March 2016

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Altamura M, Padalino FA, Stella E, Balzotti A, Bellomo A, Palumbo R, Di Domenico A, Mammarella N, Fairfield B. Facial Emotion Recognition in Bipolar Disorder and Healthy Aging. J Nerv Ment Dis 2016;204(3):188-93.Abstract

Emotional face recognition is impaired in bipolar disorder, but it is not clear whether this is specific for the illness. Here, we investigated how aging and bipolar disorder influence dynamic emotional face recognition. Twenty older adults, 16 bipolar patients, and 20 control subjects performed a dynamic affective facial recognition task and a subsequent rating task. Participants pressed a key as soon as they were able to discriminate whether the neutral face was assuming a happy or angry facial expression and then rated the intensity of each facial expression. Results showed that older adults recognized happy expressions faster, whereas bipolar patients recognized angry expressions faster. Furthermore, both groups rated emotional faces more intensely than did the control subjects. This study is one of the first to compare how aging and clinical conditions influence emotional facial recognition and underlines the need to consider the role of specific and common factors in emotional face recognition.

Annunziata R, Kheirkhah A, Aggarwal S, Cavalcanti BM, Hamrah P, Trucco E. Two-Dimensional Plane for Multi-Scale Quantification of Corneal Subbasal Nerve Tortuosity. Invest Ophthalmol Vis Sci 2016;57(3):1132-9.Abstract

PURPOSE: To assess the performance of a novel system for automated tortuosity estimation and interpretation. METHODS: A supervised strategy (driven by observers' grading) was employed to automatically identify the combination of tortuosity measures (i.e., tortuosity representation) leading to the best agreement with the observers. We investigated 18 tortuosity measures including curvature and density of inflection points, computed at multiple spatial scales. To leverage tortuosity interpretation, we propose the tortuosity plane (TP) onto which each image is mapped. Experiments were carried out on 140 images of subbasal nerve plexus of the central cornea, covering four levels of tortuosity. Three experienced observers graded each image independently. RESULTS: The best tortuosity representation was the combination of mean curvature at spatial scales 2 and 5. These tortuosity measures were the axes of the proposed TP (interpretation). The system for tortuosity estimation revealed strong agreement with the observers on a global and per-level basis. The agreement with each observer (Spearman's correlation) was statistically significant (αs = 0.05, P < 0.0001) and higher than that of at least one of the other observers in two out of three cases (ρOUR = 0.7594 versus ρObs3 = 0.7225; ρOUR = 0.8880 versus ρObs1 = 0.8017, ρObs3 = 0.7315). Based on paired-sample t-tests, these improvements were significant (P < 0.001). CONCLUSIONS: Our automated system stratifies images by four tortuosity levels (discrete scale) matching or exceeding the accuracy of experienced observers. Of importance, the TP allows the assessment of tortuosity on a two-dimensional continuous scale, thus leading to a finer discrimination among images.

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Bingham CM, Sivak-Callcott JA, Gurka MJ, Nguyen J, Hogg JP, Feldon SE, Fay A, Seah L-L, Strianese D, Durairaj VD, Uddin J, Devoto MH, Harris M, Saunders J, Osaki TH, Looi A, Teo L, Davies BW, Elefante A, Shen S, Realini T, Fischer W, Kazim M. Axial Globe Position Measurement: A Prospective Multicenter Study by the International Thyroid Eye Disease Society. Ophthal Plast Reconstr Surg 2016;32(2):106-12.Abstract

