Adhesion molecules in iris biopsy specimens from patients with uveitis

BACKGROUND/AIMS: Earlier studies on intraocular tissue have demonstrated that T lymphocytes play a major role in the pathogenesis of uveitis. Adhesion molecules are immunoregulatory molecules for the interaction between T lymphocytes and vascular endothelium and they play an important role in the recruitment of specific T lymphocytes from the circulation into inflamed tissue. In uveitis an increased expression of some of these adhesion molecules may be expected. METHODS: The presence of adhesion molecules was investigated in iris biopsy specimens from 11 patients with uveitis and eight controls (patients with primary open angle glaucoma) immunohistochemically with a panel of monoclonal antibodies: LECAM (CD 62L), ICAM-1 (CD 54), LFA-1 (CD 11a/18), VCAM-1 (CD 106), VLA-4 (CD 49d), and HECA-452, a marker for high endothelial venules. RESULTS: Positive staining for ICAM-1, LFA-1 and VCAM-1 was found in the iris in a significantly higher number of uveitis patients than in controls. The remaining adhesion molecules were also found in a higher number of uveitis patients than in controls, but this difference did not reach statistical significance. CONCLUSION: An increased expression of adhesion molecules was found in the iris of patients with uveitis, indicating an immunoregulatory function for adhesion molecules in the pathogenesis of uveitis

Smaller Foveal Avascular Zone in Deep Capillary Plexus Is Associated with Better Visual Acuity in Patients after Macula-off Retinal Detachment Surgery

Purpose: To associate the change in the foveal avascular zone (FAZ) and vessel density (VD) with final best corrected visual acuity (BCVA) in eyes after macula-off rhegmatogenous retinal detachment surgery, and to investigate the evolution of FAZ and VD during 12 months of follow-up. Methods: We prospectively evaluated 47 patients with macula-off rhegmatogenous retinal detachment and healthy fellow eyes. At 1.5, 3.0, 6.0, and 12.0 months postoperatively, optical coherence tomography angiography scans were obtained from both eyes on a 3.0 × 3.0 mm macula-centered grid. En face images of the superficial vascular plexus, intermediate capillary plexus and deep capillary plexus were used to quantify FAZ and VD. BCVA was assessed with ETDRS-charts (logarithm of the minimal angle of resolution). At 12 months postoperatively, the association between the change in optical coherence tomography angiography parameters and visual function in study eyes was evaluated using the Spearman correlation coefficient. We calculated the BCVA difference and the percentage difference of FAZ and VD between the study and control eye. The evolution of FAZ and VD was investigated with linear mixed-effects models with nested random effects (eyes nested within patients). Results: At 12 months postoperatively, FAZ difference of the deep capillary plexus and BCVA difference were correlated (P = 0.0004, rs = 0.5). Furthermore, there was no evidence that FAZ and VD changed during follow-up. Conclusions: Although FAZ and VD remained stable during 12 months after surgery for macula-off rhegmatogenous retinal detachment, a smaller FAZ in the deep capillary plexus is associated with better BCVA. Translational relevance: Reduction in FAZ area may be caused by angiogenesis to counteract ischemia, therefore therapeutic stimulation of angiogenesis could be beneficial to visual recovery

Clinical aspects and etiology of Fuchs' heterochromic cyclitisKlinische aspecten en etiologie van de heterochrome cyclitis van Fuchs

