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PubMed2004

The blood-retinal barriers system. Basic concepts and clinical evaluation.

Morphological studies demonstrating the presence in the retinal vessels of 'zonulae occludente' between the endothelial cells and physiological studies examining diffusion gradients in the vitreous after systemic or intravitreal administration of fluorescein, performed under the guidance of David Maurice, established the basis of the Blood-Retinal Barrier (BRB) concept. The BRB system is briefly reviewed as well as its role in health and disease. Regulation of the microenvironment of the retina is fundamental for appropriate retinal function and vision. The diffusional characteristics and transport functions of the BRB system may be evaluated and followed by vitreous fluorometry. Its clinical use has shown the importance of BRB alterations in a variety of retinal diseases but has been restricted by the lack of disease specificity. A recent development, the Retinal Leakage Analyzer, maps BRB alterations and has opened new perspectives for multimodal macula mapping and improved evaluation of newly available drugs that show promise for stabilizing the BRB.

Biological Transport↗
PubMed2006

Cytomegalovirus retinitis in chronic lymphocytic leukaemia.

PURPOSE: To describe a rare association of cytomegalovirus (CMV) retinitis. PATIENTS AND METHODS: Report of three patients with chronic lymphocytic leukaemia (CLL) who developed CMV retinitis. RESULTS: The diagnosis was established by the detection of CMV DNA by polymerase chain reaction analysis of aqueous and/or vitreous humour. CD4+ T-lymphocyte count was reduced in two patients and normal in the third one. There was bilateral involvement in two of the three patients. There was delay of 8-10 months in diagnosis. The visual outcome was poor in four out of the five eyes involved owing to optic atrophy or total retinal detachment with proliferative vitreoretinopathy. CONCLUSION: Increased awareness of CMV retinitis in patients who have received immunosuppression for haematological malignancies, such as CLL, could lead to earlier diagnosis and possibly better visual outcome.

Aged↗
PubMed2004

Angiopoietin 1 inhibits ocular neovascularization and breakdown of the blood-retinal barrier.

Several retinal and choroidal diseases are potentially treatable by intraocular delivery of genes whose products may counter or neutralize abnormal gene expression that occurs as part of the diseases. However, prior to considering a transgene, it is necessary to thoroughly investigate the effects of its expression in normal and diseased eyes. An efficient way to do this is to combine tissue-specific promoters with inducible promoter systems in transgenic mice. In this study, we used this approach to evaluate the effects of ectopic expression of angiopoietin-1 (Ang1) in normal eyes and those with ocular neovascularization. Adult mice with induced expression of Ang1 ubiquitously, or specifically in the retina, appeared normal and had no identifiable changes in retinal or choroidal blood vessels or in retinal function as assessed by electroretinography. Increased expression of Ang1 in eyes with severe retinal ischemia or in eyes with rupture of Bruch's membrane significantly suppressed the development of retinal or choroidal neovascularization, respectively. This inhibition of ocular neovascularization is particularly interesting and noteworthy, because overexpression of Ang1 in skin stimulates neovascularization. Ang1 also significantly reduced VEGF-induced retinal vascular permeability. These data suggest that intraocular delivery of ang1 has potential for treatment of ocular neovascularization and macular edema.

Angiopoietin-1↗
PubMed2001

Intravitreal VEGF and bFGF produce florid retinal neovascularization and hemorrhage in the rabbit.