PURPOSE: Identify a reproducible measure of axial globe position (AGP) for multicenter studies on patients with thyroid eye disease (TED). METHODS: This is a prospective, international, multicenter, observational study in which 3 types of AGP evaluation were examined: radiologic, clinical, and photographic. In this study, CT was the modality to which all other methods were compared. CT AGP was measured from an orthogonal line between the anterior lateral orbital rims to the cornea. All CT measurements were made at a single institution by 3 individual clinicians. Clinical evaluation was performed with exophthalmometry. Three clinicians from each clinical site assessed AGP with 3 different exophthalmometers and horizontal palpebral width using a ruler. Each physician made 3 separate measurements with each type of exophthalmometer not in succession. All photographic measurements were made at a single institution. AGP was measured from lateral photographs in which a standard marker was placed at the anterior lateral orbital rim. Horizontal and vertical palpebral fissure were measured from frontal photographs. Three trained readers measured 3 separate times not in succession. Exophthalmometry and photography method validity was assessed by agreement with CT (mean differences calculation, intraclass correlation coefficients [ICCs], Bland-Altman figures). Correlation between palpebral fissure and CT AGP was assessed with Pearson correlation. Intraclinician and interclinician reliability was evaluated using ICCs. RESULTS: Sixty-eight patients from 7 centers participated. CT mean AGP was 21.37 mm (15.96-28.90 mm) right and 21.22 mm (15.87-28.70 mm) left (ICC 0.996 and 0.995). Exophthalmometry AGP fell between 18 mm and 25 mm. Intraclinician agreement across exophthalmometers was ideal (ICC 0.948-0.983). Agreement between clinicians was greater than 0.85 for all upright exophthalmometry measurements. Photographic mean AGP was 20.47 mm (10.92-30.88 mm) right and 20.30 mm (8.61-28.72 mm) left. Intrareader and interreader agreement was ideal (ICC 0.991-0.989). All exophthalmometers' mean differences from CT ranged between -0.06 mm (±1.36 mm) and 0.54 mm (±1.61 mm); 95% confidence interval fell within 1 mm. Magnitude of AGP did not affect exophthalmometry validity. Oculus best estimated CT AGP but differences from other exophthalmometers were not clinically meaningful in upright measurements. Photographic AGP (right ICC = 0.575, left ICC = 0.355) and palpebral fissure do not agree with CT. CONCLUSIONS: Upright clinical exophthalmometry accurately estimates CT AGP in TED. AGP measurement was reliably reproduced by the same clinician and between clinicians at multiple institutions using the protocol in this study. These findings allow reliable measurement of AGP that will be of considerable value in future outcome studies.

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Davies EC, Pavan-Langston D, Chodosh J. Herpes zoster ophthalmicus: declining age at presentation. Br J Ophthalmol 2016;100(3):312-4.Abstract

OBJECTIVE: To investigate changes in the age of occurrence of herpes zoster ophthalmicus (HZO) in patients presenting to the Massachusetts Eye and Ear Infirmary (MEEI) from 2007 through 2013. DESIGN: Retrospective chart review. SETTING: Academic tertiary referral centre for ophthalmic conditions. PARTICIPANTS: 913 patients with acute HZO. METHODS: A total of 1283 potential cases were identified by searching the MEEI electronic medical record for patient charts with International Classification of Diseases 9 codes for herpes zoster, shingles and varicella from 2007 through 2013. The cases were reviewed to confirm diagnosis of acute HZO, requiring documentation of a skin rash or pain in the V1 distribution, resulting in inclusion of 913 cases. MAIN OUTCOME MEASURES: Number of HZO cases each year, mean age of HZO cases each year, number of HZO cases with an immunodeficiency state. RESULTS: The number of patients with HZO presenting to MEEI increased from 71 cases in 2007 to 195 cases in 2013. The mean age of patients with acute HZO reduced significantly from 61.2 years in 2007 to 55.8 years in 2013 (p=0.0119). The number of patients with acute HZO in the setting of an immunodeficiency state did not change significantly over the study period. CONCLUSIONS: Ever since the introduction of varicella vaccination in children, there has been debate regarding its effect on zoster epidemiology, particularly regarding the potential to reduce population exposure and limit repeated immunological boosts against varicella zoster virus in adults. Patients presenting to MEEI with HZO were younger on average in 2013 than in 2007. Although a population-based study is necessary to test the hypothesis, our study suggests that varicella vaccination of children remains a possible explanation for the increased number of cases and reduction in mean age of newly diagnosed patients.

Durrani K, Kempen JH, Ying G-S, Kacmaz OR, Artornsombudh P, Rosenbaum JT, Suhler EB, Thorne JE, Jabs DA, Levy-Clarke GA, Nussenblatt RB, Foster SC, Foster SC. Adalimumab for Ocular Inflammation. Ocul Immunol Inflamm 2016;:1-8.Abstract

PURPOSE: To evaluate adalimumab as an immunomodulatory treatment for non-infectious ocular inflammatory diseases. METHODS: Characteristics of patients treated with adalimumab were abstracted in a standardized chart review. Main outcomes measured were control of inflammation, corticosteroid-sparing effect, and visual acuity. RESULTS: In total, 32 patients with ocular inflammation were treated with adalimumab. The most common ophthalmic diagnoses were anterior uveitis, occurring in 15 patients (47%), and scleritis, occurring in 9 patients (28%). At 6 months of therapy, among 15 eyes with active inflammation, 7 (47%) became completely inactive, and oral prednisone was reduced to ≤10 mg/day in 2 of 4 patients (50%). On average, visual acuity decreased by 0.13 lines during the first 6 months of treatment. Adalimumab was discontinued because of lack of effectiveness in four patients within 6 months. CONCLUSIONS: Adalimumab was moderately effective in controlling inflammation in a group of highly pre-treated cases of ocular inflammatory disease.

