Rosacea and Dry Eye Disease.

Ocular rosacea is a chronic potentially sight-threatening inflammatory condition, which can occur in approximately 20% of patients without skin involvement. However, an accurate diagnosis of ocular rosacea has not been defined yet due to its rather nonspecific symptoms and clinical findings. Therefore, this article updates the current recommendations for diagnosis and treatment of ocular rosacea and the previously published consensus recommendations from the ROSCO expert panel on the management of rosacea.

Drug-induced Sarcoid Uveitis with Biologics.

PURPOSE/OBJECTIVES: to evaluate new onset uveitis or reactivated uveitis by biologic agents and characterize their features. MATERIALS AND METHODS: This is a multicenter, retrospective case series. Patients under biologic therapy were included if they developed uveitis for the first time or experienced intraocular inflammation which was different in location or laterality to previous inflammation. RESULTS: Sixteen patients were identified. The underlying disorders included ankylosing spondylitis, juvenile idiopathic arthritis, rheumatoid arthritis, and Behçet's Disease. The biologic agents associated with a first episode of uveitis (n = 11) or with a new recurrence of uveitis (n = 5) were etanercept, adalimumab, abatacept, infliximab, and golimumab. Sarcoidosis based on bihilar lymphadenopathy, other computer tomography-findings, or biopsy was diagnosed in five patients under therapy with etanercep, adalimumab, and abatacept. Additionally, seven patients developed clinical changes in their uveitis pattern, suggesting sarcoid uveitis. CONCLUSIONS: Biologic treatment-induced uveitis often presents as granulomatous disease.

Importance of Treatment Duration: Unmasking Barriers and Discovering the Reasons for Undertreatment of Anti-VEGF Agents in Neovascular Age-Related Macular Degeneration.

PURPOSE: Since non-adherence (NA) to intravitreal therapy with VEGF drugs is one of the most important modifiable factors compromising treatment outcome of nAMD, the purpose of this study was to investigate the contributing factors and barriers during long-term nAMD treatment. METHODS: Barriers and potential reasons for NA were prospectively measured using the Adherence Barriers Questionnaire Intravitreal Therapy (ABQ-IVT). A random sample of patients receiving intravitreal therapy was drawn based on data for different treatment periods. Three age-sex matched groups included the treatment periods of ≤30 months (group 1), between >30 months and ≤60 months (group 2), and >60 months (group 3). The occurrence of gaps between treatments and/or OCT visits was evaluated. RESULTS: NA with gaps of >56 days after the scheduled appointment was detected in 39%, 89%, and 100% of patients in group 1, 2, and 3, respectively (groups 1 and 2 vs group 3, p < 0.001). Two or more of such gaps were observed in 6%, 72%, and 94% of patients in group 1, 2, and 3, respectively. The overall ABQ-IVT score showed corresponding differences between the groups: 25.89 ± 7.68 (group 1, 95% CI 22.07-29.71), 34.72 ± 10.32 (group 2, 95% CI: 29.59-38.86), and 33.28 ± 9.04 (group 3, 95% CI 28.78-37.77). Accordingly, the score was inversely correlated with the number of regular follow-up visits in groups 2 and 3 (Pearson correlation coefficient r = -0.65 (p = 0.003) and r = -0.5 (p = 0.034), respectively). Within the groups of longer treatment duration, univariate logistic regression analysis showed higher odds of time commitment and challenge accompanying person to be relevant barriers. CONCLUSION: NA is an arising problem with increasing duration of intravitreal therapy. Treatment barriers, detected by the ABQ-IVT, might change or increase during the course of the treatment.

Vitreoretinal Lymphoma.

Vitreoretinal lymphoma (VRL) is a rare variant of primary central nervous system lymphoma (PCNSL), mostly of diffuse large B cell lymphoma, which affects the retina and/or the vitreous with or without optic nerve involvement. The disease course is aggressive. Up to 90% of the patients develop central nervous system lymphoma within one year. The diagnosis of VRL is challenging due to nonspecific chronic and relapsing uveitis and is made by anterior chamber tab or vitreous aspirate biopsy. There is no established treatment protocol for VRL patients with bilateral involvement without CNS involvement. There are suggestions to use only intravitreal chemotherapy with methotrexate and/or rituximab. Alternatively, systemic high-dose MTX treatment or external beam radiotherapy is used. Further studies are needed to prove and confirm the prophylactic systemic therapy in preventing CNS involvement in limited VRL.

