Publications by authors named "Justis P Ehlers"

166 Publications

Epiretinal Membrane Surgery Using Intraoperative OCT-guided Membrane Removal in the DISCOVER Study versus Conventional Membrane Removal.

Ophthalmol Retina 2021 Feb 26. Epub 2021 Feb 26.

The Tony and Leona Campane Center for Excellence in Image-Guided Surgery and Advanced Imaging Research, Cole Eye Institute, Cleveland Clinic, Cleveland OH; Vitreoretinal Service, Cole Eye Institute, Cleveland Clinic, Cleveland OH. Electronic address:

Purpose: To provide a comparative assessment of clinical outcomes between subjects undergoing intraoperative optical coherence tomography (OCT) and conventional surgery for pars plana vitrectomy (PPV) with epiretinal membrane (ERM) peel.

Design: Case-control retrospective comparative assessment SUBJECTS: Subjects undergoing PPV with membrane peel for ERMs with eyes pooled from the prospective intraoperative OCT (iOCT) DISCOVER study and eyes undergoing conventional ERM surgery without intraoperative OCT.

Methods: Visual acuity and OCT assessment before ERM surgery and at 1-, 3-, 6-, and 12-month follow up after standard small gauge pars plana vitrectomy (PPV) with iOCT feedback (iOCT DISCOVER group) or PPV with compulsory ILM peeling (conventional group). Visual acuity, central subfield thickness (CST), re-operation rate and ERM recurrence were determined by record review and post-hoc assessment of clinical OCTs after ERM peel.

Main Outcome Measures: Visual acuity and ERM recurrence RESULTS: A total of 262 eyes were included. Visual Acuity (VA) improved 12.9 letters in the iOCT group (p < 0.0001) and 11.5 letters in the conventional group (p < 0.0001) at 12 months after ERM surgery. VA improvement did not differ between iOCT and conventional group at 1, 3, 6, or 12 months after surgery (p > 0.05 for each time point). Preoperative mean central subfield thickness (CST) decreased in the iOCT group (p < 0.0001) and conventional group (p < 0.0001) with no difference between groups in CST reduction at 12 months (p = 0.36). There were no re-operations or visually significant recurrent ERMs in both cohorts.

Conclusions: iOCT-guided ERM removal without mandated ILM peeling provided similar visual acuity and anatomic results to conventional ILM peeling for ERM. Future randomized prospective studies are needed to fully assess the possible role for iOCT in ERM surgery and evaluate the potential impact of non-foveal ERM persistence/recurrence in comparison to conventional surgery.
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http://dx.doi.org/10.1016/j.oret.2021.02.013DOI Listing
February 2021

Longitudinal Assessment of Ellipsoid Zone Integrity, Subretinal Hyperreflective Material, and Sub-RPE Disease in Neovascular AMD.

Ophthalmol Retina 2021 Feb 25. Epub 2021 Feb 25.

The Tony and Leona Campane Center for Excellence in Image-Guided Surgery and Advanced Imaging Research, Cleveland Clinic, Cleveland, OH, USA; Center for Ocular Research and Evaluation, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA.

Purpose: To longitudinally assess the effect of anti-vascular endothelial growth factor (VEGF) treatment on ellipsoid zone (EZ) integrity, subretinal hyperreflective material (SHRM), and the sub-retinal pigment epithelium (sub-RPE) compartment in eyes with neovascular age-related macular degeneration (nAMD).

Design: This study was a post hoc analysis of the OSPREY clinical trial, a prospective, double-masked, phase 2 study comparing brolucizumab 6 mg with aflibercept 2 mg over 56 weeks.

Participants: Participants with treatment-naïve nAMD at the initiation of the trial were included in the analysis.

Methods: Eyes were evaluated with spectral domain optical coherence tomography (SD-OCT) at 4-week intervals in the OSPREY trial (n=81). SD-OCT scans collected from each visit were automatically. segmented using a proprietary, machine learning enabled higher-order feature-extraction platform for retinal layer, SHRM, and sub-RPE boundary lines, which were evaluated and corrected as needed by masked trained graders. The current analysis focused only on subjects evaluated with Cirrus (Zeiss) platform, n=28).

Main Outcome Measures: Outcome measures included change from baseline in EZ-RPE volume, EZ-RPE central subfield thickness (CST), total EZ attenuation, SHRM volume, SHRM CST, and total sub-RPE volume. The correlation between each of these measures and best corrected visual acuity (BCVA) at each visit was evaluated.

