunodeficiency. We envision systemic cytokine immunotherapy as an altemative or adjunct to traditional antiviral chemotherapy for optimal management of AIDS-related HCMV retinitis.

AIDS-Related Opportunistic Infections↗

Development and pathology of the hyaloid, choroidal and retinal vasculature.

During embryogenesis, the development and differentiation of the eye requires the concomitant formation of the neural/glial elements along with a dense vascular network. The adult neural retina is supported by two distinct vascular systems, the proper retinal vessels and the choroidal vessels. The two beds differ not only in their pattern of embryonic differentiation, but also in their function in the adult organism. The retinal vasculature has barrier properties similar to those observed in the brain, whereas the choroidal vessels display a highly fenestrated phenotype. The hyaloid vasculature is a transient embryonic vascular bed which is complete at birth in mammals and regresses contemporaneously with the formation of the retinal vasculature. The dependence of the retina on its blood supply makes it highly vulnerable to any vascular changes and indeed ocular diseases, such as proliferative retinopathy, age-related macular degeneration and the hyperplastic primary vitreous, which are associated with abnormalities of the different vascular beds of the eye. A number of factors have been implicated in developmental and pathological changes in vessel formation and regression, including fibroblast growth factors, platelet-derived endothelial growth factor and vascular endothelial growth factor, among others. The purpose of this review is to describe and discuss new insights into the mechanisms and molecular cues involved in the development of the normal and pathological vascular systems of the eye. The characterization of the molecules and cell-cell interactions involved in the formation, stabilization and regression of new vessels has led to the identification of potential control points for therapeutic intervention.

Animals↗

Rhegmatogenous retinal detachment in phakic eyes after posterior chamber phakic intraocular lens implantation for severe myopia.

OBJECTIVE: To report the clinical presentation, surgical management, and outcomes of rhegmatogenous retinal detachment (RRD) in patients with severe myopia corrected by posterior chamber phakic (PCP) intraocular lens (IOL) implantation. DESIGN: Retrospective, noncomparative, interventional case series. PARTICIPANTS: Sixteen eyes of 15 patients in whom retinal detachment developed after PCP IOL implantation. METHODS: The 16 eyes with retinal detachment after PCP IOL implantation underwent scleral buckling and pars plana vitrectomy. MAIN OUTCOME MEASURES: Uncorrected visual acuity, refraction, best spectacle-corrected visual acuity (BSCVA), time between refractive procedure and RRD, vitreoretinal findings, and anatomic reattachment rate. RESULTS: The incidence of RRD after PCP IOL implantation was 2.07%. Mean patient age was 32.9 years (range, 23-46). Nine patients underwent bilateral PCP IOL implantation (60%). Primary RRD developed in 16 eyes of 15 patients. Prophylactic laser photocoagulation was performed in 3 eyes of 3 patients (18.75%). Mean preoperative spherical equivalent (SE) was -17.3+/-2.47 diopters (D) (range, -13.75 D to -22 D). Rhegmatogenous retinal detachment occurred from 1 to 70 months after PCP IOL implantation (mean, 29.12 months). Each of 11 RRDs (68.75%) had 1 causative break. Fourteen breaks (60.86%) were horseshoe tears and 9 (39.14%) were atrophic holes. Scleral buckling was performed in 10 eyes (62.5%). Pars plana vitrectomy alone was performed in 5 cases (31.25%) with posterior breaks. Initial reattachment rate was 90.9%. Final retinal reattachment was 100%. Mean postoperative BSCVA was 20/28 (decimal fraction, 0.72+/-0.25). Mean follow-up after retinal detachment surgery was 35.25+/-17.29 months (range, 12-67 months). CONCLUSIONS: Rhegmatogenous retinal detachment after PCP IOL implantation is rare. Case-control studies are warranted to determine whether this surgical procedure increases the risk of retinal detachment in these patients. The characteristics of RRD do not differ from the natural history of retinal detachment. Surgical management of RRD was successful in restoring vision in our patients. This article contains additional online-only material available at .