Fuchs' heterochromic cyclitis is characterized by a chronic, low-grade non-granulomatous anterior uveitis with widely scattered small keratic precipitates, a variable degree of atrophy and depigmentation of the iris, and no synechiae. It is usually unilateral, although bilateral involvement has been reported in up to 10 % of cases. Fuchs' heterochromic cyclitis occurs in approximately 5 % of all patients with uveitis and is regarded as a distinct nosological entity. The typical age of onset is in the third or fourth decade, and there is an equal incidence among men and women. Because not all characteristic clinical signs are present at the same time, the diagnosis of Fuchs' heterochromic cyclitis is often difficult to make, especially in the earlier stages of the disease. No minimal clinical diagnostic criteria, pathognomonic for this eye disease, have been internationally accepted yet, and no laboratory tests are available to confirm the diagnosis of Fuchs' heterochromic cyclitis. Fuchs' heterochromic cyclitis may even be considered as the most commonly misdiagnosed form of uveitis. Cataract and glaucoma are two major complications in Fuchs' heterochromic cyclitis. A subcapsular cataract develops in almost all cases, whereas glaucoma occurs in approximately 20 % of the cases. Cataract extractions with or without intraocular lens implantation currently have excellent results. Glaucoma is considered to be the most serious complication, because the therapy of glaucoma (medical and surgical), as reported in the literature, has a poor outcome. The origin of Fuchs' heterochromic cyclitis is still unknown and many hypotheses for the etiology of this eye disease have been proposed since Ernst Fuchs presented his theory in 1906. In chronological order, these theories are the following: Sympathetic Theory, Hereditary Theory, Association with Toxoplasmosis, Vascular Theory and Immunologic Theory. Until now. no definite proof has been obtained to accept or to reject any of these theories. AIM OF THE THESIS The aim of this thesis was to study the clinical aspects and etiology of Fuchs' heterochromic cyclitis. An update of the literature on Fuchs' heterochromic cyclitis is presented in chapter 2. Clinical Aspects Based on an analysis of clinical findings in 51 patients, clinical diagnostic criteria for Fuchs' heterochromic cyclitis are proposed in chapter 3. In chapter 4, the severity and prognosis{ of secondary glaucoma are evaluated, based on a larger series of patients with Fuchs' heterochromic cyclitis who needed medical and surgical intervention for glaucoma. Iris translucency, an important clinical feature, is quantified in patients with Fuchs' heterochromic cyclitis by a modification of the direct compensation technique for the measurement of intraocular stray light in chapter 5. Etiology Different approaches have been used to study the various etiological theories on Fuchs' heterochromic cyclitis. One case report and a short review of the literature to support the sympathetic theory and the association between Fuchs' heterochromic cyclitis and the Parry Romberg syndrome are presented in chapter 6. Two cases with Fuchs' heterochromic cyclitis and a definite (congenital) ocular toxoplasmosis (chapter 7 and 8), and clinical and laboratory examinations for ocular toxoplasmosis in a larger series of patients with Fuchs' heterochromic cyclitis (chapter 9) are reported to elucidate the association between Fuchs' heterochromic cyclitis and toxoplasmosis-like chorioretinal lesions. The alternative hypothesis for the chorioretinal lesions in Fuchs' heterochromic cyclitis, namely that of autoimmunity directed against retinal antigens, was evaluated in chapter 10. Chapter 11 describes the detection of circulating autoantibodies against the anterior segment (uvea, cornea) of the eye in patients with Fuchs' heterochromic cyclitis. In chapter 12 the hypothesis of an immune complex vasculitis of the iris vessels was assessed with an immunofluorescence technique on peripheral iridectomies of patients with Fuchs' heterochromic cyclitis

Immunological Factors in the Pathogenesis and Treatment of Age-Related Macular Degeneration