Results: EZ-RPE volume and EZ-RPE CST showed significant increases, and total EZ attenuation, SHRM volume, SHRM CST, and total sub-RPE volume showed significant decreases from baseline at each visit from Week 4-56 (P<.05 at each visit). EZ integrity measures and SHRM volume significantly correlated with BCVA at most visits (P<.05). No significant correlation was found between total sub-RPE volume and BCVA.

Conclusions: EZ integrity, SHRM, and sub-RPE disease features in eyes with nAMD showed improvement as early as Week 4 of anti-VEGF treatment. EZ integrity measures and SHRM volume were predictors of visual acuity over the first year of treatment.
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http://dx.doi.org/10.1016/j.oret.2021.02.012DOI Listing
February 2021

Comparative Assessment of Ergonomic Experience with Heads-Up Display and Conventional Surgical Microscope in the Operating Room.

Clin Ophthalmol 2021 29;15:347-356. Epub 2021 Jan 29.

Tony and Leona Campane Center for Excellence in Image-Guided Surgery and Advanced Imaging Research, Cleveland Clinic, Cleveland, OH, USA.

Purpose: Musculoskeletal pain issues are prevalent in ophthalmic surgeons and can impact surgeon well-being and productivity. Heads-up displays (HUD) can improve upon conventional microscopes by reducing ergonomic stress. This study compared ergonomic outcomes between HUD and a conventional optical microscope in the operating room, as reported by ophthalmic surgeons in the US.

Methods: An online questionnaire was distributed to a sample of surgeons who had experience operating with HUD. The questionnaire captured surgeon-specific variables, the validated Nordic Musculoskeletal Questionnaire, and custom questions to compare HUD and conventional microscope. A multivariable model was built to identify variables that were likely to predict improvement in pain-related issues.

Results: Analysis was conducted on 64 surgeons (37 posterior-segment, 25 anterior-segment, and two mixed) with a mean 14.9 years of practice and 2.3 years using HUD. Most surgeons agreed or strongly agreed that HUD reduced the severity (64%) and frequency (63%) of pain and discomfort, improved posture (73%), and improved overall comfort (77%). Of respondents who experienced headaches, or pain and discomfort during operation, 12 (44%) reported their headaches improved and 45 (82%) reported feeling less pain and discomfort since they started using HUD. The multivariable model indicated the odds of reporting an improvement in pain since introducing the HUD in the operating room were 5.12-times greater for those who used HUD in >50% of their cases (=0.029).

Conclusion: This study indicates that heads-up display may be an important tool for wellness in the operating room as it can benefit ophthalmic surgeons across several ergonomic measures.
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http://dx.doi.org/10.2147/OPTH.S292152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854362PMC
January 2021

Real-Time Photographic- and Fluorescein Angiographic-Guided Management of Diabetic Retinopathy: Randomized PRIME Trial Outcomes.

Am J Ophthalmol 2021 Jan 30;226:126-136. Epub 2021 Jan 30.

Retina Consultants of Texas, Houston, Texas, USA; Blanton Eye Institute (CCW), Houston Methodist Hospital, Houston, Texas, USA. Electronic address:

Purpose: To assess the safety and efficacy of as-needed (PRN) intravitreal aflibercept injections (IAI) in managing diabetic retinopathy (DR) guided by the real-time DR severity scale (DRSS) level or panretinal leakage index (PLI) assessment among eyes without diabetic macular edema (DME).

Design: Prospective, randomized phase 2 trial (PRIME).

Methods: A total of 40 eyes with nonproliferative (NPDR) or proliferative DR (PDR) received monthly IAIs until a DRSS improvement of ≥2 steps was achieved and eyes were randomized (1:1) to DRSS-guided or PLI-guided management strategies graded by a central reading center. Main outcome measurements included safety and changes in DRSS and PLI.

Results: Through week 52, 95% of eyes achieved a DRSS improvement of ≥2 steps. Following DRSS improvement, 97% of eyes required at least 1 PRN IAI. In eyes requiring PRN IAI and completing week 52, 100% and 59% experienced DRSS worsening (P = .01) in the DRSS- and PLI-guided arms, respectively. Through week 52, mean PLI decreased 18.2% (P = .49) and 54.6% (P <.0001), respectively, in the DRSS- and PLI-guided arms. NPDR versus PDR eyes at baseline achieved a DRSS improvement of ≥2 steps after a mean 4.9 and 3.6 IAIs (P = .03). Two eyes developed a PDR event at week 52 following 5 months of quiescence.

Conclusions: The randomized PRIME study analyzed 2 imaging-based biomarkers to guide PRN management with IAI of DR without DME: DRSS level and PLI. Within the context of this study with limitations, most patients required IAI re-treatment every 3-4 months, and deterioration of PLI appeared to precede DRSS level worsening. Finally, these findings reaffirm the fact that close clinical follow-up is important even among eyes that achieve substantial DRSS improvements with apparently quiescent disease.
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http://dx.doi.org/10.1016/j.ajo.2021.01.024DOI Listing
January 2021

COVID-19 and the eye.

