Incidence and visual outcomes of acute endophthalmitis post intravitreal injection of anti-vascular endothelial growth factors in a single referral center.

BACKGROUND: To describe the incidence and factors predicting visual outcome in patients with infectious endophthalmitis following intravitreal anti-VEGF injection. METHODS: Retrospective, single-site, cohort study. Patients with acute endophthalmitis within 6 weeks of intravitreal anti-VEGF injection who were referred to our practice after inciting injection or were injected by us between January 2010 and July 2017 were included. All patients received intravitreal antibiotics with either vitreous/anterior chamber tap (TAP) or pars plana vitrectomy. Visual outcomes pre/post treatment, baseline variables (age, gender, ocular disease) and cultures results were studied. RESULTS: Seventy eyes of 69 patients were included. Presenting VA was the strongest factor associated with final visual outcome after adjusting for other variables including culture status and baseline VA (p = .0002). Cultures were positive in 62.8% of eyes and were associated with worse visual outcome (p = .0087). Growth of Streptococcus or microorganisms other than coagulase negative Staphylococci (CNS) was also associated with worse prognosis, regardless of baseline and presenting VA (p = .0002). The crude incidence of post-injection endophthalmitis was 0.028% in our practice (40 eyes in 143,628 injections) during the study time. No significant difference was found between pre-filled bevacizumab versus ranibizumab or aflibercept drawn from a vial. CONCLUSIONS: In a large, single center, retrospective study, the incidence of acute endophthalmitis post anti-VEGF injection was relatively low. Worse visual acuity at presentation of endophthalmitis and growth of Streptococcus or organisms other than CNS were associated with the worst visual outcomes.

Association of retinal detachment with age 50 years or younger at onset in patients with acute retinal necrosis.

BACKGROUND: Due to the guarded prognosis of acute retinal necrosis (ARN), it is relevant to develop a strategy to early categorize those patients in a higher risk of worse outcomes. The purpose of this study is to describe clinical features and predictive factors for retinal detachment (RD) in patients with ARN. METHODS: Retrospective observational case series of 34 adult patients (38 eyes) with ARN examined between January 2005 and July 2015 in the National Eye Institute (Bethesda, USA), the Department of Ophthalmology, University of Chile (Santiago, Chile), and APEC (CDMX, Mexico). RESULTS: A total of 16 males and 18 females with a mean age at presentation of 44.5 ± 16.8 years were included. Twenty-seven patients (79.4%) received intravenous acyclovir as first-line treatment, and 7 patients received either oral antiviral (4 patients) or oral plus intravitreal antiviral (3 patients). All subjects were treated with prednisone, with a mean initial dose of 57.7 ± 16.3 mg per day. Seventeen patients (50.0%) developed retinal detachment. An association of retinal detachment with age at onset was observed (p = 0.04), with patients younger than 50 years presenting a higher risk (OR = 14.86, p = 0.0009). Additionally, patients in this higher risk group had more inflammation in both anterior chamber and vitreous (p = 0.04 and 0.03, respectively). No other predictive factor for retinal detachment was found in the present study. CONCLUSIONS: RD represents an important complication in patients with ARN. Younger patients may be at higher risk of this complication, possibly secondary to the presence of a higher level of inflammation.

Logistic Regression Classification of Primary Vitreoretinal Lymphoma versus Uveitis by Interleukin 6 and Interleukin 10 Levels.

