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2.  Fundus autofluorescence features in the inflammatory maculopathies 
To describe the fundus autofluorescence (FAF) features of the inflammatory maculopathies and develop a quantification method for FAF analysis.
This is a retrospective, consecutive case series of patients with inflammatory maculopathies from two tertiary centers. The clinical findings, demographics, and FAF imaging characteristics were reviewed. Foveal autofluorescence (AF) was analyzed. Median and standard deviation (SD) of foveal AF intensity were measured.
Thirty eyes of 15 patients were evaluated with both qualitative and quantitative FAF analysis. In acute macular neuroretinopathy, the active phase showed foveal hypoautofluorescence, which became hypoautofluorescent with resolution. In acute posterior multifocal placoid pigment epitheliopathy, multiple lesions with hypoautofluorescent centers with hyperautofluorescent borders were observed in active disease and became hypoautofluorescent with disease convalescence. In multifocal choroiditis and punctate inner choroiditis, the active hyperautofluorescent lesions progressed to inactive, hypoautofluorescent scars. Active serpiginous choroiditis showed hyperautofluorescent borders adjacent to a helicoid-shaped, hypoautofluorescent scar. Active unilateral acute idiopathic maculopathy (UAIM) showed a complex pattern of hypo- and hyperautoflourescence in the macula. The median foveal AF was the greatest in acute macular neuroretinopathy and UAIM among the maculopathies, while the greatest SD of foveal AF intensity was observed in UAIM.
The active phase of the majority of inflammatory maculopathies was characterized by hyperautofluorescent lesions. Increased SD of foveal AF correlated with a mixture of hypo-and hyperautoflourescence. Median and SD may be useful metrics in foveal AF and quantifiable values that may be assessed over time as a disease process evolves. Improvements in quantification methods of FAF imaging may allow us to objectively evaluate posterior uveitis.
PMCID: PMC4189704  PMID: 25302012
posterior uveitis; foveal autofluorescence; quantification; fundus autofluorescence imaging
4.  Relationship between Systemic Cytokines and Complement Factor H Y402H Polymorphism in Patients With Dry Age-Related Macular Degeneration 
American journal of ophthalmology  2013;156(6):1176-1183.
To investigate the relationship between systemic cytokines, the complement factor H (CFH) Y402H polymorphism, drusen load, and subfoveal choroidal thickness in patients with dry age-related macular degeneration (AMD).
Cross-sectional study.
Forty-four dry AMD patients under care of the Retina Service at the University of British Columbia were enrolled. Drusen load was measured with an automated software algorithm in spectral-domain optical coherence tomography; subfoveal choroidal thickness was measured manually using enhanced depth imaging. Bio-Plex suspension assays (Bio-Rad Laboratories) were used to analyze cytokines in plasma and CFH Y402H was genotyped. Statistical analyses included analysis of covariance and Pearson correlation, corrected for multiple comparisons.
The levels of 3 of 4 studied cytokines were significantly different among patients with CC, CT, or TT variants of the CFH Y402H polymorphism (P < .01). Patients with the at-risk CC variant had higher systemic levels of interleukin-6, interleukin-18, and tumor necrosis factor α than those with the CT variants, the TT variant, or both (P < .01). Interleukin-1β did not reach significance (P = .02), but did demonstrate a consistent trend. No correlation was found between plasma cytokines and drusen load or choroidal thickness (all P >.15).
The elevated systemic levels of selected proinflammatory cytokines, including those representing products of inflammasome activation, were associated with the CC at-risk variant of the Y402H polymorphism and suggest that genetic factors regulate the inflammatory status in dry AMD patients. Our data support the central role of inflammation in the pathogenesis of AMD and provide further evidence of a systemic involvement in AMD etiology.
PMCID: PMC3947379  PMID: 24083687 CAMSID: cams4151
Retina (Philadelphia, Pa.)  2013;33(5):1005-1010.
Spectral domain optical coherence tomography can be used to measure both choroidal thickness and drusen load. The authors conducted an exploratory study using spectral domain optical coherence tomography to determine if a correlation between choroidal thickness and drusen load exists in patients with dry age-related macular degeneration.
