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Most uveitis entities are rare diseases but, taken together, are responsible for 5-10% of worldwide visual impairment which largely affects persons of working age. As with many rare diseases, there is a lack of high-level evidence regarding its clinical management, partly due to a dearth of reliable and objective quantitative endpoints for clinical trials. This review provides an overview of available structural outcome measures for uveitis disease activity and damage in an anatomical order from the anterior to the posterior segment of the eye. While there is a multitude of available structural outcome measures, not all might qualify as endpoints for clinical uveitis trials, and thorough testing of applicability is warranted. Furthermore, a consensus on endpoint definition, standardization, and "core outcomes" is required. As stipulated by regulatory agencies, endpoints should be precisely defined, clinically important, internally consistent, reliable, responsive to treatment, and relevant for the respective subtype of uveitis. Out of all modalities used for assessment of the reviewed structural outcome measures, optical coherence tomography, color fundus photography, fundus autofluorescence, and fluorescein/indocyanine green angiography represent current "core modalities" for reliable and objective quantification of uveitis outcome measures, based on their practical availability and the evidence provided so far., (© 2021 S. Karger AG, Basel.)

Purpose: To investigate the efficacy and safety of a single dexamethasone intravitreal implant (Ozurdex®, 700 µg). Methods: In this prospective noncomparative case series, 84 patients (54 females) received a dexamethasone intravitreal implant. At weeks 4, 12 and 24 after the injection, vitreous haze, macular thickness and best corrected visual acuity (BCVA) were assessed and adverse events reported. Results: Clearance of vitreous haze could be achieved after 4 weeks in 61% of all eyes (p < 0.001) and remained significant until week 24 (p < 0.001). This was paralleled by a reduction of central retinal thickness after 4 (p < 0.001), 12 (p < 0.001) and 24 weeks (p < 0.006). Significant and fast improvement of BCVA was already achieved after 4 weeks (p < 0.001) but vanished by week 24. Intraocular pressure reached ≥35 mm Hg in 3 eyes and was significantly more frequent in intermediate uveitis compared to posterior uveitis (p < 0.016). Conclusions: The dexamethasone implant is effective in controlling intraocular posterior segment inflammation and reduces central retinal thickness fast and effectively. © 2014 S. Karger AG, Basel.

Toxoplasma gondii is an extremely successful opportunistic parasite which infects approximately one third of the human population worldwide. The impact of this parasite on human health becomes particularly manifest in congenital damage with infection and subsequent inflammation of neuronal tissues including the retina. Although advances in our understanding could be achieved in ocular toxoplasmosis, large gaps still exist on factors influencing the epidemiology and pathophysiology of this potentially blinding disease. We are only at the beginning of understanding the complex biology of this parasite and its mechanisms of invasion, virulence and interaction with the host's immune response. Since it is a preventable cause of blindness, it is necessary to assess factors that have the potential to control this disease in the future. This mini review will focus on recent advances in postnatal acquired ocular infection and the factors that may influence its prevalence and functional outcome., (© 2014 S. Karger AG, Basel.)

Aims: To investigate the ocular surface temperature gradient in eyes with bacterial corneal ulcers., Methods: Prospective examination of 12 eyes with bacterial corneal ulcers (group 1) and 12 control eyes (group 2). Infrared thermal imaging (Tomey TG 1000) was used to study the temperature of the ocular surface. The mean, minimum and maximum temperature of the ocular surface and temperature course over a time period of 10 s of sustained eye opening were evaluated. Furthermore, a correlation between the overall corneal temperature and the temperature at the base of the corneal ulcers was determined., Results: A significant difference between both groups was present. Mean corneal temperature was 35.6°C ± 0.9 in group 1 and 34.8°C ± 0.8 in group 2 (p = 0.033). The temperature course over 10 s of sustained eye opening was -0.6°C ± 0.4 in group 1 and -0.3°C ± 0.2 in group 2 (p = 0.045). There was a close correlation between the mean temperature at the base of the corneal ulcer and the overall corneal temperature (r = 0.92, p < 0.001)., Conclusion: Infrared thermal imaging can be used to objectively determine the increased ocular surface temperature in patients with bacterial corneal ulcers. The use of dynamic thermography may offer new options to monitor ocular surface alterations., (Copyright © 2012 S. Karger AG, Basel.)

