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In recent years, syphilis (Treponema pallidum) has become increasingly prevalent in Canada, and as a result, rates of ocular syphilis are also rising. Classically, syphilis was seen primarily in men who have sex with men; now, it is increasingly seen in people of all age groups, sexes, and sexual orientations. We present a series of 26 cases of ocular syphilis from London, Ontario, 5 of which are discussed in detail to illustrate the varied presentations and diagnostic challenges of ocular syphilis. The presentations include uveitis, iris granuloma (gumma), retinitis (acute syphilitic posterior placoid chorioretinitis), vasculitis, optic neuritis, and serous retinal detachment. The 5 cases are mostly middle-aged heterosexual men and women without the typical risk factors that would alert the examiner to suspect syphilis. We emphasize the importance of testing for syphilis when assessing and treating inflammatory eye disease, regardless of demographics and known risk factors, given the increasing prevalence of this disease. Diagnosis of syphilis relies on serologic testing, which is complex and has undergone significant changes from historical reliance on the Venereal Disease Research Laboratory test. We provide an overview of the strategy and rationale for modern serologic testing. The mainstay of treatment remains intravenous penicillin G, with alternative antibiotics (e.g., ceftriaxone) being less effective.

To determine classification criteria for acute retinal necrosis (ARN).Machine learning of cases with ARN and 4 other infectious posterior uveitides / panuveitides.Cases of infectious posterior uveitides / panuveitides were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on diagnosis, using formal consensus techniques. Cases were split into a training set and a validation set. Machine learning using multinomial logistic regression was used on the training set to determine a parsimonious set of criteria that minimized the misclassification rate among the infectious posterior uveitides / panuveitides. The resulting criteria were evaluated on the validation set.Eight hundred three cases of infectious posterior uveitides / panuveitides, including 186 cases of ARN, were evaluated by machine learning. Key criteria for ARN included (1) peripheral necrotizing retinitis and either (2) polymerase chain reaction assay of an intraocular fluid specimen positive for either herpes simplex virus or varicella zoster virus or (3) a characteristic clinical appearance with circumferential or confluent retinitis, retinal vascular sheathing and/or occlusion, and more than minimal vitritis. Overall accuracy for infectious posterior uveitides / panuveitides was 92.1% in the training set and 93.3% (95% confidence interval 88.2, 96.3) in the validation set. The misclassification rates for ARN were 15% in the training set and 11.5% in the validation set.The criteria for ARN had a reasonably low misclassification rate and seemed to perform sufficiently well for use in clinical and translational research.

Purpose Determine the efficacy of combination intravitreal and systemic antiviral therapy for the treatment of acute retinal necrosis (ARN) and risk factors impacting visual acuity (VA) and retinal detachment (RD) outcomes. Design Single-center retrospective case series. Participants Patients with an ARN diagnosis based on clinical features and polymerase chain reaction confirmation who were treated at a tertiary referral, university-based academic practice. Methods Patient records were reviewed for demographic information including age and gender. Snellen VA, disease findings including RD outcomes, optic nerve involvement, and treatments were recorded. Incidence rates of major VA and RD outcomes were calculated based on the number of events and exposure times. Cox proportional hazards regression modeling and survival analyses were used to identify factors related to VA and RD outcomes over time. Main Outcome Measures Logarithm of the minimal angle of resolution VA, 2-line or more VA gain, severe vision loss (SVL) of 20/200 or worse, RD development, and fellow eye involvement. Results Twenty-three eyes of 21 patients (11 male, 10 female) were reviewed. Thirteen patients (62%) had herpes simplex virus and 8 patients (38%) had varicella zoster virus. The event rate for 2-line or more VA gain was 0.49 events/eye-year (95% confidence interval [CI], 0.26–0.86 events/eye-year), whereas the rate of SVL was 0.61 events/eye-year (95% CI, 0.34–1.02 events/eye-year). Retinal detachment development was observed at a rate of 0.59 events/eye-year (95% CI, 0.33–1.00 events/eye-year). Thirteen of 23 eyes (57%) demonstrated RD with a mean time of 120 days after ARN diagnosis. With each additional quadrant of retina involved, a greater risk of RD development over time was observed (hazard ratio, 2.21; 95% CI, 1.12–4.35). Nine percent of eyes progressed with additional quadrantic involvement, despite combination systemic and intravitreal antiviral therapy; however, none of the 19 patients demonstrating unilateral ARN showed fellow-eye involvement after initiation of therapy. Conclusions Combination intravitreal and systemic antiviral therapy for ARN can be effective in improving VA and limiting retinitis progression. Each additional quadrant of retina involved was associated with a 2.2-fold greater risk of RD, which may impact monitoring, timing of intervention, and patient counseling.

Introduction Bartonella henselae causes cat scratch disease (CSD), spread by a cat scratch or bite. Cats are its main reservoir. This sometimes results in optic neuritis or neuroretinitis. Objective To review these conditions in Gipuzkoa (Spain), 2014−2019. Methods A retrospective review of serology registries and clinical registries, selecting those with consistent clinical signs, contact with cats and positive serology for B. henselae (IgG-IFA ≥1/256). Results Sixty-four patients had CSD. Of these, one had optic neuritis and 3 had neuroretinitis (4/64; 6.3%). In 3 patients, flu-like symptoms preceded eye symptoms. Two suffered from loss of visual acuity at discharge, despite prolonged treatment with antibiotics and corticosteroids. Conclusion Optic neuritis and neuroretinitis caused by B. henselae are severe complications with a non-negligible incidence among patients with CSD in Gipuzkoa. We recommend ruling out CSD in patients with symptoms of optic neuritis or neuroretinitis (sudden vision loss, etc.) and contact with cats.

Case report A case is presented of a 60-year-old patient with loss of visual acuity in both eyes after fever and skin rash with palmoplantar involvement. After a complete examination and relevant complementary tests, the diagnosis of retinitis was made in the context of rickettsia conorii infection. The evolution after treatment with doxycycline and prednisone at 6 weeks with significant anatomical and functional improvement is presented. Rickettsiosis is an emerging zoonosis that can present with ocular involvement. This is usually a multifocal retinitis affecting posterior pole with macular serous detachment and vitritis. Clinical suspicion will require serological confirmation for a definitive diagnosis. Treatment with antibiotics and corticosteroids has been shown to be effective. It should be taken into account in Mediterranean endemic areas, and in in the summer period, where the risk is much higher.