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Eidet JR, Reppe S, Pasovic L, Olstad OK, Lyberg T, Khan AZ, Fostad IG, Chen DF, Utheim TP. The Silk-protein Sericin Induces Rapid Melanization of Cultured Primary Human Retinal Pigment Epithelial Cells by Activating the NF-κB Pathway. Sci Rep 2016;6:22671.Abstract

Restoration of the retinal pigment epithelial (RPE) cells to prevent further loss of vision in patients with age-related macular degeneration represents a promising novel treatment modality. Development of RPE transplants, however, requires up to 3 months of cell differentiation. We explored whether the silk protein sericin can induce maturation of primary human retinal pigment epithelial (hRPE) cells. Microarray analysis demonstrated that sericin up-regulated RPE-associated transcripts (RPE65 and CRALBP). Upstream analysis identified the NF-κB pathway as one of the top sericin-induced regulators. ELISA confirmed that sericin stimulates the main NF-κB pathway. Increased levels of RPE-associated proteins (RPE65 and the pigment melanin) in the sericin-supplemented cultures were confirmed by western blot, spectrophotometry and transmission electron microscopy. Sericin also increased cell density and reduced cell death following serum starvation in culture. Inclusion of NF-κB agonists and antagonists in the culture medium showed that activation of the NF-κB pathway appears to be necessary, but not sufficient, for sericin-induced RPE pigmentation. We conclude that sericin promotes pigmentation of cultured primary hRPE cells by activating the main NF-κB pathway. Sericin's potential role in culture protocols for rapid differentiation of hRPE cells derived from embryonic or induced pluripotent stem cells should be investigated.

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García-Posadas L, Contreras-Ruiz L, Soriano-Romaní L, Dartt DA, Diebold Y. Conjunctival Goblet Cell Function: Effect of Contact Lens Wear and Cytokines. Eye Contact Lens 2016;42(2):83-90.Abstract

This review focuses on conjunctival goblet cells and their essential function in the maintenance of eye health. The main function of goblet cells is to produce and secrete mucins that lubricate the ocular surface. An excess or a defect in those mucins leads to several alterations that makes goblet cells central players in maintaining the proper mucin balance and ensuring the correct function of ocular surface tissues. A typical pathology that occurs with mucous deficiency is dry eye disease, whereas the classical example of mucous hyperproduction is allergic conjunctivitis. In this review, we analyze how goblet cell number and function can be altered in these diseases and in contact lens (CL) wearers. We found that most published studies focused exclusively on the goblet cell number. However, recent advances have demonstrated that, along with mucin secretion, goblet cells are also able to secrete cytokines and respond to them. We describe the effect of different cytokines on goblet cell proliferation and secretion. We conclude that it is important to further explore the effect of CL wear and cytokines on conjunctival goblet cell function.

Greiner JV. Long-Term (3 Year) Effects of a Single Thermal Pulsation System Treatment on Meibomian Gland Function and Dry Eye Symptoms. Eye Contact Lens 2016;42(2):99-107.Abstract

PURPOSE: The present study examined the long-term (3 years) effects of a single (12 min) thermal pulsation system (TPS) treatment on symptomatic patients with evaporative dry eye disease (DED) secondary to meibomian gland dysfunction (MGD). METHODS: In this prospective, cohort, observational, single-center study design, signs (meibomian gland secretion [MGS] scores and tear film breakup time [TBUT]) and symptoms (Ocular Surface Disease Index [OSDI] and Standard Patient Evaluation of Eye Dryness [SPEED] questionnaires) were determined in 20 patients (40 eyes) with MGD and dry eye symptoms at baseline (BL), 1 month, and 3 years post-TPS treatment using LipiFlow. RESULTS: Meibomian gland secretion scores increased from BL (4.5±0.8) to 1 month (12.0±1.1, P≤0.001). Improvement persisted at 3 years (18.4±1.4) relative to BL (P≤0.001). Meibomian gland secretion scores in all regions of the lower eyelid were improved over BL at 1 month (nasal [P≤0.001], central [P≤0.001], temporal [P≤0.01]) and 3 years (nasal [P≤0.001], central [P≤0.001], temporal [P≤0.001]). TBUT increased from BL (4.1±0.4) to 1 month (7.9±1.4, P≤0.05) but was not significantly different than BL at 3 years (4.5±0.6, P>0.05). The OSDI scores decreased from BL (26.0±4.6) to 1 month (14.7±4.3, P≤0.001) but returned to BL levels at 3 years (22.5±5.4, P>0.05). The SPEED scores decreased from BL (13.4±1.0) to 1 month (6.5±1.3, P≤0.001), and this improvement persisted at 3 years (9.5±1.6, P≤0.001). CONCLUSIONS: Thermal pulsation may be a uniquely efficacious treatment option for DED secondary to MGD in that a single 12-min procedure is associated with significant improvement in MGS and SPEED scores for up to 3 years.

