Posterior scleritis with choroidal detachments and periaortitis associated with IgG4-related disease: A case report.

BACKGROUND: IgG4-related diseases (IgG4-RDs) are known to disrupt the functioning of multiple organs and are usually associated with mass lesions. Periaortitis, an inflammation of the adventitia and tissues surrounding the aorta, is an example of an IgG4-RD. In ophthalmology, an enlargement of the lacrimal gland is a well-known IgG4-RD, and scleritis has also been reported to be an IgG4-RD although it is rare. We report our findings in a case with periaortitis and posterior scleritis that were present at the same time, and they responded well to systemic steroid therapy. PATIENTS CONCERNS: A 79-year-old man with dementia and Lewy bodies was referred to our hospital because of uveitis in both eyes that did not respond to topical steroid therapy. DIAGNOSIS: We found anterior scleritis in the right eye and uveitis with shallow anterior chambers in both eyes. B-mode echography showed choroidal detachments (CDs) and a T sign in the right eye. The CDs were assumed to have progressed to the posterior scleritis which then caused the severe vision reduction. The patient was referred to the Internal Medicine Department because the systemic inflammatory disease was suspected due to the high levels of C-reactive protein (CRP) and the fast erythrocyte sedimentation rate. Systemic CT scans showed periaortitis only at the lumbar region. Because of the high levels of IgG4, the patient was diagnosed with IgG4-RD. INTERVENTIONS: The patient received intravenous and oral steroid therapy. The first 125 mg of methylprednisolone (mPSL) for 3 days was intravenous, after which it was switched to oral prednisolone (PSL) therapy and the dosage was gradually reduced. OUTCOMES: The posterior scleritis and periaortitis responded well to the systemic steroid therapy. One year and a half after the onset of the disease, the patient is still taking 5 mg of PSL. CONCLUSIONS: Scleritis with multiple CDs and periaortitis were strongly suspected to be due to IgG4-RD although no definitive diagnosis was made by biopsy of the lesions. Clinicians should be aware that IgG4-RD should be considered as one of the causes of posterior scleritis.

TNF-alpha mediated apoptosis plays an important role in the development of early diabetic retinopathy and long-term histopathological alterations.

PURPOSE: The pathophysiology of diabetic retinopathy involves leukocyte adhesion to retinal vasculature, early blood-retinal barrier breakdown, capillary nonperfusion, and endothelial cell death. We investigated the involvement of tumor necrosis factor alpha (TNF-alpha) in diabetes-related histopathological changes in two relevant rodent models. METHODS: In short-term studies, Long-Evans rats with streptozotocin-induced diabetes were treated with or without the TNF-alpha inhibitor, etanercept. For long-term studies, tumor necrosis factor receptor I (TNF-RI)-deficient mice and TNF-RII-deficient mice, as well as C57/Bl6 wild-type mice, were fed 30% galactose for up to 20 months. The retinal histopathological alterations of hypergalactosemia were analyzed in trypsin digest preparations. Endothelial cell injury and apoptosis in rat retinas were evaluated by propidium iodide, TUNEL, CytoDeath staining, and DNA fragmentation ELISA. Caspase 3 and 8 activity was evaluated by immunoblotting and quantitative enzymatic activity assay. RESULTS: Etanercept suppressed caspase activation, retinal cell injury, and apoptosis in short-term diabetic rats. Pericyte and endothelial cell loss were also reduced in long-term hypergalactosemic mice. Long-term studies demonstrated that pericyte loss and endothelial cell loss were reduced in comparison to wild-type diabetic controls. CONCLUSIONS: Our study identifies an important role for TNF-alpha in the pathogenesis of signature diabetic retinopathy pathologies and demonstrates that etanercept can inhibit retinal cell death and long-term complication of diabetes. Taken together, our results suggest that etanercept could prove beneficial in preventing both early and late vascular diabetic complications.

Comparison of intact and denuded amniotic membrane as a substrate for cell-suspension culture of human limbal epithelial cells.

