Sonja Prager

Disorganization of the Retinal Inner Layers as a Predictor of Visual Acuity in Eyes With Center-Involved Diabetic Macular Edema

IMPORTANCE Biomarkers that predict future visual acuity (VA) in eyes with baseline diabetic macular edema (DME) would substantively improve risk assessment, management decisions, and selection of eyes for clinical studies targeting DME. OBJECTIVE To determine whether baseline or early change in the novel spectral domain-optical coherence tomography (SD-OCT) parameter disorganization of the retinal inner layers (DRIL) is predictive of VA in eyes with center-involved DME. DESIGN, SETTING, AND PARTICIPANTS At a tertiary care referral center for diabetic eye disease, a retrospective, longitudinal cohort study obtained demographics, VA, and SD-OCT images from baseline, 4-month, and 8-month visits in 96 participants (120 eyes) with diabetes mellitus and baseline center-involved DME (SD-OCT central subfield thickness, ≥ 320 µm for men and ≥ 305 µm for women). Exclusion criteria included substantial media opacity, cataract surgery within 6 months, and nondiabetic retinal pathology affecting VA. On SD-OCT, the 1-mm-wide retinal area centered on the fovea was evaluated by masked graders for DRIL extent, cysts, hyperreflective foci, microaneurysms, cone outer segment tip visibility, and external limiting membrane or photoreceptor disruption and reflectivity. MAIN OUTCOMES AND MEASURES Visual acuity and SD-OCT-derived retinal morphology. RESULTS Greater DRIL extent at baseline correlated with worse baseline VA (point estimate, 0.04; 95% CI, 0.02-0.05 per 100 µm; P < .001). An increase in DRIL during 4 months was associated with VA worsening at 8 months (point estimate, 0.03; 95% CI, 0.02-0.05 per 100 µm; P < .001). A multivariate model that included a 4-month change in VA, DRIL, and external limiting membrane disruption was predictive of an 8-month VA change (r = 0.80). Each approximately 300-µm DRIL increase during 4 months predicted a 1-line, 8-month VA decline. When DRIL increased at least 250 µm at 4 months, no eyes had VA improvement of at least 1 line at 8 months. When DRIL decreased at least 250 µm at 4 months, no eyes had VA decline of at least 1 line at 8 months, and 77.7% had VA improvement of at least 1 line. CONCLUSIONS AND RELEVANCE Disorganization of the retinal inner layers in the 1-mm foveal area is associated with VA, and change in DRIL predicts future change in VA. Early change in DRIL prospectively identifies eyes with a high likelihood of subsequent VA improvement or decline. Therefore, DRIL warrants further study as a robust, readily obtained, and noninvasive biomarker of future VA response in eyes with DME.

A Systematic Correlation between Morphology and Functional Alterations in Diabetic Macular Edema

PURPOSE The aim of this study was to correlate different types of retinal morphologic alterations secondary to diabetic macular disease with their characteristic impact on retinal function. METHODS In the present cross-sectional study, 26 eyes of 26 diabetic patients with clinically significant macular edema were examined. All patients underwent complete standardized ophthalmologic examination, including SD-OCT and microperimetry. Microperimetric values were projected over the scanning laser ophthalmoscope image of the OCT device, allowing direct correlation of functional and morphologic parameters. Results over all 1066 individual areas were analyzed using a general linear model. RESULTS All the characteristic morphologic alterations demonstrated a significant effect on retinal function (P < 0.0002), except for outer nuclear layer (ONL) hyporeflectivity and small ONL cysts. Large ONL cysts (>220 μm) and serous retinal detachment had the greatest estimated negative effect on retinal sensitivity (-3.86 and -3.66 dB), followed by medium-sized ONL cysts, hard exudates associated with an extinction of the scan signal, and inner nuclear layer cysts. CONCLUSIONS In diabetic macular edema, serous retinal detachment and large ONL cysts are the two morphologic changes with the greatest negative impact on retinal function.