Adult↗

Relationships between vitreoretinal and refractive surgery.

OBJECTIVE: To describe retinal complications after posterior chamber phakic intraocular lens (PCPIOL) implantation and refractive surgery complications after scleral buckling surgery. DESIGN: Retrospective, noncomparative, small case series. PARTICIPANTS: Four patients in whom retinal detachment developed after PCPIOL implantation and two patients with previously placed encircling scleral buckles in whom corneal steepening developed after laser in situ keratomileusis (LASIK). INTERVENTION: The four patients with retinal detachment after PCPIOL implantation underwent vitreoretinal surgery. One of the two patients in whom corneal steepening developed after LASIK underwent buckle removal. MAIN OUTCOME MEASURES: The main parameters evaluated were vitreoretinal findings, corneal topography, and pachymetry. RESULTS: Retinal attachment was achieved for all patients. Mean postoperative best-corrected visual acuity (BCVA) was 20/30. One patient lost one line of BCVA. One patient with corneal steepening achieved partial corneal flattening after buckle removal. CONCLUSIONS: Vitreous base stimulation related to PCPIOL implantation and manipulation during LASIK may trigger retinal complications. Laser in situ keratomileusis in patients with previously placed scleral buckles may result in unexpected corneal steepening.

Adult↗

Morphological plasticity of axotomized retinal ganglion cells following intravitreal transplantation of a peripheral nerve segment.

During normal development of retinal ganglion cells when the axons are growing, transient dendritic spines have been observed. Similar dendritic spine-like processes are also exhibited by retinal ganglion cells undergoing axonal regeneration into a peripheral nerve grafted to the damaged optic axons. Here we show, using the intracellular injection of Lucifer Yellow, that when a segment of peripheral nerve is transplanted to the vitreous body, a procedure which induces ectopic sprouting of axon-like processes from the cell bodies and dendrites of some retinal ganglion cells, similar spine-like processes appear on the dendrites of cells with ectopic sprouts. Quantitative analysis indicated that there were significant changes with posttransplantation survival time in the distributions of spine-like processes and axon-like processes on these sprouting retinal ganglion cells following the intravitreal transplantation of a piece of peripheral nerve. The remodelling of the spine-like processes and axon-like processes correlated with one another suggesting that plastic changes can occur in certain dendritic subcompartments independent of the growth activity of the other dendritic subcompartments.

Animals↗

Bilateral simultaneous central retinal artery occlusions in atherosclerosis.

An 82-year-old woman with atherosclerosis developed central retinal artery occlusions (CRAOs) in both eyes within an interval of 5 minutes. There was no evidence of a thromboembolic source, systemic hypotension, vasculitis, migraine, or hypercoagulable state. Virtually simultaneous binocular CRAOs have been rarely reported, and suggest the possibility of a systemic but still undefined "hypercoagulable trigger."

Aged↗

Exposure to alternating hypoxia and hyperoxia causes severe proliferative retinopathy in the newborn rat.

Exposure to variable hyperoxia has recently been shown to be much more effective at producing proliferative retinopathy in the newborn rat than exposure to constant hyperoxia. To incorporate a more clinically relevant oxygen-exposure paradigm in our studies, we have now used a cycle between 50 and 10% oxygen and have compared its effects with those found using new exposures to the previously used 80/40% cycle. Starting at birth and continuing for 14 d, rats were exposed to environments that cycled between 50 and 10% oxygen or 80 and 40% oxygen every 24 h. After exposure, some rats were killed for assessment of retinal vascular development. Others were removed to room air for 4 d before killing and evaluation for the presence of abnormal neovascularization--a clinical consequence believed to be promoted by termination of oxygen therapy. The 50/10% cycle resulted in greater retardation of retinal blood vessel development during oxygen than that found in the 80/40% exposure group. After 4 d postexposure in room air, the incidence of preretinal neovascularization was 97% in the 50/10% rats and 72% in the 80/40% group. Clearly, the overall amount of oxygen the subject receives is less critical than other parameters of its administration in producing proliferative retinopathy. Also, the range of variation (40% in both cases) is not the controlling characteristic. Our results suggest that consistency of oxygen level and avoidance of hypoxic levels should be important concerns in neonatal oxygen therapy.