Uveitis is a sight-threatening intraocular inflammatory disease that accounts for almost 10% of blindness worldwide. NF-κB signaling plays pivotal roles in inflammatory diseases. We have reported that IMD-0354, which inhibits NF-κB signaling via selective blockade of IKK-β, suppresses inflammation in several ocular disease models. Here, we examined the therapeutic effect of IMD-0354 in an experimental autoimmune uveoretinitis (EAU) model, a well-established animal model for endogenous uveitis in humans. Systemic administration of IMD-0354 significantly suppressed the clinical and histological severity, inflammatory edema, and the translocation of NF-κB p65 into the nucleus of retinas in EAU mice. Furthermore, IMD-0354 treatment significantly inhibited the levels of several Th1/Th17-mediated pro-inflammatory cytokines in vitro. Our current data demonstrate that inhibition of IKKβ with IMD-0354 ameliorates inflammatory responses in the mouse EAU model, suggesting that IMD-0354 may be a promising therapeutic agent for human endogenous uveitis.

Purpose Collapsin response-mediator protein 5 (CRMP5) immunoglobulin G (IgG) has been associated with paraneoplastic optic neuritis, vitritis, retinitis, or a combination thereof, but few reports of these findings exist in the literature. We reviewed the neuro-ophthalmic findings and visual outcomes in a large series of CRMP5 IgG–positive patients to characterize further its clinical phenotype and response to treatment. Design Retrospective case series. Participants Seventy-six patients with CRMP5 autoimmunity examined at the Mayo Clinic, Rochester, Minnesota. Methods Single academic medical center chart review of all CRMP5 IgG–positive (serum titer, >1:240) patients seen between 2001 and 2017. Main Outcome Measures Neuro-ophthalmic manifestations and outcomes of CRMP5 autoimmunity, coexisting neural autoantibody presence and paraneoplastic associations, and the impact of immunosuppressant therapy. Results Twenty-nine of 76 patients (38%) demonstrated neuro-ophthalmic manifestations. Of the 29 patients with neuro-ophthalmic findings, the median age was 67 years (range, 33–88 years) and 20 (69%) were women. Cancer was diagnosed in 62% of the patients (small-cell carcinoma in 83%). Neuro-ophthalmic symptoms occurred before the diagnosis of cancer in 72%. Seventeen of 29 patients (59%) showed ocular (i.e., anterior visual pathway or intraocular) manifestations; presenting median visual acuity was 20/50 (range, 20/20–counting fingers) and the final median visual acuity was 20/40 (range, 20/20–hand movements). Fourteen of 17 patients (82%) demonstrated optic neuropathy, with 12 of these patients also showing retinitis or uveitis. Three of 17 patients (18%) showed retinitis or uveitis without optic neuropathy. All 12 patients with optic neuropathy and a documented fundus examination at visual symptom onset demonstrated optic disc edema. No patients showed optic nerve enhancement on magnetic resonance imaging. Twelve of 29 patients (41%) demonstrated ocular motility dysfunction consisting of central nystagmus and diplopia. Among those receiving immunosuppressive therapy, visual function improved in 50%. Conclusions In our cohort of 29 CRMP5 IgG–positive patients with neuro-ophthalmic manifestations, optic neuropathy presented with optic disc edema, often associated with uveitis, retinitis, or both. The combination of retinitis, vitritis, and optic disc edema without optic nerve enhancement should prompt serologic testing for CRMP5 IgG to expedite vision-sparing immunosuppressant therapy and a targeted search for a systemic cancer.

Chikungunya, a zoonotic disease caused by the Chikungunya virus (CHIKV), is transmitted by infected Aedes spp mosquitoes. CHIKV has now spread to more than 100 countries and is listed on the WHO Blueprint priority pathogens. After an incubation period of 1 to 12 days, symptoms similar to other febrile infections appear, with a sudden onset of high fever, nausea, polyarthralgia, myalgia, widespread skin rash, and conjunctivitis. Serious complications include myocarditis, uveitis, retinitis, hepatitis, acute renal disease, severe bullous lesions, meningoencephalitis, Guillain-Barre syndrome, myelitis, and cranial nerve palsies. Treatment is supportive; there is no specific antiviral treatment and no effective vaccine.

A descriptive study is presented on a case series of 3 patients, with IgM an IgG serology diagnosis of Chikungunya in whom other metabolic, autoimmune and infectious diseases were ruled out. They presented with other ocular manifestations with vascular changes and inflammatory characteristics. They were treated at the Retinovascular and Retinal and Vitreous clinics at the “Dr. Rodolfo Robles Valverde Hospital” and “Benemerito Comite Pro-ciegos y Sordos” in Guatemala City during 2019. Guatemala is a country with a high prevalence of vector-borne diseases, including chikungunya. In recent years cases of this disease has increased in recent years, and complications are currently seen more frequently. Within these complications, there have been reports of cases of optic neuritis, iridocyclitis, episcleritis, retinitis, uveitis, and blood dyscrasia that can affect the retina. It is important to consider these as an important differential diagnosis of ocular vascular alterations.

A 51 year-old man with hairy cell leukaemia was treated with pentostatin. While receiving the treatment, he was diagnosed with herpes retinitis in his right eye. After the last cycle of pentostatin the patient developed a mild vitritis and cystoid macular oedema. There were no signs of herpes retinitis reactivation. After excluding other possible causes of intraocular inflammation, a diagnosis of immune recovery uveitis was made. The patient was treated with 2-monthly retro-septal injections of triamcinolone, oral corticosteroids, intravitreal dexamethasone implants and, finally, pars plana vitrectomy. An immune recovery uveitis-like response is possible in HIV negative individuals. The immune reconstitution after the treatment of hairy cell leukaemia may have led to intraocular inflammation. Management of immune recovery uveitis is challenging and difficult. Pars plana vitrectomy may be necessary. Ophthalmologists should be alert to the possibility of immune recovery uveitis in HIV negative patients.

Vascular inflammation plays a critical role in the pathogenesis of diabetic retinopathy. Recently, Interleukin-6 (IL-6) trans-signaling via soluble IL-6 receptor (sIL-6R) has emerged as a prominent regulator of inflammation in endothelial cells. This study was designed to test the hypothesis that selective inhibition of the IL-6 trans-signaling pathway will attenuate inflammation and subsequent barrier disruption in retinal endothelial cells. Human retinal endothelial cells (HRECs) were exposed to IL-6 and sIL-6R to induce IL-6 trans-signaling and the commercially available compound sgp130Fc (soluble gp-130 fused chimera) was used to selectively inhibit IL-6 trans-signaling. IL-6 trans-signaling activation caused a significant increase in STAT3 phosphorylation, expression of adhesion molecules, ROS production and apoptosis in HRECs whereas a significant decrease in mitochondrial membrane potential and NO production was observed in IL-6 trans-signaling activated cells. These changes were not observed in cells pre-treated with sgp130Fc. IL-6 trans-signaling activation was sufficient to cause barrier disruption in endothelial monolayers and pre-treatment of HRECs with sgp130Fc, maintained endothelial barrier function similar to that of untreated cells. Thus, in conclusion, these results indicate that IL-6 trans-signaling is an important mediator of inflammation, apoptosis and barrier disruptive effects in the retinal endothelial cells and inhibition of the IL-6 trans-signaling pathway using sgp130-Fc attenuates vascular inflammation and endothelial barrier disruption.