Forty-four patients with dry age-related macular degeneration were recruited. The drusen area and volume were determined using the automated software algorithm of the spectral domain optical coherence tomography device, and choroidal thickness was measured using enhanced depth imaging. Correlations were determined using multivariable and univariable analyses.
The authors found an inverse correlation between choroidal thickness and drusen load (r = −0.35, P = 0.04). Drusen load was also correlated with visual acuity (r = 0.32, P = 0.04). A correlation between choroidal thickness and visual acuity was suggested (r = −0.22, P = 0.21).
Spectral domain optical coherence tomography can be used to assess the correlation between drusen load and choroidal thickness, both of which show a relationship with visual acuity. The measurement of these outcomes may serve as important outcome parameters in routine clinical care and in clinical trials for patients with dry age-related macular degeneration.
PMCID: PMC3947382  PMID: 23474546 CAMSID: cams4157
adult choroid/anatomy and histology; choroid/blood supply; disease progression; humans; macular degeneration/pathology; retinal photoreceptors/pathology; retinal drusen/etiology; retinal drusen/pathology; tomography; optical coherence
6.  Pro-inflammatory and anti-angiogenic effects of bisphosphonates on human cultured retinal pigment epithelial cells 
The British journal of ophthalmology  2013;97(8):1074-1078.
Bisphosphonates have been shown to induce ocular inflammatory diseases such as uveitis and scleritis, while being protective against angiogenic diseases like neovascular age-related macular degeneration (AMD). Therefore, we studied the effects of bisphosphonates on primary culture of human fetal retinal pigment epithelium (hRPE), a cell type known to secrete both inflammatory and angiogenic factors. Alendronate and etidronate were selected for this experiment as they are members of the two structurally different classes of bisphosphonates.
Primary cultures of hRPE were serum-starved for 24 h and then treated for 24 h with alendronate (0.0001, 0.1, 100 μM) or etidronate (0.01, 1 μM). Cell viability was measured using the MTT assay. Investigation of secreted cytokines induced by bisphosphonates was performed using a human cytokine 29-Plex Panel (Bio-Plex) array and the results were analysed with an analysis of variance (ANOVA).
Etidronate, at the lower concentration, significantly increased the expression of interleukin (IL)-6 (p=0.03) and IL-8 (p=0.04). At the higher concentration, etidronate significantly decreased the expression of granulocyte macrophage colony-stimulating factor (p=0.02) and basic fibroblast growth factor (bFGF) (p=0.02). Alendronate, at the highest concentration, significantly increased the expression of IL-8 (p=0.02) and decreased the expression of eotaxin (p=0.02). Alendronate also significantly decreased the expression of bFGF at all concentrations (p<0.05) and demonstrated a trend towards decreasing vascular endothelial growth factor expression at low concentration.
Alendronate and etidronate display dose dependent effects in hRPE cells. Alendronate and etidronate administration resulted in concentration dependent elevations in inflammatory cytokines. Furthermore, alendronate and etidronate administration resulted in reduced expression of a number of angiogenic factors. These findings may explain the increased incidence of ocular inflammation as well as the therapeutic effect on neovascular AMD which have been described with bisphosphonates.
PMCID: PMC3947383  PMID: 23766431 CAMSID: cams4155
7.  Central Serous Chorioretinopathy: Update on Pathophysiology and Treatment 
Survey of ophthalmology  2013;58(2):103-126.
Recent technological advances have led to an improved understanding of central serous chorioretinopathy (CSC): new pathophysiological insights, new imaging techniques for diagnosis and management, and new treatments. The primary role of the choroid has become more widely accepted with widespread use of indocyanine green angiography. Optical coherence tomography (OCT), and particularly enhanced depth imaging OCT, demonstrate a thickened and engorged choroid. Adaptive optics, fundus autofluorescence, multifocal electroretinography, microperimetry, and contrast sensitivity testing reveal that patients with even a mild course suffer previously undetected anatomic and functional loss. While focal laser and photodynamic therapy are the current standard of care for persistent subretinal fluid in CSC, they are not appropriate in all cases, and the optimal timing of intervention remains unclear.
PMCID: PMC3574296  PMID: 23410821
central serous chorioretinopathy; diffuse retinal pigment epitheliopathy; photodynamic therapy; corticosteroids; indocyanine green angiography; fundus autofluorescence; optical coherence tomography
8.  Treatment of Geographic Atrophy With Subconjunctival Sirolimus: Results of a Phase I/II Clinical Trial 
To investigate the safety and effects of subconjunctival sirolimus, an mTOR inhibitor and immunosuppressive agent, for the treatment of geographic atrophy (GA).