The eye is probably the most attractive site of the body for treatment using locally delivered therapeutic agents. An ideal indication for such an approach is noninfectious posterior uveitis. Since intraocular structures of the posterior segment are difficult to reach and are otherwise accessible only by systemic treatment, current interest is focused on the pros and cons of intravitreal drug delivery. Because of its chronic and recurrent nature, the long-term release of anti-inflammatory agents is a major treatment goal. Intravitreal injections, intravitreal implants and biodegradable devices are the most commonly used and approved approaches to deliver various agents to the vitreous. Because of their broad and potent effects, corticosteroids (CS) have been the first-line candidates for intraocular delivery. An increasing spectrum of CS preparations including nondegradable and biodegradable devices is currently available. Since repeated and long-term applications bear the risk of steroid-related complications such as increased intraocular pressure and cataract, alternative agents are currently being tested. Intravitreal injection of methotrexate, anti-VEGF (vascular endothelial growth factor), anti-TNFα (tumor necrosis factor α) and sirolimus have also been applied in patients with conflicting results. Intravitreal treatment has significantly reduced the incidence of adverse effects compared to systemic application, but due to greater ocular side effects there are still some limitations., (Copyright © 2012 S. Karger AG, Basel.)

Background: Large full-thickness eyelid defects are conventionally reconstructed by either a Hughes flap or Cutler-Beard bridge flap. Since the structure of the eyelid and its components are necessary for the tear film production and stability, we investigated the outcome after eyelid reconstruction focusing on dry eye symptoms using a new thermographic device, the TG-1000., Methods: Seventeen eyes of patients formerly treated with Hughes flaps (n = 16) and a Cutler-Beard bridge flap (n = 1) were compared to untreated healthy eyes (n = 17) regarding the functional and aesthetic outcome. The follow-up ranged from 3 to 63 months (mean 24.88 ± 17.86)., Results: There was no significant difference in Schirmer's test, break-up time and ocular surface temperature (p > 0.05) between patients after full-thickness eyelid reconstruction and a control group. Eleven patients had minor postoperative complications such as notching of the lid margin (11/17), epiphora (1/17), superficial punctate keratitis (6/17), trichiasis (2/17) and a mild tendency to eversion of the lid margin (6/17). More than 75% of the patients rated their postoperative aesthetic outcome as good or even excellent., Conclusion: The new TG-1000 device is a simple and quick tool for screening of dry eye. This study shows that tarsoconjunctival grafts offer good aesthetic and functional outcome with sufficient tear film composition and stability., (Copyright © 2012 S. Karger AG, Basel.)

Aims: To evaluate the efficacy and safety of topically applied mycophenolate mofetil (MMF) for the prophylaxis of corneal graft rejection in an experimental keratoplasty model., Methods: A total of 12 female Lewis rats received 3.5-mm MHC I/II-incompatible corneal grafts from DA donors. Recipients were randomly assigned to receive either topical MMF + beta-cyclodextrin therapy (1%), beta-cyclodextrin therapy alone or to remain untreated. Therapy was applied every 2 h (over 24 h) during the first 3 postoperative days, then twice hourly during daytime. Grafts were graded every day based on a rejection score including the parameters transplant clarity and edema., Results: The mean survival time (MST) of the grafts in the MMF-treated group was 12 days, the MST in the vehicle-treated group was 14.3 days and the MST in the untreated group was 13.3 days. So, the survival curves of the 3 treatment groups did not differ significantly., Conclusion: Topical MMF is ineffective for prophylaxis of corneal graft rejection., ((c) 2009 S. Karger AG, Basel.)