Consensus Recommendations for the Diagnosis of Vitreoretinal Lymphoma.

PURPOSE: To provide recommendations for diagnosis of vitreoretinal lymphoma (VRL). METHODS: Literature was reviewed for reports supporting the diagnosis of VRL. A questionnaire (Delphi 1 round) was distributed to 28 participants. In the second round (Delphi 2), items of the questionnaire not reaching consensus (75% agreement) were discussed to finalize the recommendations. RESULTS: Presenting symptoms include floaters and painless loss of vision, vitreous cells organized into sheets or clumps. Retinal lesions are usually multifocal creamy/white in the outer retina. Other findings include retinal lesions with "leopard-skin" appearance and retinal pigment epithelium atrophy. Severe vitreous infiltration without macular edema is the most likely presentation. Diagnostic vitrectomy should be performed. Systemic corticosteroid should be discontinued at least 2 weeks before surgery. An interleukin (IL)-10:IL-6 ratio > 1, positive mutation for the myeloid differentiation primary response 88 gene and monoclonality are indicators of VRL. Multi-modal imaging (optical coherence tomography, fundus autofluorescence) are recommended. CONCLUSIONS: A consensus meeting allowed the establishment of recommendations important for the diagnosis of VRL.

Viral anterior uveitis.

Viral anterior uveitis (VAU) needs to be suspected in anterior uveitis (AU) associated with elevated intraocular pressure, corneal involvement, and iris atrophic changes. Common etiologies of VAU include herpes simplex, varicella-zoster, cytomegalovirus, and rubella virus. Clinical presentations can vary from granulomatous AU with corneal involvement, Posner-Schlossman syndrome, Fuchs uveitis syndrome, and endothelitis. Due to overlapping clinical manifestations between the different viruses, diagnostic tests like polymerase chain reaction and Goldmann-Witmer coefficient analysis on the aqueous humor may help in identifying etiology to plan and monitor treatment.

Slit lamps and lenses: a potential source of nosocomial infections?

PURPOSE: The aim of the study was to evaluate the bacterial contamination level of contact surfaces on slit lamps and the grip areas of lenses. METHODS: Within unannounced audits, two regions of the slit lamps (headrest and joystick), indirect ophthalmoscopy devices, and ultrasound probes were obtained with rayon-tipped swab. Non-contact lenses used for indirect fundoscopy were pressed on RODAC (Replicate Organism Detection and Counting) plates. One hundred and eighty-one surfaces were sampled. The total number of colony-forming units was assessed and bacterial species were identified. Spa-typing and antimicrobial susceptibility testing were performed from Staphylococcus aureus isolates. RESULTS: Among the total bacterial isolates from ophthalmological equipment (lenses: 51 of 78, slit lamps: 43 of 88, ophthalmoscopy helmets: 3 of 8, ultrasound probes: 2 of 7), coagulase-negative staphylococci (CNS) was most frequently found, followed by Micrococcus spp. (lenses vs. slit lamps: P < 0.001 and P = 0.01, respectively). The bacterial contamination of lenses (76%) was significantly higher than that of slit lamps (54%) (P < 0.003). A significantly higher contamination with CNS was observed on lenses from residents vs. from consultants (78% vs. 35%, P = 0.01). A total of seven different spa-types of S. aureus were isolated. No correlation was found between S. aureus contamination of different ophthalmological equipments (Spearman's rank correlation coefficient, ρ = 0.04, P = 0.75). Methicillin-resistant S. aureus was not detected. CONCLUSION: Bacterial species of the normal skin flora were isolated from the ophthalmological equipment. The bacterial contamination of the portable devices was significantly higher than that of slit lamps. Therefore, proper hygiene of the mobile instruments should be monitored in order to prevent transmission of bacteria in residents and consultants.

Long-term Follow-up of Patients with Tubulointerstitial Nephritis and Uveitis (TINU) Syndrome.