The study was a single-center, open-label phase II trial, enrolling 11 participants with bilateral GA; eight participants completed 24 months of follow-up. Sirolimus (440 μg) was administered every 3 months as a subconjunctival injection in only one randomly assigned eye in each participant for 24 months. Fellow eyes served as untreated controls. The primary efficacy outcome measure was the change in the total GA area at 24 months. Secondary outcomes included changes in visual acuity, macular sensitivity, central retinal thickness, and total drusen area.
The study drug was well tolerated with few symptoms and related adverse events. Study treatment in study eyes was not associated with structural or functional benefits relative to the control fellow eyes. At month 24, mean GA area increased by 54.5% and 39.7% in study and fellow eyes, respectively (P = 0.41), whereas mean visual acuity decreased by 21.0 letters and 3.0 letters in study and fellow eyes, respectively (P = 0.03). Substantial differences in mean changes in drusen area, central retinal thickness, and macular sensitivity were not detected for all analysis time points up to 24 months.
Repeated subconjunctival sirolimus was well-tolerated in patients with GA, although no positive anatomic or functional effects were identified. Subconjunctival sirolimus may not be beneficial in the prevention of GA progression, and may potentially be associated with effects detrimental to visual acuity. ( number, NCT00766649.)
Subconjunctival sirolimus was investigated as a treatment in geographic atrophy in a Phase I/II trial. The study drug was well tolerated but was not associated with any positive anatomic or functional effects.
PMCID: PMC3638660  PMID: 23548622
age-related macular degeneration; geographic atrophy; sirolimus; rapamycin; clinical trial
9.  Subconjunctival sirolimus in the treatment of diabetic macular edema 
Diabetic macular edema (DME) is a leading cause of blindness in the developed world. Sirolimus has been shown to inhibit the production, signaling, and activity of many growth factors relevant to the development of diabetic retinopathy. This phase I/II study assesses the safety of multiple subconjunctival sirolimus injections for the treatment of DME, with some limited efficacy data.
In this phase I/II prospective, open-label pilot study, five adult participants with diabetic macular edema involving the center of the fovea and best-corrected ETDRS visual acuity score of ≤74 letters (20/32 or worse) received 20 μl (440 μg) of subconjunctival sirolimus at baseline, month 2 and every 2 months thereafter, unless there was resolution of either retinal thickening on OCT or leakage on fluorescein angiography. Main outcome measures included best-corrected visual acuity and central retinal thickness on OCT at 6 months and 1 year, as well as safety outcomes.
Repeated subconjunctival sirolimus injections were well-tolerated, with no significant drug-related adverse events. There was no consistent treatment effect related to sirolimus; one participant experienced a 2-line improvement in visual acuity and 2 log unit decrease in retinal thickness at 6 months and 1 year, two remained essentially stable, one had stable visual acuity but improvement of central retinal thickness of 1 and 3 log units at 6 months and 1 year respectively, and one had a 2-line worsening of visual acuity and a 1 log unit increase in retinal thickness at 6 months and 1 year. Results in the fellow eyes with diabetic macular edema, not treated with sirolimus, were similar.
Subconjunctival sirolimus appears safe to use in patients with DME. Assessment of possible treatment benefit will require a randomized trial.
PMCID: PMC3183290  PMID: 21567211
Sirolimus; Diabetic retinopathy; Macular edema; mTOR
10.  High-Definition Optical Coherence Tomography Features of Primary Vitreoretinal Lymphoma 
Primary vitreoretinal lymphoma is a high-grade in-traocular malignancy that presents as a vitritis with creamy subretinal lesions. In cases where the vitritis is dense, the characteristic subretinal lesions can be dif-ficult to see on clinical examination. Novel high-definition imaging techniques that allow for deeper penetration through opaque media could have diagnostic utility in such cases. The authors present a case of a patient who presented with a dense vitritis that precluded visualization of fundus details. Spectral-domain optical coherence tomography using high-definition raster imaging demonstrated subretinal deposits along with outer retinal atrophy. These findings were suggestive of primary vitreoretinal lymphoma and prompted diagnostic vitrectomy. Pathological examination of the vitreous specimen confirmed the diagnosis of primary vitreoretinal lymphoma.