PURPOSE: To assess the diagnostic performance and generalizability of logistic regression in classifying primary vitreoretinal lymphoma (PVRL) versus uveitis from intraocular cytokine levels in a single-center retrospective cohort, comparing a logistic regression model and previously published Interleukin Score for Intraocular Lymphoma Diagnosis (ISOLD) scores against the interleukin 10 (IL-10)-to-interleukin 6 (IL-6) ratio. DESIGN: Retrospective cohort study. PARTICIPANTS: Patient histories, pathology reports, and intraocular cytokine levels from 2339 patient entries in the National Eye Institute Histopathology Core database. METHODS: Patient diagnoses of PVRL versus uveitis and associated aqueous or vitreous IL-6 and IL-10 levels were collected retrospectively. From these data, cytokine levels were compared between diagnoses with the Mann-Whitney U test. A logistic regression model was trained to classify PVRL versus uveitis from aqueous and vitreous IL-6 and IL-10 samples and compared with ISOLD scores and IL-10-to-IL-6 ratios. MAIN OUTCOME MEASURES: Area under the receiver operating characteristic curve (AUC) for each classifier and sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) at the optimal cutoff (maximal Youden index) for each classifier. RESULTS: Seventy-seven lymphoma patients (10 aqueous samples, 67 vitreous samples) and 84 uveitis patients (19 aqueous samples, 65 vitreous samples) treated between October 5, 1999, and September 16, 2015, were included. Interleukin 6 levels were higher and IL-10 levels were lower in uveitis patients compared with lymphoma patients (P < 0.01). For vitreous samples, the logistic regression model, ISOLD score, and IL-10-to-IL-6 ratio achieved AUCs of 98.3%, 97.7%, and 96.3%, respectively. Sensitivity, specificity, PPV, and NPV at the optimal cutoffs for each classifier were 94.2%, 96.9%, 97%, and 94% for the logistic regression model; 92.7%, 100%, 100%, and 92.9% for the ISOLD score; and 94.2%, 95.3%, 95.6%, and 93.9% for the IL-10-to-IL-6 ratio. All models achieved complete separation between uveitis and lymphoma in the aqueous data set. CONCLUSIONS: The accuracy of the logistic regression model and generalizability of the ISOLD score to an independent patient cohort suggest that intraocular cytokine analysis by logistic regression may be a promising adjunct to cytopathologic analysis, the gold standard, for the early diagnosis of primary vitreoretinal lymphoma. Further validation studies are merited.

Memory Stem T Cells in Autoimmune Disease: High Frequency of Circulating CD8+ Memory Stem Cells in Acquired Aplastic Anemia.

Memory stem T cells (TSCMs) constitute a long-lived, self-renewing lymphocyte population essential for the maintenance of functional immunity. Hallmarks of autoimmune disease pathogenesis are abnormal CD4(+) and CD8(+) T cell activation. We investigated the TSCM subset in 55, 34, 43, and 5 patients with acquired aplastic anemia (AA), autoimmune uveitis, systemic lupus erythematosus, and sickle cell disease, respectively, as well as in 41 age-matched healthy controls. CD8(+) TSCM frequency was significantly increased in AA compared with healthy controls. An increased CD8(+) TSCM frequency at diagnosis was associated with responsiveness to immunosuppressive therapy, and an elevated CD8(+) TSCM population after immunosuppressive therapy correlated with treatment failure or relapse in AA patients. IFN-γ and IL-2 production was significantly increased in various CD8(+) and CD4(+) T cell subsets in AA patients, including CD8(+) and CD4(+) TSCMs. CD8(+) TSCM frequency was also increased in patients with autoimmune uveitis or sickle cell disease. A positive correlation between CD4(+) and CD8(+) TSCM frequencies was found in AA, autoimmune uveitis, and systemic lupus erythematosus. Evaluation of PD-1, CD160, and CD244 expression revealed that TSCMs were less exhausted compared with other types of memory T cells. Our results suggest that the CD8(+) TSCM subset is a novel biomarker and a potential therapeutic target for AA.

Pharmacologic Treatment of Noninfectious Uveitis.

Uveitis encompasses a spectrum of diseases whose common feature is intraocular inflammation, which may be infectious or noninfectious in etiology (Nussenblatt and Whitcup 2010). Infectious causes of uveitis are typically treated with appropriate antimicrobial therapy and will not be discussed in this chapter. Noninfectious uveitides are thought have an autoimmune component to their etiology and are thus treated with anti-inflammatory agents.

Fenofibrate and Diabetic Retinopathy.

Diabetic retinopathy, a common and sight-threatening microvascular complication of diabetes mellitus, is a leading cause of blindness among working-aged adults. Medical therapies including intensive control of hyperglycemia and hypertension have been shown to reduce the incidence and progression of diabetic retinopathy. The association of dyslipidemia and treatment with statins with diabetic retinopathy is inconsistent in epidemiologic studies. However, two recent randomized clinical trials have demonstrated beneficial effects of systemic fenofibrate therapy in reducing the progression of diabetic retinopathy independently of serum lipid levels. These findings suggest that fenofibrate may be an effective strategy for reducing the progression of diabetic retinopathy, thus reducing the large and growing public health burden of treating the sight-threatening complications of diabetic retinopathy.