PURPOSE: To evaluate the response to treatment in patients with tubulointerstitial nephritis and uveitis (TINU) syndrome over a long-term follow-up period. METHODS: Nine patients with TINU syndrome were retrospectively reviewed. The mean follow-up was 54.8 months (range: 24-133 months). RESULTS: The mean number of recurrences per year declined from 1.7 in the 1st year to 0.66 in the 2nd year of treatment. The ocular inflammation responded to local corticosteroids in two patients, systemic corticosteroids in two patients, immunosuppressive therapy in four patients, and anti-TNF-α blocking agent in one patient. The therapy could be discontinued in six (67%) patients after a mean treatment period of 29.5 months. In five patients, remission with the recurrence-free period of 12.8 months was achieved. CONCLUSIONS: TINU syndrome was characterized by limited responsiveness to corticosteroid therapy and less by severe complications. A long-term course of immunosuppressants or biologics was necessary to control the uveitis and led to induction of remission.

Correction to: pH of anti-VEGF agents in the human vitreous: low impact of very different formulations.

[This corrects the article DOI: 10.1186/s40942-017-0075-x.].

pH of anti-VEGF agents in the human vitreous: low impact of very different formulations.

BACKGROUND: The aim of the study was to measure pH changes of the human vitreous caused by the intravitreal drugs bevacizumab, ranibizumab, aflibercept, and ziv-aflibercept. METHODS: Fresh human vitreous samples were obtained during core vitrectomy (23-gauge) from patients with epiretinal gliosis. Aliquots of bevacizumab, ranibizumab, aflibercept or ziv-aflibercept (2 µl) were added consecutively to 200 µl of vitreous samples or 0.9% NaCl saline. The pH was measured using a pH-sensitive microelectrode. Rituximab, in off-label use against intraocular lymphoma, was tested as an IgG1 antibody. RESULTS: The pH of the administered drugs was 5.91 for bevacizumab (95% CI 5.63-6.19), 5.32 for ranibizumab (95% CI 5.0-5.63), 6.05 for aflibercept (95% CI 5.78-6.31), ziv-aflibercept 6.1 (95% CI 6.05-6.15), and 6.29 for rituximab (95% CI 5.97-6.61). While the fresh and undiluted vitreous fluid showed pH values of 7.0-7.4, pH values increased if saline or rituximab were added. In contrast, the pH decreased slightly if aflibercept, bevacizumab, ranibizumab or ziv-aflibercept were supplemented. The observed pH decreases were not significant after ranibizumab was added. Significant changes were only notable with higher-than-normal amounts of bevacizumab (26-40 µl). The vitreous showed the most robust buffering capacity towards ranibizumab and rituximab. CONCLUSIONS: The pH changes in vitreous samples elicited by the usual intravitreal anti-VEGF drugs differed clearly, but only by much higher concentrations than used in the clinical routine. Although the ingredient solution of ranibizumab showed the lowest pH, it caused only moderate changes of vitreal pH compared to bevacizumab, aflibercept or ziv-aflibercept.

Tocilizumab in Uveitic Macular Edema Refractory to Previous Immunomodulatory Treatment.

PURPOSE: To analyze the efficacy of tocilizumab in uveitic macular edema (ME) resistant to various immunomodulatory drugs. METHODS: Patients received tocilizumab every 4 weeks intravenously. Central foveal thickness (CFT) was assessed by optical coherence tomography (OCT). RESULTS: Five patients (8 eyes) who were ineffectively pretreated with systemic prednisolone, at least one immunosuppressive drug, and at least one biologic drug for uveitic macular edema were included in the study. At 3 months, a response of ME (≥25% reduction in CFT) was observed in 6 eyes (75.0%) of 5 patients. During follow-up, complete resolution of ME was achieved in 5 eyes (62.5%) of 4 patients. Improvement of BCVA was observed in 3 eyes of 3 patients, and stabilization in 3 eyes of 3 patients. Tocilizumab was well tolerated, and no severe side effects occurred. CONCLUSIONS: Treatment with tocilizumab can be considered in chronic uveitic macular edema even if previous immunomodulatory therapy has failed.

