Jan Lammer

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.

In Vivo Retinal Morphology after Grid Laser Treatment in Diabetic Macular Edema

PURPOSE To analyze immediate in vivo intraretinal morphologic changes secondary to standardized grid photocoagulation using spectral domain optical coherence tomography (SD OCT). DESIGN Prospective clinical trial. PARTICIPANTS Thirteen consecutive patients with treatment-naïve clinically significant diabetic macular edema (DME). METHODS Before and 1 day after standardized grid photocoagulation using the PASCAL system (Pattern Scan Laser, OptiMedica Corporation, Santa Clara, CA), Spectralis OCT (Heidelberg Engineering, Heidelberg, Germany) examinations based on an eye-tracking system, infrared fundus imaging, color fundus photography, and biomicroscopy were performed. A standardized visual acuity assessment (Early Treatment Diabetic Retinopathy Study protocol) and fluorescein angiography were performed at baseline. MAIN OUTCOME MEASURES Morphologic changes secondary to grid laser treatment. RESULTS One day after laser therapy, immediate morphologic alterations of only the outer retinal layers, that is, the retinal pigment epithelium (RPE), the photoreceptor layer (PRL), and the outer nuclear layer (ONL), were observed. The shape of the laser-induced lesions did not show a sagittal alteration pattern throughout all 3 of the layers, however, but rather seemed to follow an oblique pathway throughout the ONL, changing direction at the level of the external limiting membrane and proceeding sagittally through the PRL and RPE. These morphologic changes also induced biometric changes, such as a decrease in central retinal thickness combined with local thickening at the lesion site, especially in the PRL. CONCLUSIONS Spectral domain optical coherence tomography provides new insight into the immediate morphologic changes after laser treatment using the PASCAL laser system. Standardized grid photocoagulation induces characteristic homogenous alteration in the neurosensoric retinal layers. Biometric changes, indicating an immediate effect, were observed within 1 day after treatment.

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.

Detection and analysis of hard exudates by polarization-sensitive optical coherence tomography in patients with diabetic maculopathy.

PURPOSE To image and analyze hard exudates (HEs) and their precursors in patients with diabetic macular edema (DME) by using polarization-sensitive optical coherence tomography (PS-OCT). METHODS Twenty-two eyes of 16 patients with DME were imaged by using color fundus photography (CF) and PS-OCT. In PS-OCT, HEs were automatically detected by their distinct polarization-scrambling qualities. Color fundus images were manually graded for the presence of HEs by two masked graders and correlated with the corresponding PS-OCT HE maps: corresponding images were overlaid and an identical grid of 128 × 128 fields was used for correlation of detected HEs. RESULTS In all eyes, HEs were present owing to DME. Agreement of a pixel-to-pixel analysis of HEs in CF images was 0.72 (Cohens κ) between graders and 0.44 between graders and automated detection by PS-OCT. Mean ± SD detection of HEs was significantly higher in PS-OCT than in manual grading (1180.5 ± 1009.8 fields versus 828.8 ± 695.0 fields; P = 0.02). The higher detection rate of PS-OCT was confirmed by a linear regression analysis with a slope of β = 1.18 (r = 0.81). CONCLUSIONS PS-OCT enables not only two-dimensional imaging of the extent of HEs, as in CF, but also allows tissue-specific, three-dimensional imaging of HEs throughout retinal layers, based on their distinct polarization-scrambling characteristics. The higher detection rate in PS-OCT images indicates an increased sensitivity of PS-OCT imaging over conventional CF.

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.

Imaging Retinal Pigment Epithelial Proliferation Secondary to PASCAL Photocoagulation In Vivo by Polarization-sensitive Optical Coherence Tomography

Purpose To image the retinal pigment epithelium (RPE) after macular laser and to monitor healing responses over time in vivo in patients with diabetic maculopathy using polarization-sensitive optical coherence tomography (OCT). Design Prospective, nonrandomized clinical trial. Methods In this single-center trial (Department of Ophthalmology and Optometry, Medical University of Vienna, Vienna, Austria), 13 patients (13 eyes) underwent grid photocoagulation for diabetic maculopathy. Retinal healing processes were continuously followed over the course of 3 months. A polarization-sensitive OCT prototype was used, allowing detection and measurement of the RPE changes based on their specific polarization-scrambling qualities. Results After 1 day, the intraretinal photocoagulation lesions were sharply demarcated, whereas RPE changes were rather subtle. At 1 week, all lesions exhibited traction of the inner retinal layers toward the RPE and loss of photoreceptor cells. In tissue-sensitive polarization-sensitive OCT imaging, polarization-scrambling columns were found at the level of the RPE. During follow-up, different healing responses were seen in the polarization-scrambling RPE layer, ranging from hyperproliferation to focal atrophy. Conclusion Because of the properties of the polarization state of backscattered light, polarization-sensitive OCT revealed specific morphologic changes in the RPE and outer retinal layers secondary to retinal laser treatment undetectable with intensity-based spectral-domain OCT. The increase in polarization-scrambling tissue over the course of 3 months indicates a more intense healing reaction and proliferation of RPE cells than previously characterized in rodent studies.