The case is presented of a 52-year-old woman with scleroderma, mixed connective tissue disease, and interstitial lung disease, who developed chronic cytomegalovirus necrotising retinitis while on treatment with prednisone, mycophenolate, and hydroxychloroquine. Initially diagnosed as macular hole, the patient underwent a pars plana vitrectomy. Two months after surgery, due to progressive worsening, the diagnosis was made and treatment started (intravenous and intravitreal ganciclovir). The patient developed severe macular atrophy with final visual acuity of counting fingers. A chronic retinal necrosis can be caused by cytomegalovirus infection in non-HIV patients with partial immune dysfunction from other causes, characterised by a slowly progressive granular retinitis with occlusive vasculitis.

It is by-far known that COVID-19 has affected all the aspects of life but it is lesser known that it has also an unprecedented effect on overall eye health. Many studies have shown that COVID-19 also affects the eye and clinical symptoms like conjunctivitis, anterior uveitis, retinitis, and optic neuritis has been found in the patient but it still needs to be studied more. The virus has not only affected the eye directly but also impacted it with the challenges that have been imposed by the lockdown. Isolation has been cautious by restricting own self in digital systems, it is the bigger consequence of COVID-19 as it has affected people all over the globe. In this article, we will study the effect of the digital system on eye health and it is found that longer use of the digital system causes serious eye health problems.

Changes in permeability of retinal blood vessels contribute to macular edema and the pathophysiology of numerous ocular diseases, including diabetic retinopathy, retinal vein occlusions, and macular degeneration. Vascular endothelial growth factor (VEGF) induces retinal permeability and macular thickening in these diseases. However, inflammatory agents, such as tumor necrosis factor-α (TNF-α), also may drive vascular permeability, specifically in patients unresponsive to anti-VEGF therapy. Recent evidence suggests VEGF and TNF-α induce permeability through distinct mechanisms; however, both require the activation of atypical protein kinase C (aPKC). We provide evidence, using genetic mouse models and therapeutic intervention with small molecules, that inhibition of aPKC prevented or reduced vascular permeability in animal models of retinal inflammation. Expression of a kinase-dead aPKC transgene, driven by a vascular and hematopoietic restricted promoter, reduced retinal vascular permeability in an ischemia-reperfusion model of retinal injury. This effect was recapitulated with a small-molecule inhibitor of aPKC. Expression of the kinase-dead aPKC transgene dramatically reduced the expression of inflammatory factors and blocked the attraction of inflammatory monocytes and granulocytes after ischemic injury. Coinjection of VEGF with TNF-α was sufficient to induce permeability, edema, and retinal inflammation, and treatment with an aPKC inhibitor prevented VEGF/TNF-α-induced permeability. These data suggest that aPKC contributes to inflammation-driven retinal vascular pathology and may be an attractive target for therapeutic intervention.

The definition of the negative response of the full field electroretinogram is the presence of a b-wave with less amplitude than the a-wave (b/a ratio

In the present study, therapeutic effect of topically applied everolimus (EV)-loaded methoxy-poly(ethylene-glycol)-hexyl substituted poly (lactic acid) (mPEGhexPLA) nanocarriers on experimental autoimmune uveoretinitis (EAU) were investigated. EAU was induced in B10.RIII mice via immunization with human interphotoreceptor retinoid-binding protein peptide 161-180 (hIRBPp161-180) in complete Freund's adjuvant. Everolimus-loaded mPEGhexPLA (EV/mPEGhexPLA) nanocarriers were prepared by using a solvent evaporation method. On days 12-21 postimmunization (p.i.), the right eyes were treated five times daily either with 10 μl of 0.5% everolimus formulation or PBS (control). The EAU score of the eyes was determined histologically. On day 21 p.i., the peripheral immune responses were measured in serum, cervical lymph nodes (LN), and spleens via hIRBPp161-180-specific serum antibodies, cytokine secretion (ELISA), lymphocyte proliferation, and FoxP3+ regulatory T cells (Treg; flow cytometry). Compared to the PBS-treated mice, unilateral topical everolimus treatment significantly reduced EAU severity in both eyes (p .05). The treatment reduced the antigen (Ag)-specific hIRBPp161-180-induced proliferation (p .05), IL-2, IL-17, and IFN-γ secretion from cells isolated from the left and right cervical LN (p .05). Under everolimus treatment, IL-10 secretion and CD4

Cytomegalovirus (CMV) retinitis is a vision-threatening disease that principally afflicts immunosuppressed patients. For the management of the disease, Ganciclovir (GCV) is usually administered systemically, where patients may suffer severe untoward effects. The ocularly-applied alternatives are either the intravitreal injections, which are frequently administered due to GCV short half-life, or the sustained-release implants, which require surgical removal upon drug depletion. Both therapies are invasive and should be completed by a medical expert. The objective of this research was to formulate a non-invasive alternative represented in GCV loaded ultra-fluidic glycerosomes (UFGs), which are glycerosomes containing sodium taurocholate as an edge activator (EA), then incorporating the optimal UFGs in polylactic acid (PLA)-based 3D printed ocusert to prolong the release of GCV. The experimental design, the statistical analysis, and the optimization were performed via Design-Expert® software. The optimal formulation (UFGs 6; composed of 600 mg Phosphatidylcholine (PC), 20 mg cholesterol, 0.1:1 weight molar ratio of EA: PC and 1 gm glycerol) possessed nanovesicles (441.70 ± 1.13 nm) that entrapped 69.33 ± 0.28 % of GCV, with zeta potential value of −37.00 ± 0.42 mV and deformability index value of 74.68 ± 0.71. The confocal microscopy results showed the supreme penetration power of UFGs through the rabbit’s cornea, compared to edge-activated vesicles and conventional glycerosomes from the laden ocusert. Moreover, the topical application of the ocusert laden with the optimal GCV loaded UFGs to the rabbits’ eyes evidenced their safety as per the histopathological findings. Furthermore, a pharmacokinetic study in the rabbit’s aqueous humor demonstrated the sustained release of GCV from the ocusert laden with the optimal GCV loaded UFGs over 5 days. Inclusively, the ocusert laden with UFGs could be considered as a non-invasive sustaining drug delivery system of GCV for the management of CMV retinitis.