Animals↗

Spatio-temporal patterns of retinal ganglion cell death during Xenopus development.

During development of the retina in mammals and birds, most retinal ganglion cells (RGC) that are produced are eliminated later in development by cell death. In lower vertebrates, however, such massive cell death has not been observed; total ganglion cell number increases linearly during most of development. Using 3H-thymidine or 5-bromodeoxyuridine labeling of retinal cell nuclei, we have been able to identify postmitotic RGC populations in Xenopus central retina at different developmental stages and follow their fate during development to postmetamorphic stages. RGC populations that become postmitotic between embryonic stages 32 and 49, during the initial stages of retinal growth, lose 40-77% of their cells during metamorphosis (approximately 4,000-5,000 cells). Twenty percent of the RGC present at stage 54, which later disappear, represent the same population of dying RGC that were present at stage 49. This suggests that the ganglion cells that became postmitotic between stage 49 and 53/54 show no apparent decline in numbers during metamorphosis. Since thyroxine is known to stimulate an increase in RGC number as well as the extent of fiber projection on the tectum, we suggest that this reduction in RGC numbers is not due to thyroxine-induced neuronal cell death. After stage 54, however, binocular vision develops in Xenopus (Keating, '74) and ipsilateral fibers begin to grow into thalamic visual neuropils (Hoskins and Grobstein, '85). We suggest, therefore, that as in mammals, in which RGC elimination correlates with binocular segregation of contralateral and ipsilateral retinal axons in visual centers, a similar process may occur in the frog among those RGC projecting to thalamic visual neuropils.

Animals↗

The role of nAChR-mediated spontaneous retinal activity in visual system development.

In the developing vertebrate retina, nAChR synapses are among the first to appear. This early cholinergic circuitry plays a key role in generating "retinal waves," spontaneously generated waves of action potentials that sweep across the ganglion cell layer. These retinal waves exist for a short period of time during development when several circuits within the visual system are being established. Here I review the cholinergic circuitry of the developing retina and the role these early circuits play in the development of the retina itself and of retinal projections to the lateral geniculate nucleus of the thalamus.

Action Potentials↗

Does the early exuberant retinal projection to the superior colliculus in the neonatal rat develop synaptic connections?

The retinal projections of newborn rats are more extensive than those of the adult and retract to form the adult pattern during the first week after birth. In this study, the retinal projections from one eye of newborn hooded rats were labeled by anterograde transport of horseradish peroxidase (HRP) following intravitreal injection of the tracer, and HRP-labeled axons and terminals were then sought by electron microscopy in coronal sections of the superior colliculus cut at 3 levels: rostral, middle and caudal. Labeled presynaptic profiles were present in the superior colliculus on the side contralateral to the injection at all rostro-caudal levels and in the rostral portion of the ipsilateral superior colliculus. But in approximately 37 sections analyzed in detail from 11 animals, only one example was found of an unequivocally presynaptic profile in the middle or caudal regions of the ipsilateral superior colliculus. Thus it would appear that in the newborn hooded rat, the exuberant ipsilateral projections to the middle and caudal parts of the superior colliculus form no or very few transient synaptic connections.

Animals↗

Funduscopic findings following cataract extraction by means of phacoemulsification in diabetic dogs: 52 cases (1993-2003).