Retinal Pigment Epithelial Features in Central Serous Chorioretinopathy Identified by Polarization-Sensitive Optical Coherence Tomography

PURPOSE To determine the subclinical RPE lesions detected by tissue selective polarization-sensitive optical coherence tomography (PS-OCT) in eyes with central serous chorioretinopathy (CSC) and to compare PS-OCT findings to current imaging standards. METHODS In this prospective observational case series, individuals with unilateral or bilateral active CSC were imaged using PS-OCT at baseline and after resolution of serous retinal detachment. Features seen on PS-OCT were compared with corresponding lesions as seen on conventional, intensity-based spectral-domain OCT (SD-OCT), fluorescein angiography, and indocyanine green angiography (ICGA). Features of RPE evaluated by PS-OCT were as follows: area and volume of pigment epithelium detachment (PED), presence of RPE aggregations, RPE skip lesions, RPE thickening, and RPE atrophy. RESULTS Twenty-five study eyes and 23 fellow eyes of 25 participants (2 women, 23 men; mean age ± standard deviation = 40.5 ± 7.4 years) were included and followed for 6.1 ± 3 months. Study eyes and fellow eyes with recurrent CSC showed more RPE abnormalities in PS-OCT than eyes with acute CSC, which correlated well with lesions in ICGA. Closure of the leakage site was observed only in eight (32%) eyes after resolution of subretinal fluid (SRF). All study eyes showed widespread RPE aggregates and 23 (92%) eyes showed RPE skip lesions after resolution of SRF. CONCLUSIONS Features of RPE indicative of previous episodes of CSC detected by PS-OCT correspond well to choroidal lesions in ICGA. In addition, noninvasive PS-OCT imaging enables detection of RPE microrips and aggregations invisible to clinical examination or SD-OCT, thus providing valuable information about disease processes in vivo.

SAVE: a grading protocol for clinically significant diabetic macular oedema based on optical coherence tomography and fluorescein angiography

Aim To analyse a new grading protocol for clinically significant diabetic macular oedema (CSME) based on spectral domain optical coherence tomography (SD-OCT) and fluorescein angiography (FA). Methods 56 eyes of 40 patients with CSME were examined by Cirrus OCT (Carl Zeiss Meditec), Spectralis HRA and OCT (Heidelberg Engineering) on the same day. Three graders analysed images based on a newly developed grading protocol integrating all relevant information from OCT and FA. The protocol defined four categories: (1) subretinal fluid (category ‘S’); (2) the planimetrically measured oedematous area (category ‘A’); (3) vitreo-retinal interface abnormalities (category ‘V’); and (4) CSME aetiology (category ‘E’) defining the leakage source. Results The new grading protocol allowed for a detailed characterisation of each individual type of CSME. It defines four aetiological types of CSME and analyses four further categories important in diagnosis and during follow-up in clinical and study settings. Atrophic, a new type of CSME, was described and characteristic combinations of triggers of CSME were revealed. Inter-grader agreement, analysed using Fleiss’ κ values for Cirrus OCT and Spectralis OCT, respectively, was good for ‘S’ (0.9; 0.82), ‘A’ (1.0; 1.0) and ‘E’ (range 0.63–0.8; 0.57–0.77), and lower for ‘V’ (0.25; 0.42). Conclusions The ‘SAVE’ grading protocol of CSME integrates information from two imaging techniques, OCT and FA. Its clinical approach allows examiners to define and further categorise clinical characteristics to find tailored therapeutic strategies.

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.

Computational fluid dynamics assisted characterization of parafoveal hemodynamics in normal and diabetic eyes using adaptive optics scanning laser ophthalmoscopy.

Diabetic retinopathy (DR) is the leading cause of visual loss in working-age adults worldwide. Previous studies have found hemodynamic changes in the diabetic eyes, which precede clinically evident pathological alterations of the retinal microvasculature. There is a pressing need for new methods to allow greater understanding of these early hemodynamic changes that occur in DR. In this study, we propose a noninvasive method for the assessment of hemodynamics around the fovea (a region of the eye of paramount importance for vision). The proposed methodology combines adaptive optics scanning laser ophthalmoscopy and computational fluid dynamics modeling. We compare results obtained with this technique with in vivo measurements of blood flow based on blood cell aggregation tracking. Our results suggest that parafoveal hemodynamics, such as capillary velocity, wall shear stress, and capillary perfusion pressure can be noninvasively and reliably characterized with this method in both healthy and diabetic retinopathy patients.