DELINEATION OF CHOROIDAL AND RETINAL LESIONS IN POSTERIOR UVEITIS BY MULTISPECTRAL WIDE-FIELD SCANNING LASER OPHTHALMOSCOPY.

PURPOSE: To investigate whether wide-field multispectral scanning laser ophthalmoscopy could assist in determining depth of chorioretinal pathology in posterior uveitis. METHODS: Cross-sectional retrospective review of patients with birdshot chorioretinopathy (BCR; 42 eyes of 21 patients) or active primary vitreoretinal lymphoma (PVRL; 18 eyes of 10 patients) who had multispectral wide-field scanning laser ophthalmoscopy (Optos) images. Images acquired with 532 nm and 635 nm lasers were analyzed separately using Optos V Vantage Pro Review software. RESULTS: All 42 eyes with birdshot chorioretinopathy and 8/18 eyes with active primary vitreoretinal lymphoma had lesions on 635 nm imaging, while 26/42 of the birdshot chorioretinopathy eyes and 18/18 eyes with active primary vitreoretinal lymphoma had lesions on 532 nm imaging. The difference between the 2 groups on both 635 nm and 532 nm was statistically significant (P < 0.05). CONCLUSION: Retinal and choroidal lesions in patients with posterior uveitis can be differentially visualized with Optos 532 nm and 635 nm lasers, respectively, allowing determination of depth of pathology.

Coagulase-negative staphylococcal endophthalmitis: clinical severity and outcomes based on speciation.

OBJECTIVE: To identify characteristics and visual outcomes of coagulase-negative staphylococcal (CoNS) endophthalmitis in the era after the Endophthalmitis Vitrectomy Study. DESIGN: Single-centre retrospective analysis. PARTICIPANTS: Forty-two samples from 40 patients with documented CoNS endophthalmitis. METHODS: Visual acuity outcomes of CoNS endophthalmitis were assessed in relation to species and type of treatment instituted (i.e., pars plana vitrectomy [PPV] versus vitreous tap and injection of intravitreal antibiotics [T&I]) on 42 samples from 40 patients. RESULTS: Staphylococcus epidermidis was the most prevalent CoNS in our study. Cataract surgery and intravitreal injections were the most common sources for acute CoNS endophthalmitis. Eyes presenting with hand motion or better vision had similar mean final vision after either intravitreal antibiotics or PPV, whereas those with light perception or worse vision at onset had better outcomes after PPV only. Subanalysis showed that patients with S. epidermidis endophthalmitis (n = 39 eyes) had similar visual outcomes with either intravitreal injections or PPV regardless of visual acuity. Hypopyon and vitritis are not always present. CONCLUSIONS: Patients with S. epidermidis endophthalmitis may benefit similarly from either early vitrectomy or intravitreal antibiotic injections regardless of visual acuity. This finding may be a supplement to the complements the management standards set forth by the Endophthalmitis Vitrectomy Study.

Retinal Thinning in People With Well-Controlled HIV Infection.

BACKGROUND: Retinal measurements correlate with disease progression in patients with multiple sclerosis; however, whether they associate with neurologic disease in people with controlled HIV is unknown. Using spectral domain optical coherence tomography, we evaluated retinal differences between people with HIV and HIV-negative controls and investigated clinical correlates of retinal thinning. METHODS: People with HIV on antiretroviral therapy for at least 1 year and HIV-negative controls recruited from the same communities underwent spectral domain optical coherence tomography, ophthalmic examination, brain MRI, and neuropsychological testing. Retinal nerve fiber layer (RNFL) and ganglion cell inner plexiform layer (GC-IPL) thicknesses were compared between groups using analysis of covariance with relevant clinical variables as covariates. Linear regression was used to explore associations of HIV history variables, cognitive domain scores, and MRI volume measurements within the HIV group. RESULTS: The HIV group (n = 69), with long-duration HIV infection (median time from diagnosis 19 years) and outstanding viral control have thinner retinal layers than HIV-negative controls (n = 28), after adjusting for covariates (GC-IPL: P = 0.002; RNFL: P = 0.024). The effect of HIV on GC-IPL thickness was stronger in women than in men (Women: P = 0.011; Men: P = 0.126). GC-IPL thickness is associated with information processing speed in the HIV group (P = 0.007, semipartial r = 0.309). No associations were found with retinal thinning and MRI volumes or HIV factors. CONCLUSIONS: People with HIV on antiretroviral therapy have thinning of the RNFL and GC-IPL of the retina, and women particularly are affected to a greater degree. This retinal thinning was associated with worse performance on tests of information processing speed.