Background: Everolimus is a novel proliferation signal inhibitor that has potent immunosuppressive activity. As previously shown, systemic administration of the drug could effectively enhance the mean survival time (MST) of corneal allografts. Commonly, the topical application of immunomodulatory agents is preferred over systemic use, in order to reduce the side effects., Purpose: To investigate the efficacy of topically applied everolimus to prevent corneal graft rejection in an experimental model., Methods: A total of 45 female Lewis rats received 3.5-mm grafts of MHCI/II incompatible Dark Agouti donors. Recipients were randomly assigned to receive either: (1) 0.05% everolimus microemulsion, (2) 0.025% everolimus microemulsion or (3) a vehicle as the control. Treatment was started on the day of surgery and applied 5 times daily. Grafts were graded every day and a rejection score was generated based on cornea clarity and oedema., Results: Local administration of 0.05 or 0.025% everolimus was effective in prolonging the mean survival time of corneal grafts (MST = 21 +/- 6.57 days and 16.4 +/- 2.3 days, respectively) as compared to vehicle control group (MST = 13.3 +/- 1.7 days; p < 0.001 and p < 0.001). Real-time PCR demonstrated that topical administration of everolimus increased the mRNA levels of CD25, IL-10 and IFN-gamma, but this was significant only for IL-10 (p = 0.015)., Conclusions: These data indicate that topically applied everolimus is effective in prolonging corneal allograft survival in an experimental keratoplasty model., (Copyright 2008 S. Karger AG, Basel.)

Background/aims: This study investigates the survival of HSV in infected mouse corneas, in the conditions of normal human eye bank preservation., Methods: Hundred seventy-two BALB/C mice infected with herpes simplex virus 1 (HSV-1) (KOS) were randomly assigned to either: no preservation in group 1 (n = 62), 31 degrees C preservation for 3 weeks in group 2 (n = 70) or 4 degrees C preservation for 8 days in group 3 (n = 40). The presence of HSV-1 was thereafter detected by viral culture and PCR., Results: In groups 1, 2 and 3, HSV-1 was detected by culture in 22 (35.5%), 1 (1.4%) and 0 (0.0%) of the corneas, and by PCR in 27 (43.7%), 3 (4.2%) and 7 (17.5%) of the corneas respectively. When compared to group 1, HSV was detected significantly less often in groups 2 (p < 0.0001) and 3 (p < 0.0001)., Conclusions: HSV-1 DNA undergoes a degradation during corneal preservation., (Copyright 2008 S. Karger AG, Basel.)

Purpose: Spironolactone has recently been shown to have suppressive effects on several immunoactive and proinflammatory cytokines. In this study, we investigated the effects of spironolactone on the prevention of corneal allograft rejection in a MHC class I/II mismatch rat corneal transplant model., Methods: Grafted animals for corneal survival analysis were assigned to receive either spironolactone suspension (orally, 100 mg/kg/day, n = 7), phosphate-buffered saline (PBS, orally, same volume as spironolactone, n = 9) or remained untreated (n = 16). Additional grafted rats treated with spironolactone (n = 6) or PBS (n = 8) were sacrificed on day 12 for quantitative RT-PCR analysis for mechanistic studies., Results: Mean (+/-SEM) graft survival was significantly prolonged in animals receiving spironolactone (14.9 +/- 2.0 days) compared with both PBS-treated (12.3 +/- 1.2 days, p = 0.007) and untreated controls (13.0 +/- 1.0 days, p = 0.01). We found a decrease in corneal neovascularization in spironolactone-treated rats compared with the PBS-treated group, although the difference was not statistically significant. Spironolactone affected both systemic (down-regulation of CD25+ cells in spleen) and local immune response (up-regulation of IL-10 in cornea)., Conclusion: We present initial results demonstrating anti-inflammatory effects of spironolactone., ((c) 2007 S. Karger AG, Basel.)