BACKGROUND: We have previously developed a limbal epithelial culture system using a cell-suspension method on denuded amniotic membrane (AM). However, other workers reported that intact AM is advantageous for limbal epithelial culture in that it preserves stem cell characteristics. In this study, we cultivated human limbal epithelial cell-suspensions on both intact and denuded AM and compared the morphology and adhesion of the limbal epithelial cells on these two substrates. METHODS: Human limbal epithelial cells were dissociated from donor eyes using dispase and gentle pipetting and then seeded onto intact and denuded AM as cell suspension. Limbal epithelial cells on AM were co-cultured with a MMC-treated 3T3 fibroblast feeder layer and epithelial differentiation was promoted by air lifting. Cultures were examined by light, scanning and transmission electron microscopy and differences in cellular attachments and intercellular spacing were quantified. Basement membrane complexes were examined by indirect immunofluorescence. RESULTS: Limbal cells grown on denuded AM were well stratified and differentiated. Cells were well attached to each other and to the basement membrane. In contrast, limbal cells cultured on intact AM failed to stratify and in places formed a monolayer. The culture on denuded AM had significantly (P<0.001) more desmosomal junctions as well as significantly (P<0.001) more junctional attachments to the carrier than the intact culture. In addition, the intercellular spaces between cells cultivated on denuded AM were significantly (P<0.001) smaller than those between cells grown on the intact substrate. In cultures on both denuded and intact AM, the basement membrane zone displayed a positive staining for collagen VII, integrins alpha-6 and beta-4 and laminin 5. CONCLUSIONS: We successfully cultivated well-stratified and -differentiated limbal cells on denuded AM, while on the intact AM limbal cells failed to stratify and in places formed only a monolayer of cells. The limbal cells cultivated on denuded AM were well attached to the AM stroma and were morphologically superior to the limbal epithelium cultivated on intact AM. We conclude that for purposes of transplantation of differentiated epithelial sheets, denuded AM is probably the more practical carrier for human limbal epithelial cell cultures when using our cell-suspension culture system.

Transforming growth factor beta(2) increases in subretinal fluid in rhegmatogenous retinal detachment with subretinal strands.

PURPOSE: To compare transforming growth factor (TGF) beta(2) levels in subretinal fluid of rhegmatogenous retinal detachment with or without subretinal strand formation. METHODS: We assessed total and mature TGF-beta(2) levels in subretinal fluid obtained from 24 eyes with rhegmatogenous retinal detachment using an enzyme-linked immunosorbent assay. Group I comprised 18 specimens from eyes without subretinal strands, while group II comprised 6 specimens from eyes with subretinal strands. RESULTS: Total and mature TGF-beta(2) levels were higher in group II than in group I (p=0.01 and p=0.07, respectively). CONCLUSION: The concentrations of total and mature TGF-beta(2) were higher in cases of rhegmatogenous retinal detachment associated with subretinal strand formation compared to those without subretinal strand formation.

A central role for inflammation in the pathogenesis of diabetic retinopathy.

Diabetic retinopathy is a leading cause of adult vision loss and blindness. Much of the retinal damage that characterizes the disease results from retinal vascular leakage and nonperfusion. Diabetic retinal vascular leakage, capillary nonperfusion, and endothelial cell damage are temporary and spatially associated with retinal leukocyte stasis in early experimental diabetes. Retinal leukostasis increases within days of developing diabetes and correlates with the increased expression of retinal intercellular adhesion molecule-1 (ICAM-1) and CD18. Mice deficient in the genes encoding for the leukocyte adhesion molecules CD18 and ICAM-1 were studied in two models of diabetic retinopathy with respect to the long-term development of retinal vascular lesions. CD18-/- and ICAM-1-/- mice demonstrate significantly fewer adherent leukocytes in the retinal vasculature at 11 and 15 months after induction of diabetes with STZ. This condition is associated with fewer damaged endothelial cells and lesser vascular leakage. Galactosemia of up to 24 months causes pericyte and endothelial cell loss and formation of acellular capillaries. These changes are significantly reduced in CD18- and ICAM-1-deficient mice. Basement membrane thickening of the retinal vessels is increased in long-term galactosemic animals independent of the genetic strain. Here we show that chronic, low-grade subclinical inflammation is responsible for many of the signature vascular lesions of diabetic retinopathy. These data highlight the central and causal role of adherent leukocytes in the pathogenesis of diabetic retinopathy. They also underscore the potential utility of anti-inflammatory treatment in diabetic retinopathy.

Visual outcome of patients with macular edema after pars plana vitrectomy and indocyanine green-assisted peeling of the internal limiting membrane.