OBJECTIVE: To determine prevalence of retinal hemorrhages and microaneurysms in dogs with diabetes mellitus following cataract extraction by means of phacoemulsification and identify potential risk factors. DESIGN: Retrospective study. PROCEDURE: Medical records of dogs undergoing phacoemulsification between 1993 and 2003 were reviewed, and information was recorded on signalment, history, physical examination findings, ophthalmic examination findings, results of laboratory testing, electroretinographic findings, and surgical findings. Glycemic control was classified as poor, intermediate, or good on the basis of baseline blood glucose concentration, perioperative body weight loss, daily insulin dosage, and presence of glucosuria and ketonuria. Data from diabetic and nondiabetic dogs were analyzed to determine prevalence and risk factors for development of retinal hemorrhages or microaneurysms following phacoemulsification. RESULTS: 11 of the 52 (21%) dogs with diabetes mellitus developed ophthalmoscopic signs of retinal hemorrhages or microaneurysms, compared with 1 of the 174 (0.6%) nondiabetic dogs. Median time from onset of diabetes mellitus to diagnosis of retinopathy was 1.4 years (range, 0.5 to 3.2 years). No risk factors for development of retinopathy were identified. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that retinal hemorrhages and microaneurysms may be more common and develop earlier in diabetic dogs than previously reported. This may affect treatment, as diabetic dogs survive longer with improved glycemic control.

Animals↗

Retinal microvascular patency in the diabetic rat.

PURPOSE: To study whether the patency to erythrocytes in retinal microvessels of diabetic rats is reduced or blocked before the vessels lose their patency to plasma flow. METHODS: We used recognized techniques to induce diabetic and galactose related microvascular retinal lesions in rats: (1) alloxan induction (2) streptozotocin induction (3) galactose-containing diet. The rats were followed up to 17 months. We used our vascular trichrome technique to observe the effects of the ongoing diabetes on the retinal microcirculation. RESULTS: A focal leakage of a plasma-borne fluorescent dye was noted around the junction of the deep retinal capillaries and the ascending venules to the superficial retinal circulation in the streptozotocin and alloxan diabetic rats by the 14th month, and, by the 16th month, retinal capillary non-perfusion and retinal vascular malformations were present. The affected vessels showed patency to microspheres (0.2 microm in diameter) but no perfusion of erythrocytes. No such changes were seen in the galactose-fed rats. CONCLUSIONS: (1) The location between the deep retinal capillary net and the ascending venules may be the site of early vascular leakage in the diabetic rat model, (2) the erythrocytes' passage in the affected retinal microcirculation was blocked before the development of complete blockage to plasma in diabetic rats. The logical assumption that during the development stage of retinal capillary occlusion there may be a transient stage of microvascular insufficiency was examined. The lathyrogen, imino-diproprionitrile (IDPN), had previously been effective for creating a fast-developing model of retinal vasculopathy. Using that model, we demonstrated a stage in which the retinal microvasculature was blocked to erythrocytes but not to plasma [1]. However, we questioned the applicability of our findings to more slowly developing microvasculopathies, such as diabetic retinopathy. We designed the current study to examine the presence of such stage in slowly developing microvasculopathy. Animal models that are known to induce "diabetic retinopathy-like" changes used [2-4]. The diabetic animals were followed for a period of 17 months. Starting at the 12th month, a few animals of each group were killed and the retains were examined with our trichrome method [1] for relative capillary patency to erythrocytes and plasma, for functionality of endothelial cells, and for disturbances in the blood-retinal barrier. The results of this study support the hypothesis that retinal microvascular insufficiency does exist as a temporary stage that precedes the development of complete capillary blockage in long-term developing rat models of diabetic retinopathy.

Alloxan↗

Neural prostheses for vision: designing a functional interface with retinal neurons.

A number of prevalent eye diseases exist which may lead to partial or total blindness, and for which there are currently no cures or means by which to restore lost sight. Based on recent progress, it has become apparent that artificial prosthetic devices, which would use electrical stimulation of neurons in the visual pathway to elicit visual percepts, are likely to some day become a viable treatment for patients blinded by these diseases. A number of recent scientific reviews have summarized general functional electrical stimulation (FES) approaches related to the visual system, and many of the technical considerations regarding fabrication, biocompatibility, stimulation thresholds and electrotoxicity. This review will address a principal outstanding question in retinal prosthesis development: the design and implementation of a functional interface with the retina. A functional interface between electrodes and retinal neurons will be stable, biocompatible, and will convey useful information to the visual system. Several parameters related to both the artificial and biological aspects of the interface must be considered; this paper will emphasize electrode design. Additional issues central to the development of prosthesis interface design, including retinal physiology, eye diseases, and existing animal models of retinal degeneration, are also summarized.