Cleve Clin J Med 2020 Dec 8. Epub 2020 Dec 8.

Tony and Leona Campane Center for Excellence for Image-Guided Surgery and Advanced Imaging Research, Department of Ophthalmology, Cole Eye Institute, Cleveland Clinic

As evidence on COVID-19 continues to emerge, its impact on the eyes is becoming more apparent, leading to a better understanding of ocular manifestations and transmission. This article details the recent information regarding COVID-19 from an ophthalmologic context, including prevalence, clinical features, impact on the clinic logistics, and key information for practitioners.
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http://dx.doi.org/10.3949/ccjm.87a.ccc068DOI Listing
December 2020

Retinal Fluid Volatility Associated With Interval Tolerance and Visual Outcomes in Diabetic Macular Edema in the VISTA Phase III Trial.

Am J Ophthalmol 2020 Nov 28;224:217-227. Epub 2020 Nov 28.

Tony and Leona Campane Center for Excellence in Image-Guided Surgery and Advanced Imaging Research, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, USA; Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, USA.

Purpose: To describe longitudinal retinal fluid dynamics on spectral domain OCT and to identify imaging biomarkers that predict the worsening of DME with interval extension during anti-vascular endothelial growth factor (VEGF) therapy.

Design: A post hoc sub-analysis of phase III, VISTA-DME study.

Methods: Eyes received either intravitreal aflibercept injection 2 mg every 4 weeks (2q4) or every 8 weeks after 5 initial monthly injections (2q8), and eyes imaged with the Cirrus HD-OCT system were included. The macular cube was analyzed for 10 time-points from baseline through week 100. Retinal OCT images were evaluated using a novel software platform to extract retinal fluid features for calculation of volumetric fluid parameters, including the retinal fluid index (RFI): the percentage of retinal volume that was occupied by intraretinal fluid.

Results: Fifty-five eyes were included in the 2q4 group, and 58 eyes were included in the 2q8 group. Early RFI volatility with a central macular RFI increase by ≥5 points from week 4 to 8 (P = .004, odds ratio [OR] 31.3, 95% confidence interval [CI] 3.0 to 329) and cumulative RFI volatility with an aggregate increase in macular RFI by ≥10 points from those timepoints with increased RFI between baseline to week 20, P = .005, OR 10.2, 95% CI 2.1 to 51.3) were both significant predictors for the worsening of DME and visual acuity when the treatment interval was extended to 8 weeks in the 2q8 group.

Conclusions: Early fluid dynamics as measured by (1) early RFI volatility and (2) cumulative RFI instability with aggregate increased RFI were associated with intolerance of interval extension.
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http://dx.doi.org/10.1016/j.ajo.2020.11.010DOI Listing
November 2020

Longitudinal assessment of quantitative ultra-widefield ischaemic and vascular parameters in sickle cell retinopathy.

Br J Ophthalmol 2020 Oct 31. Epub 2020 Oct 31.

The Tony and Leona Campane Center for Excellence in Image-Guided Surgery and Advanced Imaging Research, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, USA

Purpose: To evaluate longitudinal quantitative ischaemic and vasculature parameters, including ischaemic index, vessel area, length and geodesic distance in sickle cell retinopathy (SCR) on ultra-widefield fluorescein angiography (UWFA).

Methods: Optimal UWFA images from two longitudinal timepoints of 74 eyes from 45 patients with SCR were aligned and a common region of interest was determined. A deep-learning augmented ischaemia and vascular segmentation platform was used for feature extraction. Geodesic distance maps demonstrating the shortest distance within the vascular masks from the centre of the optic disc were created. Ischaemic index, vessel area, vessel length and geodesic distance were measured. Paired t-test and linear mixed effect model analysis were performed.

Results: Overall, 25 (44 eyes) patients with HbSS, 14 (19 eyes) with HbSC, 6 (11 eyes) with HbSthal and other genotypes were included. Mean age was 40.1±11.0 years. Mean time interval between two UWFA studies was 23.0±15.1 months (range: 3-71.3). Mean panretinal ischaemic index increased from 10.0±7.2% to 10.9±7.3% (p<0.005). Mean rate of change in ischaemic index was 0.5±0.7% per year. Mean vessel area (p=0.020) and geodesic distance (p=0.048) decreased significantly. Multivariate analysis demonstrated baseline ischaemic index and Goldberg stage are correlated with progression.