PMCID: PMC3429941  PMID: 21956854
11.  Inflammatory ocular adverse events with the use of oral bisphosphonates: a retrospective cohort study 
There have been several published reports of inflammatory ocular adverse events, mainly uveitis and scleritis, among patients taking oral bisphosphonates. We examined the risk of these adverse events in a pharmacoepidemiologic cohort study.
We conducted a retrospective cohort study involving residents of British Columbia who had visited an ophthalmologist from 2000 to 2007. Within the cohort, we identified all people who were first-time users of oral bisphosphonates and who were followed to the first inflammatory ocular adverse event, death, termination of insurance or the end of the study period. We defined an inflammatory ocular adverse event as scleritis or uveitis. We used a Cox proportional hazard model to determine the adjusted rate ratios. As a sensitivity analysis, we performed a propensity-score–adjusted analysis.
The cohort comprised 934 147 people, including 10 827 first-time users of bisphosphonates and 923 320 nonusers. The incidence rate among first-time users was 29/10 000 person-years for uveitis and 63/10 000 person-years for scleritis. In contrast, the incidence among people who did not use oral bisphosphonates was 20/10 000 person-years for uveitis and 36/10 000 for scleritis (number needed to harm: 1100 and 370, respectively). First-time users had an elevated risk of uveitis (adjusted relative risk [RR] 1.45, 95% confidence interval [CI] 1.25–1.68) and scleritis (adjusted RR 1.51, 95% CI 1.34–1.68). The rate ratio for the propensity-score–adjusted analysis did not change the results (uveitis: RR 1.50, 95% CI 1.29–1.73; scleritis: RR 1.53, 95% CI 1.39–1.70).
People using oral bisphosphonates for the first time may be at a higher risk of scleritis and uveitis compared to people with no bisphosphonate use. Patients taking bisphosphonates must be familiar with the signs and symptoms of these conditions, so that they can immediately seek assessment by an ophthalmologist.
PMCID: PMC3348220  PMID: 22470169
12.  Finasteride for Chronic Central Serous Chorioretinopathy 
Retina (Philadelphia, Pa.)  2011;31(4):766-771.
To evaluate the safety and efficacy of finasteride, an inhibitor of dihyroxytestosterone (DHT) synthesis, in the treatment of chronic central serous chorioretinopathy (CSC).
Five patients with chronic CSC were prospectively enrolled in this pilot study. Patients were administered finasteride (5mg) daily for 3 months, following which study medication was withheld and patients were observed for 3 months. Main outcome measures included best-corrected visual acuity (BCVA), center-subfield macular thickness and subretinal fluid volume as assessed by optical coherence tomography (OCT). Serum DHT, serum testosterone, and urinary cortisol were also measured.
There was no change in mean BCVA. Mean center-subfield macular thickness and subretinal fluid volume reached a nadir at 3 months, and rose to levels that were below baseline by 6 months. The changes in both OCT parameters paralleled changes in serum DHT level. In four patients, center-subfield macular thickness and/or subretinal fluid volume increased following discontinuation of finasteride. In the remaining patient, both OCT parameters normalized with finasteride and remained stable when the study medication was discontinued.
Finasteride may represent a novel medical treatment for chronic CSC. Larger controlled clinical trials are needed to further assess the efficacy of finasteride for the treatment of CSC.
Pilot study to evaluate finasteride for treatment of chronic central serous chorioretinopathy suggests efficacy and tolerability.
PMCID: PMC3116973  PMID: 21273946
Finasteride; Chronic Central Serous Chorioretinopathy; Retina; Optical Coherence Tomography
13.  Gallium Scintigraphy in the Investigation of Retinal Inflammatory Vasculopathy 
Acta ophthalmologica  2010;88(7):e291-e292.
PMCID: PMC2965263  PMID: 19878127
Ocular Inflammation; Retinal Vasculitis; Sarcoidosis; Gallium Scintigraphy
14.  Optical Coherence Tomography-Based Decision Making in Exudative Age-related Macular Degeneration: Comparison of Time- versus Spectral-Domain Devices 
Eye (London, England)  2009;24(5):775-783.