Effect of retinal photocoagulation on intraretinal lipid exudates in diabetic macular edema documented by optical coherence tomography.

PURPOSE To study the changes in the distribution and morphologic features of intraretinal microexudates after macular photocoagulation. DESIGN Prospective cohort study. PARTICIPANTS Thirteen treatment-naïve patients with clinically significant macular edema in type 2 diabetes. METHODS Patients were treated with focal macular photocoagulation. Changes in the localization of hyperreflective foci were analyzed by spectral domain (SD) optical coherence tomography (OCT) during follow-up at day 1, week 1, and months 1, 2, 3, and 4 in defined areas. Further, fundus photography and infrared imaging were performed at all visits and findings were correlated to OCT results. MAIN OUTCOME MEASURES Changes in retinal morphologic features detected in OCT. RESULTS A dynamic change in the distribution pattern of hyperreflective foci was observed over 4 months after the photocoagulation. With the decrease of retinal thickness, the dots either resolved completely or became confluent at the apical border of the outer nuclear layer, and finally formed ophthalmoscopically detectable hard exudates during extended follow-up. In the event of retinal thickening despite laser treatment, the hyperreflective dots maintained their previous distribution throughout all retinal layers. As a fourth response, dissemination of plaques of hard exudates into multiple, separate, hyperreflective foci were detected. CONCLUSIONS Hyperreflective foci in the retina seem to represent precursors or components of hard exudates. Their specific localization depends greatly on the presence of microvascular extravasation and intraretinal fluid accumulation. Retinal photocoagulation has a major impact on retinal edema and subsequently on the distribution of intraretinal lipid deposits. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Neural Retinal Disorganization as a Robust Marker of Visual Acuity in Current and Resolved Diabetic Macular Edema

Despite treatment advances, diabetic eye disease remains a leading cause of visual acuity (VA) loss worldwide. No methods to prospectively determine which patients will gain or lose vision exist, limiting individualized risk assessment and management. We investigated whether noninvasive, readily obtainable spectral domain optical coherence tomography parameters were correlated with VA in eyes with current or resolved center-involved diabetic macular edema (DME). Images were evaluated for disorganization of the retinal inner layers (DRIL), cysts, epiretinal membranes, microaneurysms, subretinal fluid, and outer layer disruption/reflectivity. DRIL affecting ≥50% of the 1-mm central retinal zone was associated with worse VA in all eyes, eyes with current edema, and eyes with resolved edema. Furthermore, early 4-month change in DRIL extent predicted VA change from baseline to 1 year. These data suggest that DRIL is a robust predictor of VA in eyes with present or previous DME and more highly correlated with VA than other widely used measures, such as retinal thickness. If further studies confirm DRIL as a predictive biomarker of future VA, physicians would gain a new tool of substantial clinical and investigative importance that could significantly change the approach to ophthalmic counseling and therapeutic management in patients with diabetes.

Intravitreal bevacizumab (Avastin) versus triamcinolone (Volon A) for treatment of diabetic macular edema: one-year results

PurposeThe objective was to compare retinal morphology and function following intravitreal injections of bevacizumab (Avastin) or triamcinolone (Volon A) in patients with early diabetic macular edema (DME).Patients and methodsThe study was planned as a randomized, prospective, interventional clinical trial. A total of 30 diabetic patients with treatment-naïve, clinically significant macular edema were included in this study and randomized to two equal groups. One group initially received three injections of 2.5 mg bevacizumab in monthly intervals. The second group received a single injection of 8 mg triamcinolone, followed by two sham interventions. Functional and anatomic results were evaluated monthly using ETDRS vision charts and spectral-domain optical coherence tomography. According to the study protocol, retreatment after 3 months was dependent on functional and anatomic outcome in a PRN regimen.ResultsBaseline best corrected visual acuity (BCVA) was 0.30 logMAR and central retinal subfield thickness (CSRT) was 505 μm in the bevacizumab group and 0.32 logMAR and 490 μm CSRT in the triamcinolone group. After 3 months, BCVA improved to 0.23 logMAR (bevacizumab) and 358 μm CRST and 0.26 logMAR (triamcinolone) and 308 μm CSRT. After 12 months, BCVA further recovered in the bevacizumab group (0.18 logMAR) but slightly decreased in the triamcinolone group (0.36 logMAR).ConclusionIntravitreal bevacizumab and triamcinolone are both equally effective in reducing CSRT in early DME. After 6 months, rehabilitation of vision was comparable in both treatment arms, whereas at the final follow-up at month 12, BCVA was superior in the bevacizumab than in the triamcinolone sample. This may be related to cataract development following steroid treatment, as well as to substance-specific mechanisms within the angiogenic versus the inflammatory cascade.

