Long-Term Mortality in Diabetic Patients with Tractional Retinal Detachments.

PURPOSE: To determine the long-term, all-cause mortality rate of diabetic patients requiring vitrectomy surgery for tractional retinal detachment (TRD). DESIGN: Institutional review board-approved, retrospective, comparative study. PARTICIPANTS: Four hundred eyes of 316 patients undergoing vitrectomy surgery from 2005 to 2015. METHODS: Long-term, all-cause mortality rates in the study population were compared with mortality in a historical control group of diabetic patients with minimal to no retinopathy. Subgroup analysis was done based on bilaterality of TRD and initial vision. Other concurrent associated diabetic comorbidities, use of insulin, and type 1 diabetes are also reported. Data were used to create Kaplan-Meier survival curves. MAIN OUTCOME MEASURE: Long-term, all-cause mortality rate of diabetic patients undergoing vitrectomy surgery from 2005 to 2015. RESULTS: Mean survival after diagnosis of TRD requiring vitrectomy surgery was 2.7 years (median, 2 years; range, 0.17-9.00 years). Kaplan-Meier survival curve analysis revealed a 48.7% (154/316 patients) long-term, all-cause mortality rate for diabetics requiring vitrectomy surgery for TRDs at 10 years, compared with a mean 2% long-term, all-cause mortality rate in diabetics with minimal to no retinopathy. Subgroup analysis of those patients with bilateral TRDs requiring surgery revealed a 48.9% mortality rate with a mean survival after diagnosis of TRD of 2.6 years (median, 2 years; range, 0.25-9.00 years). Those patients with count fingers or worse vision in one or both eyes at diagnosis had a 52.0% mortality rate (P < 0.05), with a mean survival after diagnosis of 2.6 years (median, 2 years; range, 0.17-9.00 years). CONCLUSIONS: In our population, diabetic patients with TRDs requiring surgery have a 48.7% long-term, all-cause mortality rate, with those presenting with count fingers or worse vision having a higher mortality rate. Diabetic TRD requiring vitrectomy surgery is a marker of poor long-term survival.

Outcomes of chronic macular hole surgical repair.

PURPOSE: To report visual and anatomic outcomes of chronic macular hole surgery, with analysis of pre-operative OCT-based hole size and post-operative closure type. SETTINGS AND DESIGN: An IRB-approved, retrospective case series of 26 eyes of 24 patients who underwent surgery for stage 3 or 4 idiopathic chronic macular holes at a tertiary care referral center. STATISTICAL ANALYSIS: Student's t-test. RESULTS: Nineteen of 26 eyes (73%) had visual improvement after surgery on most recent exam. Twenty-one of 26 eyes (81%) achieved anatomic closure; 16 of 26 eyes (62%) achieved type 1, and five of 26 eyes (19%) achieved type 2 closure. Post-operative LogMAR VA for type 1 closure holes (0.49) was significantly greater than for type 2 closure and open holes (1.26, P < 0.003 and 1.10, P < 0.005, respectively), despite similar pre-operative VA (P = 0.51 and 0.68, respectively). Mean pre-operative hole diameter for eyes with type 1 closure, type 2 closure, and holes that remained open were 554, 929, and 1205 microns, respectively. Mean pre-operative hole diameter was significantly larger in eyes that remained open as compared to eyes with type 1 closure (P = 0.015). CONCLUSION: Vitrectomy to repair chronic macular holes can improve vision and achieve long-term closure. Holes of greater than 3.4 years duration were associated with a greater incidence of remaining open and type 2 closure. Larger holes (mean diameter of 1205 microns) were more likely to remain open after repair.

Choroidal lymphoma: clinical features and association with systemic lymphoma.

PURPOSE: To describe the clinical and histopathologic features of choroidal lymphoma (CL) and its association with systemic lymphoma. DESIGN: Observational case series. PARTICIPANTS: Fifty-nine patients (73 eyes) with CL. METHODS: Retrospective chart review. MAIN OUTCOME MEASURES: Clinical features, histopathology, and systemic lymphoma. RESULTS: Of 59 patients with CL, systemic lymphoma was absent in 41 (primary CL; 69%) and present in 18 (secondary CL; 31%). Of 18 patients with systemic lymphoma at presentation, 14 (78%) had known systemic lymphoma and 4 (22%) were diagnosed with systemic lymphoma shortly after presentation. The most common types of systemic lymphoma in patients with secondary CL were diffuse large cell lymphoma (n = 5, 28%), chronic lymphocytic leukemia/lymphoma (n = 4, 22%), multiple myeloma (n = 2, 11%), Waldenstrom's macroglobulinemia (n = 2, 11%), extranodal marginal zone lymphoma (n = 2, 11%), plasmablastic lymphoma (n = 1, 6%), and unspecified non-Hodgkin lymphoma (n = 2, 11%). Compared with patients with primary CL, patients with secondary CL had a shorter mean duration of ocular symptoms (5 vs. 17 months), had less often received steroids before referral (11% vs. 46%), and were more likely to have bilateral ocular involvement (33% vs. 20%). Eyes with secondary CL had a higher rate of poor vision (≤20/200) (46% vs. 12%), iris (20% vs. 4%) or ciliary body (30% vs. 8%) lymphoma, episcleral vascular congestion (40% vs. 16%), anterior chamber reaction (30% vs. 14%), hyphema (15% vs. 0%), vitreous cellular infiltration (30% vs. 4%), and severe media haziness (20% vs. 0%). Secondary CL was morphologically more high grade (50% diffuse large cell lymphoma) compared with primary CL (37% low-grade non-Hodgkin lymphoma, 27% extranodal marginal zone lymphoma). None of the 33 patients with primary CL and subsequent follow-up developed systemic lymphoma during a mean follow-up of 50 months (median, 35 months; range, 2-231 months). CONCLUSIONS: Secondary CL is morphologically high grade and associated with more severe ocular findings. Patients with CL and no known systemic lymphoma at presentation should undergo systemic evaluation to rule out the possibility of undiagnosed concurrent systemic lymphoma. However, none of the patients with primary CL in our study had late development of systemic lymphoma.