Conclusion: Longitudinal ischaemic index and retinal vascular parameter measurements demonstrate statistically significant progression in SCR. The clinical significance of these relatively small magnitude changes remains unclear but may provide insights into the progression of retinal ischaemia in SCR.
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http://dx.doi.org/10.1136/bjophthalmol-2020-317241DOI Listing
October 2020

Patient-Reported Complications after Intravitreal Injection and Their Predictive Factors.

Ophthalmol Retina 2020 Oct 12. Epub 2020 Oct 12.

Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio.

Purpose: The intravitreal injection (IVI) of pharmacologic agents is the most commonly performed ocular procedure and is associated with a host of complications. Most IVI-related complications data are derived from randomized controlled clinical trials, which report a high adverse event rate. The nature of these protocol-driven trials limit their applicability to the diverse circumstances seen in routine clinical practice. The goal of this study was to determine the prevalence of patient-reported IVI-related complications, their risk factors, and the manner in which patients sought treatment at a tertiary eye care center.

Design: Retrospective, institutional review board-approved study.

Participants: Forty-four thousand seven hundred thirty-four injections in 5318 unique patients at the Cleveland Clinic Cole Eye Institute from 2012 through 2016.

Methods: Intravitreal injection.

Main Outcome Measures: Complication occurrence within 15 days of injection.

Results: From 2012 through 2016, a total of 44734 injections were performed in 5318 unique patients. Overall, complication rates were low, representing 1.9% of all injections, with 1031 unique complications in 685 patients (12.9%). The most common minor complications, or those not requiring intervention, were irritation (n = 312) and subconjunctival hemorrhage (n = 284). The most common serious complications, or those requiring intervention, were corneal abrasion (n = 46) and iritis (n = 31). Most complications (66%) were managed adequately by a telephone or Epic (Epic Systems Corp., Verona, WI) electronic message encounter only. Importantly, no injection protocol parameter, such as type of anesthesia, preparation, or post-injection medication, increased the risk of a complication. However, a patient's gender, age, number of previous injections, and provider strongly influenced the risk of patient-reported complications.

Conclusions: Overall, complication rates seen in routine clinical practice were low compared with clinical trial reporting. Providers should feel confident in the safety and administration of IVI during times when follow-up office visits and resources may be limited. When performing an IVI, factors such as a patient's gender, age, number of previous injections, and provider must be taken into account to ensure the best possible outcomes.
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http://dx.doi.org/10.1016/j.oret.2020.09.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548755PMC
October 2020

Automated Quality Assessment and Image Selection of Ultra-Widefield Fluorescein Angiography Images through Deep Learning.

Transl Vis Sci Technol 2020 09 17;9(2):52. Epub 2020 Sep 17.

The Tony and Leona Campane Center for Excellence in Image-Guided Surgery and Advanced Imaging Research, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA.

Purpose: Numerous angiographic images with high variability in quality are obtained during each ultra-widefield fluorescein angiography (UWFA) acquisition session. This study evaluated the feasibility of an automated system for image quality classification and selection using deep learning.

Methods: The training set was comprised of 3543 UWFA images. Ground-truth image quality was assessed by expert image review and classified into one of four categories (ungradable, poor, good, or best) based on contrast, field of view, media opacity, and obscuration from external features. Two test sets, including randomly selected 392 images separated from the training set and an independent balanced image set composed of 50 ungradable/poor and 50 good/best images, assessed the model performance and bias.

Results: In the randomly selected and balanced test sets, the automated quality assessment system showed overall accuracy of 89.0% and 94.0% for distinguishing between gradable and ungradable images, with sensitivity of 90.5% and 98.6% and specificity of 87.0% and 81.5%, respectively. The receiver operating characteristic curve measuring performance of two-class classification (ungradable and gradable) had an area under the curve of 0.920 in the randomly selected set and 0.980 in the balanced set.

Conclusions: A deep learning classification model demonstrates the feasibility of automatic classification of UWFA image quality. Clinical application of this system might greatly reduce manual image grading workload, allow quality-based image presentation to clinicians, and provide near-instantaneous feedback on image quality during image acquisition for photographers.

Translational Relevance: The UWFA image quality classification tool may significantly reduce manual grading for clinical- and research-related work, providing instantaneous and reliable feedback on image quality.
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http://dx.doi.org/10.1167/tvst.9.2.52DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500112PMC
September 2020

Aqueous Cytokine Expression and Higher Order OCT Biomarkers: Assessment of the Anatomic-Biologic Bridge in the IMAGINE DME Study.

Am J Ophthalmol 2021 02 5;222:328-339. Epub 2020 Sep 5.