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Hymowitz MB, Chang D, Feinberg EB, Roy S. Increased Intraocular Pressure and Hyperglycemic Level in Diabetic Patients. PLoS One 2016;11(3):e0151833.Abstract

PURPOSE: To determine whether hyperglycemic levels as determined from high hemoglobin A1c (HbA1c) levels influence intraocular pressure (IOP) in patients with non-proliferative diabetic retinopathy (NPDR). METHODS: A retrospective chart review was performed on subjects with a diagnosis of NPDR and a corresponding HbA1c level measured within 90 days before or after an IOP measurement over a two-year period. Exclusion criteria included a diagnosis of glaucoma or treatment with IOP lowering medications or oral or topical steroids. RESULTS: Using 14.5mmHg as a baseline mean value for IOP, 42 subjects had an IOP < 14.5mmHg and mean HbA1c of 8.1±1.1, while 72 subjects had an IOP ≥ 14.5mmHg and a mean HbA1c of 9.0±2.1. Although there was an overlap in the confidence intervals, a significant difference (P = 0.01) in the mean HbA1c level was observed in regression analysis between the two groups. Importantly, diabetic subjects with elevated HbA1c levels rarely (<1%) exhibited reduced IOP levels. CONCLUSIONS: Diabetic subjects with elevated HbA1c levels exhibited significantly higher IOPs compared to those with lower HbA1c levels. Findings from this study indicate an association between hyperglycemia and elevated IOP and that poor glycemic control may contribute to increased IOP levels in long-term diabetic patients.

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Iacovelli J, Rowe GC, Khadka A, Diaz-Aguilar D, Spencer C, Arany Z, Saint-Geniez M. PGC-1α Induces Human RPE Oxidative Metabolism and Antioxidant Capacity. Invest Ophthalmol Vis Sci 2016;57(3):1038-51.Abstract

PURPOSE: Oxidative stress and metabolic dysregulation of the RPE have been implicated in AMD; however, the molecular regulation of RPE metabolism remains unclear. The transcriptional coactivator, peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α) is a powerful mediator of mitochondrial function. This study examines the ability of PGC-1α to regulate RPE metabolic program and oxidative stress response. METHODS: Primary human fetal RPE (hfRPE) and ARPE-19 were matured in vitro using standard culture conditions. Mitochondrial mass of RPE was measured using MitoTracker staining and citrate synthase activity. Expression of PGC-1 isoforms, RPE-specific genes, oxidative metabolism proteins, and antioxidant enzymes was analyzed by quantitative PCR and Western blot. Mitochondrial respiration and fatty-acid oxidation were monitored using the Seahorse extracellular flux analyzer. Expression of PGC-1α was increased using adenoviral delivery. ARPE-19 were exposed to hydrogen peroxide to induce oxidative stress. Reactive oxygen species were measured by CM-H2DCFDA fluorescence. Cell death was analyzed by LDH release. RESULTS: Maturation of ARPE-19 and hfRPE was associated with significant increase in mitochondrial mass, expression of oxidative phosphorylation (OXPHOS) genes, and PGC-1α gene expression. Overexpression of PGC-1α increased expression of OXPHOS and fatty-acid β-oxidation genes, ultimately leading to the potent induction of mitochondrial respiration and fatty-acid oxidation. PGC-1α gain of function also strongly induced numerous antioxidant genes and, importantly, protected RPE from oxidant-mediated cell death without altering RPE functions. CONCLUSIONS: This study provides important insights into the metabolic changes associated with RPE functional maturation and identifies PGC-1α as a potent driver of RPE mitochondrial function and antioxidant capacity.