PURPOSE: Vascular endothelial growth factor (VEGF) causes widespread retinal vascular dilation, produces breakdown of the blood-retinal barrier, and is implicated in ocular neovascularization (NV). Basic fibroblast growth factor (bFGF) also has been implicated in the production of ocular NV. This study was performed to investigate the ability of simultaneous sustained intravitreal release of both VEGF and bFGF to induce robust retinal NV in the rabbit. METHODS: Intravitreal implantation of sustained-release Hydron polymeric pellets containing both 20 microg of VEGF and 20 microg of bFGF was performed on adult male Dutch belted rabbits. In other animals either 20 microg or 50 microg bFGF-containing pellets was implanted intravitreally; also, either 20 microg VEGF or 50 microg VEGF-containing pellets was implanted. Control rabbits received either blank polymeric pellets or a pellet containing 30 microg bovine serum albumin. Eyes were examined by indirect ophthalmoscopy after surgery at 24 hrs, 48 hrs, 4 days, 7 days, 14 days, 21 days, and 28 days. Findings were documented by color fundus photography and fluorescein angiography (FA). Eyes were enucleated and prepared for histologic analysis at 28 days following intravitreal implantation of the VEGF/bFGF-containing pellets. RESULTS: In all eyes implanted with VEGF/bFGF pellets, dilation and tortuosity of existing blood vessels were observed within 48 hrs after pellet implantation. The progression of retinal vascular changes was rapid and occurred over the entire optic disk and medullary rays between 4 and 7 days. Hemorrhage occurred as early as 14 days after VEGF/bFGF pellet implantation. In eyes with massive hemorrhage, total traction retinal detachment developed after the second week. The presence of abnormal tissues at the vitreo-retinal interface within 28 days was demonstrated by light microscopy while FA showed profuse leakage of dye from anomalous vessels within the first week. Neither bFGF-exposed eyes nor control eyes showed any vascular changes. Eyes that received only VEGF-containing pellets exhibited tortuosity of existing vessels, but neither hemorrhaging nor retinal detachment occurred. CONCLUSIONS: These results demonstrate that retinal vascular changes leading to hemorrhaging is produced rapidly in the rabbit by simultaneous intravitreal release of both VEGF and bFGF. Understanding how these growth factors induce retinal NV may suggest novel therapeutic treatment strategies.

Animals↗
PubMed1992

[Retinal microangiopathies in diabetic children and adolescents, occurring in cases of pubertal and prepubertal onset of diabetes].

The prevalence and development of retinal microvascular complications in pre-puberty and puberty onset insulin-dependent diabetes mellitus were studied in 109 young patients with an average follow-up of 6 years. The data suggest that the earlier childhood the diabetes began, the later the microvascular abnormalities could be found by fluorescein angiography. First signs of background retinopathy were seen in average 20--22 years of age, almost independently the age at onset of diabetes. Rapid progression of retinal vascular damage occurred mainly in postpubertal but not pubertal subjects. Diabetes with puberty onset meant worse prognosis in the respect of retinal vascular complications than pre-puberty onset. Good glycemic control would be achieved more difficult in subjects with puberty onset diabetes added to a changing hormonal balance. The authors suggest that psychological factors (altered behavior during and after puberty) and other problems of adolescents (changes in social, familial and working conditions) may also contribute to poor glycemic control. Though the effect of prepubertal duration on the risk of retinal complications appears to be smaller than later years, the attendant work in prepubertal years is as important as later.

Adolescent↗
PubMed2000

Dorsal retinal pigment epithelium differentiates as neural retina in the microphthalmia (mi/mi) mouse.

PURPOSE: Microphthalmia, a bHLH-zip transcription factor associated with the onset and maintenance of pigmentation, identifies the retinal pigment epithelial (RPE) compartment during optic vesicle and optic cup development. To determine a role for microphthalmia (mi) during eye development, the effects of an mi loss of function mutation on RPE and neural retinal were investigated in the mi/mi mouse. METHODS: A series of embryonic and postnatal mi/mi and wild-type eyes were sectioned and labeled with neural retina- and RPE cell type-specific antibodies. Photoreceptor loss was quantified by counting the number of photoreceptor nuclei spanning the outer nuclear layer throughout postnatal retinal development. RESULTS: Early neural retinal differentiation is not affected in the mi/mi mouse. The mi/mi ventral retinal pigment epithelial layer begins to develop normally, but does not pigment or attain a differentiated cuboidal morphology. The dorsal region of mi/mi retinal pigment epithelium expands and forms an ectopic retina, which develops all major retinal cell types along a similar time course as the wild type. After birth, mi/mi photoreceptors begin to form rosettes, outer segments fail to elongate, and over an extended time period, the retina degenerates. CONCLUSIONS: Together these results suggest that early retinal development can proceed normally in the mi/mi mutant, but later retinal histogenesis is dependent on the presence of a differentiated retinal pigment epithelium. Most importantly, loss of mi function permits a change in cell fate from RPE to retina in the dorsal eye.

Animals↗
PubMed1997

Grid laser photocoagulation for macular edema in bilateral juxtafoveal telangiectasis.

