Fluorescein Angiography Does Not Alter the Initial Clinical Management of Choroidal Neovascularization in Age-Related Macular Degeneration.

PURPOSE: Fundus fluorescein angiography (FFA) is the standard modality to diagnose and manage choroidal neovascularization (CNV). However, FFA is costly and has considerable morbidity from allergic reactions and a mortality of 1 per 220 000. Since the advent of anti-vascular endothelial growth factor (VEGF) therapy for CNV, OCT has been used extensively to manage CNV, but FFA is still widely used. One recent study found the sensitivity and specificity of OCT compared with FFA in diagnosis of CNV were 100% and 80.8%, respectively. We hypothesize that FFA does not affect the management of patients initially suspected of having CNV to a clinically significant degree. DESIGN: Evaluation of diagnostic test using vignettes. PARTICIPANTS: A total of 99 patients (99 eyes) who had an initial presentation of later confirmed CNV. METHODS: We retrospectively extracted in de-identified form the FFA, OCT, and clinical histories of the subjects. Vignettes were created with a standard narrative clinical history, posterior-pole color fundus image, central B-scan OCT of the initial visit, and early, mid, and late FFA of the affected eye. Four masked retinal specialists reviewed, in randomized order, these vignettes without FFA images (FFA- arm) and answered a forced choice management question: observation, 3 consecutive anti-VEGF injections, or other. After re-randomization, experts again reviewed the vignettes with the addition of the FFA images (FFA+ arm). MAIN OUTCOME MEASURES: Intraobserver and interobserver concordance and reliability statistics within and between specialists. RESULTS: Among our retina specialists, intraobserver concordances were 89.7%, 88.7%, 88.7%, and 95.9% (average 90.7%, 95% confidence interval [CI], 83.7-97.6). The average interobserver concordance for the FFA- arm was 84.0% (95% CI, 72.6-95.4), and for the FFA+ arm, 81.8% (95% CI, 68.5-95.2); paired t testing demonstrated no significant difference between the FFA- and FFA+ arms: t = 0.6, P = 0.55. CONCLUSIONS: Our data suggest a high degree of agreement in clinical decision making whether FFA was used or not. There was a similar level of agreement among specialists in the FFA- and FFA+ groups, albeit at higher, not statistically significant, variability. We believe these findings further support deferring the use of FFA in the initial management of CNV in AMD, except in treatment failures and nonstandard cases.

The Role of the Immune Response in the Pathogenesis of Thyroid Eye Disease: A Reassessment.

BACKGROUND: Although thyroid eye disease is a common complication of Graves' disease, the pathogenesis of the orbital disease is poorly understood. Most authorities implicate the immune response as an important causal factor. We sought to clarify pathogenesis by using gene expression microarray. METHODS: An international consortium of ocular pathologists and orbital surgeons contributed formalin fixed orbital biopsies. RNA was extracted from orbital tissue from 20 healthy controls, 25 patients with thyroid eye disease (TED), 25 patients with nonspecific orbital inflammation (NSOI), 7 patients with sarcoidosis and 6 patients with granulomatosis with polyangiitis (GPA). Tissue was divided into a discovery set and a validation set. Gene expression was quantified using Affymetrix U133 Plus 2.0 microarrays which include 54,000 probe sets. RESULTS: Principal component analysis showed that gene expression from tissue from patients with TED more closely resembled gene expression from healthy control tissue in comparison to gene expression characteristic of sarcoidosis, NSOI, or granulomatosis with polyangiitis. Unsupervised cluster dendrograms further indicated the similarity between TED and healthy controls. Heat maps based on gene expression for cytokines, chemokines, or their receptors showed that these inflammatory markers were associated with NSOI, sarcoidosis, or GPA much more frequently than with TED. CONCLUSION: This is the first study to compare gene expression in TED to gene expression associated with other causes of exophthalmos. The juxtaposition shows that inflammatory markers are far less characteristic of TED relative to other orbital inflammatory diseases.

Orbital pseudotumor can be a localized form of granulomatosis with polyangiitis as revealed by gene expression profiling.

Biopsies and ANCA testing for limited forms of granulomatosis with polyangiitis (GPA) are frequently non-diagnostic. We characterized gene expression in GPA and other causes of orbital inflammation. We tested the hypothesis that a sub-set of patients with non-specific orbital inflammation (NSOI, also known as pseudotumor) mimics a limited form of GPA. Formalin-fixed, paraffin-embedded orbital biopsies were obtained from controls (n=20) and patients with GPA (n=6), NSOI (n=25), sarcoidosis (n=7), or thyroid eye disease (TED) (n=20) and were divided into discovery and validation sets. Transcripts in the tissues were quantified using Affymetrix U133 Plus 2.0 microarrays. Distinct gene expression profiles for controls and subjects with GPA, TED, or sarcoidosis were evident by principal coordinate analyses. Compared with healthy controls, 285 probe sets had elevated signals in subjects with GPA and 1472 were decreased (>1.5-fold difference, false discovery rate adjusted p<0.05). The immunoglobulin family of genes had the most dramatic increase in expression. Although gene expression in GPA could be readily distinguished from gene expression in TED, sarcoidosis, or controls, a comparison of gene expression in GPA versus NSOI found no statistically significant differences. Thus, forms of orbital inflammation can be distinguished based on gene expression. NSOI/pseudotumor is heterogeneous but often may be an unrecognized, localized form of GPA.

Adaptation of the steady-state PERG in early glaucoma.

PURPOSE: Previous studies have shown that the onset of high-contrast, fast reversing patterned stimuli induces rapid blood flow increase in retinal vessels in association with slow changes of the steady-state pattern electroretinogram (PERG) signal. We tested the hypothesis that adaptive PERG changes of normal controls differed from those of glaucoma suspects and patients with early manifest glaucoma. METHODS: Subjects were 42 glaucoma suspects (Standard Automated Perimetry-MD -0.89±1.8 dB), 22 early manifest glaucoma (MD -2.12±2.4 dB) with visual acuity of ≥20/20 and 16 age-matched normal controls from a previous study. The PERG signal was sampled every ~15 seconds over 4 minutes in response to gratings (1.6 cyc/degree, 100% contrast) reversing 16.28 times/s. Amplitude/phase values of successive PERG samples were fitted with a nonparametric locally weighted polynomial regression smoothing function to retrieve the initial and final values and calculate their difference (δ) and the residual SD around the fitted function. The magnitude of PERG adaptive change compared to random variability was calculated as log10 of percentage coefficient of variation (CoV)=100×residual SDr÷δ. Grand-average PERGs were also obtained by averaging all samples of the same series. RESULTS: The grand-average PERG amplitude [analysis of variance (ANOVA), P=0.02], but not phase (ANOVA, P=0.63), decreased with increasing severity of disease. Adaptive changes [log10 (CoV)] of PERG amplitude were not significantly associated with disease severity (ANOVA, P=0.27) but adaptive changes [log10 (CoV)] of PERG phase were (ANOVA, P=0.037; linear trend, P=0.011). CONCLUSIONS: The steady-state PERG signal displayed slow adaptive changes over time that could be isolated from random variability. PERG adaptive changes differed from those of grand-average PERGs (corresponding the standard steady-state PERG), thus representing a new source of biological information about retinal ganglion cell function that may have potential in the study of glaucoma and optic nerve diseases.