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Kheirkhah A, Saboo US, Marmalidou A, Dana R. Overestimation of Corneal Endothelial Cell Density in Smaller Frame Sizes in In Vivo Confocal Microscopy. Cornea 2016;35(3):363-9.Abstract

PURPOSE: To evaluate the effect of frame size on the calculated corneal endothelial cell density (CECD) in images of laser scanning in vivo confocal microscopy (IVCM). METHODS: Forty-nine corneal endothelial images acquired by laser scanning IVCM (Heidelberg Retina Tomograph 3 with Rostock Corneal Module) with different endothelial cell densities were analyzed. In each image (160,000 μm), the CECD was calculated using the fixed-frame method by counting cells in the following frame sizes: 80,000 μm, 40,000 μm, 20,000 μm, 10,000 μm, 5000 μm, and 2500 μm. The calculated CECD was then compared with that of the variable-frame method as the reference value. RESULTS: There was no significant difference in the calculated CECD between the variable-frame method (2004 ± 832 cells/mm), and the fixed-frame method using a 40,000-μm frame (2023 ± 810 cells/mm). On the other hand, the calculated CECD showed significant overestimations in frame sizes of 20,000 μm (2066 ± 820 cells/mm), 10,000 μm (2156 ± 785 cells/mm), 5000 μm (2352 ± 783 cells/mm), and 2500 μm (2715 ± 754 cells/mm), with P < 0.001 in all. This resulted in overestimations of 4.8 ± 9.8%, 11.9 ± 16.2%, 24.9 ± 23.1%, and 49.1 ± 38.8% for these frame sizes, respectively. Images with lower CECD demonstrated higher overestimations of cell density in smaller frame sizes. CONCLUSIONS: In laser scanning IVCM images, there is significant overestimation of CECD if the cells are counted in frames smaller than 25% of the image. Similar frame sizes should be used when monitoring CECD over time.

Kim C, Smith KE, Castillejos A, Diaz-Aguilar D, Saint-Geniez M, Connor KM. The alternative complement pathway aids in vascular regression during the early stages of a murine model of proliferative retinopathy. FASEB J 2016;30(3):1300-5.Abstract

Proliferative retinopathic diseases often progress in 2 phases: initial regression of retinal vasculature (phase 1) followed by subsequent neovascularization (NV) (phase 2). The immune system has been shown to aid in vascular pruning in such retinopathies; however, little is known about the role of the alternative complement pathway in the initial vascular regression phase. Using a mouse model of oxygen-induced retinopathy (OIR), we observed that alternative complement pathway-deficient mice (Fb(-/-)) exhibited a mild decrease in vascular loss at postnatal day (P)8 compared with age- and strain-matched controls (P = 0.035). Laser capture microdissection was used to isolate the retinal blood vessels. Expression of the complement inhibitors Cd55 and Cd59 was significantly decreased in blood vessels isolated from hyperoxic retinas compared with those from normoxic control mice. Vegf expression was measured at P8 and found to be significantly lower in OIR mice than in normoxic control mice (P = 0.0048). Further examination of specific Vegf isoform expression revealed a significant decrease in Vegf120 (P = 0.00032) and Vegf188 (P = 0.0092). In conjunction with the major modulating effects of Vegf during early retinal vascular development, our data suggest a modest involvement of the alternative complement pathway in targeting vessels for regression in the initial vaso-obliteration stage of OIR.-Kim, C., Smith, K. E., Castillejos, A., Diaz-Aguilar, D., Saint-Geniez, M., Connor, K. M. The alternative complement pathway aids in vascular regression during the early stages of a murine model of proliferative retinopathy.

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Maleki A, Swan RT, Silpa-Archa S, Preble JM, He Y, Foster SC. Short-Wavelength Automated Perimetry Parameters at Baseline and Following Remission in Patients With Birdshot Retinochoroidopathy. Am J Ophthalmol 2016;163:83-92.e6.Abstract

PURPOSE: To identify changes in short-wavelength automated perimetry patterns and parameters between the active and inactive states. DESIGN: Retrospective cohort study with age-matched, normal controls. METHODS: setting: Private tertiary referral center. STUDY POPULATION: Seventy-five eyes of 38 patients with active birdshot retinochoroidopathy and 37 eyes of 37 historical normal controls. INTERVENTION: Thirty-seven patients received immunomodulatory therapy. A fluocinolone acetonide intravitreal implant (Retisert) was implanted in both eyes of 1 patient as an initial treatment. MAIN OUTCOME MEASURES: Changes in short-wavelength automated perimetry total deviation scores, pattern deviation scores, mean deviation, and pattern standard deviation in the active phase and the remission state. RESULTS: Mean deviation (P = .006), pattern standard deviation (P = .001), total deviation score (P = .002), and pattern deviation score (P = .007) were significantly different from the active phase to the remission state. The length of time required to achieve remission did not significantly affect the changes in mean deviation (regression coefficient = 0.01; P = .92), pattern standard deviation (regression coefficient = 0.01; P = .87), total deviation score (regression coefficient = -0.1; P = .32), or pattern deviation score (regression coefficient = 0.1; P = .36) from the active phase to the remission state. CONCLUSION: There was significant improvement in total deviation score, pattern deviation score, mean deviation, and pattern standard deviation on short-wavelength automated perimetry as patients achieved remission. Short-wavelength automated perimetry appears to be a useful and complementary modality in monitoring disease activity in birdshot retinochoroidopathy.