Pyroptosis is a caspase-dependent programmed cell death pathway that initiates and sustains inflammation through release of pro-inflammatory cytokines interleukin (IL)-1β and IL-18 following formation of gasdermin D (GSDMD)-mediated membrane pores. To determine the possible pathogenic contributions of pyroptosis toward development of full-thickness retinal necrosis during AIDS-related human cytomegalovirus retinitis, we performed a series of studies using an established model of experimental murine cytomegalovirus (MCMV) retinitis in mice with retrovirus-induced immunosuppression (MAIDS). Initial investigations demonstrated significant transcription and translation of key pyroptosis-associated genes within the ocular compartments of MCMV-infected eyes of mice with MAIDS. Subsequent investigations compared MCMV-infected eyes of groups of wildtype MAIDS mice with MCMV-infected eyes of groups of caspase-1(−/−) MAIDS mice, GSDMD(−/−) MAIDS mice, or IL-18(−/−) MAIDS mice to explore a possible contribution of pyroptosis towards the pathogenesis of MAIDS-related MCMV retinitis. Histopathologic analysis revealed typical full-thickness retinal necrosis in 100% of MCMV-infected eyes of wildtype MAIDS mice. In sharp contrast, none (0%) of MCMV-infected eyes of MAIDS mice that were deficient in either caspase-1, GSDMD, or IL-18 developed full-thickness retinal necrosis but instead exhibited an atypical pattern of retinal disease characterized by thickening and proliferation of the retinal pigmented epithelium layer with relative sparing of the neurosensory retina. Surprisingly, MCMV-infected eyes of all groups of deficient MAIDS mice harbored equivalent intraocular amounts of infectious virus as seen in MCMV-infected eyes of groups of wildtype MAIDS mice despite failure to develop full-thickness retinal necrosis. We conclude that pyroptosis plays a significant role in the development of full-thickness retinal necrosis during the pathogenesis of MAIDS-related MCMV retinitis. This observation may extend to the pathogenesis of AIDS-related HCMV retinitis and other AIDS-related opportunistic virus infections.

AIDS-related human cytomegalovirus retinitis remains a leading cause of blindness worldwide. We compared two C57BL/6 mouse models of experimental murine cytomegalovirus (MCMV) retinitis for intraocular expression of suppressors of cytokine signaling (SOCS)1 and SOCS3, host proteins that are inducible negative feedback regulators of cytokine signaling. These mouse models differed in method of immune suppression, one by retrovirus-induced immune suppression (MAIDS) and the other by corticosteroid-induced immune suppression. Following subretinal injection of MCMV to induce retinitis, intraocular SOCS1 and SOCS3 were only mildly stimulated, and often without significance, within MCMV-infected eyes during the progression of MCMV retinitis in corticosteroid-immunosuppressed mice, contrary to MCMV-infected eyes of mice with MAIDS that showed significant high stimulation of SOCS1 and SOCS3 expression in agreement with previous findings. Frequency and severity of retinitis as well as amounts of intraocular infectious MCMV in corticosteroid-immunosuppressed mice were also unexpectedly lower than values previously reported for MAIDS animals during MCMV retinitis. These data reveal a major difference between two mouse models of experimental MCMV retinitis and suggest a possible link between the amplitude of SOCS1 and SOCS3 stimulation and severity of disease in these models.

Cytomegalovirus (CMV) retinitis is an opportunistic ocular infection most commonly observed in patients infected with human immunodeficiency virus (HIV). We present a rare case of CMV retinitis that developed in a non-HIV patient with rheumatoid arthritis (RA). Over the preceding 5 months, a family doctor had been treating the 78-year-old male patient with a combination therapy of methotrexate (MTX) and tofacitinib (TOF). CMV retinitis occurred when the patient's CD4+ T cells were low (196 cells/μl), and preceded the onset of Pneumocystis pneumonia. MTX and TOF were stopped after the diagnosis of CMV retinitis. While intravenous and intravitreal ganciclovir administration significantly improved the CMV retinitis, uveitis developed 3 months later during the maintenance therapy with oral valganciclovir, concomitantly with the recovery of the CD4+ T cell counts. As we believed this uveitis was caused by the immune reconstitution mechanism, we treated the patient with a retrobulbar injection of corticosteroids. During the 6 months following the cessation of MTX and TOF, there was no flare-up of the RA. Cases of CMV retinitis and immune recovery uveitis in RA patients have been rarely reported in the literature. In the current case, the intensive immunosuppressive therapy in this elderly patient might have been the cause of this unusual opportunistic complication of RA.

Purpose To identify determinants of adverse outcomes in acute retinal necrosis (ARN), presenting characteristics and incidence rates of vision loss and ocular complications in a cohort of polymerase chain reaction (PCR)-positive eyes were analyzed. Design Retrospective observational cohort study. Methods Forty-one eyes of 36 patients with clinically diagnosed ARN, PCR-positive for herpes simplex virus or varicella zoster virus and evaluated between January 2002 and June 2013, were included. Main outcome measures included incidence rates of vision loss and retinal detachment (RD). Results Presenting visual acuity was generally poor (20/50 to >20/200 in 27%; 20/200 or worse in 56%). The incidence rate of ≤20/200 was 0.66/eye-year (EY), (95% confidence interval [CI], 0.32/EY to 1.22/EY); the rate of light perception or no light perception vision was 0.07/EY (95% CI, 0.02/EY to 0.16/EY). During follow-up, 59% of eyes developed at least 1 RD (rate = 0.40/EY, 95% CI, 0.19/EY to 0.58/EY). Eyes with retinitis involving ≥25% of the retina at presentation detached at nearly 12 times the rate, as compared to those with P = .001). Development of an RD was the greatest determinant of adverse visual outcomes, with 4% of eyes, that had experienced at least 1 RD, achieving a best-corrected visual acuity of ≥20/40 compared to 53% of eyes that never detached ( P = .0003). Conclusions Poor outcomes in ARN were common in this cohort. RD confers the greatest risk of incident vision loss, and once 25% or more of the retina is involved the risk of RD and visual loss increases significantly.

Diabetic macular edema (DME) is caused by blood-retinal barrier breakdown associated with retinal vascular hyperpermeability and inflammation, and it is the major cause of visual dysfunction in diabetic retinopathy. Adrenomedullin (ADM) is an endogenous peptide first identified as a strong vasodilator. ADM is expressed in the eyes and is up-regulated in various eye diseases, although the pathophysiological significance is largely unknown. We investigated the effect of ADM on DME. In Kimba mice, which overexpress human vascular endothelial growth factor in their retinas, the capillary dropout, vascular leakage, and vascular fragility characteristic of diabetic retinopathy were observed. Intravitreal or systemic administration of ADM to Kimba mice ameliorated both the capillary dropout and vascular leakage. Evaluation of the transendothelial electrical resistance and fluorescein isothiocyanate-dextran permeability of an endothelial cell monolayer using TR-iBRB retinal capillary endothelial cells revealed that vascular endothelial growth factor enhanced vascular permeability but that co-administration of ADM suppressed the effect, in part by enhancing tight junction formation between endothelial cells. In addition, a comprehensive PCR array analysis showed that ADM administration suppressed various molecules related to inflammation and NF-κB signaling within retinas. From these results, we suggest that by exerting inhibitory effects on retinal inflammation, vascular permeability, and blood-retinal barrier breakdown, ADM could serve as a novel therapeutic agent for the treatment of DME.