To determine if optical coherence tomography (OCT) device-type influences clinical grading of OCT imaging in the context of exudative age-related macular degeneration (AMD).
Ninety-six paired OCT scans from 49 patients with active exudative AMD were obtained on both the time-domain Stratus™ OCT system and the spectral-domain Cirrus™ OCT system at the same visit. Three independent graders judged each scan for the presence of intraretinal fluid (IRF) or subretinal fluid (SRF). The degree of grader consensus was evaluated and the ability of the systems to detect the presence of disease activity was analyzed.
Cirrus™ OCT generated a higher degree of inter-grader consensus than Stratus OCT with higher intraclass correlation coefficients (ICC) for all parameters analyzed. A pair-wise comparison of Cirrus™ OCT to Stratus™ OCT systems revealed that Cirrus™-based gradings more frequently reported the presence of SRF and IRF and detected overall neovascular activity at a higher rate (p<0.05) compared to Stratus™-based gradings
The choice of time-domain (Stratus™) versus spectra-domain (Cirrus™) OCT systems has a measurable impact on clinical decision making in exudative AMD. Spectral-domain OCT systems may be able to generate more consensus in clinical interpretation and, in particular cases, detect disease activity not detected by time-domain systems. Clinical trials employing OCT-based clinical evaluations of exudative AMD may need to account for these inter-system differences in planning and analysis.
PMCID: PMC3016921  PMID: 19696804
Age-related macular degeneration; Optical coherence tomography; Clinical trials; neovascularization; anti-angiogenic treatment
15.  Complementary angiographic and autofluorescence findings in pseudoxanthoma elasticum 
International ophthalmology  2008;30(1):77-79.
Pseudoxanthoma elasticum (PXE) is a systemic disease with characteristic findings on fundus examination. The fundus findings may be difficult to detect with ophthalmoscopy. A case report is described as follows. A PXE patient had subtle retinal findings on fundoscopy that were more prominently seen using a combination of both fundus autofluorescence (FAF) imaging and indocyanine green (ICG) angiography. The fundus features visualized using each of these two modalities appeared different from each other. FAF imaging and ICG angiography may be able to more prominently detect pathology at the level of the retinal pigment epithelium and Bruch’s membrane, respectively. The use of these imaging modalities together may be complementary and useful in the evaluation of patients with PXE.
PMCID: PMC2997534  PMID: 18854947
Angiography; Autofluorescence; Fluorescein; Indocyanine green; Pseudoxanthoma elasticum
16.  Fundus Autofluorescence Imaging of the White Dot Syndromes 
Archives of ophthalmology  2010;128(1):46-56.
To characterize the fundus autofluorescence (FAF) findings in patients with white dot syndromes (WDSs).
Patients with WDSs underwent ophthalmic examination, fundus photography, fluorescein angiography, and FAF imaging. Patients were categorized as having no, minimal, or predominant foveal hypoautofluorescence. The severity of visual impairment was then correlated with the degree of foveal hypoautofluorescence.
Fifty-five eyes of 28 patients with WDSs were evaluated. Visual acuities ranged from 20/12.5 to hand motions. Diagnoses included serpiginous choroidopathy (5 patients), birdshot retinochoroidopathy (10), multifocal choroiditis (8), relentless placoid chorioretinitis (1), presumed tuberculosis-associated serpiginouslike choroidopathy (1), acute posterior multifocal placoid pigment epitheliopathy (1), and acute zonal occult outer retinopathy (2). In active serpiginous choroidopathy, notable hyperautofluorescence in active disease distinguished it from the variegated FAF features of tuberculosis-associated serpiginouslike choroidopathy. The percentage of patients with visual acuity impairment of less than 20/40 differed among eyes with no, minimal, and predominant foveal hypoautofluorescence (P<.001). Patients with predominant foveal hypoautofluorescence demonstrated worse visual acuity than those with minimal or no foveal hypoautofluorescence (both P<.001).
Fundus autofluorescence imaging is useful in the evaluation of the WDS. Visual acuity impairment is correlated with foveal hypoautofluorescence. Further studies are needed to evaluate the precise role of FAF imaging in the WDSs.