PURPOSE: To evaluate the efficacy of inner limiting membrane (ILM) peeling in persistent macular edema. METHODS: This retrospective review analyzed a series of 23 eyes from 23 patients with persistent macular edema treated by pars plana vitrectomy (PPV) with indocyanine green (ICG)-assisted peeling of the ILM. Thirteen female and 10 male patients with a mean age of 57.2+/-15.6 (24-77) years underwent operation between May 2000 and October 2001. The main diagnoses were uveitis (anterior, intermediate, posterior and panuveitis) ( n=9), central retinal vein occlusion (CRVO) (n=4), diabetic retinopathy (DR) ( n=5), vitreoretinal traction syndrome ( n=2), and Irvine-Gass syndrome ( n=3). Nine eyes had undergone phacoemulsification (PE) previously and two eyes had been subjected to combined PE and ILM peeling. The eyes were tamponaded with gas (3), silicone oil (5) or air (11). In four cases no endotamponade was used. Improvement in visual acuity of 2 lines or more was regarded as significant. RESULTS: Visual acuity improved after 3 months in 9 of the 23 patients. After 6 months and at the follow-up, a significant improvement was found in 6/21 and 7/21 patients. This improvement was predominantly seen in patients with uveitis (5/9), or diabetic maculopathy (3/5); One patient with Irvine-Gass syndrome showed a significant reduction, one with vitreoretinal traction an improvement in visual acuity. The group of patients with CRVO showed no significant change during the follow-up. The choice of endotamponade did not alter the visual acuity outcome. CONCLUSIONS: Different patient groups respond differently to ILM peeling. Although overall significant visual acuity improvement was observed in only one third of all cases 12 months after ILM peeling for persistent macular edema, patients with uveitis and nonproliferative diabetic maculopathy demonstrated a benefit. The lack of long-term improvement in the majority of cases is in accordance with the hypothesis that ILM peeling may reduce the intraretinal edema, but does not affect the underlying mechanism causing macular edema. So far, only diabetics have shown improvement (still unproven) from ILM peeling, and this study provides no justification for extending the treatment to macular edema of other causes. Large-scale investigations are needed to evaluate the efficacy in certain diagnosis groups.

Pharmacokinetics and safety of intravitreally delivered etanercept.

BACKGROUND: The anti-inflammatory drug etanercept may be an effective therapeutic agent in diabetic retinopathy. In order to further evaluate its potential, the pharmacokinetics and safety of this drug after intravitreal delivery were investigated. METHODS: After intravitreal administration of etanercept in rabbits, clinical examination, electroretinography (ERG), visually evoked potentials (VEP) and histology were evaluated. The pharmacokinetics and distribution of etanercept were analyzed using fluorescence-coupled protein at 0, 2, 4, and 8 weeks after injection in vitreous, retina, and choroid. RESULTS: No adverse effects and signs of toxicity were found. Etanercept showed peak concentrations after 4 weeks in the retina and choroid. CONCLUSIONS: Intravitreally delivered etanercept is safe and results in high concentrations in the retina and choroid over a long period of time.

Contribution of TNF-alpha to leukocyte adhesion, vascular leakage, and apoptotic cell death in endotoxin-induced uveitis in vivo.

PURPOSE: To investigate the effect of TNF-alpha on leukocyte adhesion, vascular leakage, and apoptotic cell death in endotoxin-induced uveitis (EIU) in the rat. METHODS: EIU was induced in Long-Evans rats by a single footpad injection of lipopolysaccharide (LPS; 350 microg/kg) from Salmonella typhimurium. A single injection of recombinant TNF receptor P75 (etanercept) was given subcutaneously 24 hours before the administration of LPS. Twenty-four hours after administration of LPS, leukocyte adhesion was evaluated in vivo with SLO-acridine orange angiography and ex vivo with concanavalin A lectin staining of retinal flatmounts. Neutrophil activation was quantified by a myeloperoxidase activity assay. Vascular leakage was assessed by Evans blue extravasation. Retinal cell death was assessed with TUNEL staining and quantified with a modified ELISA protocol. Involvement of caspase-3 and -8 was determined by M30 antibody staining, Western blot analysis, and a test for enzymatic activity. RESULTS: Twenty-four hours after the LPS injection, significant increases in leukocyte rolling, adhesion, and activation were observed. In addition, increased levels of apoptosis in the vascular endothelium and the ganglion cell and inner nuclear layers and activation of caspase-8 and -3 were observed. After administration of the TNF-alpha inhibitor, significant reduction in the leukocyte rolling, adhesion, activation, and apoptosis in all the affected layers was observed. The quantitative analysis of vascular leakage revealed a significant decrease after treatment with etanercept. Retinal cell death quantification showed a significant decrease after treatment with the TNF-alpha inhibitor. CONCLUSIONS: Anti-TNF-alpha treatment reduces the LPS-induced increases in leukocyte rolling, adhesion, and vascular leakage in this rat model of inflammatory uveitis. These results suggest the involvement of TNF-alpha in inflammatory uveitis and its potential use as a therapeutic agent in the reduction of ocular inflammation.