Reproducibility of Full-field Electroretinogram Measurements in Birdshot Chorioretinopathy Patients: An Intra- and Inter-visit Analysis.

Purpose: Aims to determine the variability of ffERG measurements in patients with clinically stable birdshot chorioretinopathy (BCR).Methods: Repeatability coefficients (RC) of ffERG amplitudes and implicit times were calculated from 11 BCR patients. Jackknife resampling estimated 95% confidence intervals of each ERG parameter's RC and the percentage change explained by variability alone was calculated.Results: Intra-visit variability in ffERG parameters was lower than inter-visit. Intravisit RCs demonstrated that for intravisit ERG testing, there was less than 30% variation in ERG amplitude for most parameters. For inter-visit ERG testing, a greater than 40% reduction in ERG amplitude may be clinically meaningful for 6 of 8 ERG parameters. Photopic single flash responses have <2 msec of test-retest variability both within and across visits.Conclusions: A 40% reduction in ERG amplitude and/or a delay of >2 msec in the photopic single flash response may be suitable criteria for meaningful change in BCR patients.

Management of herpes simplex virus stromal keratitis: an evidence-based review.

Herpes simplex virus (HSV) stromal keratitis is a leading cause of corneal opacification and an important indication for penetrating keratoplasty. Based on several observational studies and clinical trials, the current standard of care includes topical corticosteroids and antivirals. However, corticosteroids have significant side effects, and antivirals are only beneficial if replicating virus is present. High-quality clinical trials investigating therapies for HSV stromal keratitis beyond corticosteroids and antivirals are lacking. Immune regulatory drugs, such as cyclosporine A, present attractive alternatives to managing HSV stromal keratitis, given the immune-mediated pathogenesis of stromal disease. Also, inhibiting viral reactivation in the latently infected ganglia through therapeutic vaccination will likely be the most efficient avenue to reduce recurrent HSV ocular disease. Our present aim is to review the current evidence-based treatment options for HSV stromal keratitis including and beyond the use of corticosteroids and antivirals and to cultivate insights into developing therapeutic vaccination strategies to inhibit HSV stromal keratitis recurrences.

Non-invasive method of monitoring retinal vasculitis in patients with birdshot chorioretinopathy using optical coherence tomography.

BACKGROUND/AIMS: To investigate the utility of using montaged optical coherence tomography (OCT) thickness maps to monitor perivascular thickness as a marker of vasculitic activity in patients with large-vessel retinal vasculitis. METHODS: This is a retrospective cohort study of 22 eyes of 11 patients with a history of retinal vasculitis associated with birdshot chorioretinopathy (BCR). Patients had serial spectral domain 6×6 mm cube OCT scans centred on the fovea, optic nerve and proximal branches of the superior and inferior retinal vessels. OCT thickness change maps for each respective region were analysed. Changes in perivascular thickness were confirmed by assessing vasculitic activity on fluorescein angiography (FA), when clinically indicated. RESULTS: In three patients, montaged OCT scans were acquired at diagnosis and serially through initial treatment. In all three patients, montaged OCT demonstrated reduced perivascular thickening with oral prednisone treatment, which was confirmed by FA showing reduced vascular leakage in both eyes. Eight patients had serial montaged OCT scans after diagnosis and initial treatment of BCR. Four of these patients showed fluctuations in perivascular thickness during flares and treatment that were confirmed by either increased or decreased vascular leakage on FA. The other four patients remained quiet on their immunosuppressive treatment regimens, and no changes in perivascular thickness were detected. CONCLUSIONS: Evaluating large-vessel perivascular thickness on OCT scans may be a useful method for non-invasively monitoring posterior pole large-vessel retinal vasculitis.