NLRP3 A439V Mutation in a Large Family with Cryopyrin-associated Periodic Syndrome: Description of Ophthalmologic Symptoms in Correlation with Other Organ Symptoms.

OBJECTIVE: Cryopyrin-associated periodic syndrome (CAPS) is a group of inherited autoinflammatory disorders caused by mutations in the NLRP3 gene resulting in the overproduction of interleukin 1ß. NLRP3 mutations cause a broad clinical phenotype of CAPS. The aims of the study were to evaluate clinical, laboratory, and genetic features of a 5-generation family with CAPS focusing in detail on ocular symptoms. METHODS: In a retrospective observational cohort study, consecutive family members were screened for the presence of the NLRP3 mutation. Patients underwent standardized clinical, laboratory, and ophthalmological assessments. The genotype-specific risk of ophthalmological findings and other organ symptoms was determined. RESULTS: Twenty-nine patients were clinically affected. The A439V mutation encoded by exon 3 of the NLRP3 gene was found in 15 of 37 family members (41%). The most common clinical features were musculoskeletal symptoms, headaches, and ophthalmological symptoms. The mutation-positive patients were characterized by more frequent skin rashes, ocular symptoms, arthralgia, arthritis, and severe Muckle-Wells syndrome (MWS) Disease Activity Score. Rosacea was diagnosed in 8 patients. CONCLUSION: The NLRP3 mutation A439V is associated with a heterogeneous clinical spectrum of familial cold autoinflammatory syndrome/MWS-overlap syndrome. Skin rash and eye diseases, such as conjunctivitis and uveitis, were positively correlated with this mutation.

Mycophenolate sodium for the treatment of chronic non-infectious uveitis of childhood.

AIM: To assess the efficacy and tolerability of mycophenolate sodium (MPS) in the therapy of children with chronic non-infectious uveitis. METHODS: Retrospective analysis of 23 children with chronic uveitis, treated with MPS, with a follow-up of at least 6 months. The main outcome measures were time to uveitis reactivation and corticosteroid-sparing effect under MPS treatment. The secondary outcome measures were best-corrected visual acuity (BCVA) and treatment-related side effects. RESULTS: From 23 patients included in the study, 2 patients had anterior uveitis, 19 had intermediate uveitis and 2 had panuveitis. The probability of reactivation-free survival after MPS initiation was estimated as 65% at both 1 and 2 years. The probability of discontinuing systemic corticosteroids after 1 year of treatment was 39% and after 2 years 51%. The probability to taper corticosteroids to a daily dosage of ≤0.1 mg/kg after 1 and 2 years was 62% and 85%, respectively. BCVA improved or remained stable in 96% of eyes after 1 year of therapy. Treatment-related side effects were found in nine children (rate: 0.17/patient-year). No therapy discontinuation because of side effects was needed. CONCLUSION: Our data suggest that MPS is useful and well tolerated in children with chronic uveitis. MPS seems to be an effective drug for the treatment of chronic non-infectious uveitis of childhood and may be preferred as a first-line steroid-sparing agent in this form of uveitis.

Safety of monoclonal antibodies and related therapeutic proteins for the treatment of neovascular macular degeneration: addressing outstanding issues.

INTRODUCTION: The vascular endothelial growth factor (VEGF) inhibitors most widely used to treat neovascular age-dependent macular degeneration (nAMD) are different proteins with structural features potentially relevant to adverse effects (AEs). Two of these are also established in cancer therapy (with higher dosages and AEs). The importance of ocular AE and extraocular activities is still a subject of controversy and ongoing research. AREAS COVERED: Potential risks of intraocular VEGF inhibition based on prospective studies, in vitro investigations, pharmacokinetics, and hints from anti-cancer treatment. EXPERT OPINION: nAMD is a frequently observed chronic clinical condition severely affecting the visual function of elderly persons. Intravitreal injection of VEGF-inactivating proteins is highly effective to prevent loss of vision. Anti-VEGF therapy is well tolerated, and low rates of ocular and systemic AEs in smaller trials suggest a very high benefit/risk ratio. The proteins established in nAMD therapy show similar efficacies. In the controversy over the off-label use of bevacizumab purely on grounds of much lower cost, the small, but potentially relevant differences between the available drugs are easily either dramatized (by pharmaceutical companies) or trivialized (by health insurances) and even political interference is involved. Facing the lack of a convincing body of evidence regarding safety, further long-term study results seem necessary.

