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Purpose: To investigate differences in the retinal vessel area density (VAD) on optical coherence tomography angiography (OCTA) between eyes with unilateral herpetic viral anterior uveitis (VAU) (herpes-simplex virus (HSV) and varicella-zoster virus (VZV)) and the non-affected fellow eye., Methods: In this monocentric, observational, prospective case series we analyzed the VAD of the macula, optic disc, and peripapillary region in affected and non-affected eyes of 22 patients with HSV-positive and 22 patients with VZV-positive VAU using OCTA. We analyzed also the visual field mean deviation (MD), the retinal nerve fiber layer (RNFL) thickness, Bruch's Membrane Opening-Minimum Rim Width (BMO-MRW), and ganglion cell layer (GCL) thickness on OCT and correlated the results with the different VADs., Results: The macular VAD in the superficial vascular plexus (SVC) was significant lower in the affected compared to the non-affected eye for both viruses (HSV: 33.0% ± 3.3% vs. 34.7% ± 2.6%, p  = 0.011; adjusted p  = 0.040; VZV: 33.1% ± 3.2% vs. 34.3% ± 2.8%, p  = 0.012; adjusted p  = 0.050). Additionally, the VAD of the peripapillary SVC differed between the affected and non-affected eye for VZV-positive VAU (47.1% ± 6.2% vs. 50.5% ± 6.3%, p  = 0.048, adjusted p  = 0.100). For both HSV-positive and VZV-positive VAU, there were correlations between macular or peripapillary SVC VAD and BMO-MRW, GCL thickness, RNFL thickness or MD of the affected eye., Conclusion: We observed vascular dysfunction characterized by decreased macular and peripapillary VAD in the superficial plexus on OCTA in eyes with HSV- and VZV-positive VAU compared to non-affected fellow eyes. These changes might be an early sign of glaucomatous damage or may be a direct consequence of the herpes viruses themselves.

Purpose: To report the efficacy of systemic anti-TNF agents in Mooren's ulcer., Design: Retrospective, consecutive case series., Methods: We report on clinical characteristics and outcome of five patients with Mooren's ulcer with anti-TNF treatment., Results: During a mean follow-up of 30 months, relief of symptoms and arrest of corneal melting were observed in all eyes. Systemic corticosteroid treatment could be discontinued or reduced to threshold levels. No patient experienced adverse effects on bDMARDs., Conclusions: Our results suggest that bDMARDs are effective in Mooren's ulcer unresponsive to conventional treatment. This is in line with accumulating evidence in the current literature. Therefore, more targeted immunomodulatory approaches might be an effective first-line therapy in the future.

Purpose: To assess the efficacy and tolerability of intravitreal dexamethasone 0.7 mg sustained-release insert (Ozurdex ® ) in patients with sclerouveitis and recurrent cystoid macula edema (CMO) refractory to treatment., Methods: Interventional retrospective case series of five patients receiving 13 intravitreal dexamethasone inserts., Results: Three of five patients presented with an associated systemic disorder, whereas two patients had idiopathic sclerouveitis. All patients received immunosuppressive therapy. The CRT mean (SD) decreased in all eyes from 428 μm (137) (baseline) to 327 μm (149) (1 month), 342 μm (155) (3 months), 297 μm (99) (6 months) and reduced scleral inflammation. No morphologic adverse changes were noted, in particular, no scleral melting or necrosis occurred., Conclusions: Intravitreal dexamethasone may be an effective and safe therapeutic option in sclerouveitis with otherwise treatment-resistant CMO. It resolves not only CMO, but also provides a reduction of scleral inflammation and ocular pain. Nonetheless, adequate immunosuppressive treatment of an underlying disease must ensue.