PMCID: PMC3025103  PMID: 20065216
17.  Relationship between Photoreceptor Outer Segment Length and Visual Acuity in Diabetic Macular Edema 
Retina (Philadelphia, Pa.)  2010;30(1):63-70.
To quantify photoreceptor outer segment (PROS) length in patients with diabetic macular edema (DME) using spectral domain optical coherence tomography (OCT), and to describe the correlation between PROS length and visual acuity in this group of patients.
Prospective study.
Twenty-seven consecutive patients (30 eyes) with DME.
Three SD-OCT scans were performed on all eyes during each session using Cirrus™ HD-OCT. A prototype algorithm was developed for quantitative assessment of PROS length. Retinal thicknesses and PROS lengths were calculated for three parameters; macular grid (6mm × 6mm), central subfield (1mm), and center foveal point (0.33mm). Intrasession repeatability was assessed using coefficient of variation (CVW) and intraclass correlation coefficient (ICC). Association between retinal thickness and PROS length with visual acuity was assessed using linear regression and Pearson correlation analyses.
Main Outcome Measure
Intrasession repeatability of macular parameters, and correlation of these parameters with visual acuity.
Mean retinal thickness and PROS length were 298-381 μm and 30-32 μm, respectively, for macular parameters assessed in this study. CVW values were 0.75-4.13% for retinal thickness, and 1.97-14.01% for PROS length. ICC values were 0.96-0.99 and 0.73-0.98 for retinal thickness and PROS length, respectively. Slopes from linear regression analyses assessing the association of retinal thickness and visual acuity were not significantly different from zero (p>0.20), whereas the slopes of PROS length and visual acuity were significantly different from zero (p<0.0005). Correlation coefficients for macular thickness and visual acuity ranged from 0.13 to 0.22, while coefficients for PROS length and visual acuity ranged from -0.61 to -0.81.
PROS length can be quantitatively assessed using Cirrus™ HD-OCT. Although the intrasession repeatability of PROS measurements was less than that of macular thickness measurements, the stronger correlation of PROS length with visual acuity suggests that PROS measures may be more directly related to visual function. PROS length may be a useful physiologic outcome measure, both clinically and as a direct assessment of treatment effects.
PMCID: PMC3021331  PMID: 19952996
18.  Visual Acuity Outcomes after Cataract Surgery in Patients with Age-Related Macular Degeneration: Age-Related Eye Disease Study Report No. 27 
Ophthalmology  2009;116(11):2093-2100.
To evaluate visual acuity outcomes after cataract surgery in patients with varying degrees of age-related macular degeneration (AMD).
Cohort study.
A total of 4757 participants enrolled in the Age-Related Eye Disease Study (AREDS), a prospective, multicenter, epidemiological study of the clinical course of cataract and AMD and a randomized controlled trial of antioxidants and minerals.
Standardized lens and fundus photographs, performed at baseline and annual visits, were graded by a centralized reading center using standardized protocols for severity of AMD and lens opacities. History of cataract surgery was obtained every 6 months. Analyses were conducted using multivariate logistic regression.
Main Outcome Measure
The change in best-corrected visual acuity (BCVA) after cataract surgery compared with preoperative BCVA.
Visual acuity results were analyzed for 1939 eyes that had cataract surgery during AREDS. The mean time from cataract surgery to measurement of postoperative BCVA was 6.9 months. After adjustment for age at surgery, gender, type, and severity of cataract, the mean change in visual acuity at the next study visit after the cataract surgery was as follows: Eyes without AMD gained 8.4 letters of acuity (P<0.0001), eyes with mild AMD gained 6.1 letters of visual acuity (P<0.0001), eyes with moderate AMD gained 3.9 letters (P<0.0001), and eyes with advanced AMD gained 1.9 letters (P = 0.04). The statistically significant gain in visual acuity after cataract surgery was maintained an average of 1.4 years after cataract surgery.
On average, participants with varying severity of AMD benefited from cataract surgery with an increase in visual acuity postoperatively. This average gain in visual acuity persisted for at least 18 months.
PMCID: PMC3021463  PMID: 19700198
19.  Fundus autofluorescence changes in cytomegalovirus retinitis 
Retina (Philadelphia, Pa.)  2010;30(1):42.