Miller JW. VEGF: From Discovery to Therapy: The Champalimaud Award Lecture. Transl Vis Sci Technol 2016;5(2):9.Abstract

PURPOSE: Intraocular vascular diseases are leading causes of adult vision loss, and in the mid-1900s, I. C. Michaelson postulated that the retina releases a soluble, diffusible factor that causes abnormal vascular growth and leakage. What became known as "Factor X" eluded investigators for decades. METHODS: The field of cancer research, where Judah Folkman pioneered the concept of angiogenesis, provided the inspiration for the work honored by the 2014 Champalimaud Vision Award. Recognizing that tumors recruit their own blood supply to achieve critical mass, Dr Folkman proposed that angiogenic factors could be therapeutic targets in cancer. Napoleone Ferrara identified vascular endothelial growth factor (VEGF) as such an angiogenic agent: stimulated by hypoxic tumor tissue, secreted, and able to induce neovascularization. VEGF also was a candidate for Factor X, and the 2014 Champalimaud Laureates and colleagues worked individually and collaboratively to identify the role of VEGF in ocular disease. RESULTS: The Champalimaud Laureates correlated VEGF with ocular neovascularization in animal models and in patients. Moreover, they showed that VEGF not only was sufficient, but it also was required to induce neovascularization in normal animal eyes, as VEGF inhibition abolished ocular neovascularization in key animal models. CONCLUSIONS: The identification of VEGF as Factor X altered the therapeutic paradigms for age-related macular degeneration (AMD), diabetic retinopathy, retinal vein occlusion, and other retinal disorders. TRANSLATIONAL RELEVANCE: The translation of VEGF from discovery to therapy resulted in the most successful applications of antiangiogenic therapy to date. Annually, over one million patients with eye disease are treated with anti-VEGF agents.

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Patel AK, Newcomb CW, Liesegang TL, Pujari SS, Suhler EB, Thorne JE, Foster SC, Jabs DA, Levy-Clarke GA, Nussenblatt RB, Rosenbaum JT, Sen NH, Artornsombudh P, Kothari S, Kempen JH, for Group SITEDR. Risk of Retinal Neovascularization in Cases of Uveitis. Ophthalmology 2016;123(3):646-54.Abstract

PURPOSE: To evaluate the risk of and risk factors for retinal neovascularization (NV) in cases of uveitis. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients with uveitis at 4 US academic ocular inflammation subspecialty practices. METHODS: Data were ascertained by standardized chart review. Prevalence data analysis used logistic regression. Incidence data analysis used survival analysis with time-updated covariates where appropriate. MAIN OUTCOME MEASURES: Prevalence and incidence of NV. RESULTS: Among uveitic eyes of 8931 patients presenting for initial evaluation, 106 of 13 810 eyes had NV (prevalence = 0.77%, 95% confidence interval [CI], 0.60-0.90). Eighty-eight more eyes developed NV over 26 465 eye-years (incidence, 0.33%/eye-year; 95% CI, 0.27-0.41). Factors associated with incident NV include age <35 years compared with >35 years (adjusted hazard ratio [aHR], 2.4; 95% CI, 1.5-3.9), current cigarette smoking (aHR, 1.9; 95% CI, 1.1-3.4), and systemic lupus erythematosus (aHR, 3.5, 95% CI, 1.1-11). Recent diagnosis of uveitis was associated with an increased incidence of NV (compared with patients diagnosed >5 years ago, aHR, 2.4 [95% CI, 1.1-5.0] and aHR, 2.6 [95% CI, 1.2-6.0] for diagnosis within <1 year vs. 1-5 years, respectively). Compared with anterior uveitis, intermediate uveitis (aHR, 3.1; 95% CI, 1.5-6.6), posterior uveitis (aHR, 5.2; 95% CI, 2.5-11), and panuveitis (aHR, 4.3; 95% CI, 2.0-9.3) were associated with a similar degree of increased NV incidence. Active (aHR, 2.1, 95% CI, 1.2-3.7) and slightly active (aHR, 2.4, 95% CI, 1.3-4.4) inflammation were associated with an increased incidence of NV compared with inactive inflammation. Neovascularization incidence also was increased with retinal vascular occlusions (aHR, 10, 95% CI, 3.0-33), retinal vascular sheathing (aHR, 2.6, 95% CI, 1.4-4.9), and exudative retinal detachment (aHR, 4.1, 95% CI, 1.3-13). Diabetes mellitus was associated with a somewhat increased incidence of retinal NV (aHR, 2.3, 95% CI, 1.1-4.9), and systemic hypertension (aHR 1.5, 95% CI, 0.89-2.4) was associated with nonsignificantly increased NV incidence. Results were similar in sensitivity analyses excluding the small minority of patients with diabetes mellitus. CONCLUSIONS: Retinal NV is a rare complication of uveitis, which occurs more frequently in younger patients, smokers, and those with intermediate/posterior/panuveitis, systemic vasculopathy, retinal vascular disease, or active inflammation. Inflammation and retinal NV likely are linked; additional studies are needed to further elucidate this connection.