Purpose: To describe retinal vascular changes in Birdshot Retinochoroiditis (BSRC) with multimodal imaging techniques and functional values., Methods: In this single-center study, 64 eyes of 32 subjects with BSRC were classified according to disease activity and duration and underwent imaging with spectral domain optical coherence tomography, fluorescein angiography, indocyanine green angiography, fundus autofluorescence, and optical coherence tomography angiography (OCTA)., Results: Mean age of the patients was 60 years (range, 38-74). OCTA revealed capillary loops (58%), telangiectatic vessels (44%), increased intercapillary spaces (52%), altered vascular architecture (53%), and rarefication of C-scans (63%) in retinal layers. Increased rarefications of C-scans (p = 0.0056; p = 0.0046) and altered vascular architecture (p = 0.0120; p = 0.0243) in superficial and deep capillary layers were significantly correlated with disease activity., Conclusion: OCTA adds new insights in a multimodal imaging approach of retinal vascular layer visualization in BSRC and may contribute to existing methods for diagnosing severity and potentially progression of the disease.

Introduction: Intraocular inflammation (uveitis) remains a significant burden of legal blindness. Because of its immune mediated and chronic recurrent nature, common therapy includes corticosteroids, disease-modifying anti-rheumatic drugs and more recently biologics as immune modulatory agents. The purpose of this article is to identify the role of new treatment approaches focusing on small molecules as therapeutic option in uveitis. Areas covered: A MEDLINE database search was conducted through February 2017 using the terms 'uveitis' and 'small molecule'. To provide ongoing and future perspectives in treatment options, also clinical trials as registered at ClinicalTrials.gov were included. Both, results from experimental as well as clinical research in this field were included. Since this field is rapidly evolving, a selection of promising agents had to be made. Expert opinion: Small molecules may interfere at different steps of the inflammatory cascade and appear as an interesting option in the treatment algorithm of uveitis. Because of their highly targeted molecular effects and their favorable bioavailability with the potential of topical application small molecules hold great promise. Nevertheless, a careful evaluation of these agents has to be made, since current experience is almost exclusively based on experimental uveitis models and few registered trials.

Purpose: To analyze the preferred practice respective diagnosis, treatment, and complications in patients with acute retinal necrosis in Germany., Methods: The uveitis-section of the German Ophthalmologic Society developed a questionnaire with 12 questions concerning patients with acute retinal necrosis seen in the 5 years up to August 2009., Results: In total, 35 eye hospitals answered the questionnaire and reported 213 patients with acute retinal necrosis. Diagnosis was made clinically in 86%. Anterior chamber tap, vitreous biopsy, diagnostic vitrectomy, and serology were performed for confirmation. Therapy was started with acyclovir in all institutions, and continued with ganciclovir, foscarnet and brivudine in some cases. Intravitreal injections were performed in 46%. Additional oral steroids were given in 80%. A following oral antiviral treatment was performed in 94%., Conclusions: Relevant variations were seen in diagnosis and treatment practices. The survey outlines the need for a unique diagnostic and therapeutic guideline.

Introduction: Noninfectious posterior uveitis (NIPU) remains a significant burden of legal blindness. Because of its immune mediated and chronic recurrent nature, common therapy includes (systemic) corticosteroids and immune modulatory agents. Most treatments bear the risk of significant adverse effects. Therefore efforts are made to administer therapeutic agents directly into the vitreous cavity. The purpose of this article is to identify the role of intravitreally applied sirolimus as a recently approved therapeutic option in NIPU., Areas Covered: A MEDLINE database search was conducted through August 2015 using the terms: intravitreal injection, pharmacology, sirolimus, treatment and uveitis. To provide ongoing and future perspectives in treatment options, also clinical trials as registered at ClinicalTrials.gov were included. Sirolimus (Opsiria) was in licensed from SANTEN in 2015 and approved in Phase III registration trials in the US, Europe and other countries for NIPU. Current information results mainly from registration and Phase III trials., Expert Opinion: Intravitreal sirolimus appears to be an interesting option in the treatment algorithms of NIPU because of its highly targeted molecular effects, nonsteroidal nature and good safety profile. It has the advantage to avoid systemic side effects, but this has to be balanced against the fact that treatment covers one eye only and bears the risks of any intraocular procedure. Nevertheless a careful evaluation of this agent has to be made, as current experience is almost exclusively based on registration trials and long-term effects still have to be explored.