Modulation of CD8+ CTL effector function by fibroblasts derived from the immunoprivileged cornea.

PURPOSE: To examine the acquisition of lytic activity and interferon gamma (IFN-gamma) production by herpes simplex virus (HSV) type 1-specific CD8(+) cytotoxic T-lymphocyte precursors (HSV-CTLps) after exposure to in vitro HSV-1-infected fibroblasts derived from the immunoprivileged cornea (HSV-cFb) or nonprivileged skin (HSV-sFb) or to in vitro HSV-1-infected splenocytes (HSV-Spls) obtained from noninfected mice. METHODS: Chromium release assays were used to assess HSV-CTL cytotoxicity, and flow cytometry was used to assess intracellular granzyme (Gr) B content and lytic granule exocytosis through surface CD107a expression. In addition, the BLT esterase assay was used to assess functional GrA release. [(3)H]-Thymidine incorporation and total CD8(+) cell numbers, as assessed by flow cytometry, were used to assess CTLp proliferation. ELISA and intracellular flow cytometric analysis were used to assess CTL IFN-gamma production and release. RESULTS: HSV-cFb, HSV-sFb, and HSV-Spl individually induced strong cytotoxic and IFN-gamma responses by HSV-CTL. Simultaneous exposure to HSV-Spl and HSV-cFb virtually abrogated the cytotoxic response while enhancing IFN-gamma production by HSV-CTL. In contrast, exposure to HSV-sFb, in conjunction with HSV-Spl, did not alter the cytotoxic or IFN-gamma response of HSV-CTL compared with stimulation with either cell type alone. Abrogation of the cytotoxic response after simultaneous exposure to HSV-Spl and HSV-cFb was associated with reduced production, storage, or both of GrA and GrB but with unimpaired lytic granule release. CONCLUSIONS: These findings suggest that an interesting regulatory circuit protects the cornea from the potentially damaging effects of CD8(+) T-cell cytotoxic function while maintaining their ability to control virus replication through enhanced production of the antiviral cytokine IFN-gamma.

Retinal Pigment Epithelium Tear after Immunosuppressive Treatment for Sarcoidosis-related Choroidal Granuloma.

PURPOSE: To describe the formation of a retinal pigment epithelial (RPE) tear following immunosuppressive treatment of a large choroidal granuloma in a patient with sarcoidosis-related panuveitis. METHODS: A 25-year-old woman presented with bilateral sarcoidosis-related panuveitis and optic disc edema in both eyes with a large choroidal granuloma temporal to the fovea in the left eye. High-dose oral prednisone therapy was given. RESULTS: High-dose oral prednisone therapy produced improvement in her panuveitis with reduction in size of the left choroidal granuloma. An RPE tear overlying the flattening choroidal granuloma developed by 3 weeks of treatment. CONCLUSIONS: Treatment of choroidal granuloma with rapid reduction in size may result in an RPE tear.

Comparative efficacy of steroid-sparing therapies for non-infectious uveitis.

INTRODUCTION: Non-infectious uveitis encompasses a group of inflammatory eye diseases that can cause irreversible vision loss if left untreated or undertreated. In cases requiring stemic treatment, a step-wise treatment approach is often employed starting with corticosteroids for severe active disease, followed by initiation of steroid-sparing therapies to maintain inflammatory control and avoid the abundant complications of long-term corticosteroid use. AREAS COVERED: We review the current high-quality evidence comparing the efficacy of various systemic steroid-sparing agents in the treatment of non-infectious uveitis. For studies to be included, they had to have a prospective, randomized, comparative design or a retrospective design including at least 100 patients. EXPERT COMMENTARY: Given the rarity of uveitis and the heterogeneity of uveitic diseases, there are few randomized controlled studies that directly compare the relative efficacy of the various steroid-sparing immunosuppressive agents. Therefore, current treatment strategies are based mainly on data from observational series.