Animals↗

Intravitreal ganciclovir for cytomegalovirus retinitis in patients with AIDS.

OBJECTIVE: To assess the evolution of cytomegalovirus (CMV) retinitis and evaluate the possible complications associated with the use of intravitreal injections to treat this disease. DESIGN: A nonrandomized, retrospective study with case series was performed. The study took place over 34 months. SETTING: The study included patients with AIDS who developed CMV retinitis, and who were treated in the hospital, as outpatients, or both. PATIENTS: Twelve patients with AIDS and CMV retinitis diagnosed between June 1990 through April 1993 were included in the study. MAIN PATIENT PARAMETERS AND OUTCOME MEASURES: For each patient, the following data were recorded: age, risk factors, other systemic findings, dates of AIDS and CMV retinitis diagnoses, stage of AIDS, extent of the retinitis, CD4 lymphocyte count at the time of diagnosis of retinitis, visual acuity, clinical evolution of the ocular infection, therapy, complications caused by the treatment, development on nonocular CMV, and the use of zidovudine or didanosine during the study period. RESULTS: Vision improved or remained stable in nine patients and worsened in three. Two patients developed optic neuritis. The retinitis progressed to the other eye in only one of the eight patients who had unilateral involvement. The rate of relapse with maintenance therapy was 8.3% (n = 1) within the first 8 weeks. Treatment was well tolerated. There was no evidence of toxicity after a total of 226 intravitreal ganciclovir injections. All patients were able to tolerate zidovudine or didanosine concomitantly with intravitreal ganciclovir. CONCLUSIONS: Intravitreal ganciclovir appears to be an effective alternate to systemic ganciclovir in patients with severe neutropenia and in patients who choose to continue receiving systemic zidovudine or didanosine. Early treatment and long-term maintenance therapy is essential for preserving sight.

AIDS-Related Opportunistic Infections↗

Development of atrophy of the retinal pigment epithelium around disciform scars.

BACKGROUND/AIMS: Eyes with burnt out disciform scars secondary to age related macular degeneration (AMD) are regarded as visually stable. The aim of this study is to report the subsequent development of atrophy of the retinal pigment epithelium (RPE) around the scars and discuss the possible basis. METHODS: 20 eyes from 18 patients were observed to develop atrophy around choroidal neovascularisation (CNV). A method of measuring expansion of the atrophy over time is described using the Topcon Imagenet 2000 system. An additional 10 clinicopathological examples were reviewed. RESULTS: Clinically CNV became surrounded initially by a ring of pallor that progressed to an expanding band of atrophy of the RPE. It developed most rapidly in the first 3 years after CNV became quiescent but then continued to expand slowly to more than three times the size of the scar. Histopathological specimens showed large choroidal vessels entering the scars directly and a reduced number of small choroidal vessels beneath and around the scar CONCLUSIONS: Disciform scars may become surrounded by an expanding band of atrophy of the RPE, postulated to result from remodelling of the choroidal circulation. The ongoing enlargement of the resulting scotoma may need to be considered when planning management and assessing treatment outcomes.

Aged↗

[Markers of retinal-type cell differentiation in studies of eye development and regeneration in vertebrates].

Data on the use of various immunochemical markers specifically indicating cell types of the neural retina and pigment epithelium are reviewed. It is demonstrated how this approach can be applied to the analysis of specific features of vertebrate retinal development, including the order and timing of differentiation of the main cell types, their interdependence in the course of this process, and factors controlling the latter. Problems concerning the state of differentiation and its change in the cells of retinal pigment epithelium and glial cells are discussed in respect to their analysis with the aid of specific protein markers. The current state of retina regeneration research involving the use of labelled cell sources and regenerated cells in lower vertebrates is analyzed. Problems in the search for new markers of retinal photoreceptor, macroglial, and microglial cells and their use in experiments are addressed.

Animals↗