Retinal vasoproliferative tumors: comparative clinical features of primary vs secondary tumors in 334 cases.

OBJECTIVE: To compare the clinical features of primary vs secondary retinal vasoproliferative tumors (VPTs). METHODS: Retrospective case series of 334 tumors in 295 eyes of 275 patients. RESULTS: Of 275 patients with VPT, 41% (n = 113) were male and 59% (n = 162) were female, with a mean age of 44 years at presentation. Primary VPT occurred in 80% (n = 219) and secondary VPT, in 20% (n = 56) of patients. Secondary VPT (n = 67) occurred in eyes with retinitis pigmentosa (n = 15, 22%), pars planitis (n = 14, 21%), Coats disease (n = 11, 16%), previous retinal detachment surgery (n = 8, 12%), idiopathic peripheral retinal vasculitis (n = 4, 6%), familial exudative vitreoretinopathy (n = 3, 4%), and others (n = 12, 18%). The mean interval between diagnosis of underlying ocular condition and secondary VPT was 160 months. Statistically significant differences (P < .05) in clinical features (primary vs secondary VPTs) included mean age at presentation (46 vs 38 years), visual symptoms (74% vs 87%), poor visual acuity worse than 20/200 (15% vs 28%), bilaterality (4% vs 20%), multifocality (5% vs 15%), postequatorial tumor location (20% vs 33%), tumor basal dimension (6 vs 7 mm), anterior chamber cells (16% vs 30%), and vitreous cells (19% vs 48%). CONCLUSIONS: Retinal vasoproliferative tumor can be primary (80%) or secondary (20%). Compared with primary VPT, secondary VPT is more often bilateral, multiple, and larger and occurs at an earlier age associated with poorer visual acuity.

Lesions simulating retinoblastoma (pseudoretinoblastoma) in 604 cases: results based on age at presentation.

PURPOSE: To determine the types and frequency of ocular conditions that simulate retinoblastoma (pseudoretinoblastoma) based on age at presentation. DESIGN: Retrospective case series. PARTICIPANTS: Two thousand seven hundred seventy-five patients. METHODS: Chart review. MAIN OUTCOME MEASURES: Conditions simulating retinoblastoma. RESULTS: Of 2775 patients referred for management of retinoblastoma, 2171 patients (78%) had confirmed retinoblastoma and 604 patients (22%) had simulating lesions (pseudoretinoblastomas). In the pseudoretinoblastoma cohort, the mean patient age at presentation was 4 years (median, 2 years). There were 27 different pseudoretinoblastoma conditions, and the 10 most common included Coats' disease (n = 244; 40%), persistent fetal vasculature (PFV; n = 158; 28%), vitreous hemorrhage (n = 27; 5%), ocular toxocariasis (n = 22; 4%), familial exudative vitreoretinopathy (FEVR; n = 18; 3%), rhegmatogenous retinal detachment (n = 18; 3%), coloboma (n = 17; 3%), astrocytic hamartoma (n = 15; 2%), combined hamartoma of retina and retinal pigment epithelium (n = 15; 2%), and endogenous endophthalmitis (n = 10; 2%). Simulating lesions differed based on age at presentation, and children younger than 1 year were most likely to have PFV (49%), Coats' disease (20%), or vitreous hemorrhage (7%); those 2 to 5 years of age were most likely to have Coats' disease (61%), toxocariasis (8%), or PFV (7%); and those older than 5 years were most likely to have Coats' disease (57%), toxocariasis (8%), or FEVR (6%). CONCLUSIONS: The most common pseudoretinoblastomas include Coats' disease, PFV, and vitreous hemorrhage, but the spectrum varies depending on patient age.

Asymmetry of familial exudative vitreoretinopathy.

A 2-month-old male infant presented with unilateral leukocoria suspected to be retinoblastoma. Fundus examination and fluorescein angiography confirmed the diagnosis of bilateral familial exudative vitreoretinopathy with markedly asymmetric presentation (Stage 3/Type 5 in the right eye and Stage 2/Type 3 in the left eye).

A sugar binding protein cyanovirin-N blocks herpes simplex virus type-1 entry and cell fusion.