Recent findings indicate that immunological factors are involved not only in the pathogenesis of age-related macular degeneration (AMD), but also in its treatment. Earlier data showing the presence of inflammatory cells in affected areas of AMD retinas support this statement. Although a possible role for autoimmunity was initially suggested, it has never reached general acceptance. Microorganisms have also been implied in the pathogenesis of AMD. Both serum antibacterial antibody levels and positive DNA tests from neovascular membranes have pointed to a possible role for Chlamydia pneumoniae in the pathogenesis of AMD. New data is providing evidence for the hypothesis that deposits between Bruch's membrane and the retinal pigment epithelium (RPE) cell layer may act as a stimulus for the local activation of the complement system. This may lead to a further growth of the deposits due to the strong chemotactic activity of certain complement activation products (such as C5a) with an influx of inflammatory cells. The buildup of cells and extracellular deposits may lead to local ischemia resulting in the activation of RPE cells. These activated RPE cells are thought to release angiogenic stimuli leading to choroidal neovascularization, which is the most serious complication of AMD. The fact that immunosuppressive drugs such as triamcinolone acetonide and anecortave acetate are capable of inhibiting choroidal neovascularization is consistent with an inflammatory component in the pathogenesis of AMD. Specific immunotherapy directed at certain cytokines or growth factors is now being investigated at both the animal and patient levels. Various clinical trials involving engineered antibodies are now being applied to block angiogenic factors such as the vascular endothelial growth factor (VEGF). An approach using gene therapy to influence angiogenesis by inducing the production of the pigment epithelium-derived factor (PEDF) was able to block neovascularization in an experimental murine model. Besides trying to block ongoing processes in AMD, retinal transplantation is now also being investigated as a treatment option. The fact that the retina is possibly an immunoprivileged tissue in combination with experimental data showing that the subretinal space is an immunoprivileged site is an indication that transplantation would not suffer from the rejection process. A larger obstacle is the question whether transplanted retinal tissue will regain its functional propertie

Postoperative aqueous flare values as a surrogate marker for proliferative vitreoretinopathy development

Ophthalmic researc

Increased nitric oxide (NO) pathway metabolites in the vitreous fluid of patients with rhegmatogenous retinal detachment or diabetic traction retinal detachment

BACKGROUND: Nitric oxide (NO) plays a significant role in physiological and pathological processes in the retina. In the L-arginine-NO pathway, NO synthase (NOS) converts L-arginine to NO and L-citrulline. Increased NO production, mediated by inducible NOS has been implicated in the pathogenesis of various vitreoretinal diseases. In the present study it is hypothesized that in rhegmatogenous retinal detachment (RRD), the production of NO pathway metabolites might be upregulated. METHODS: Using high-pressure liquid chromatography citrulline, arginine and nitrite were measured in vitreous fluid of 93 eyes with RRD, nine eyes with a traction retinal detachment due to proliferative diabetic retinopathy (PDR), and in 49 control samples of vitreous fluid from eyes without retinal detachment. RESULTS: The mean vitreous concentrations of citrulline and arginine were significantly increased in eyes with RRD (9.6+/-4.3 and 97.3+/-29.2; respectively) or in eyes with a traction retinal detachment (25.8+/-10.3 and 130.7+/-23.7; respectively) as compared to control eyes (7.1+/-3.2 and 75.9+/-18.1; respectively). The mean level of nitrite was also higher in vitreous fluid of patients with RRD (2.24+/-1.4) or patients with a traction retinal detachment (2.21+/-0.72) than in the controls (2.01+/-0.72), although not significantly so. CONCLUSIONS: We found increased levels of NO pathway metabolites in the vitreous fluid of eyes with retinal detachment, which may reflect a possible role of NO in the pathogenesis of this disease

Balance of vascular endothelial growth factor and pigment epithelial growth factor prior to development of proliferative vitreoretinopathy