Purpose: To investigate ocular surface temperature in eyes with pterygium and dry eye disease., Methods: Eighteen eyes of 18 patients with pterygium (group 1), 18 eyes of 18 patients diagnosed with dry eye disease (group 2), and 22 eyes of 22 healthy subjects with no signs of dry eye (group 3), were included in this prospective study. Schirmer's test I and II, and tear film break up time (BUT) were evaluated. Infrared thermal imaging (Tomey TG 1000, Tomey Corp, Nagoya, Japan) was used to study the temperature of the ocular surface. All measurements were performed by one examiner only., Results: No significant difference in temperature course over ten seconds of eye opening was present between groups 1 and 2 (p=0.551). However, a significant difference was present between groups 1 and 3 (p=0.001) and between groups 2 and 3 (p=0.003). Comparing group 1 and group 2, statistically significant differences in Schirmer's test I (p<0.001) and II (p<0.001) and BUT (p=0.04) were present. There were also significant differences in Schirmer`s test I (p<0.001) and II (p<0.001) and BUT (p<0.001) between group 2 and group 3. No significant difference in Schirmer's test I (p=0.785) and II (p=0.871) was present between group 1 and group 3. However, a statistically significant difference in BUT was noted (p<0.001)., Conclusion: During sustained eye opening, a significant decrease in corneal surface temperature occurred in eyes with pterygium and dry eye disease. Thermography, in addition to other investigations, might be used to objectively identify dry eye symptoms in patients with pterygium. In addition to cosmetic appearance, increasing astigmatism, and expanding growth towards the center of the cornea, this new supplementary data may help to determine the proper time for intervention.

Purpose: To investigate the routine use and applicability of a new ocular thermography device (TG 1000; Tomey Corp, Nagoya, Japan) in healthy individuals., Methods: Sixty eyes of 30 healthy subjects were included in this prospective study. Intraobserver reproducibility was tested with an ocular surface-oriented infrared radiation thermographic device in a non-contact manner. Using a standard examination protocol, the ocular surface temperature was assessed by dynamic thermal imaging over a time period of 10 s. The procedure was repeated three times during a single session by one examiner. Intraclass correlation coefficients (ICC) were calculated., Results: Ocular surface temperature measurements were highly reproducible. The mean ocular surface temperature was 34.02°C ± 0.22. The ICC was 0.947%, 0.949%, and 0.955% for minimum, maximum, and mean temperatures, respectively., Conclusion: Ocular surface temperature measurements made using the Tomey TG 1000 in healthy subjects showed excellent intraobserver reproducibility. This novel non-invasive technique offers new options for increased understanding of the physiology of the ocular surface.

Background: TNF-alpha inhibitory drugs are widely used with beneficial effect in the treatment of rheumatic diseases, such as juvenile idiopathic arthritis and ankylosing spondylitis. Due to the complex immune regulatory function of TNF-alpha, induction of inflammation in several organs including the eye, skin, and gastrointestinal tract has been reported. This report describes the occurrence of intraocular inflammation after treatment with the TNF-alpha antagonist etanercept., Methods: In this observational case series, we followed and examined six patients receiving etanercept for juvenile idiopathic arthritis, ankylosing spondylitis, adult Still's disease, or psoriasis., Result: All patients responded well to their joint affliction, but developed endogenous uveitis for the first time after application of etanercept. Following acute intervention with corticosteroids, etanercept was discontinued and instead an antibody-based anti-TNF treatment using infliximab was instituted. We documented visual acuity before and after change from etanercept to treatment with the anti-TNF-alpha antibody infliximab. Interestingly, prompt long-term remission (mean 34 months) of uveitis without recurrence could be induced in all patients., Conclusions: Our observations may indicate that immunodysregulatory and even proinflammatory effects of etanercept are of relevance in clinical practice. Further randomized controlled clinical trials are necessary to investigate possible side effects of anti-TNF therapy using etanercept and infliximab.