Summary Accumulating evidence shows that extracellular vesicles (EVs) produced by mesenchymal stem/stromal cells (MSCs) exert their therapeutic effects in several disease models. We previously demonstrated that MSCs suppress autoimmunity in models of type 1 diabetes (T1D) and experimental autoimmune uveoretinitis (EAU). Therefore, here, we investigated the therapeutic potential of MSC-derived EVs using our established mouse models for autoimmune diseases affecting the pancreas and the eye: T1D and EAU. The data demonstrate that MSC-derived EVs effectively prevent the onset of disease in both T1D and EAU. In addition, the mixed lymphocyte reaction assay with MSC-derived EVs indicated that EVs inhibit activation of antigen-presenting cells and suppress development of T helper 1 (Th1) and Th17 cells. These results raise the possibility that MSC-derived EVs may be an alternative to cell therapy for autoimmune disease prevention., Highlights • MSC-derived EVs prevent the onset of T1D and EAU • MSC-derived EVs suppress Th1 and Th17 cell development • MSC-derived EVs suppress activation of antigen-presenting cells and T cells, In this article, Ryang Hwa Lee and colleagues show that mesenchymal stem/stromal cell-derived extracellular vesicles prevent the onset of autoimmune disease in two murine models, type 1 diabetes and experimental autoimmune uveoretinitis, by mainly suppressing Th1 and Th17 cell development.

Purpose To evaluate the rates of new-onset cytomegalovirus (CMV) retinitis and worsening existing CMV retinitis in patients with AIDS after initiating combination antiretroviral therapy (cART) and the role of an immune recovery inflammatory syndrome (IRIS). Design Cohort study. Methods Immune recovery was defined as an increase in CD4 + T cells to ≥100 cells/μL; rates of new-onset CMV retinitis and of worsening of CMV retinitis (either increasing border activity or retinitis progression) were compared between those with and without immune recovery. Results Among patients without CMV retinitis, 1 of 75 patients with immune recovery developed CMV retinitis in the first 6 months after initiating cART vs 1 of 31 without immune recovery ( P = .14). Among patients with CMV retinitis, the rates of retinitis progression and increasing retinitis border activity among patients during the first 6 months after initiating cART in those with immune recovery were 0.11 per person-year (PY; 95% confidence interval [CI] 0–0.62) and 0.11 per PY (95% CI 0–0.62), respectively, vs 0.67 per PY (95% CI 0.22–1.56) and 0.40 per PY (95% CI 0.08–1.17), respectively, for those without immune recovery ( P = .11 and .47). Conclusions Among persons with AIDS who experience immune recovery, there was neither an increased rate of new-onset CMV retinitis nor worsening of existing CMV retinitis in the first 6 months after initiating cART vs those without immune recovery. These data are consistent with the known 3- to 6-month lag in recovery of specific immunity to CMV after initiating cART and suggest that "immune recovery retinitis," a proposed immune recovery inflammatory syndrome phenomenon, is rare.

Introduction In transplant recipients, CMV infection RR to prior antiviral Tx is associated with significant morbidity and mortality. Existing antivirals are not approved for RR CMV infection and are limited by their toxicities. A prior Phase 2 dose-ranging study of MBV for RR CMV (67% of patients [pts] achieved undetectable CMV DNA within 6 wks) motivated initiation of a Phase 3 trial with the concept of an investigator-assigned (IA) Tx comparator arm. Objective To assess the efficacy and safety of MBV compared with IA anti-CMV therapies in HSCT/SOT recipients with RR CMV infection. Methods In this Phase 3, randomized, open-label, multicenter, active-controlled study (NCT02931539), HSCT/SOT recipients (≥12 years old) with RR CMV infection are randomized 2:1 to MBV (400 mg BID) or IA Tx (ganciclovir [GCV], valganciclovir [VGC], foscarnet [FSC], cidofovir [CDV]) for 8 wks. Pts in the IA Tx group discontinuing Tx early (lack of response and/or intolerance; investigator discretion) are assessed Wks 3–7 to enter MBV rescue arm. Pts are followed for 12 wks after the 8-wk Tx period. Inclusion criteria include: documented CMV infection with screening value ≥2730 IU/mL / ≥910 IU/mL (whole blood / plasma) in 2 consecutive tests ≥1 day apart; current refractory CMV infection: documented failure to achieve >1 log10 decrease in CMV DNA after ≥14 days of the same anti-CMV Tx. Pts with ≥1 genetic mutation associated with GCV/VGC, FSC or CDV resistance must also meet refractory criteria. Pts with tissue invasive CMV disease with CNS involvement including the retina, eg CMV retinitis, are excluded. A central specialty laboratory quantifies plasma CMV DNA (COBAS ‘AmpliPrep/TaqMan' CMV test). The primary efficacy endpoint is confirmed CMV viremia clearance (defined as plasma CMV DNA concentrations Results Planned enrollment is 351 pts across ∼140 sites (North America, Europe, Asia Pacific). Study start, Dec 2016; completion ∼Sep 2020. Conclusions The comparator arm of this Phase 3 study is valid for evaluating efficacy and safety of MBV for RR CMV compared with available anti-CMV Tx, whilst allowing for personalized Tx for pts in the comparator group.

Experimental autoimmune uveoretinitis (EAU) represents an experimental model for human endogenous uveitis, which is caused by Th1/Th17 cell-mediated inflammation. Natural killer T (NKT) cells recognize lipid antigens and produce large amounts of cytokines upon activation. To examine the role of NKT cells in the development of uveitis, EAU was elicited by immunization with a peptide from the human interphotoreceptor retinoid-binding protein (hIRBP1-20) in complete Freund's adjuvant and histopathology scores were evaluated in C57BL/6 (WT) and NKT cell-deficient mice. NKT cell-deficient mice developed more severe EAU pathology than WT mice. When WT mice were treated with ligands of the invariant subset of NKT cells (α-GalCer or RCAI-56), EAU was ameliorated in mice treated with RCAI-56 but not α-GalCer. IRBP-specific Th1/Th17 cytokines were reduced in RCAI-56-treated compared with vehicle-treated mice. Although the numbers of IRBP-specific T cells detected by hIRBP3-13/I-Ab tetramers in the spleen and the draining lymph node were the same for vehicle and RCAI-56 treatment groups, RORγt expression by tetramer-positive cells in RCAI-56-treated mice was lower than in control mice. Moreover, the eyes of RCAI-56-treated mice contained fewer IRBP-specific T cells compared with control mice. These results suggest that invariant NKT (iNKT) cells suppress the induction of Th17 cells and infiltration of IRBP-specific T cells into the eyes, thereby reducing ocular inflammation. However, in sharp contrast to the ameliorating effects of iNKT cell activation during the initiation phase of EAU, iNKT cell activation during the effector phase exacerbated disease pathology. Thus, we conclude that iNKT cells exhibit dual roles in the development of EAU.