OBJECTIVE: The purpose of the study is to report the efficacy of laser photocoagulation treatment for macular edema in bilateral juxtafoveal telangiectasis (BJT). DESIGN: The study design was a retrospective, clinical study. PARTICIPANTS: The authors observed 14 patients with BJT, studying the visual acuities and retinal changes of treated and untreated eyes. MAIN OUTCOME MEASURES: Visual acuity, presence of macular edema, and associated retinal findings were measured. RESULTS: Of 28 eyes, 10 (8 patients) received 15 laser photocoagulation treatments for macular edema. Neither treated nor untreated eyes had visual improvement of two or more lines. After treatment, five eyes (50%) had increased retinal vascular distortion develop, three (30%) had new draining retinal venules, five (50%) had intraretinal fibrovascular tissues, and four (40%) had retinal and preretinal hemorrhages develop. CONCLUSIONS: Grid laser photocoagulation therapy for macular edema in patients with BJT appears to neither improve nor stabilize long-term visual acuity. In addition, treatment is associated with retinal pigment epithelial changes, increased postoperative retinal vascular distortion, postoperative vascularized retinal scars, and postoperative retinal hemorrhages. These changes, however, do not appear to cause a further loss of vision.

Aged↗
PubMed1989

Cytomegalovirus retinitis and acquired immunodeficiency syndrome.

In a series of 157 patients with acquired immunodeficiency syndrome (AIDS), 46 (29%) developed cytomegalovirus (CMV) retinitis. In five patients, CMV retinitis was the initial AIDS-defining opportunistic infection (11% of patients with CMV retinitis and 3% of patients with AIDS). Retinal detachments developed in seven patients (15%) and in four were present before the institution of ganciclovir therapy. Bilateral CMV retinitis was present in 35% of patients at presentation and subsequently developed in nine (60%) of 15 patients while not being treated with ganciclovir. Conversely, none of 18 patients with unilateral disease developed bilateral disease while receiving ganciclovir. Of patients treated with ganciclovir for their CMV retinitis, 81% had a response to the drug, and 61% achieved a complete response, resulting in a nonprogressive and inactive scar. Patients who achieved a complete response with ganciclovir had a significantly longer survival than those who did not, suggesting greater immune compromise in those patients who failed to respond to ganciclovir.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Apical orientation of the microtubule organizing center and associated gamma-tubulin during the polarization of the retinal pigment epithelium in vivo.

Simple epithelial cells express a morphological and functional polarity along their apical-to-basal axis. During the development of epithelia, a unique reorganization of microtubule arrays is thought to play a fundamental role in the establishment of cell polarity. To begin to understand this process in vivo, we have determined the distribution of gamma-tubulin within developing chicken retinal pigment epithelium (RPE). gamma-Tubulin is a recently discovered centrosomal protein that plays a role in nucleating microtubule growth from the centrosome. Although the RPE monolayer becomes established during embryonic Day 3, cell polarity gradually develops and matures over the next 10-13 days. Our studies reveal that gamma-tubulin is located in a distinct focus subjacent to the apical membrane by embryonic Day 3, the beginning of the polarization process. Using primary cell cultures, we examined the relationship between the establishment of junctional complexes and the reorganization of microtubule arrays. Despite the recovery of junctional complexes and a transepithelial electrical resistance, cultured cells failed to relocate gamma-tubulin foci to a position subjacent to the apical membrane. Rather, these foci remained in the juxtanuclear region. These data indicate that the rearrangement of unique, epithelial microtubule arrays requires more than cell-cell and cell-basement membrane interactions.

Animals↗
PubMed2005

[Viral and nonviral gene therapy for treatment of retinal diseases].

The development of gene therapeutic approaches offers new perspectives for the treatment of retinal diseases. The use of both, nonviral methods employing oligonucleotides as well as viral expression vectors provide the possibility to treat neovascularization defects and retinal degeneration, respectively. The mechanism by which the therapeutic oligonucleotides (antisense oligonucleotides, aptamers and siRNA) work is based on degradation of specific transcripts. Consequently, a reduction of the corresponding protein, which is involved in the particular pathogenesis, follows. In contrast, viral vector transduction can substitute the disease-associated gene with an intact copy. So far, animal models have successfully contributed to the development of gene therapeutic medication and further treatments are at the recruiting phase of clinical trials.

Animals↗
PubMed2002

Pathogenesis of retinopathy of prematurity.