Purpose: Understanding of the role of cytokines in uveitis may provide new clues to its treatment. Therefore, the purpose of our study was to evaluate systemic cytokine receptor expression in patients with noninfectious uveitis., Method: Serum concentrations of soluble interleukin-2 receptor alpha (IL-2 s Ralpha) and soluble tumor necrosis factor receptor-1 (sTNF-R1) were measured in patients with intermediate uveitis (n = 26), posterior uveitis (n = 23) and healthy controls (n = 12) using ELISA. All patients were identified in a consecutive series of 996 uveitis patients who had been diagnosed between 1998 and 2002 and classified according to the recommendations of the International Uveitis Study Group. Inclusion criteria were idiopathic, active intraocular inflammation, uveitis as a primary process and no systemic anti-inflammatory treatment at the time of blood sampling. None of the patients had an underlying systemic disease., Results: Serum concentrations of IL-2 s Ralpha were significantly increased in patients with posterior (p < 0.005) and intermediate uveitis (p < 0.005) as compared to healthy controls. Similarly, concentrations of sTNF-R1 appeared to be increased in posterior (p < 0.005) and intermediate (p < 0.005) uveitis patients when compared to controls., Conclusions: Our results may suggest that patients with noninfectious uveitis express systemic cytokine receptors such as TNF-R1 and IL-2 Ralpha, which may have an important role in the immune response of the eye and may lead to new immunomodulatory approaches., (Copyright (c) 2005 S. Karger AG, Basel.)

Topical corticosteroids, although effective in the treatment of ocular immune-mediated diseases, are well known for their ocular side-effects. Not surprisingly, a variety of alternative immunomodulatory agents have been tested for topical use including cyclosporin A (CsA), mycophenolate mofetil (MMF), tacrolimus (FK506), rapamycin (sirolimus) and leflunomide. Local application bears the possibility to avoid the severe side-effects of systemic therapy. The effect of topical therapy is naturally restricted to local immune response mechanisms, such as antigen presentation by Langerhans and dendritic cells. Moreover, many immunomodulatory agents (e.g. CsA) are lipophilic and thus have low water solubility and penetrate insufficiently intra-ocularly, often being stored in the lipophilic corneal epithelial barrier. Therefore, the therapeutical success is limited for intra-ocular immune-mediated diseases like anterior uveitis. However, a multitude of strategies have been introduced to circumvent these problems including complexing substances such as cyclodextrins (CDs) and liposomes. In the prevention and treatment of transplant rejection after keratoplasty, many attempts to introduce topical immunomodulatory therapy have failed; on the other hand, further therapeutic options not primarily expected are being evaluated today such as treatment of severe keratoconjunctivitis sicca. In our own studies, we investigated the pharmacokinetics of topical treatment with different agents including MMF and evaluated the efficacy of topical treatment in animal models for uveitis and keratoplasty. Taken together, topical immunomodulatory therapy will not replace systemic therapy but further treatment options can be expected., (Copyright (c) 2004 S. Karger AG, Basel.)

CG5601 is a novel immunomodulatory substance showing anti-inflammatory properties comparable to thalidomide. To investigate the anti-inflammatory effects of CG5601 in endotoxin-induced uveitis (EIU) and to evaluate its influence on leukocyte-endothelium interaction, the anterior chamber inflammatory reaction was assessed and intravital fluorescence microscopy was carried out at 2, 4, 8 and 24 h. Lewis rats received an intraperitoneal injection of CG5601 (200 mg/kg b.w.) at the time of lipopolysaccharide injection. At 8 and 24 h, CG5601 inhibited the cell migration and protein concentration in the aqueous humor compared to untreated EIU (p < 0.0001). There was no significant difference between nontreated animals and vehicle controls. The treatment of CG5601 reduced the number of rolling leukocytes. At early time points (2 and 4 h), inhibition of rolling leukocyte flux was significant (p < 0.005). The rise of serum TNF-alpha levels in EIU at 2 h was reduced. CG5601 exerts potent anti-inflammatory effects in EIU., (Copyright 2003 S. Karger AG, Basel)