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Robert M-C, Frenette M, Zhou C, Yan Y, Chodosh J, Jakobiec FA, Stagner AM, Vavvas D, Dohlman CH, Paschalis EI. A Drug Delivery System for Administration of Anti-TNF-α Antibody. Transl Vis Sci Technol 2016;5(2):11.Abstract

PURPOSE: To describe the fabrication, evaluation, and preliminary in vivo safety of a new drug delivery system (DDS) for topical anti-TNF-α antibody administration. METHODS: A DDS was fabricated using inverse template fabrication of a hydrophobic three-dimensional porous scaffold (100-300 μm in diameter porosity) loaded with 10% polyvinyl alcohol hydrogel carrying 5 mg/ml (weight/volume) of anti-TNF-α antibody. Drug-loaded DDS was sterilized with 25 kGy of gamma irradiation. Long-term in vitro antibody affinity and release was evaluated at room temperature or 37°C using enzyme-linked immunosorbent assay (ELISA) and protein fluorescence. In vivo clinical and histolopathological assessment was performed by subcutaneous implantation in BALB/c mice for 3 months. RESULTS: Gamma irradiation, repeated dry/wet cycles, and storage at room temperature for 1 year or 37°C for 1 month had no deleterious effects on antibody affinity. Anti-TNF-α release was high during the first minutes of aqueous exposure, followed by stabilization and gradual, low-dose, antibody release over the next 30 days. Histopathologic evaluation of explanted DDS showed a fibrous pseudocapsule and a myxoid acute/chronic inflammation without granuloma formation surrounding the implants. CONCLUSIONS: Sustained local delivery of anti-TNF-α antibody is feasible using the described DDS, which provides stability of the enclosed antibody for up to 1 year of storage. Preliminary results show good in vivo tolerance following subcutaneous placement for 3 months. The proposed fabrication and sterilization process opens new possibilities for the delivery of biologic agents to the anterior surface of the eye. TRANSLATIONAL RELEVANCE: The described DDS will facilitate the treatment of ocular surface diseases amenable to biologic therapy.

Robert M-C, Črnej A, Shen LQ, Papaliodis GN, Dana R, Foster SC, Chodosh J, Dohlman CH. Infliximab after Boston Keratoprosthesis in Stevens-Johnson Syndrome: An Update. Ocul Immunol Inflamm 2016;:1-5.Abstract

PURPOSE: To report our experience using intravenous infliximab for the treatment of tissue melt after Boston keratoprosthesis (B-KPro) types I and II in patients with autoimmune disease. METHODS: Case series. RESULTS: We identified four patients who were treated with intravenous infliximab in the context of tissue melt after B-KPro. Stevens-Johnson syndrome-associated corneal blindness was the primary surgical indication for B-KPro implantation in all patients. Two patients received a B-KPro type I and two patients received a B-KPro type II. The patients received intravenous infliximab for skin retraction around B-KPro type II, melting of the carrier graft or leak. Treatment resulted in a dramatic decrease in inflammation and, in some cases, arrest of the melting process. Cost and patient adherence were limiting factors to pursuing infliximab therapy. In addition, one patient developed infusion reactions. CONCLUSIONS: Intravenous infliximab may be considered as globe- and sight-saving therapy for tissue melt after B-KPro.