UNLABELLED: Retinopathy of prematurity (ROP) is a blinding disease, initiated by delayed retinal vascular growth after premature birth. There are both oxygen-regulated and non-oxygen-regulated factors, which contribute to both normal vascular development and retinal neovascularization. One important oxygen-regulated factor, critical to both phases of ROP, is vascular endothelial growth factor (VEGF). A critical non oxygen-regulated growth factor is insulin-like growth factor (IGF-1). In knockout mice, lack of IGF-1 prevents normal retinal vascular growth, despite the presence of VEGF, important to vessel development. In vitro, low IGF-1 prevents vascular endothelial growth factor-induced activation of Akt, a kinase critical for vascular endothelial cell survival. Premature infants who develop ROP have lower levels of serum IGF-1 than age-matched infants without disease. CONCLUSION: IGF-1 is critical to normal vascular development. Low IGF-1 predicts ROP and restoration of IGF-1 to normal levels may prevent ROP.

Animals↗
PubMed1996

Hedgehog, transmitted along retinal axons, triggers neurogenesis in the developing visual centers of the Drosophila brain.

The development of the visual centers of the Drosophila brain is tightly regulated by the ingrowth of retinal axons from the developing eye. In the first optic ganglion, the lamina, arriving retinal axons trigger the precursors of their synaptic partners to complete a final cell division and commence neural differentiation. The secreted product of the hedgehog gene regulates the temporal assembly of photoreceptor precursor cells into ommatidial clusters in the compound eye. Here, we show that Hedgehog is transmitted along the retinal axons to serve as the inductive signal in the brain. Hedgehog acts in the first of two retinal axon-mediated steps in the assembly of lamina synaptic cartridges. These observations provide a novel insight into the molecular interactions that orchestrate the assembly of neural precursor cells into precise synaptic circuits.

Animals↗
PubMed1997

Significance of refractive status in branch retinal vein occlusion. A case-control study.

PURPOSE: To evaluate the significance of refractive error in cases of branch retinal vein occlusion. METHODS: Of 354 patients with branch retinal vein occlusion who attended our clinic between 1989 and 1995, 75 patients with unilateral branch retinal vein occlusion were compared with an equal number of matched controls with similar inclusion and exclusion criteria. The spherical equivalents of the refractive errors of patients in both groups were compared using the chi-square test, student's t test, and multivariate logistic regression. RESULTS: Hypermetropia was present in 53 patients with branch retinal vein occlusion (70.7%) and in 33 control patients (44.0%; P = 0.0001). Myopia was present in 11 patients with branch retinal vein occlusion (14.7%) and in 30 controls (40.0%; P = 0.0005). Emmetropia was present in 11 patients with branch retinal vein occlusion (14.7%) and in 12 controls (16.0%; P = 0.820). The odds ratio of developing branch retinal vein occlusion among patients with hypermetropia was 3.42 (95% Confidence Interval [CI], 1.62-7.2; P = 0.001) when compared with patients with no hypermetropia and 5.3 (95% CI, 2.1-13.3; P = 0.0003) when compared with patients with myopia alone. CONCLUSION: Hypermetropia is significantly more common in patients with branch retinal vein occlusion than in the general population, whereas myopia is significantly less common in these patients.

Aged↗
PubMed2000

Reduced rate of retinal detachment following silicone oil removal.

PURPOSE: To investigate the rate of retinal redetachment and other complications after silicone oil removal over a 4-year period. METHODS: Retrospective analysis of charts of patients who underwent vitrectomy and silicone oil injection between January 1994 and June 1998 followed by oil removal. RESULTS: Sixty-eight eyes of 67 patients were included. The average follow-up time after oil removal was 15 months. Significant retinal redetachment developed in 6 eyes (8.8%). The redetachment rate was slightly higher in the 32 eyes with proliferative vitreoretinopathy (9.3%) than in the 36 eyes with other pathologies (8.3%). The average time to redetachment was 4.2 months. These eyes were reoperated and reattached, and at the end of the follow-up, three retained silicone oil. Two other eyes without redetachment were hypotonus after oil removal. Cataract extraction and intraocular lens implantation were performed at the time of oil removal in 18 eyes; 2 (11%) developed redetachment. Visual acuity improved significantly after oil removal (P < 0.001). CONCLUSION: The rate of retinal redetachment after removal of silicone oil in recent years is low compared with previous series. The authors attribute this reduction to the improved surgical management of complicated retinal detachments; particularly, the introduction of perfluorocarbon liquids and wide-field viewing systems and the widespread use of endolaser.