Systemic Sunitinib Malate Treatment for Advanced Juxtapapillary Retinal Hemangioblastomas Associated with von Hippel-Lindau Disease.

PURPOSE: To describe the clinical course of advanced juxtapapillary retinal capillary hemangioblastomas (RCH) associated with von Hippel-Lindau (VHL) disease treated with systemic sunitinib malate, an agent that inhibits both anti-vascular endothelial growth factor and anti-platelet-derived growth factor signaling. DESIGN: Observational case review. PARTICIPANTS: Three patients with advanced VHL-related juxtapapillary RCH treated with systemic sunitinib malate. METHODS: Patient 1 was followed routinely every 4 months while on systemic sunitinib prescribed by her oncologist for metastatic pancreatic neuroendocrine and kidney tumors. Patients 2 and 3 were part of a prospective clinical trial evaluating the use of systemic sunitinib for ocular VHL lesions during a period of 9 months. Visual acuity, size of RCH, and degree of exudation were recorded at each visit. Optical coherence tomography (OCT) and fluorescein angiography were also obtained at some visits. MAIN OUTCOME MEASURES: Visual acuity, size of RCH, and degree of exudation. RESULTS: Three patients with advanced VHL-associated juxtapapillary RCH were treated with systemic sunitinib malate. While none of the patients lost vision during therapy, treatment with sunitinib malate did not improve visual acuity or reduce the size of RCH. Improvements in RCH-associated retinal edema were observed in two patients. All patients experienced multiple adverse effects, including thyroid toxicity, thrombocytopenia, nausea, fatigue, jaundice, and muscle aches. Two of the three patients had to discontinue treatment prematurely and the third required dose reduction. CONCLUSIONS: Systemic sunitinib malate may be useful in slowing progression of ocular disease from VHL-associated RCH. However, significant systemic adverse effects limited its use in this small series, and systemic sunitinib malate may not be safe for treatment of RCH when used at the doses described in this report. Further studies are required to determine if this medication used at lower doses with different treatment strategies, other medications in the same class or drugs directed at multiple targets in the tumor, may be safer and more effective for the treatment of advanced VHL-associated RCH.

Gradient Boosted Decision Tree Classification of Endophthalmitis Versus Uveitis and Lymphoma from Aqueous and Vitreous IL-6 and IL-10 Levels.

PURPOSE: To investigate the effectiveness of gradient boosting to classify endophthalmitis versus uveitis and lymphoma by intraocular cytokine levels. METHOD: Patient diagnoses and aqueous and vitreous levels of interleukin (IL)-6 and IL-10 were retrospectively extracted from a National Eye Institute Histopathology Core database and compared by Kruskal-Wallis and post hoc Dunn tests. A gradient-boosted decision tree classifier was trained to differentiate endophthalmitis versus uveitis and lymphoma from vitreous IL-6 and IL-10, vitreous IL-6 only, and aqueous IL-6 only data sets; and was tested with 80-20 train-test split and 3-fold cross-validation of the training set. RESULTS: Seven endophthalmitis, 29 lymphoma, and 49 uveitis patients were included. IL-6 was higher in endophthalmitis than uveitis (P = 0.0713 aqueous, 0.0014 vitreous) and lymphoma (P = 0.0032 aqueous, 0.0001 vitreous). IL-10 was significantly higher in lymphoma than uveitis (P = 0.0017 aqueous, 0.0014 vitreous). Three-fold cross validation demonstrated 95% ± 5%, 95% ± 4%, and 97% ± 5% predictive accuracy for vitreous IL-6 and IL-10, vitreous IL-6 only, and aqueous IL-6 only data sets. Upon validation with the testing set, vitreous IL-6 and IL-10 and aqueous IL-6 only data sets achieved 100% predictive accuracy and vitreous IL-6 only data achieved 93% predictive accuracy with 100% sensitivity, 92% specificity, and an area under the receiver operating characteristic curve (ROC/AUC) of 96%. CONCLUSIONS: With limited sample size, gradient boosting can differentiate endophthalmitis from uveitis and lymphoma by IL-6 and IL-10 with high sensitivity and specificity; however, a larger cohort is needed for further validation.

Multimodal Imaging of the White Dot Syndromes and Related Diseases.