Purpose: Gene transfer of immunoregulatory cytokines could contribute to reduce rejection of corneal grafts. The aim of our study was to examine the gene transfer efficiency of liposomal vehicles compared to adenoviral vectors for transferring the Epstein-Barr-virus-derived interleukin 10 homologue (viral IL-10, vIL-10) into corneal endothelial cells and organ-cultured human corneas (HC) in vitro., Method: To test liposomal efficiency, 2 lipid formulations (SP-Chol/DOPE 20/80 and DDAB/DOPE 30/70 in various concentrations) were complexed with a plasmid containing the vIL-10 cDNA in an eukaryotic expression vector (pcDSRalpha-BCRF-I). The complexes were transferred to (1) subconfluent bovine corneal endothelial cells (BCEC) after 1 passage and to (2) HC stored in organ culture. In addition, BCEC and HC were transduced with the recombinant adenoviral vector encoding for vIL-10 (AdvIL-10). Secretion of vIL-10 in the supernatants from both transfected BCEC and HC was measured by specific ELISA., Results: For gene transfer in BCEC, both transfection methods (liposomes and adenovirus) led to high secretion of vIL-10 [>2 ng/ml (liposomes) and <150 ng/ml (adenovirus) per 5,000 initially planted BCEC]. Expression levels in BCEC were dependent on the concentration of applied liposomes. For gene transfer in HC, only the adenoviral transduction technique achieved a high production of vIL-10, whereas liposomal transfection led only to low vIL-10 secretion (4.8 microg/ml vs. 95 pg/ml per quarter of cornea)., Conclusion: For transfection of corneal endothelial cells in culture, liposomes can be considered as a safe and useful alternative method of gene transfer avoiding side-effects of viral vectors. However, for transfection of organ-cultured HC, adenoviral vectors are superior to liposomal vehicles., (Copyright 2003 S. Karger AG, Basel)

Background: Keratolysis in rheumatoid arthritis is a well-known disorder that may rapidly destroy the entire corneal stroma, resulting in descemetocele formation and eventually corneal perforation. The purpose of this study was to determine the anatomical and functional results of therapeutic penetrating keratoplasty (PK) in these patients., Patients and Methods: We reviewed the charts of patients having undergone PK over a 5-year period and evaluated the outcome. In 16 eyes of 15 patients, PKs were performed (graft diameter 3.0-11.0 mm) because of corneal melting with perforation or descemetocele formation. In 9 eyes, we used topical cyclosporine A (2%) as an adjunct therapy after transplantation in addition to systemic immunosuppressive agents., Results: Following a mean follow-up time of 17 months, anatomical success could be achieved in all eyes; none of the eyes underwent enucleation or evisceration. Postoperative complications following the first PK were epithelial keratopathy in 8 eyes (50%), corneal ulceration in 5 eyes (31%), fistulation in 4 eyes (25%), suture loosing in 4 eyes (25%) and graft rejection in 2 eyes (13%). Additionally 5 regrafts were required because of recurrence of corneal melting or persistent deep stromal defects. Comparison of complications of the patients receiving topical cyclosporine A to the control group showed a statistically significant lower incidence of epithelial keratopathy (p < 0.025) and ulcer recurrence in the cyclosporine A group during the first 3 months postoperatively (p < 0.05). The final best corrected visual acuity was 20/40 in 4 eyes but was limited to 20/200 or less in 7 eyes., Conclusion: Whereas PK can be successful to restore the anatomical integrity of severely altered eyes, the high prevalence of complications limits the indication for PK as a last stage procedure when other methods of management have failed. The use of topical cyclosporine A as adjunct therapy needs further evaluation., (Copyright 2002 S. Karger AG, Basel)