Adolescent↗
PubMed1996

Inadvertent perforation of the globe during regional anaesthesia.

PURPOSE: This retrospective study was undertaken to review the clinical signs and management of patients with perforating eye injuries associated with regional anaesthesia for ophthalmic surgery. METHODS: Fifteen consecutive patients presenting with inadvertent perforation of the globe were evaluated. Eleven required vitreoretinal surgery. The indications were retinal detachment (six eyes), vitreous haemorrhage (four) and an epiretinal membrane (one eye). RESULTS: Those eyes with retinal detachments generally had a poor functional outcome in spite of the retinae being attached in five of the six eyes. The operative findings of those eyes with vitreous haemorrhage but attached retina demonstrated varying retinal tear configurations. CONCLUSIONS: Eyes with perforating injuries following intraorbital anaesthesia are at risk of developing a retinal detachment. In those eyes presenting with dense vitreous but attached retina, consideration of vitrectomy and laser photocoagulation is advised.

Adult↗
PubMed1998

Müller (glial) cell development in vivo and in retinal explant cultures: morphology and electrophysiology, and the effects of elevated ammonia.

Retinal explant cultures have been established as a useful tool to study both the normal development of the mammalian retina and the effects of pathogenic agents. We used such cultures as a model for the (ammonia-induced) hepatic retinopathy, earlier observed in humans with chronical liver failure, and ascribed to a breakdown of Müller (glial) cell function. In the explant cultures, one day exposure to elevated (7 mM) ammonia was sufficient to cause Müller cell reactivity as indicated by increasing immunopositivity for glial fibrillary acidic protein. After 4 days in elevated ammonia, the Müller cells were severely deformed, the layered structure of the retinae became disorganized, and significant neuronal cell death occurred. Using whole-cell voltage-clamp recordings, the expression of K+ channels was compared in Müller cells isolated from retinae of rabbits at postnatal days 9 to 12 and from neonatal explants cultured for 9 to 12 days, respectively. Müller glial cells grown both in vivo and in vitro express the same set of K+ channels in their membranes: (i) inwardly rectifying K+ (K(IR)) channels which were selectively blocked by Ba2+ ions; (ii) large-conductance, Ca2+-activated K+ (BK(Ca)) channels which were blocked by iberiotoxin and were activated by phloretin; and (iii) delayed rectifying voltage-gated K+ channels. The presence of K(IR) channels indicates successful differentiation of the Müller cells grown in vitro, as these channels are not expressed in cells from neonatal animals. Four days of elevated ammonia in the culture medium caused a complete loss of K(IR) channels in Müller cell membranes, and a significant decrease of the membrane potential. The results indicate that in hepatic retinopathy, the well-known morphological and enzymatical alterations of Müller glial cells may be accompanied by changes in their membrane permeability for K+.

4-Aminopyridine↗
PubMed1992

Results of silicone oil removal from eyes treated with retinectomies.

We reviewed the results of silicone oil removal from 32 eyes that had been treated with peripheral retinectomies during vitrectomy for retinal detachment with proliferative vitreoretinopathy. With a minimum follow-up of 6 months, 3 developed a retinal detachment after silicone oil removal. Twenty-eight eyes attained a final visual acuity of 0.1 or better and 15 eyes attained 0.2 or better. Only in 3 eyes was visual acuity decreased after silicone oil removal, whereas 20 eyes showed an improvement in vision. One eye was hypotonous and 11 eyes required antiglaucomatous agents at the last examination. Final visual acuity as well as final intraocular pressure did not correlate with either the retinectomy size or with the duration of the silicone oil tamponade.

Adolescent↗
PubMed1992

An atypical fulminant course of choroidal osteoma in two siblings.

We studied two cases of bilateral choroidal osteoma in an otherwise healthy 5-year-old boy and his only sibling, a 7-year-old sister. Both children were known to have normal fundus appearances at younger ages. The tumor showed slow growth in all four eyes, but severe visual acuity loss developed in three eyes because of neovascular complications that could not be effectively treated by photocoagulation. Secondary retinal cysts developed in three eyes.

Child↗