Herpes simplex virus type-1 (HSV-1) causes significant health problems from periodic skin and corneal lesions to encephalitis. It is also considered a cofactor in the development of age-related secondary glaucoma. Inhibition of HSV-1 at the stage of viral entry generates a unique opportunity for preventative and/or therapeutic intervention. Here we provide evidence that a sugar binding antiviral protein, cyanovirin-N (CV-N), can act as a potent inhibitor of HSV-1 entry into natural target cells. Inhibition of entry was independent of HSV-1 gD receptor usage and it was observed in transformed as well as primary cell cultures. Evidence presented herein suggests that CV-N can not only block virus entry to cells but also, it is capable of significantly inhibiting membrane fusion mediated by HSV glycoproteins. While CV-N treated virions were significantly deficient in entering into cells, HSV-1 glycoproteins-expressing cells pretreated with CV-N demonstrated reduced cell-to-cell fusion and polykaryocytes formation. The observation that CV-N can block both entry as well as membrane fusion suggests a stronger potential for this compound in antiviral therapy against HSV-1.

Role of nectin-1, HVEM, and PILR-alpha in HSV-2 entry into human retinal pigment epithelial cells.

PURPOSE: Herpes simplex virus-type 2 (HSV-2) can cause acute retinal necrosis (ARN), which can lead to exudative and rhegmatogenous retinal detachment, yet little is known about the cellular and molecular mechanisms of HSV-2 entry into retinal pigment epithelial (RPE) cells. The goal of this study was to establish the identity of the critical receptors used by the virus for infection. METHODS: A reporter HSV-2 virus, which expresses beta-galactosidase, was used to quantify entry into RPE cells, and viral replication was ascertained using a plaque assay. Flow cytometry and immunocytochemistry were used to determine cellular expression of entry receptors. Localization of these receptors to the apical or basal surface of RPE cells was determined with immunocytochemistry. The necessity of these receptors, individually and in combination, for viral entry was established using receptor-specific antibodies and siRNAs. RESULTS: RPE cells are highly susceptible to HSV-2 entry and replication. Several assays demonstrated the expression of the entry receptors nectin-1, HVEM, and PILR-alpha and their localization primarily to the apical surfaces of RPE cells. Receptor-specific antibodies and siRNA knockdown of receptors significantly reduced viral entry and implicated nectin-1 as an important receptor, with HVEM and PILR-alpha potentially also contributing to entry. CONCLUSIONS: HSV-2 is capable of developing a productive infection in RPE cells by using nectin-1 as an important entry receptor. To lesser degrees, HVEM and PILR-alpha may also contribute to HSV-2 entry into RPE cells.

Role for nectin-1 in herpes simplex virus 1 entry and spread in human retinal pigment epithelial cells.

Herpes simplex virus 1 (HSV-1) demonstrates a unique ability to infect a variety of host cell types. Retinal pigment epithelial (RPE) cells form the outermost layer of the retina and provide a potential target for viral invasion and permanent vision impairment. Here we examine the initial cellular and molecular mechanisms that facilitate HSV-1 invasion of human RPE cells. High-resolution confocal microscopy demonstrated initial interaction of green fluorescent protein (GFP)-tagged virions with filopodia-like structures present on cell surfaces. Unidirectional movement of the virions on filopodia to the cell body was detected by live cell imaging of RPE cells, which demonstrated susceptibility to pH-dependent HSV-1 entry and replication. Use of RT-PCR indicated expression of nectin-1, herpes virus entry mediator (HVEM) and 3-O-sulfotransferase-3 (as a surrogate marker for 3-O-sulfated heparan sulfate). HVEM and nectin-1 expression was subsequently verified by flow cytometry. Nectin-1 expression in murine retinal tissue was also demonstrated by immunohistochemistry. Antibodies against nectin-1, but not HVEM, were able to block HSV-1 infection. Similar blocking effects were seen with a small interfering RNA construct specifically directed against nectin-1, which also blocked RPE cell fusion with HSV-1 glycoprotein-expressing Chinese hamster ovary (CHO-K1) cells. Anti-nectin-1 antibodies and F-actin depolymerizers were also successful in blocking the cytoskeletal changes that occur upon HSV-1 entry into cells. Our findings shed new light on the cellular and molecular mechanisms that help the virus to enter the cells of the inner eye.

Herpes simplex virus type 2 entry into cultured human corneal fibroblasts is mediated by herpesvirus entry mediator.

Herpes simplex virus type 2 (HSV-2) infections in the eye are becoming increasingly common in adults. The most likely point of entry for HSV-2 into the eye is through the cornea. By using primary cultures of human corneal fibroblasts (CFs), a natural target-cell type for infection, it was demonstrated that CFs are highly susceptible to HSV-2 entry and replication. RT-PCR and flow-cytometry analyses demonstrated expression of herpesvirus entry mediator (HVEM), a known mediator for HSV-2 entry into cells. Blocking of virus entry into CFs by anti-HVEM antibody implicated HVEM as a potential receptor for HSV-2 infection. These results indicate that HVEM may play a crucial role in HSV-2-induced corneal infections.