Purpose: To evaluate the expression and presence of the surfactant proteins (SP) B and C in the lacrimal apparatus at the ocular surface and in tear fluid., Methods: Expression of SP-B and SP-C was analyzed by RT-PCR in healthy lacrimal gland, conjunctiva, meibomian gland, accessory lacrimal glands, cornea, and nasolacrimal ducts. The deposition of the hydrophobic proteins SP-B and SP-C was determined by Western blot and immunohistochemistry in healthy tissues, tear fluid, and aqueous humor., Results: The presence of both SP-B and SP-C on mRNA and protein level was evidenced in healthy human lacrimal gland, conjunctiva, cornea, and nasolacrimal ducts. Moreover, both proteins were present in tear fluid but were absent in aqueous humor. Immunohistochemical investigations revealed production of both peptides by acinar epithelial cells of the lacrimal gland and additionally by accessory lacrimal glands of the eyelid as well as epithelial cells of the conjunctiva and nasolacrimal ducts. Immunohistochemically, healthy cornea and goblet cells revealed no reactivity., Conclusions: Besides the recently detected surfactant-associated proteins SP-A and SP-D, our results show that SP-B and SP-C are also peptides of the tear film, the ocular surface, and the lacrimal apparatus. Based on the current knowledge of lowering surface tension in alveolar lung cells, a similar effect of SP-B and SP-C may be assumed concerning the tear film.

Purpose: Liposome preparations of FK506 improve the penetration of topically administered drug into the aqueous humor. The purpose of the experiment was to compare topically administered highdose oil-dissolved FK506 (OD-FK506) and low-dose liposome-bound FK506 (LB-506) for the treatment of endotoxin-induced uveitis (EIU)., Methods: Endotoxin-induced uveitis was produced in female Lewis rats with Salmonella typhimurium endotoxin. Four hours prior to endotoxin injection, one eye received 20 mul eyedrops every four hours containing either high-dose OD-FK506 at 3 mg/ml (N = 20), low-dose LB-FK506 at 0.16 mg/ml (N = 19), prednisolone acetate 1% (N = 20), or empty liposomes (N = 20). Eyes were enucleated 24 hours after endotoxin injection and inflammatory cells were counted on histologic sections by two masked observers., Results: The mean number of infiltrating inflammatory cells per section +/- S.E.M. was 127.8 +/- 20.1, 76.8 +/- 16.7, 75.0 +/- 19.1, and 3.6 +/- 0.4 for animals treated with empty liposomes, LB-FK506, OD-FK506, and prednisolone acetate, respectively. The difference in inflammation between the empty liposome controls and the LB-FK506- and OD-FK506-treated animals was statistically significant (p = 0.03 and p = 0.02, respectively). The difference in inflammation between the high-dose OD-FK506- and low-dose LB-FK506-treated animals was not statistically significant (0 = 0.94)., Conclusion: In this study, low-dose LB-FK506 and high-dose (OD-FK506) were both effective in inhibiting EIU. Higher concentrations of LB-FK506 are being developed and should augment the therapeutic effect of topical FK506.

Corneal allograft rejection culminates in a series of interactions between different classes of antigen presenting cells, cytokines and leukocytes. Tumor necrosis factor-alpha (TNF-alpha) was recently reported to be elevated in acute rejection of solid organ transplants. This cytokine is released early in immune activation and may be detected in the peripheral circulation. Serial determinations of TNF-alpha serum levels were performed following experimental corneal allografts. Lewis rats received 3.5 mm orthotopic corneal grafts of MHC-incompatible Wistar-Furth donors. TNF-alpha concentrations were measured in serum samples collected pre- and postoperatively and measured by micro ELISA. Clinical observations revealed graft rejection in 65.5% of corneal transplants 14 +/- 4 days following grafting. The mean serum level of TNF-alpha in control animals without corneal graft (group I) was 41 +/- 12 pg/ml. Animals following keratoplasty without allograft rejection (group II) showed a mean TNF-alpha level of 54 +/- 16 pg/ml that did not differ from group I. The rejection group III displayed significantly higher TNF-alpha levels (98 +/- 16 pg/ml, p < 0.05). These significantly elevated levels were found even before the diagnosis of rejection was established by clinical criteria. These data suggest systemic immunoreactivity to corneal allografts. Elevated levels of cytokines may provide valuable information in recipients undergoing rejection and may also provide a rationale for systemic immunotherapy in some instances.