The white dot syndromes encompass a group of rare posterior uveitis conditions that are characterized by outer retinal and/or choroidal hypopigmented lesions that are thought to be inflammatory in nature. The size, shape, and location of lesions in the fundus aid in differentiating these conditions. Multimodal imaging, including modalities such as fundus autofluorescence, optical coherence tomography, fluorescein angiography, and indocyanine green angiography, among others, has become integral in diagnosing and monitoring many of the white dot syndromes. Furthermore, multimodal imaging modalities have provided insights into the pathogenesis and exact sites within the retina and choroid affected by white dot syndromes.

High-Risk Corneal Graft Rejection in the Setting of Previous Corneal Herpes Simplex Virus (HSV)-1 Infection.

PURPOSE: The "high-risk phenotype" of corneal graft recipients is considered to be related to preexisting vascularization such as that associated with herpes simplex virus-1 (HSV-1) keratitis (HSK). The purpose of this study was to investigate the immunologic mechanisms underlying accelerated corneal graft rejection using a mouse model of HSK. METHODS: Herpes simplex virus type 1 keratitis was induced in BALB/c mice. Syngeneic and allogeneic (C57BL/6 mice) corneal grafts were performed in mice with HSK at different times after infection. Some grafts were performed on HSV-infected CD4 T cell-deficient BALB/c mice. Clinical, histologic, immunologic, and virus detection studies were performed on samples of cornea, draining lymph node (LN), and trigeminal ganglion (TG) cells. RESULTS: Corneal grafts in mice with HSK rejected with higher frequency and more rapid tempo compared with grafts in uninfected mice. In corneas with HSK and vascularization at the time of grafting, both syngeneic and allogeneic corneal grafts failed with similar frequency and tempo. However, in the absence of preexisting inflammation and vascularization, syngeneic grafts were accepted when the grafts were performed at a late time point after HSV infection (42 days), whereas allografts were rejected at this time. In contrast, syngeneic grafts in nonvascularized HSV-infected recipients failed if they were performed within 10 days of HSV infection, an effect that was dependent on CD4 T cells, as demonstrated using CD4 deficient mice. Importantly, a variably sustained but strongly positive anti-HSV T-cell response was detected in allografted HSK recipients with a similar but lesser response in syngeneic hosts. CONCLUSIONS: A previous HSV-1 corneal infection predisposes donor grafts to a high risk of failure by both innate and adaptive immune mechanisms in which an anti-HSV CD4 T-cell response plays a prominent role.

Enhanced Depth Imaging Optical Coherence Tomography in Uveitis: An Intravisit and Interobserver Reproducibility Study.

PURPOSE: To determine the intravisit and interobserver reproducibility of subfoveal choroidal thickness (SFCT) measurements in patients with noninfectious uveitis. DESIGN: Reliability analysis. METHODS: Two consecutive enhanced depth imaging optical coherence tomography (EDI-OCT) scans were obtained at a single clinic visit for 97 uveitic eyes from patients ≥16 years of age with noninfectious anterior (n = 10), intermediate (n = 11), posterior (n = 26), and panuveitis (n = 13) at the National Eye Institute. SFCT was manually measured by 2 ophthalmologists using manufacturer's software. Intravisit and interobserver reproducibility of SFCT measurements were assessed by using the Bland-Altman method to determine the estimate of bias (mean difference in SFCT measurements), 95% limits of agreement, and coefficients of repeatability. The reproducibility of these measurements was also compared between groups by anatomic location and clinical activity. RESULTS: Of 97 eyes, 65 (67.0%) were clinically quiet, 18 (18.6%) were minimally active, and 14 (14.4%) were active at the time the scans were obtained. Manual SFCT measurements were reproducible within 32.4 ± 3.8 µm between sessions for the same observer and 51.4 ± 8.5 µm between observers for the same session. Coefficients of repeatability did not differ significantly by anatomic location or disease activity. CONCLUSIONS: Manual SFCT measurements obtained by EDI-OCT are reproducible in uveitis patients, with coefficients of repeatability that are nearly comparable to those published for normal eyes. This study provides guidance for using manual SFCT measurements in clinical practice, but further studies are still needed to determine their utility in clinical trials.