Tony and Leona Campane Center for Excellence in Image-Guided Surgery and Advanced Imaging Research, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, USA; Vitreoretinal Service, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, USA. Electronic address:

Purpose: To identify biomarkers for predicting response to anti-vascular endothelial growth factor (VEGF) therapy in diabetic macular edema (DME) and evaluate any links between cytokine expression and optical coherence tomography (OCT) phenotype.

Design: The IMAGINE is a post hoc image analysis and cytokine expression assessment of the Efficacy & Safety Trial of Intravitreal Injections Combined With PRP for CSME Secondary to Diabetes Mellitus (DAVE) randomized clinical trial.

Methods: Subjects were categorized as anatomical responders or nonresponders, and within the responder group as rebounders and non-rebounders based on quantitative, longitudinal OCT criteria. Retinal layer and fluid features were extracted using an OCT machine-learning augmented segmentation platform. Responders were further sub-classified by rapidity of response. Aqueous concentrations of 54 cytokines were measured at multiple timepoints. Expression was compared between responder groups and correlated with OCT imaging biomarkers.

Results: Of the 24 eyes studied, 79% were anatomical responders with 38% super responders, 17% early responders, and 25% slow responders. Twenty-one percent were nonresponders. Super responders had increased baseline vascular endothelial growth factor (VEGF) (880.0 pg/mL vs 245.4 pg/mL; P = .012) and decreased monocyte chemotactic protein-1 (MCP-1) (513.3 pg/mL vs 809.5 pg/mL; P = .0.042) concentrations compared with nonresponders. Interleukin-6 (-24.9 pg/mL vs 442.8 pg/mL; P = .032) concentrations increased among nonresponders during therapy. VEGF concentrations correlated with central subfield thickness (r = 0.49; P = .01). Panmacular retinal volume correlated with increased interleuckin-6 (r = 0.47; P = .02) and decreased MCP-1 (r = -0.45; P = .03). Matrix metallopeptidase-1 correlated with subretinal fluid volume (r = 0.50; P = .01).

Conclusions: OCT imaging biomarkers correlated with both intraocular cytokines and responsiveness to anti-VEGF therapy, which indicated a possible link to underlying pathways and their relevance to DME prognosis. Baseline concentrations of VEGF and MCP-1 are associated with anatomic response to anti-VEGF therapy.
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http://dx.doi.org/10.1016/j.ajo.2020.08.047DOI Listing
February 2021

Correlation between brain volume and retinal photoreceptor outer segment volume in normal aging and neurodegenerative diseases.

PLoS One 2020 3;15(9):e0237078. Epub 2020 Sep 3.

The Tony and Leona Campane Center for Excellence in Image-guided Surgery and Advanced Imaging Research, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.

Purpose: To investigate the association between outer retinal layer metrics, including photoreceptor outer segment volume, on spectral-domain optical coherence tomography (OCT) and brain volume on MRI in normal aging, Alzheimer's disease and Parkinson's disease.

Methods: This was an exploratory analysis of a cross-sectional cohort study that was approved by the Cleveland Clinic Institutional Review Board to evaluate neurodegenerative disorders. Subjects aged ≥ 50 were recruited. A comprehensive neurological exam, brain MRI with volumetric evaluation, and OCT were performed for each subject. Outer retinal layer parameters, including ellipsoid zone (EZ) to retinal pigment epithelium (RPE) volume (i.e., surrogate for panmacular photoreceptor outer segment volume), were evaluated with a novel OCT analysis platform.

Results: Of 85 subjects, 64 eyes of 64 subjects met MRI and OCT quality control criteria. Total brain volume (%ICV) significantly correlated with EZ-RPE volume in the normal cognition control group (n = 31, Pearson correlation coefficient 0.514, P < .01), the Parkinson's disease group (n = 19, Pearson correlation coefficient 0.482, P = .04), and the Alzheimer's dementia group (n = 14, Pearson correlation coefficient 0.526, P = .05). Multiple linear regression analysis revealed that photoreceptor outer segment (i.e., EZ-RPE) volume was an independent, influential factor on total brain volume in all study subjects (Coefficient 15.2, 95% confidence interval 7.8-22.6, P < .001).

Conclusion: Outer retinal parameters on OCT may serve as a novel biomarker related to brain volume. This correlation was noted in control subjects suggesting a possible developmental link between retina and brain volume. This relationship was also maintained with atrophic neurodegenerative disorders. Further research is needed to explore possible threshold differences for underlying neurodegenerative disorders.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237078PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470418PMC
October 2020

Longitudinal panretinal microaneurysm dynamics on ultra-widefield fluorescein angiography in eyes treated with intravitreal aflibercept for proliferative diabetic retinopathy in the recovery study.