Background: Pigment epithelium-derived factor (PEDF) and vascular endothelial growth factor (VEGF) are imbalanced in eyes with proliferative diabetic retinopathy or proliferative vitreoretinopathy (PVR). It is not known whether such an imbalance is already present in early PVR stages. We therefore analyzed VEGF and PEDF concentrations in subretinal fluids prior to PVR development. Methods: A large number (n = 137) of subretinal fluid samples were obtained at the time of scleral buckling surgery for rhegmatogenous retinal detachment (RRD). Thirty patients developed PVR within 6 months after surgery. One hundred and seven patients undergoing the same surgery but without complications served as controls. Furthermore, vitreous from 16 patients with macular hole or pucker (MHP) served as reference for baseline intraocular concentrations. PEDF and VEGF concentrations were measured by commercial ELISAs. Results: PEDF levels were substantially higher (9.6 µg/ml) compared to MHP vitreous (0.3 µg/ml, p <0.001). VEGF levels were also higher (RRD: 0.07 ng/ml; MHP: 0.01 ng/ml, p <0.05). Subretinal concentrations were not significantly different between PVR and control RRD patients. Conclusions: Although both VEGF and PEDF are increased at first surgery for RRD, they do not predict PVR development later on. The high PEDF concentrations and its known antiangiogenic activity suggest a protective role against neovascularizatio

High TGF-ß2 levels during Primary Retinal Detachment May Protect against Proliferative Vitreoretinopathy.

PURPOSE. Transforming growth factor (TGF)-beta2 and hepatocyte growth factor (HGF) have been implicated in the pathogenesis of proliferative vitreoretinopathy (PVR) after retinal detachment surgery. The exact role of these factors in the early events, immediately after primary retinal detachment, is not yet known, and determining their roles was therefore the purpose of this study. METHODS. Subretinal fluids were collected prospectively from 144 patients during surgery for scleral buckling. TGF-beta2 and HGF were measured with commercially available ELISA kits. Thirty patients in whom a redetachment caused by postoperative PVR developed, were compared with 114 patients with an uncomplicated retinal detachment. The controls included 18 vitreous samples from patients with macular hole or pucker. Multivariate regression analysis was used to compare the relative roles of growth factors and clinical factors in the development of PVR. RESULTS. The median amount of subretinal TGF-beta2 was approximately two times lower in patients with postoperative PVR (1.9 ng/mL) than in the uncomplicated detachment group (3.3 ng/mL; P = 0.002). TGF-beta2 levels in the PVR-positive group were similar to control vitreous levels (1.8 ng/mL). Subretinal HGF concentrations were not significantly different between the two groups of patients (PVR positive: 8.8 ng/mL; PVR negative: 8.9 ng/mL), but were higher than control vitreous levels (4.6 ng/mL; P = 0.01). Stepwise multivariate logistic regression analysis revealed that of all factors under study, decreased TGF-beta2 content was the exclusive predictor of postoperative PVR (P = 0.01). CONCLUSIONS. High TGF-beta2 levels in subretinal fluid at the time of primary retinal detachment may protect a patient against subsequent development of PVR

Incidence of redetachment 6 months after scleral buckling surgery.

Purpose: The preoperative and intraoperative clinical variables associated with redetachment and/or a poor visual outcome following scleral buckling (SB) surgery for rhegmatogenous retinal detachment (RRD) have mainly been studied after a short follow-up. This study aimed to analyse long-term effects by following patients for at least 6 months. Methods: In a retrospective survey we evaluated the data of 436 eyes that underwent SB surgery. Postoperative data were collected at 3-month intervals. Results: After a mean follow-up period of 51 months, anatomic reattachment was achieved in 76% after one SB procedure, with a final reattachment rate of 97% after additional vitreoretinal procedures. In total, 104 eyes developed redetachment during follow-up. After more than 6 and 12 months of follow-up, 32 eyes (7%) and 20 eyes (5%), respectively, developed redetachment. Multivariate regression analysis showed that recurrent redetachment and more than 7 days of visual field loss were significant predictors for a poor postoperative visual outcome at 12 months. A cumulative size of the tear of more than three disc diameters was a significant predictor of recurrent RRD. Conclusion: Conventional SB surgery is a reliable procedure in a selected group of eyes with primary RRD. However, in eyes with a retinal tear with a cumulative size of more than three disc diameters, a primary vitrectomy should be considered. Taking into account that 7% of eyes developed redetachment after 6 months, a longer follow-up period seems necessary to evaluate the anatomical and visual outcomes after SB surgery