A retrospective case series was undertaken to evaluate nine eyes of six patients with active CMV retinitis. Patients were evaluated with a comprehensive ophthalmic examination, fundus autofluorescence imaging, and fundus photography. Oral valganciclovir, intravitreal ganciclovir, intravitreal foscarnet, or a ganciclovir implant was administered as clinically indicated.
PMCID: PMC2818550  PMID: 19996825
20.  Alterations in the Intraocular Cytokine Milieu after Intravitreal Bevacizumab 
Clinically significant changes in the concentrations of intraocular cytokines following treatment with intravitreal bevacizumab are described.
Several complications after intravitreal bevacizumab (IVB) treatment have been described including tears of the retinal pigment epithelium and tractional retinal detachment. The etiology of these complications remains unclear. The purpose of this study was to characterize changes in the intraocular levels of inflammatory cytokines after IVB as a possible explanation for these complications.
Twenty-nine patients with proliferative diabetic retinopathy (PDR) undergoing pars plana vitrectomy (PPV) for vitreous hemorrhage (VH) with IVB pretreatment were prospectively enrolled. Aqueous humor samples were taken at the time of IVB pretreatment and approximately 1 week later at the time of PPV. Multiplex cytokine arrays were used to assay 20 different cytokines. Multivariate general linear regression was performed to determine differences in cytokine levels between the two study visits. Proportional hazards regression was performed to determine the relationship between cytokine levels at PPV and postoperative outcomes.
After treatment with IVB, vascular endothelial growth factor (VEGF) concentrations in the aqueous humor decreased (P = 0.0003), whereas the concentrations of IL-8 and transforming growth factor (TGF)-β2 increased after IVB (P < 0.03). The level of IL-8 at the time of PPV was associated with the occurrence of recurrent VH after surgery (hazard ratio, 1.32; P = 0.02).
Alterations in the intraocular inflammatory cytokine milieu occur after IVB injection, possibly as a compensatory mechanism in response to VEGF inhibition. The increased concentrations of inflammatory cytokines after IVB may be clinically significant and may be responsible for some of the complications after IVB.
PMCID: PMC2868488  PMID: 20007836
21.  Hypoxia‐inducible factor expression in human RPE cells 
The British Journal of Ophthalmology  2007;91(10):1406-1410.
Hypoxia‐inducible factor (HIF) is a common transcription factor for many angiogenic proteins. Retinal pigment epithelial (RPE) cells are an important source of angiogenic factors in the retina. The expression of HIF, its regulation by proline hydroxylase (PHD) enzymes, and its downstream regulation of angiogenic factors like vascular endothelial growth factor (VEGF) and erythropoietin (EPO) was studied in RPE cells in order to determine some of the molecular mechanisms underlying ischaemic retinal disease.
ARPE‐19 cells were cultured for various times under hypoxic conditions. Cellular HIF and PHD isoforms were analysed and quantified using western blot and densitometry. VEGF and EPO secreted into the media were assayed using enzyme‐linked immunosorbent assay (ELISA). Messenger RNA (mRNA) was quantified using real‐time quantitative reverse transcriptase polymerase chain reaction (qPCR). RNA interference was achieved using siRNA techniques.
HIF‐1α was readily produced by ARPE‐19 cells under hypoxia, but HIF‐2α and HIF‐3α could not be detected even after HIF‐1α silencing. HIF‐1α protein levels showed an increasing trend for the first 24 h while HIF‐1α mRNA levels fluctuated during this time. After 36 h HIF‐1α protein levels declined to baseline levels, a change that was coincident with a rise in both PHD2 and PHD3. Silencing HIF‐1α significantly decreased VEGF secretion. Significant production of EPO could not be detected at the protein or mRNA level.
HIF‐1α appears to be the main isoform of HIF functioning in ARPE‐19 cells. Under hypoxia, HIF‐1α levels are likely self‐regulated by a feedback loop that involves both transcriptional and post‐translational mechanisms. VEGF production by human RPE cells is regulated by HIF‐1α. EPO was not produced in significant amounts by RPE cells under hypoxic conditions, suggesting that other cells and/or transcription factors in the retina are responsible for its production.
PMCID: PMC2001032  PMID: 17567660
diabetic retinopathy; VEGF; erythropoietin; hypoxia‐inducible factor; proline hydroxylase
22.  Fundus Autofluorescence in Type 2 Idiopathic Macular Telangiectasia: Correlation with Optical Coherence Tomography and Microperimetry 
American journal of ophthalmology  2009;148(4):573-583.