Cytomegalovirus can cause severe disease in immunocompromised patients including encephalomyelitis, hepatitis, pneumonitis, colitis and retinitis. CMV induced myelitis and hepatitis are rare in immunocompetent patients. Following a thorough search on the literature using pubmed, there were only 10 well documented CMV-induced transverse myelitis cases reported worldwide. We report a healthy young male who developed longitudinal extensive transverse myelitis and acute hepatitis secondary to CMV infection. Our case is different from the other cases as our patient had concurrent acute hepatitis and received plasma exchange therapy (PLEX) in addition to pulsed steroids and antivirals. The patient recovered well and had an excellent outcome.

Idiopathic retinal vasculitis, aneurysms and neuroretinitis (IRVAN) syndrome is a rare entity of unknown etiology for which many hypotheses have been proposed with inflammation being the most commonly accepted hypothesis. We report cases of a 9 year old girl and a 22 year old male patient with diagnosis of IRVAN syndrome. The conclusions drawn from the clinical examination and multimodal imaging including optical coherence tomography angiography of the patients are discussed. Our conclusions and interpretation point towards IRVAN being a developmental vascular anomaly rather than a consequence of inflammation. It is thus proposed to be renamed as Idiopathic retinal arteriolar aneurysm syndrome (IRAA).

Introduction Acute retinal necrosis manifests as necrotizing retinitis, vitritis, occlusive vasculitis and retinal detachment with loss of vision. It is most commonly caused by Varicella Zoster Virus (VZV), Cytomegalovirus (CMV), Toxoplasmosis, and Herpes Simplex Virus (HSV) and can occur in immunocompetent and immunocompromised individuals. Case Report Our patient is a 63 year old female with a history of end stage ischemic cardiomyopathy who underwent orthotopic heart transplantation. She received thymoglobulin for induction and her first year post-transplant was notable for no episodes of rejection or infection. She was maintained on antiviral prophylaxis with valgancylovir until 7 months post-transplant. By 1 year post-transplant she was maintained on a regimen of Tacrolimus and Mycophenolate Mofetil (MMF). Her Allomap levels were Summary Isolated retinal necrosis due to VZV is a rare but important complication after solid organ transplant. Early recognition and treatment is crucial in preventing permanent vision loss. Adjustment of immunosuppression regimen is key in clearing active infection and preventing transplant rejection. Proactive reduction of immunosuppression should be considered to prevent viral reactivations after 1 year. Post-transplant vaccination against zoster may also be helpful.

Purpose To describe a rare case of von Szily reaction (VSR) accompanied by a comprehensive review of the literature. Observations A 57-year-old woman with herpes zoster ophthalmicus (HZO) associated with ipsilateral sectoral scleritis and anterior uveitis (sclerouveitis) subsequently developed contralateral necrotizing retinitis, leading to a diagnosis of VSR. A literature review revealed 10 additional cases of VSR. The full VSR cohort of 11 subjects included six women and five men, had a median age of 39 years (range 21–78 years), and most presented with HZO (n = 7, 63.6%), often associated with either ipsilateral anterior uveitis (n = 5; 45.5%) or keratitis (n = 4; 36.4%). All 11 cases developed necrotizing retinitis in the fellow eye, at a median of six weeks following onset in the sentinel eye. The most frequently implicated agent was varicella zoster virus (VZV; n = 8, 72.7%). A high proportion of the eight patients with VZV-associated VSR were identified as having increased risk of VZV reactivation, including age of 50 years or greater (n = 5, 62.5%), an underlying malignancy (n = 3, 37.5%), and/or use of immunosuppressive medication (n = 2, 25.0%). Conclusion This was the first reported case of VSR presenting as HZO-associated with sclerouveitis. A comprehensive literature review revealed that most previously reported cases presented with HZO associated with isolated anterior uveitis and/or keratitis, and that all reported cases of VSR developed necrotizing retinitis in the fellow eye, typically within two months of initial presentation. Patients with VZV-associated VSR often had known risk factors for VZV reactivation.

Revascularization of ischemic tissue is a highly desirable outcome in multiple diseases, including cardiovascular diseases and ischemic retinopathies. Oxidative stress and inflammation are both known to play a role in suppressing reparative angiogenesis in ischemic disease models including oxygen-induced retinopathy (OIR), but the regulatory molecules governing these pathophysiologic processes in retinal ischemia are largely unknown. Nrf2 is a major stress-response transcription factor that has been implicated in regulating ischemic angiogenesis in the retina and other tissue beds. Using Nrf2-deficient mice, we investigated the effects of Nrf2 in regulating revascularization and modulating the retinal tissue milieu during ischemia. Strikingly, Nrf2’s beneficial effect on reparative angiogenesis only became manifested in the later phase of ischemia in OIR, from postnatal day 14 (P14) to P17. This was temporally associated with a reduction in both oxidative stress and inflammatory mediators in wild-type compared to Nrf2(−/−) mice. Nrf2(−/−) retinas exhibited an increase in VEGF but also induction of anti-angiogenic Dll4-Notch signaling. NADPH oxidase (NOX), and especially NOX2, is a major pathogenic molecule and a particularly important contributor to oxidative stress in multiple retinal disease processes. Nrf2(−/−) mice exhibited a significant exacerbation of NOX2 induction in OIR that manifested in the later phases of ischemia. Pharmacologic inhibition of NADPH oxidase abrogated the adverse effect of Nrf2 deficiency on reparative angiogenesis. Taken together, this suggests that Nrf2 is an important regulator of the retinal milieu during tissue ischemia, and that the Nrf2/NOX2 balance may play a critical role in determining the fate of ischemic revascularization.