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Sainz-de-la-Maza M, Molins B, Mesquida M, Llorenç V, Zarranz-Ventura J, Sala-Puigdollers A, Matas J, Adan A, Foster SC. Interleukin-22 serum levels are elevated in active scleritis. Acta Ophthalmol 2016;Abstract
PURPOSE: To evaluate serum cytokine profile from patients with active scleritis in a two-centre prospective case-control study. METHODS: The serum of 20 active scleritis patients not treated with any local, periocular, or systemic immunomodulatory therapy (IMT) was analysed with multiplex assay to determine the levels of 11 cytokines interleukin (IL)-1β, IL-6, IL-2, IFN-γ, IL-10, IL-12p40, IL-13, IL-17A, IL-5, TNF-α, and TNF-β, and with ELISA to determine the levels of TGF-β1, IL-22, and IL-23. Twenty-five age-matched healthy volunteers were used as controls. In a subgroup of 13 patients with active disease, a second serum sample was obtained when the disease was inactive and levels of IL-22 were determined. Serum IL-22 levels from patients with active scleritis were correlated with type of scleritis (non-necrotizing and necrotizing), degree of inflammation (0-4+ :≤2+ and >2+), and associated systemic disease. RESULTS: Serum levels of IL-22 were elevated in active scleritis patients compared to controls (6.41 ± 1.52 pg/ml versus 1.93 ± 0.39 pg/ml, p = 0.012) and significantly decreased after scleritis remission with the use of IMT (p = 0.005). There was no statistical association with scleritis type, degree of inflammation, or associated systemic disease. The serum levels of other cytokines were not significantly different from controls. CONCLUSION: In our study cohort, IL-22 serum levels were significantly elevated in active scleritis patients compared to controls and decreased significantly after remission. Our results suggest that IL-22, a T helper (Th) 17- and Th22- derived cytokine, may play a critical role in the physiopathology of scleritis.
Shields PW, Jakobiec FA, Stagner AM, Yoon MK. Spitz nevus arising in the eyelid of a teenager. Surv Ophthalmol 2016;61(2):228-35.Abstract

A 16-year-old boy developed over a 2-month interval a lightly pigmented left upper eyelid lesion measuring 1.5 mm in greatest diameter that, when excised, microscopically was hypercellular and composed almost exclusively of nonpigmented epithelioid cells that created florid, large intraepidermal junctional nests and sheets and nests of subepidermal cells. The diagnosis was a Spitz nevus. HMB-45, MART-1, and microphthalmia-associated transcription factor were all positive and established the melanocytic nature of the benign tumor. The Ki-67 proliferation index (5%) and 2 mitoses/mm(2) were both low; p16 protein was immunohistochemically identified in the nevoid cells. We review the clinical, histopathologic, and other immunohistochemical features of this entity and provide a brief differential diagnosis (including separation from a Spitzoid melanoma). This is only the third eyelid Spitz nevus reported in the literature and is the most fully characterized immunohistochemically. At their present stage of development, contemporary immunohistochemical biomarkers, while providing supplemental information, nonetheless remain less than definitive in terms of reliably distinguishing benign from malignant Spitz lesions.

Silva PS, Cavallerano JD, Haddad NMN, Tolls D, Thakore K, Patel B, Sehizadeh M, Tolson AM, Sun JK, Aiello LP. Comparison of Nondiabetic Retinal Findings Identified With Nonmydriatic Fundus Photography vs Ultrawide Field Imaging in an Ocular Telehealth Program. JAMA Ophthalmol 2016;134(3):330-4.Abstract

IMPORTANCE: Ultrawide field imaging (UWFI) is increasingly being used in teleophthalmology settings. Given the greater area of the retina imaged, we evaluated the ability of UWFI vs nonmydriatic fundus photography (NMFP) to detect nondiabetic retinal findings in a teleophthalmology program. OBSERVATION: We conducted a retrospective single-center comparative cohort study from January 1, 2011, to June 30, 2013, imaging 3864 and 3971 consecutive teleophthalmology patients (7728 and 7942 eyes) using NMFP and UWFI, respectively. Standard diabetic retinopathy evaluation and nondiabetic findings were compared between the 2 imaging modalities. In patients without diabetic retinopathy (2243 by NMFP and 2252 by UWFI), the rate of identification of nondiabetic findings by NMFP (451 patients [20.1%]) and UWFI (490 [21.8%]) were comparable (P = .19). Ultrawide field imaging increased the identification of choroidal nevi by 27% (406 eyes [5.3%] by NMFP vs 545 eyes [6.9%] by UWFI; P < .001) and chorioretinal atrophy or scarring by 116% (50 eyes [0.6%] by NMFP vs 101 eyes [1.3%] by UWFI; P < .001). No peripheral retinal findings were identified with NMFP, while UWFI detected 25 retinal tears (0.3%; P < .001), 54 lattice and peripheral degenerations (0.7%; P < .001), and 142 cases of vitreous detachment or floaters (1.8%; P < .001). Data analysis was performed from November 1, 2013, to May 1, 2014. CONCLUSIONS AND RELEVANCE: In eyes without diabetic retinopathy, approximately 20% may have ocular findings identified on retinal imaging, which emphasizes the role of retinal imaging in patients with diabetes mellitus type 1 and type 2 regardless of the severity of retinopathy. In this cohort, UWFI increased the identification of peripheral retinal and vitreous pathologic findings.

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