Br J Ophthalmol 2020 Aug 22. Epub 2020 Aug 22.

The Tony and Leona Campane Center for Excellence in Image-guided Surgery and Advanced Imaging Research, Cleveland Clinic, Cleveland, Ohio, USA

Background/aims: Quantifying microaneurysms (MAs) turnover may be an objective measure for therapeutic response in diabetic retinopathy. This study assesses changes in MA counts on ultra-widefield fluorescein angiography (UWFA) in subjects undergoing treatment with intravitreal aflibercept injection (IAI) for proliferative diabetic retinopathy (PDR) in the Intravital Afliberept for Retinal Nn-Perfusion in Proliferatie Diabtic etinopath(RECOVERY) study using an automated MA detection platform.

Methods: RECOVERY is a prospective study that enrolled 40 subjects with PDR randomised 1:1 to receive 2 mg IAI every 4 weeks(q4wk) or every 12 weeks (q12wk). UWFA images were obtained at baseline, 6 months and 1 year. Images were analysed using an automated segmentation platform to detect and quantify MAs. Zones 1, 2 and 3 correspond to the macula, mid-periphery and far-periphery, respectively.

Results: The q4wk cohort demonstrated a significant decline in MAs in all zones and panretinally at baseline versus month 6, baseline versus year 1, and month 6 versus year 1 (-20.0% to -61.8%; all p<0.001). In the q12wk cohort, baseline versus month 6 showed a significant decline panretinally (mean: -34.2%; p<0.001) and in zone 3 (mean -44.18%; p<0.001). Addiitonally, baseline to year 1 in the q12wk group demonstrated significant decline panretinally (mean: -47.7%; p<0.001) and in zone 3 (mean: -59.8%; p<0.001). All zones demonstrated significantly decline from month 6 to year 1 in the q12wk group.

Conclusion: Therapy with IAI demonstrates significantly reduced panretinal MA counts in PDR at 1 year in both treatment groups. The use of automated platforms to detect and quantify MAs may provide a novel imaging marker for evaluating disease activity and therapeutic impact.

Trial Registration Number: NCT02863354.
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http://dx.doi.org/10.1136/bjophthalmol-2020-316952DOI Listing
August 2020

Radiomics-based assessment of ultra-widefield leakage patterns and vessel network architecture in the PERMEATE study: insights into treatment durability.

Br J Ophthalmol 2020 Aug 19. Epub 2020 Aug 19.

The Tony and Leona Campane Center for Excellence in Image-Guided Surgery and Advanced Imaging Research, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH, USA

Aim: To evaluate the potential of radiomics-based ultra-widefield fluorescein angiography (UWFA)-derived imaging biomarkers in retinal vascular disease for predicting therapeutic durability of intravitreal aflibercept injection (IAI).

Methods: The Peripheral and Macular Retinal Vascular Perfusion and Leakage Dynamics in Diabetic Macular Edema and Retinal Venous Occlusions During Intravitreal Aflibercept Injection (IAI) Treatment for Retinal Edema (PERMEATE) study prospectively evaluated quantitative UWFA dynamics in diabetic macular oedema or macular oedema secondary to retinal vascular occlusion. 27 treatment-naïve eyes were treated with 2 mg IAI q4 weeks for the first 6 months, and then administered q8 weeks. Morphological and graph-based attributes were used to model the spatial distribution of leakage areas, while tortuosity measures were used to model the vessel network disorder. Eyes were grouped based on functional tolerance of the first 8-week treatment interval challenge. 'Non-rebounders' (N=15) maintained/improved best-corrected visual acuity (BCVA) following the 8-week challenge. 'Rebounders' (N=12) exhibited worsened BVCA. The image biomarkers were used with a machine learning classifier to preliminarily evaluate their ability to predict BCVA stability.

Results: Two new UWFA image-derived biomarkers were identified and extracted. The cross-validated area under the receiver operating characteristic curve (AUC) was 0.77±0.14 using baseline leakage distribution features and 0.73±0.10 for the UWFA baseline tortuosity measures. Additionally, the change in vascular tortuosity between month 4 and baseline yielded an AUC of 0.73±0.08. Three baseline clinical features of letter score, macular volume and central subfield thickness yielded a corresponding AUC of 0.42±0.09.

Conclusions: Two computer-extracted UWFA radiomics-based descriptors were identified as potential biomarkers for predicting treatment durability and tolerance of longer treatment intervals. Conventional treatment parameters were not significantly different between these same groups.
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http://dx.doi.org/10.1136/bjophthalmol-2020-317182DOI Listing
August 2020

iOCT-assisted macular hole surgery: outcomes and utility from the DISCOVER study.