To employ multiple modality imaging to described patients with type 2 idiopathic macular telangiectasia (IMT) at different disease severity stages so as to characterize and categorize disease progression through the full spectrum of disease phenotypes.
Observational case series.
Twelve patients with type 2 IMT (22 eyes) with type 2 IMT examined with fundus photography, angiography, optical coherence tomography (OCT) imaging, fundus autofluorescence (FAF), and microperimetry (MP) testing in an institutional setting.
Eyes examined by multiple modality imaging were classified into five proposed categories (0–4): Category 0 (fellow) eyes were normal on all imaging modalities. Category 1 eyes had increased foveal autofluorescence on FAF imaging as the only imaging abnormality. Category 2 eyes had increased foveal autofluorescence together with funduscopic and angiographic features typical of type 2 IMT. Category 3 had additional evidence of foveal atrophy on OCT and while category 4 has all the above features plus clinically evident pigment clumping. FAF signal increased in intensity in the foveal region from category 0 through category 3, while category 4 eyes demonstrated a mixed pattern of increased and decreases FAF signal.
The findings here outline a sequence of progressive changes seen with multiple imaging modalities in advancing stages of disease. Increases in foveal autofluorescence is an early anatomical change in type 2 IMT that may precede typical clinical and angiographic changes. Loss of macular pigment density in the fovea and a changing composition of flurophores in the retinal pigment epithelium may underlie these changes in FAF in the fundus.
PMCID: PMC2753760  PMID: 19573860
23.  CD4+Foxp3+ T-regulatory cells in non-infectious uveitis 
Archives of ophthalmology  2009;127(4):407-413.
To evaluate CD4+Foxp3+ regulatory T cell populations in uveitis patients and to determine if T-regulatory cell populations are associated with disease features.
Uveitis patients were evaluated for CD4+Foxp3+ T-regulatory cells by flow cytometry. Systemic and ocular diagnoses, disease activity, and the presence of cystoid macular edema were reviewed. CD4+Foxp3+ lymphocyte percentages were compared for patients with inactive versus active disease, systemic versus ocular diagnoses, and the presence or absence of cystoid macular edema. RT-PCR testing was performed on two patients with extremely low CD4+Foxp3+ cell populations to assess Foxp3 mRNA.
20 patients with intermediate, posterior and panuveitis were evaluated. Mean age was 40.6 years and mean visual acuity was 20/57. CD4+Foxp3+ cell percentages were lower in patients with active uveitis compared to inactive disease (p<0.05). No differences in T-regulatory cells were observed between the other subgroups. Two patients with recalcitrant uveitis who demonstrated <1% CD4+Foxp3+ lymphocytes showed extremely low or absent Foxp3 mRNA.
T-regulatory cells were reduced in patients with active disease compared to inactive patients. Severe depletion of CD4+Foxp3+ T-cells and Foxp3 mRNA in two patients with severe uveitis suggests that loss of T-regulatory cells of uveitis may be a salient feature in certain patients.
PMCID: PMC2928652  PMID: 19365016
Uveitis; Foxp3; regulatory T-cell; cystoid macular edema; intermediate uveitis; posterior uveitis; panuveitis; Wegener’s granulomatosis; sarcoidosis; birdshot retinochoroidopathy
24.  Orbital Lymphoma Masquerading as Panuveitis 
To describe a case of orbital mucosa-associated lymphoid tissue (MALT) lymphoma masquerading as unilateral panuveitis.
Retrospective chart review.
A 53-year-old female patient with unilateral vitritis and exudative retinal detachment refractory to immunosuppressive treatment was eventually diagnosed with orbital MALT lymphoma. Following treatment with radiotherapy and rituximab, the patient's intraocular inflammation and retinal detachment resolved.
Orbital MALT lymphoma can masquerade as refractory unilateral panuveitis with exudative retinal detachment and appears to respond to a combination of radiotherapy and specific B-cell-targeted systemic therapy.
PMCID: PMC2927482  PMID: 20482392
MALT lymphoma; orbital MALT lymphoma; Rituximab; uveitis; masquerade syndrome

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