Different Effects of Ranibizumab and Bevacizumab on Platelet Activation Profile.

PURPOSE: The aim of the study was to evaluate the potential influence of ranibizumab and bevacizumab on platelet activation and aggregation, which are critical processes in the pathogenesis of arterial thromboembolic events (ATEs). METHODS: For the assessment of platelet function, flow cytometry and aggregometry were employed. Platelets were isolated from healthy volunteers and exposed to ranibizumab (1 mg/ml and 150 ng/ml) and bevacizumab (2.5 mg/ml and 3 µg/ml) or their solvents for 10 and 30 min prior to the addition of TRAP (25 µM), PAR-4-AP (25 µM) or thrombin (0.02 U/ml). The surface expression of activated GP IIb/IIIa, P-selectin (CD62P) and platelet-bound stromal cell-derived factor-1 (SDF-1) was measured on resting (nonactivated) and activated platelets by flow cytometry. The platelet aggregation capacity was examined using light transmission aggregometry. RESULTS: The expression of surface activation markers did not differ significantly between nonstimulated and TRAP-, PAR-4-AP- or thrombin-activated platelets after incubating with ranibizumab. However, GP IIb/IIIa, CD62P and SDF-1 were significantly downregulated in PAR-4-AP- and thrombin-activated platelets after exposure to bevacizumab 2.5 mg/ml. In addition, ranibizumab- and bevacizumab-FITC were significantly increased in all activated platelets. No significant differences were observed in the aggregation of activated platelets after incubation with ranibizumab or bevacizumab. CONCLUSION: All ranibizumab concentrations as well as the bevacizumab concentration of 3 µg/ml had no influence on platelet activation and aggregation. Therefore, this in vitro study did not show any relationship between the exposition of activated platelets to ranibizumab or bevacizumab and the development of ATEs. However, the highest level of bevacizumab interfered with platelet activation, leading to downregulation of platelet activation markers. This observation might explain why the systemic treatment with high-dose bevacizumab could be associated with an increased risk of bleeding. Regarding the use of lower intravitreal dosages, further research should focus on the complex interactions between platelets and other cells, such as endothelial cells, which might stronger relate to a potentially increased risk of ATEs and depend on systemic vascular endothelial growth factor levels. Facing the different activation profiles, the diverse effects of the drugs on the cellular level have to be critically scrutinized for their clinical relevance.

Cytotoxic Effect of Voriconazole on Human Corneal Epithelial Cells.

BACKGROUND: To assess the cytotoxic properties of voriconazole and sulfobutylether-ß-cyclodextrin (SBECD) on cultured primary human corneal epithelial cells. METHODS: Human corneal epithelial cells were cultured and exposed to various concentrations of SBECD (0.016-32 mg/ml) and voriconazole (0.001-2 mg/ml). Cellular cytotoxicity of SBECD and voriconazole on human corneal epithelial cells was evaluated using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide test and the LIVE/DEAD Viability/Cytotoxicity Assay with fluorescence microscopy analysis. Cell damage was assessed with phase-contrast microscopy after 24 h of exposure to SBECD and voriconazole. RESULTS: The cytotoxicity tests and the morphological characteristic demonstrated the dose-dependent toxic effect of SBECD and voriconazole on human corneal epithelial cells. No corneal epithelial cytotoxicity was observed below the concentration of 0.08 and 0.025 mg/ml after 24-hour exposure to SBECD and voriconazole, respectively. CONCLUSIONS: The results of the study reveal the dose-dependent cytotoxic effect of SBECD and voriconazole on cultured human corneal epithelial cells. Therefore, voriconazole eye drops should be used cautiously in the treatment of fungal corneal ulcers.

Carl Friedrich Richard Foerster (1825-1902) - the inventor of perimeter and photometer.