Br J Ophthalmol 2021 Mar 6;105(3):403-409. Epub 2020 May 6.

The Tony and Leona Campane Center for Excellence in Image-Guided Surgery and Advanced Imaging Research, Cole Eye Institute, Cleveland, Ohio, USA

Background/aims: This study aimed to characterise the clinical outcomes and utility of intraoperative optical coherence tomography (iOCT)-assisted macular hole (MH) repair.

Methods: This was a post hoc analysis of eyes in the etermination of feasibility of ntraoperative pectral domain microscope ombined/integrated CT isualization during n face etinal and ophthalmic surgery (DISCOVER) study undergoing surgical MH repair with use of iOCT. Functional and surgical outcome data were collected through 12 months postoperatively. MH closure rate, postoperative visual acuity (VA), percentage of cases in which iOCT provided valuable feedback and altered surgical decision making were measured.

Results: Eighty-four eyes were included in this study. The mean preoperative VA measured 20/114. The mean postoperative VA improved to 20/68 (p<0.001) at month 1, 20/48 (p<0.001) at month 3 and 20/45 (p<0.001) at month 12 or later. In 43 cases (51%), surgeons reported that iOCT provided valuable information (eg, confirming release of vitreomacular traction and identification of occult residual membranes). In 10 cases (12%), iOCT data specifically altered surgical decision making. Postoperative day 1 transtamponade OCT confirmed tissue apposition and apparent hole closure in 74% of eyes (21/26). All five open holes on postoperative day 1 closed following positioning. Single-surgery MH closure was achieved in 97.6% of cases. One persistent MH was successfully closed with a subsequent surgical repair for a final overall closure rate of 98.8%. Due to chronicity and MH size, additional repair was not recommended for the single remaining persistent MH.

Conclusion: This study suggests that iOCT may have important utility in MH surgery, including impacting surgical decision making. iOCT-assisted MH surgery resulted in significant improvement in VA and high single-surgery success rate.
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http://dx.doi.org/10.1136/bjophthalmol-2020-316045DOI Listing
March 2021

Conventional Microscope-Integrated Intraoperative OCT Versus Digitally Enabled Intraoperative OCT in Vitreoretinal Surgery in the DISCOVER Study.

Ophthalmic Surg Lasers Imaging Retina 2020 04;51(4):S37-S43

Background And Objective: To compare conventional microscope-integrated intraoperative optical coherence tomography (iOCT) and digitally enabled microscope-integrated iOCT in vitreoretinal surgery.

Patients And Methods: In this post-hoc analysis of the DISCOVER prospective iOCT study, two surgical groups were compared: (1) conventional iOCT and (2) digitally enabled iOCT. Surgeon questionnaires were collected immediately following surgery.

Results: A total of 187 subjects were included in the study: 91 in the conventional iOCT group and 96 in the digitally enabled iOCT group. There were no differences in surgeon-perceived iOCT utility between the two groups. There was significantly higher surgical field-based visualization of the iOCT datastream in the digitally enabled iOCT group (67.7% vs. 3.3%; P < .0001). Reported significant back discomfort (1.0% vs. 18.7%; P < .0001) and headaches (5.2% vs. 20.9%; P < .002) were lower in the digitally enabled iOCT group.

Conclusions: Feasibility and utility of iOCT were similar in both groups. Digitally enabled iOCT datastream enabled increased attention on the surgical field during OCT review. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:S37-S43.].
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http://dx.doi.org/10.3928/23258160-20200401-05DOI Listing
April 2020

Use of OCTA Capillary Perfusion Density Measurements to Detect and Grade Macular Ischemia.

Ophthalmic Surg Lasers Imaging Retina 2020 04;51(4):S30-S36

Background And Objective: To compare optical coherence tomography angiography (OCTA) capillary perfusion density (CPD) measurements of normal eyes and eyes with macular ischemia (MI).

Patients And Methods: AVATAR is an institutional review board-approved, prospective, observational imaging study using the Avanti RTVue XR HD. OCTA reports were reviewed for the presence of MI. Qualitative MI grading was performed, and CPD metrics in the superficial and deep fovea and parafovea were analyzed. A normal eye cohort was identified for comparative assessment.

Results: The MI and normal cohorts included 55 and 58 eyes, respectively. Compared to normal eyes, eyes with MI had significantly lower CPD values in all regions. There was a statistically significant correlation between qualitative MI grade and VA in the superficial (P = .003) and deep plexuses (P = .029). Only deep parafoveal CPD values demonstrated correlation with VA (P = .043).