Distribution of intraretinal exudates in diabetic macular edema during anti-vascular endothelial growth factor therapy observed by spectral domain optical coherence tomography and fundus photography.

Purpose: To evaluate changes in the distribution and morphology of intraretinal microexudates and hard exudates (HEs) during intravitreal anti-vascular endothelial growth factor therapy in patients with persistent diabetic macular edema. Methods: Twenty-four patients with persistent diabetic macular edema after photocoagulation were investigated in this prospective cohort study. Each eye was assigned to a loading dose of three anti-vascular endothelial growth factor treatments at monthly intervals. Additional single treatments were performed if diabetic macular edema persisted or recurred. Intraretinal exudates were analyzed over 6 months using spectral domain optical coherence tomography (SD-OCT) and fundus photography. Results: Before treatment, microexudates were detected by SD-OCT as hyperreflective foci in 24 eyes, whereas HEs were seen in 22 eyes. During therapy, HE increased significantly in number and size. This was accompanied by accumulation of microexudates in the outer retina. Enlargement of hyperreflective structures in SD-OCT was accompanied by enlargement of HE at corresponding fundus locations. A rapid reduction in diabetic macular edema was seen in all patients, but to varying degrees. Patients with hemoglobin A1c levels <7% and serum cholesterol <200 mg/dL formed fewer HEs and featured more edema reduction and visual acuity gain. Conclusion: Diabetic macular edema reduction during intravitreal anti-vascular endothelial growth factor therapy was accompanied by dynamic rearrangement of intraretinal exudates at corresponding locations in fundus photography and SD-OCT. Intraretinal aggregates of microexudates detectable as hyperreflective foci by SD-OCT may compose and precede HE before they become clinically visible.

Photoreceptor layer regeneration is detectable in the human retina imaged by SD-OCT after laser treatment using subthreshold laser power.

PURPOSE We evaluated the morphologic changes in retinal structure after laser photocoagulation using supra- and subthreshold laser fluence. METHODS In a prospective cohort study 10 consecutive patients received scatter laser photocoagulation. Treatment was performed using a semiautomated patterned scanning laser system. In a study area adjacent to the temporal vessel arcades, 2 × 2 pattern laser spots were applied with halving the flux of the laser power in a stepwise manner starting from a power producing a typical grayish lesion. The study areas then were imaged on days one, three, and seven, and on months one, two, three, and six using color fundus photography, autofluorescence (AF), infrared (IR) imaging, and spectral domain optical coherence tomography (SD-OCT). RESULTS The starting threshold power lesions each were visible on color fundus photography, IR, and AF in all patients, and showed characteristic changes on OCT throughout the follow-up period. The halved flux laser burns (first step) were undetectable ophthalmoscopically during the laser session, but during the follow-up always were detectable on IR and AF images, and sometimes on fundus photography. On OCT they showed changes similar to the suprathreshold laser scars, but were much smaller in diameter, and in some instances an inward migration of the photoreceptor layer was observed. CONCLUSIONS Subthreshold laser burns with halved energy flux produced similar morphologic changes in the retina as threshold power, but with a smaller size. They induced less collateral damage to the neuroretina, and permit a level of reorganization in the outer retina. (ClinicalTrials.gov number, NCT00682240.).