Purpose: Liposomes and collagen corneal shields (CCS) have been used as ophthalmic drug delivery devices. With regard to a possibly combined application, we studied the effects of surface charge and bilayer fluidity of liposomes on their uptake and release by CCS., Methods: 12-hours-CCS were soaked in large unilamellar liposomes, which had been labelled with 4,5-carboxyfluorescein (CF) and N-(lissamine rhodamine B sulfonyl)-diacyl-phosphatidylethanolamine (PE-RhB) in the aqueous space and in the liposome bilayer, respectively. Released fluorophores were determined fluorometrically in the elution buffer at intervals from 1 to 240 min after immersion., Results: The CF concentration in the CCS soaked in a CF solution was two to seven times higher than immersion in the liposome suspensions. Among those, the negatively charged, cholesterol-containing preparation led to the highest CF concentration in the CCS. The PE-RhB concentration was highest after soaking the CCS in neutral, cholesterol-free liposomes. All types of liposomes were found inside the CCS by freeze fracture electron microscopy. The release kinetics data indicate a first order release. More than 90% of CF was released by the CCS within the first 30 min. This was equal after soaking the CCS in the CF solution or in liposomes. With DOPC-liposomes, the maximal release was already attained after 10 min. In general, the differences in the release kinetics of both hydrophilic and lipophilic markers, obtained by the various liposome types were small., Conclusions: Our results indicate that surface charge and bilayer fluidity are of minor importance for the interaction with collagen corneal shields. However, since the release kinetics of a liposome-encapsulated hydrophilic or lipophilic substance are similar to the release of a non-encapsulated drug, the combination of liposomes with collagen shields may be useful mainly with respect to the encapsulation of drugs which do not penetrate the ocular surface as well as to prolong corneal contact time of the liposomes.

We investigated the ability of liposomes to deliver the immunosuppressive agent cyclosporine A (CsA) to the cornea, anterior sclera, aqueous humor, and vitreous in rabbit eyes. One drop (10 microliters) of liposome-encapsulated CsA (CsA-LIP) or olive oil drops containing an equivalent concentration of CsA (CsA-DR) were administered at 15-minute intervals within the first hour and then one hourly over a 6-hour period. In addition, collagen shields soaked for 30 minutes in the liposome preparation (CsA-LIP-CS) were tested in vitro and in vivo as a new drug delivery approach. CsA levels were measured by fluorescence-immunoassay after 1, 3, or 6 hours of drug administration. CsA levels in this study were highest in cornea and anterior sclera. In animals receiving either CsA-DR or CsA-LIP, CsA levels generally increased from 1 to 6 hours. In animals receiving a single application of CsA-CS-LIP, CsA levels peaked at 3 hours and declined at 6 hours in cornea and sclera. CsA-LIP and CsA-CS-LIP delivered significantly higher levels of CsA to the cornea and sclera at 1 and 3 hours than CsA-DR. In aqueous and vitreous humor, CsA levels increased from 1 to 6 hours in animals receiving either CsA-DR or CsA-LIP. On the other hand, animals receiving a single application of CsA-CS-LIP had lower levels of CsA at 6 hours than at the earlier time points. Animals receiving CsA-LIP or CsA-CS-LIP had significantly higher levels of CsA in aqueous and vitreous humor at 1, 3, and 6 hours than animals receiving CsA-DR.(ABSTRACT TRUNCATED AT 250 WORDS)