COMPARISON OF GANGLION CELL INNER PLEXIFORM LAYER THICKNESS BY CIRRUS AND SPECTRALIS OPTICAL COHERENCE TOMOGRAPHY IN DIABETIC MACULAR EDEMA.

PURPOSE: Reduced thickness of the ganglion cell inner plexiform layer indicates diabetic neurodegeneration and can be assessed by spectral domain optical coherence tomography. The authors investigated the comparability of ganglion cell inner plexiform layer measurements from two spectral domain optical coherence tomography devices in patients with diabetic macular edema (DME). METHODS: Analysis of optical coherence tomography data sets of eyes with and fellow eyes without DME. Macular cube scans of sufficient signal strength on Cirrus (Carl Zeiss Meditec) were compared with correlating scans on Spectralis (Heidelberg Engineering, Germany) being acquired within 1 hour. RESULTS: Eighty-one equivalent data sets for 20 eyes with DME (20 patients; 6 female) and 33 for 9 fellow eyes without DME (9 patients; 2 female) were included from each device. In DME eyes, mean ganglion cell inner plexiform layer thicknesses were 62.5 ± 20.4 µm on Cirrus and 91.2 ± 9.3 µm on Spectralis. Ganglion cell inner plexiform layer was significantly thicker on Spectralis analyzing eyes with and without signs of DME (P < 0.001). The ganglion cell inner plexiform layer variance (54.2%) related to device differences decreased to 34.8% in eyes without DME. CONCLUSION: Ganglion cell inner plexiform layer data from different devices vary considerably and cannot be used interchangeably. As spectral domain optical coherence tomography is indispensable for identifying ganglion cell loss associated with diabetic neurodegeneration, clinicians should be aware of the difference when monitoring patients.

Analysis of retinal layer thickness in diabetic macular oedema treated with ranibizumab or triamcinolone.

PURPOSE: To evaluate detailed changes in retinal layer thickness in spectral-domain optical coherence tomography (SD-OCT) images during a 1-year follow-up of patients treated for diabetic macula oedema (DME). METHODS: Post hoc analysis of retinal layer thickness changes applying the automated layer segmentation of SD-OCT images in eyes with DME that were randomly assigned to receive pro re nata (PRN) treatment with either 0.5 mg ranibizumab or 8 mg triamcinolone. In each patient, seven retinal layers were segmented in 49 scans covering a 20° × 20° area of the macula at baseline and after 1 year of treatment. Changes in individual layer thickness were correlated with visual acuity (VA) and compared between treatment arms. RESULTS: Twenty-five patients (seven female, 60.2 ± 15.1 years) were evaluated. Thickness decrease of retinal nerve fibre layer (RNFL) was associated with a gain in VA over 12 months (r > 0.54; p < 0.05). Decrease in ganglion cell layer (GCL) and GCL+IPL thickness pooled for nasal Early Treatment of Diabetic Retinopathy Study (ETDRS) subfields correlated with VA as follows: ranibizumab r = 0.74 (GCL) and r = 0.63 (GCL+IPL); and triamcinolone r = 0.45 (GCL) and r = 0.46 (GCL+IPL). CONCLUSION: In DME therapy, reduction in RNFL thickness may have a considerable impact on retinal function, unrelated to the type of pharmacological treatment. Precise morphologic quantification of neurosensory layers by SD OCT offers new insight into disease pathology and therapeutic targets.

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.

Cone Photoreceptor Irregularity on Adaptive Optics Scanning Laser Ophthalmoscopy Correlates With Severity of Diabetic Retinopathy and Macular Edema.

Purpose: To determine whether cone density, spacing, or regularity in eyes with and without diabetes (DM) as assessed by high-resolution adaptive optics scanning laser ophthalmoscopy (AOSLO) correlates with presence of diabetes, diabetic retinopathy (DR) severity, or presence of diabetic macular edema (DME). Methods: Participants with type 1 or 2 DM and healthy controls underwent AOSLO imaging of four macular regions. Cone assessment was performed by independent graders for cone density, packing factor (PF), nearest neighbor distance (NND), and Voronoi tile area (VTA). Regularity indices (mean/SD) of NND (RI-NND) and VTA (RI-VTA) were calculated. Results: Fifty-three eyes (53 subjects) were assessed. Mean ± SD age was 44 ± 12 years; 81% had DM (duration: 22 ± 13 years; glycated hemoglobin [HbA1c]: 8.0 ± 1.7%; DM type 1: 72%). No significant relationship was found between DM, HbA1c, or DR severity and cone density or spacing parameters. However, decreased regularity of cone arrangement in the macular quadrants was correlated with presence of DM (RI-NND: P = 0.04; RI-VTA: P = 0.04), increasing DR severity (RI-NND: P = 0.04), and presence of DME (RI-VTA: P = 0.04). Eyes with DME were associated with decreased density (P = 0.04), PF (P = 0.03), and RI-VTA (0.04). Conclusions: Although absolute cone density and spacing don't appear to change substantially in DM, decreased regularity of the cone arrangement is consistently associated with the presence of DM, increasing DR severity, and DME. Future AOSLO evaluation of cone regularity is warranted to determine whether these changes are correlated with, or predict, anatomic or functional deficits in patients with DM.