Cytomegalovirus (CMV) retinitis is a late complication of organ and hematopoietic stem cell transplant, the risk of which depends on the degree of immunosuppression. With the institution of preemptive ganciclovir therapy early after transplant, most patients survive episodes of life-threatening CMV infection during the early months (usually the first 3 months) after transplant and hence late onset of CMV disease, such as CMV retinitis, is being recognized more frequently. Direct involvement of the macula or optic head remains the leading cause of visual loss in patients with CMV retinitis, but there are few studies investigating the management of this condition.Herein, we present the case of 28-year-old man who had acute myeloid leukemia and developed CMV retinitis with bilateral cystoid macular edema and optic swelling in the right eye 6 months after bone marrow transplant. He received treatment with intravitreal methotrexate in the right eye in combination with oral valganciclovir. Visual acuity improved 1 month after four weekly injections of intravitreal methotrexate 400 μg/0.1 mL. Resolved disc swelling and regression of macular edema were also observed. By comparing binocular outcome, we present our findings and discuss the possible efficacy and safety of this treatment with respect to regression of anatomical damage and improvement in visual acuity.

To evaluate clinical features and long-term visual outcome of cytomegalovirus (CMV) retinitis in patients without human immunodeficiency virus (HIV) infection, and to determine factors that predict visual outcome.Retrospective cohort study.Consecutive patients with CMV retinitis without HIV infection were reviewed. Main outcome measures included clinical features, proportion of eyes with 6-month and final visual acuity (VA)20/70 and20/400, and odds ratios of factors associated with poor visual outcome.A total of 20 eyes from 13 patients were included with a median follow-up time of 17 months. All had at least 6 months of follow-up except 1 patient who died from sepsis at 1 month. At presentation, 50% of eyes had VA20/70 and 25% had VA20/400. Zone 1 involvement occurred in 55% and vitreous haze ≥grade 2+ occurred in 25%. Recurrence occurred in 33.3% at a mean time of 6.4 ± 3.3 weeks after discontinuation of anti-CMV therapy. The retinal detachment rate was 21.7% per eye-year and mortality rate was 11.7% per person-year. At final visit, 60% had VA20/70 and 35% had VA20/400. Macular involvement was significantly associated with poor final VA20/400 (odds ratio = 25.00, P = .016).CMV retinitis without HIV infection was often aggressive at presentation. Significant intraocular inflammation was not uncommon. The long-term visual outcome was poor, especially in those with macular involvement.

Herpes simplex virus 1 (HSV-1) is a nearly ubiquitous human pathogen, remaining dormant in its human host the majority of the time. The interaction between HSV-1 and the immune system represents a complicated balance of power that allows the virus to persist in the host for a lifetime. However, disruptions in the immune system can activate the virus with the potential to cause devastating infections in the central nervous system (CNS). We present a patient who suffered three consecutive yearly HSV-1 CNS episodes (encephalitis, seizure, and retinitis), each within days of his influenza vaccination. We highlight subtle immunologic defects in this patient that may have allowed unchecked viral replication and resultant disease manifestations, as well as the potential role of influenza vaccine in tipping this balance in favor of HSV-1.

Purpose To report the case of an immunocompetent adult presenting with endogenous Fusarium endophthalmitis. Observations A woman in her thirties presented with symptoms and signs of a unilateral anterior uveitis. After initial improvement with topical corticosteroids, she continued to develop a panuveitis with an associated drop in vision to counting fingers. A vitreous biopsy confirmed Fusarium solani by 18S rRNA fungal gene detection and PCR sequencing. Despite treatment with pars plana vitrectomy, intravitreal amphotericin B and systemic voriconazole her visual outcome was poor. Detailed review of her antecedent history revealed the route of acquisition to be a thorn prick to the hand two weeks prior to presentation. Conclusions and importance This patient's endophthalmitis most likely resulted from cutaneous inoculation of Fusarium solani with subsequent hematogenous spread. Endogenous Fusarium endophthalmitis is well recognized in the immunocompromised but is very rarely seen in the immunocompetent. This case highlights the importance of thorough history-taking and consideration of fungal endophthalmitis in the differential diagnosis of a treatment-refractory uveitis.

Recently, peeling of internal limiting membrane (ILM) has become one of the most common and effective surgical procedures for macular disorders. The authors discuss the adverse effects of such procedures and explore the possible functions of the membrane. We also suggest a barrier function of this membrane in addition to its possible other physiological roles. Thus, apart from the well-known inner and outer retinal barriers, ILM might be the third and innermost retinal barrier. The possible evidences supporting this hypothesis are presented.

IFN-γ and IL-17A can each elicit ocular autoimmunity independently of the other. Since absence of IFN-γ or IL-17A individually failed to abolish pathology of experimental autoimmune uveitis (EAU), we examined EAU development in the absence of both these cytokines. Ifng(−/−)Il17a(−/−) mice were fully susceptible to EAU with a characteristic eosinophilic ocular infiltrate, as opposed to a mononuclear infiltrate in WT mice. Retinal pathology in double-deficient mice was ameliorated when eosinophils were genetically absent or their migration was blocked, supporting a pathogenic role for eosinophils in EAU in the concurrent absence of IFN-γ and IL-17A. In EAU-challenged Ifng(−/−)Il17a(−/−) mice, ocular infiltrates contained increased GM-CSF-producing CD4(+) T cells, and supernatants of retinal antigen-stimulated splenocytes contained enhanced levels of GM-CSF that contributed to activation and migration of eosinophils in vitro. Systemic or local blockade of GM-CSF ameliorated EAU in Ifng(−/−)Il17a(−/−) mice, reduced eosinophil peroxidase levels in the eye and in the serum and decreased eosinophil infiltration to the eye. These results support the interpretation that, in the concurrent absence of IFN-γ and IL-17A, GM-CSF takes on a major role as an inflammatory effector cytokine and drives an eosinophil-dominant pathology. Our findings may impact therapeutic strategies aiming to target IFN-γ and IL-17A in autoimmune uveitis.

Ageing of the retina is associated with the gradual accumulation of basal deposits and the formation of drusen. However, in some individuals this process is exacerbated and causes development of age-related macular degeneration. Late features of age-related macular degeneration include geographic atrophy of the neuroretina or choroidal neovascularization. Such changes lead to blurred vision, metamorphopsia, and scotoma, and is the leading cause of vision loss in developed countries. Chronic low-grade inflammation has been investigated because of its relationship to ageing and its role in the gap between chronological and biological ageing. Here, we systematically reviewed studies investigating systemic C-reactive protein in patients with age-related macular degeneration. We identified 53 studies with 60,598 participants (10,392 patients and 38,901 controls). Our meta-analyses revealed that early age-related macular degeneration was not associated to systemic C-reactive protein (Cohen's d = 0.03 [-0.04 to 0.10]; OR = 1.06 [0.93-1.20]; P = 0.39) whereas late age-related macular degeneration (Cohen's d = 0.38 [0.24 to 0.51]; OR = 1.99 [1.55-2.52]; P 0.0001), and neovascular age-related macular degeneration (Cohen's d = 0.40 [0.24 to 0.56]; OR = 2.07 [1.55-2.76]; P 0.0001) was associated with a small-to-moderate increase in systemic C-reactive protein. Our review provides an overview of this extensively studied field, provide summary estimates that provide insight into when and to what extent systemic C-reactive protein is associated with age-related macular degeneration, and help in distinguishing the potentially reversible disease processes from that of irreversible retinal ageing.