Predictive imaging biomarkers relevant for functional and anatomical outcomes during ranibizumab therapy of diabetic macular oedema

Background/aims The objective is to identify imaging biomarkers in optical coherence tomography predicting functional/anatomical outcomes in diabetic macular oedema (DMO). Methods The presented study is a post hoc analysis of the RESTORE/RESTORE-extension studies. Best-corrected visual acuity (BCVA) was analysed using general estimating equation models using treatment group/morphological features as predictor variables. In addition, linear multiple regression models analysed BCVA gain up to 12 and 36 months with BCVA/morphological baseline characteristics as independent predictor variables. The correlations between central retinal thickness (CRT)/BCVA were calculated as Spearman’s/Pearson’s correlation coefficients. Results A weak negative linear correlation between CRT/BCVA was observed in all study arms at baseline (r=−0.34, p<0.001) and at month 36 (r=−0.26, p<0.001). Patients with baseline height of intraretinal cystoid fluid (IRC) ≤380 µm had better baseline BCVA compared with patients with IRC height >380 µm (64.84±10.63 vs 61.66±9.92 letters; p=0.0071, respectively), which was maintained until the end of month 12 (70.5±12.33 vs 67.0±14.09 letters; p=0.0252, respectively). With laser, there was a trend for patients with subretinal fluid (SRF) at baseline to lose BCVA letters at month 12 (−5.38±16.54 vs 2.49±9.72 letters; p=0.1038), whereas ranibizumab patients trended towards higher BCVA gains (10.28±7.14 vs 6.76±7.67; p=0.0563), compared with those without SRF. With combined therapy, all patients had similar BCVA gains regardless of SRF (p=0.3768). Conclusion With ranibizumab treatment, the height of IRC spaces at baseline was a better predictor of functional/anatomical improvement than CRT alone. There was also a trend for SRF to show a positive impact on ranibizumab therapy response and a negative impact on laser therapy response.

Visualization of micro-capillaries using optical coherence tomography angiography with and without adaptive optics.

The purpose of this work is to investigate the benefits of adaptive optics (AO) technology for optical coherence tomography angiography (OCTA). OCTA has shown great potential in non-invasively enhancing the contrast of vessels and small capillaries. Especially the capability of the technique to visualize capillaries with a lateral extension that is below the transverse resolution of the system opens unique opportunities in diagnosing retinal vascular diseases. However, there are some limitations of this technology such as shadowing and projection artifacts caused by overlying vasculature or the inability to determine the true extension of a vessel. Thus, the evaluation of the vascular structure and density based on OCTA alone can be misleading. In this paper we compare the performance of AO-OCT, AO-OCTA and OCTA for imaging retinal vasculature. The improved transverse resolution and the reduced depth of focus of AO-OCT and AO-OCTA greatly reduce shadowing artifacts allowing for a better differentiation and segmentation of different vasculature layers of the inner retina. The comparison is done on images recorded in healthy volunteers and in diabetic patients with distinct pathologies of the retinal microvasculature.

Multi-modal adaptive optics system including fundus photography and optical coherence tomography for the clinical setting

We present a new compact multi-modal imaging prototype that combines an adaptive optics (AO) fundus camera with AO-optical coherence tomography (OCT) in a single instrument. The prototype allows acquiring AO fundus images with a field of view of 4°x4° and with a frame rate of 10fps. The exposure time of a single image is 10 ms. The short exposure time results in nearly motion artifact-free high resolution images of the retina. The AO-OCT mode allows acquiring volumetric data of the retina at 200kHz A-scan rate with a transverse resolution of ~4 µm and an axial resolution of ~5 µm. OCT imaging is acquired within a field of view of 2°x2° located at the central part of the AO fundus image. Recording of OCT volume data takes 0.8 seconds. The performance of the new system is tested in healthy volunteers and patients with retinal diseases.