Clinical Decision Support for the Classification of Diabetic Retinopathy: A Comparison of Manual and Automated Results.

The management of diabetic retinopathy, a frequent ophthalmological manifestation of diabetes mellitus, consists of regular examinations and a standardized, manual classification of disease severity, which is used to recommend re-examination intervals. To evaluate the feasibility and safety of implementing automated, guideline-based diabetic retinopathy (DR) grading into clinical routine by applying established clinical decision support (CDS) technology. We compared manual with automated classification that was generated using medical documentation and an Arden server with a specific medical logic module. Of 7169 included eyes, 47% (n=3373) showed inter-method classification agreement, specifically 29.4% in mild DR, 38.3% in moderate DR, 27.6% in severe DR, and 65.7% in proliferative DR. We demonstrate that the implementation of a CDS system for automated disease severity classification in diabetic retinopathy is feasible but also that, due to the highly individual nature of medical documentation, certain important criteria for the used electronic health record system need to be met in order to achieve reliable results.

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.

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.

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.

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.

Refractive changes after pharmacologic resolution of diabetic macular edema.

PURPOSE: To determine precisely the mean change in refractive power induced by treatment in patients with diabetic macular edema (DME). DESIGN: Prospective, randomized study. PARTICIPANTS: Fifty eyes of 50 consecutive patients with clinically significant macular edema receiving all 3 types of current state-of-the-art treatment with intravitreal antiedematous substances (ranibizumab, bevacizumab, or triamcinolone). METHODS: Patients were followed up at monthly intervals and were treated following a standardized pro re nata regimen according to protocol. Best-corrected visual acuity (BCVA) was determined by certified visual acuity examiners. The refractive power of the treated eyes was determined using a push-plus technique. The change in refraction between baseline and the visit when the macula was completely dry or when the central subfield thickness (CST) measured by optical coherence tomography had reached the thinnest level was analyzed. MAIN OUTCOME MEASURES: Spherical equivalent refraction (SER) and CST. RESULTS: Fifty eyes of 50 patients received intravitreal therapy using ranibizumab (n = 11), bevacizumab (n = 20), or triamcinolone (n = 19). Mean BCVA was 0.33±0.23 logarithm of the minimum angle of resolution (logMAR) and mean CST was 492±130 µm. The mean SER was 0.41±2.06 diopters (D) at baseline. The BCVA at the time of optimal retinal morphologic features was 0.24±0.2 logMAR, mean CST was 300±78 µm, and mean change in SER was -0.01±0.46 D. Changes is BCVA and CST were statistically significant (P < 0.0001), but the SER change was not (P = 0.824). CONCLUSIONS: Appropriate spectacle correction can be prescribed to patients with DME any time during ongoing therapy using antiedematous substances because resolution of retinal thickening is not associated with an increased risk of a myopic shift.

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.).

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.

High-resolution imaging of the human retina in vivo after scatter photocoagulation treatment using a semiautomated laser system.

PURPOSE: To image the ultrastructural morphology of retinal laser effects and their healing response in vivo using spectral domain optical coherence tomography (SD-OCT). DESIGN: Prospective, interventional study. PARTICIPANTS: Ten patients undergoing panretinal photocoagulation for proliferative diabetic retinopathy. METHODS: Panretinal photocoagulation (PRP) was performed using a semiautomated patterned scanning laser system providing a raster of effects with homogenous intensity. Retinal morphology and localization of effects owing to laser-tissue interaction were imaged at 1 day, 1 week, and at monthly intervals for 6 months. The characteristic, specific structural changes during the healing process were followed over time using an SD-OCT device (Spectralis OCT) allowing for high-resolution raster scanning of the entire lesion pattern with identification of identical retinal sites (tracking modality). MAIN OUTCOME MEASURES: Retinal morphology and localization of effects of photocoagulation on SD-OCT images. RESULTS: At day 1 after PRP, the photocoagulation effects were sharply delineated from the surrounding unaffected retina and all spots seemed to be identical in size and location. The area of tissue destruction was confined to the outer retinal layers, extending from the outer nuclear layer (ONL) to the retinal pigment epithelium (RPE). At 1 week, images showed a progressive loss of the affected outer retinal layers, namely, the ONL and the outer plexiform layer. Concomitant distortion of the inner nuclear and plexiform layers generated a pattern of "archways" between adjacent laser spots. The photoreceptor layers (PRL) seemed to be eliminated in the photocoagulated area, particularly at the borders of each lesion. The lesion center contained a condensed RPE and PRL segment. The ONL recovered partially, but the PRL inner and outer segments remained absent. During the long-term follow-up, RPE cells migrated to the center of the lesion, forming a hyperplastic scar. CONCLUSIONS: The characteristic morphology of retinal photocoagulation effects in vivo and over time was identified for the first time in human eyes using SD-OCT. The OCT imaging demonstrated a well-defined reproducible area of destruction confined to the outer retinal layers. Healing proceeded as the condensation of the RPE and PRL in the lesion center.