To investigate the effects of thalidomide on leukocyte-endothelium interaction in iris vessels of rats with an endotoxin-induced uveitis (EIU), intravital fluorescence microscopy was used to quantify leukocyte adhesion to the vascular endothelium of iris venules in Lewis rats at 2, 4, 8 and 24 h after induction of EIU. Animals (n = 84) received a single intraperitoneal dose of either thalidomide (80 mg/kg body weight) or prednisolone (10 mg/kg body weight). Both drugs significantly reduced firm adhesion of leukocytes at 4, 8 and 24 h. Thalidomide caused earlier suppression of leukocyte rolling than prednisolone (4 vs. 8 h). TNF-alpha plasma levels peaked at 2 h and were not significantly reduced in any group compared with controls. Cell count and protein concentration in aqueous humor were significantly reduced by prednisolone and thalidomide at 24 h (p < 0.05). Thalidomide exerts its anti-inflammatory effects by an inhibition of leukocyte-endothelium interaction. Compared with prednisolone, thalidomide shows earlier inhibition of leukocyte rolling, indicating modulation of adhesion molecule expression and/or function., (Copyright 2001 S. Karger AG, Basel)

Allograft rejection remains the single largest impediment to success in corneal transplantation. This article briefly reviews our current understanding of some fundamental aspects of corneal immunology and the pathogenetic mechanisms underlying corneal graft rejection. As knowledge increases, it is hoped that a better understanding of the immunobiology may result in improved preventive and therapeutic measures., (Copyright 2001 S. Karger AG, Basel)

Background: Ciprofloxacin (CFLX) is a fluoroquinolone antibiotic with a broad antimicrobial spectrum. This study was performed to examine the retinal toxicity of free and liposome-incorporated CFLX in rabbit eyes after intravitreal injection., Materials and Methods: Free CFLX in doses of 100, 250, 500, 1,000 and 2,000 microg was injected into the midvitreous of rabbit eyes (n = 28). To prolong the intravitreal antibacterial level, CFLX was incorporated into multilamellar liposomes: 0.1 ml of this suspension ( wedge 273.6 microg CFLX) was injected into the midvitreous of a second group of rabbit eyes (n = 6). The other eye served as a control and received normal saline solution or empty liposomes, respectively. Before injection and at the end of follow-up an electroretinogram (ERG) was obtained. After a follow-up of 1, 14 and 28 days the animals were perfused with glutaraldehyde and the eyes were examined by light and transmission electron microscopy., Results: Significant reduction of the ERG was observed after 2,000 microg free CFLX in 4 out of 6 eyes after 14 days. Fourteen days after injection of 2,000 microg CFLX the central retina showed pigmentary changes in 4 out of 6 eyes. In the second group the ERG as well as the histologic studies did not reveal any pathologic changes after injection of liposome-incorporated CFLX compared to the control eyes., Conclusion: In therapeutic doses of 100-500 microg, free CFLX does not have retinal toxicity in rabbit eyes. No retinal toxicity was observed after intravitreal injection of liposome-incorporated CFLX.

The outer surface of the eye is constantly exposed to a wide array of microorganisms. To protect the integrity or the ocular surface and to retain corneal transparency, a number of defense mechanisms have evolved. This article discusses the host mechanisms of the eyelids-, tears, cornea and conjunctiva. These host defense mechanisms are identified as either a native, nonspecific defense or a specifically acquired immunological defense requiring previous exposure to an antigen and the development of specific immunity. Nonspecific components that protect the eye include the eyelids, ocular surface epithelium, normal flora and tear proteins. Specifically acquired immunity in tears, cornea and conjunctiva involves the interaction of antigen-presenting cells, lymphocytes and humoral components of the immune system.