Purpose To summarize the case of a 13 year-old boy diagnosed with a BRAO secondary to B. henselae infection. Observations The patient presented with a sudden, unilateral, and painless scotoma. Fundoscopic findings and multimodal imaging were consistent with a BRAO with associated areas of intraretinal whitening along the involved artery. Upon further questioning, the patient reported having 15 cats at home. Antibodies were positive for B. henselae. The patient was treated with oral doxycycline 100 mg twice daily for 2 months with complete resolution of the retinal findings and the scotoma. Conclusions and importance B. henselae should be considered as a potential cause of retinitis and BRAO, even in pediatric-aged patients.

Elevated inflammatory cytokines contribute to the pathogenesis of various retinal diseases such as diabetic retinopathy, retinal vasculitis and retinitis. However, the underlying mechanism of retinal inflammation remains largely unknown. Recent studies demonstrated that acetylcholinesterase (ACHE) is an inflammatory indicator in central neural system. This study was aimed to dissect the role of ACHE in retinal inflammation, and its mechanism of action. Retinal inflammation was induced by intravitreal injection of tumor necrosis factor-α (TNF-α) in heterozygous ACHE knockdown mice (ACHE+/-) and wild type mice (ACHE+/+). Donepezil, a well-known ACHE inhibitor, was administrated by daily gavage. Expression of ACHE and intercellular adherent molecule-1 (ICAM-1), infiltration of CD11b+ inflammatory cells, retinal leukostasis and vascular leakage was determined in both ACHE+/- and ACHE+/+ mice. ARPE-19 cells, a human retinal pigment epithelial cell line, were cultured for in vitro assay. Knockdown of ACHE was achieved by lipofectamine-mediated siRNA transfection and pharmaceutical suppression of ACHE was manipulated by donepezil. Cellular expression and distribution of ACHE, ICAM-1, and phosphorylation of NF-κB, IκB and IKKα/β were detected by western-blot analysis or immunocytochemistry. Retinal expression of ACHE was dramatically upregulated, in parallel with increased ICAM-1 expression, enhanced leukostasis and augmented CD11b+ inflammatory cell infiltration as well as vascular hyperpermeability in ACHE+/+ mice injected with TNF-α. However, TNF-α-injected ACHE+/- mice showed lower level of ICAM-1, less leukostasis and fewer infiltrated CD11b+ cells. Moreover, TNF-α-induced retinal vascular leakage was significantly reduced in ACHE+/- mice. Similarly, TNF-α-induced retinal inflammatory response were also attenuated by donepezil intervention. In addition, TNF-α treatment resulted in significant induction of ACHE, upregulation of ICAM-1 and nuclear translocation of NF-κB, phosphorylation of IκB and IKKα/β in ARPE-19 cells. However, inhibition of ACHE reduced TNF-α-induced phosphorylation of NF-κB, IκB and IKKα/β in ARPE-19 cells. The present study reveals a pivotal role of ACHE in retinal inflammation. Inhibition of ACHE attenuates retinal inflammation and retinal leakage likely through suppressing NF-κB signaling activation.

Ganciclovir (GCV) is an antiviral drug approved for treatment of cytomegalovirus (CMV) retinitis. It can be delivered to the eye via systemic administrations. However, local delivery of GCV that targets the retina is considered as an alternative to increase efficacy of the treatment and lessen side effects. Thus, this study aimed to develop formulations of transferrin (Tf)-conjugated liposomes containing GCV (Tf-GCV-LPs) for intravitreal injection and topical instillation. Tf-GCV-LPs were prepared by the reverse-phase evaporation technique and then conjugated to Tf. Their physicochemical properties were evaluated. The optimized formulation was selected and subjected to the cytotoxicity test, cellular uptake study in the human retinal pigment epithelial cells (the ARPE-19 cells) and antiviral activity evaluation. The results showed that physicochemical properties of Tf-GCV-LPs were affected by formulation compositions. The optimized Tf-GCV-LPs had a particle size lower than 100 nm with a negative value of zeta potential. They were safe for the ARPE-19 cells. These Tf-GCV-LPs were taken up by these cells via Tf receptors-mediated endocytosis and showed inhibitory activity on CMV in the infected cells. Therefore, the optimized Tf-GCV-LPs could be accepted as a promising drug delivery system for targeted GCV delivery to the retina in the treatment of CMV retinitis.

Highlights • Bartonella henselae-associated neuroretinitis is an ocular complication of cat-scratch disease. • The cat flea is the main vector to transmit Bartonella henselae although it is also found on other animals. • As cat fleas may reside on non-feline hosts, pet mammals may act as carriers of Bartonella henselae. • Neuroretinitis may result from contact with infected fleas on family pets., To describe the ocurrence of Bartonella-associated neuroretinitis secondary to non-feline pet exposure, we retrospectively reviewed medical records and imaging from patients with a clinical and serologic diagnosis of Bartonella henselae (BH). Retinal imaging included color fundus photography, optical coherence tomography (OCT) and fluorescein angiography (FA). Four eyes of two patients with cat-scratch disease were included in this study, with a mean age of 35 years. The mean follow-up was 13 months, after presentation of infectious neuroretinitis. Both patients suffered from bilateral neuroretinitis after direct contact with family pets (ferret and guinea pig). All patients were treated with a long-term systemic antimicrobial therapy. Visual acuity in all improved to 20/30 or better at six months. In conclusion, humans may develop cat-scratch disease when they are exposed to Bartonella henselae (BH) in the saliva of infected cats or BH-containing flea feces reaching the systemic circulation through scratches or mucous membranes. As the cat flea (Ctenocephalides felis) may reside on non-feline mammals, Bartonella-associated neuroretinitis may result from contact with other furred family pets.

Purpose: To report a case of an immunocompetent 64-year-old man who developed cytomegalovirus (CMV) retinitis after using topical difluprednate. Observations: A 64-year-old man with type 2 diabetes developed hemorrhagic retinitis while using topical difluprednate after penetrating keratoplasty. Polymerase chain reaction of the vitreous was positive for CMV DNA. Complete blood count was within normal limits and 4th generation human immunodeficiency virus assay was negative. The retinitis resolved with oral valgancyclovir and intravitreal foscarnet injections. Conclusion and importance: CMV retinitis may occur after topical difluprednate in an immunocompetent patient. Keywords: Cytomegalovirus retinitis, Topical steroid, Difluprednate