Intentional complete interruption of a retinal vein after vitrectomy might improve the rate of successful chorioretinal venous anastomosis formation in central retinal vein occlusion.

BACKGROUND: Laser or surgical chorioretinal venous anastomosis has not become widespread as suitable treatment for central retinal vein occlusion (CRVO). We report here the effectiveness of cutting off a retinal vein with vitrectomy in making a chorioretinal venous anastomosis in CRVO. METHODS: We performed a vitrectomy accompanied by a chorioretinal venous anastomosis procedure for seven consecutive patients with CRVO. These patients had shown no improvement in their visual acuity in the month following their first visit to our hospital and had a visual acuity of less than 20/200. Their preoperative visual acuity ranged from counting fingers to 20/300. The procedure included the complete cutting of the affected retinal vein, and the making of a small incision at both sides of the vein interruption through the full thickness of the retina, the retinal pigment epithelium and Bruch's membrane. RESULTS: In five of the seven patients, successful chorioretinal venous anastomosis was observed. All five patients showed an improvement of two or more lines in visual acuity 6 months postoperatively. In three of the five, visual acuity was 20/100 or better. A postoperative complication of recurrent vitreous hemorrhage and fibrous proliferation was observed in one patient, and a second operation was necessary. CONCLUSIONS: Surgical interruption of an affected vein was a feasible procedure and could raise the rate of successful chorioretinal venous anastomosis in CRVO.

Peeling the fibrous membrane from the anterior capsule for capsulorhexis contraction after phacoemulsification in aphakic patients.

We report a method for peeling the fibrous membrane from the anterior capsule without damaging the posterior capsule in patients with capsule contraction syndrome after cataract surgery. We also report 2 cases in which the technique was successfully used.

Spontaneous remodelling of retinal veins accidentally severed during vitreous surgery.

BACKGROUND: To report the spontaneous remodelling of retinal veins inadvertently severed during vitreous surgery. METHODS: Four diabetic patients who underwent vitrectomy during which retinal veins were damaged were followed for at least 6 months. Haemorrhages from severed veins were controlled by raising intraocular pressure and by endodiathermy of the distal ends of the veins. This was followed by fluid/gas exchange. RESULTS: Remodelling of venous channels in the damaged areas was observed in all eyes. In three of the four eyes we found evidence of collateral veins. In the other eye we noted the connection of two ends of an interrupted vein. No signs of retinal vein occlusion (e.g. superficial retinal haemorrhages and retinal oedema) were observed. CONCLUSION: These findings suggest that a spontaneous remodelling mechanism to repair damaged venous channels may exist in retina.

Nonsteroidal anti-inflammatory drugs prevent early diabetic retinopathy via TNF-alpha suppression.

Leukocyte adhesion to the diabetic retinal vasculature results in blood-retinal barrier breakdown, capillary nonperfusion, and endothelial cell injury and death. Intercellular adhesion molecule-1 (ICAM-1) and the leukocyte integrin CD18 are required for these processes. Diabetes was induced in Long Evans rats, resulting in a two- to threefold increase in retinal leukocyte adhesion. Following one week of diabetes, neutrophil CD11a, CD11b, and CD18 expression was increased significantly, as were retinal ICAM-1 levels. Animals were treated with aspirin, a cyclooxygenase 2 (COX-2) inhibitor (meloxicam), or a soluble tumor necrosis factor alpha (TNF-alpha) receptor/Fc construct (TNFR-Fc, etanercept). High-dose aspirin, etanercept, and high-dose meloxicam each reduced leukocyte adhesion and suppressed blood-retinal barrier breakdown. High-dose aspirin also reduced the expression of CD11a, CD11b, and CD18, whereas meloxicam and etanercept did not. High-dose aspirin, etanercept, and high-dose meloxicam each reduced retinal ICAM-1 expression. Aspirin and meloxicam both lowered retinal TNF-alpha levels. Notably, aspirin, meloxicam, and etanercept did not change retinal vascular endothelial growth factor levels. High-dose aspirin, etanercept and high-dose meloxicam, each suppressed the retinal expression of eNOS and the DNA-binding capacity of retinal nuclear factor-kappaB. High-dose aspirin also suppressed Erk kinase activity, which is involved in CD18 up-regulation. Taken together, these data identify COX-2 and TNF-alpha as operative in the early signature pathologies of diabetic retinopathy, a newly recognized inflammatory disease.