Carl Friedrich Richard Foerster (1825-1902) was a German who was born in the Polish city Leszno. He studied medicine at the Medical Faculty of Breslau (now Wroclaw, Poland) University, and later in Heidelberg and Berlin. From 1855, he worked in Breslau, where he established in 1857 the first ophthalmology clinic. Later, he became a professor in ophthalmology, the first director of the Department of Ophthalmology at the University of Breslau, and even the rector of this University. Forster did many pioneering works on visual fields, invented a photometer and the first perimeter, known for many years as the Foerster perimeter. Moreover, he studied night blindness, visual field changes due to different pathologies, and many eye diseases, including glaucoma, cataract, retinal and choroidal diseases.

Treatment strategies in primary vitreoretinal lymphoma: a 17-center European collaborative study.

IMPORTANCE: The best treatment option for primary vitreoretinal lymphoma (PVRL) without signs of central nervous system lymphoma (CNSL) involvement determined on magnetic resonance imaging or in cerebrospinal fluid is unknown. OBJECTIVE: To evaluate the outcomes of treatment regimens used for PVRL in the prevention of subsequent CNSL. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study was conducted at 17 referral ophthalmologic centers in Europe. We reviewed clinical, laboratory, and imaging data on 78 patients with PVRL who did not have CNSL on presentation between January 1, 1991, and December 31, 2012, with a focus on the incidence of CNS manifestations during the follow-up period. INTERVENTIONS: The term extensive treatment was used for various combinations of systemic and intrathecal chemotherapy, whole-brain radiotherapy, and peripheral blood stem cell transplantation. Therapy to prevent CNSL included ocular radiotherapy and/or ocular chemotherapy (group A, 31 patients), extensive systemic treatment (group B, 21 patients), and a combination of ocular and extensive treatment (group C, 23 patients); 3 patients did not receive treatment. A total of 40 patients received systemic chemotherapy. MAIN OUTCOMES AND MEASURES: Development of CNSL following the diagnosis of PVRL relative to the use or nonuse of systemic chemotherapy and other treatment regimens. RESULTS: Overall, CNSL developed in 28 of 78 patients (36%) at a median follow-up of 49 months. Specifically, CNSL developed in 10 of 31 (32%) in group A, 9 of 21 (43%) in group B, and 9 of 23 (39%) in group C. The 5-year cumulative survival rate was lower in patients with CNSL (35% [95% CI, 50% to 86%]) than in patients without CNSL (68% [95% CI, 19% to 51%]; P = .003) and was similar among all treatment groups (P = .10). Adverse systemic effects occurred in 9 of 40 (23%) patients receiving systemic chemotherapy; the most common of these effects was acute renal failure. CONCLUSIONS AND RELEVANCE: In the present series of patients with isolated PVRL, the use of systemic chemotherapy was not proven to prevent CNSL and was associated with more severe adverse effects compared with local treatment.

One-staged aptamer-based isolation and application of endothelial progenitor cells in a porcine myocardial infarction model.

A multitude of stem cell types has been extensively studied and used for myocardial regenerative therapy. Amongst these endothelial progenitor cells form a promising source. In our present study, we investigated a one-staged approach for isolation and application of autologous endothelial progenitor cells in a pig model of myocardial infarction. Endothelial progenitor cell isolation was performed by immediately preprocedural bone marrow aspiration and consecutive positive selection by aptamer-based magnetic cell sorting. Animals were divided in three groups receiving endothelial progenitor cells, saline, or no intramyocardial injection respectively. Postprocedural follow-up consisted of weekly echocardiographic evaluations. Postmortem histological analysis after four weeks focused on detection of transplanted PKH26-positive endothelial progenitor cells and neovascularization within the infarcted myocardium. A significant difference in left ventricular ejection fraction could not be shown between the three groups. PKH26-stained endothelial progenitor cells could be found in the endothelial progenitor cells transplanted group, although detection was scarce. Large-sized capillaries were found to be significantly more in endothelial progenitor cells treated myocardium. The one-stage approach of endothelial progenitor cells isolation and application presented herein offers a new therapeutic concept. Even though a beneficial impact on myocardial function could not be assessed, increased neovascularization may indicate positive effects on remodeling processes. Being able to harvest endothelial progenitor cells right before application provides a wider scope of action in urgent cases.