Conclusions: Eyes with MI determined by masked qualitative OCTA grading demonstrated significantly reduced CPD values compared to normal eyes. Categorical assessment of MI severity correlated with VA. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:S30-S36.].
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http://dx.doi.org/10.3928/23258160-20200401-04DOI Listing
April 2020

Posterior Vitreous Detachment: Methods for Detection.

Ophthalmol Retina 2020 02;4(2):119-121

The Tony and Leona Campane Center for Excellence for Image-Guided Surgery and Advanced Imaging Research, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio; Vitreoretinal Service, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio. Electronic address:

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http://dx.doi.org/10.1016/j.oret.2019.12.014DOI Listing
February 2020

Intraoperative OCT-Assisted Retinal Detachment Repair in the DISCOVER Study: Impact and Outcomes.

Ophthalmol Retina 2020 04 9;4(4):378-383. Epub 2019 Nov 9.

The Tony and Leona Campane Center for Excellence in Image-Guided Surgery and Advanced Imaging Research, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio; Vitreoretinal Service, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio. Electronic address:

Purpose: The purpose of this study is to evaluate intraoperative OCT (iOCT) utility and outcomes during retinal detachment (RD) repair.

Design: The Determination of Feasibility of Intraoperative Spectral-Domain Microscope Combined/Integrated OCT Visualization during En Face Retinal and Ophthalmic Surgery (DISCOVER) intraoperative OCT study is a prospective Institutional Review Board-approved study.

Participants: Participants in the DISCOVER study undergoing surgical repair for RD.

Methods: This was a post hoc analysis of eyes in the DISCOVER study undergoing surgical repair for RDs. Inclusion criteria included iOCT after perfluorocarbon liquid placement and at least 6 months follow-up. Exclusion criteria included severe retinal pathology unrelated to RD. Surgeons completed standardized questionnaires after each case evaluating the iOCT instrument's utility. Functional and surgical outcome data were collected at the latest available time point between 6 and 12 months. Outcomes were evaluated in 2 groups: uncomplicated primary and complex cases.

Main Outcome Measures: Intraoperative OCT utility, single-surgery success, and visual acuity outcomes.

Results: A total of 103 eyes were included in this study: 51 uncomplicated primary and 52 complex cases. Intraoperative OCT provided valuable information in 36% of cases. In 12% of cases, iOCT data directly altered surgical decision making. There was a significantly higher rate of valuable iOCT feedback in complex cases compared with primary cases (50% vs. 22%, P < 0.01). Among primary cases, 48 (94%) had successful single surgery repair with a mean postoperative visual acuity of 20/47 compared with the complex group's 75% single surgery success (n=39) and mean postoperative visual acuity of 20/92.

Conclusions: This study affirms the potential impact of iOCT in assisting select cases of RD repair, particularly with complex pathology. The single surgery success rate was good with more than 80% of cases successfully repaired with 1 surgery.
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http://dx.doi.org/10.1016/j.oret.2019.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150644PMC
April 2020

Impact of Drusen Burden on Incidence of Subclinical CNV With OCTA.

Ophthalmic Surg Lasers Imaging Retina 2019 12;51(1):22-30

Background And Objective: To evaluate the impact of drusen burden on the detection of subclinical choroidal neovascularization (CNV) on optical coherence tomography angiography (OCTA) in nonexudative age-related macular degeneration (AMD).

Patients And Methods: A subanalysis of the AVATAR study, subjects diagnosed with nonexudative AMD without subfoveal atrophy were included. Subclinical CNV was assessed using OCTA software, and drusen burden was graded utilizing the advanced retinal pigment epithelium (RPE) analysis.

Results: Among eligible 58 eyes, 26 eyes (45%) had high drusen burden. Of the three eyes (5%) that demonstrated subclinical CNV, only one eye had high drusen burden, and all three eyes had neovascular AMD in the fellow eye. Extrafoveal RPE atrophy (odds ratio [OR] = 20.0; 95% confidence interval [CI], 1.53-261) and older age (OR = 1.27; 95% CI, 1.01-1.59) were predictive factors for subclinical CNV.

Conclusion: Extrafoveal RPE atrophy, older age, and fellow-eye CNV were significant risk factors for underlying subclinical CNV in nonexudative AMD. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:22-30.].
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http://dx.doi.org/10.3928/23258160-20191211-03DOI Listing
December 2019

RETINAL LEAKAGE INDEX DYNAMICS ON ULTRA-WIDEFIELD FLUORESCEIN ANGIOGRAPHY IN EYES TREATED WITH INTRAVITREAL AFLIBERCEPT FOR PROLIFERATIVE DIABETIC RETINOPATHY IN THE RECOVERY STUDY.

Retina 2020 Nov;40(11):2175-2183

Vitreoretinal Service, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio.

Purpose: Characterization of leakage indices on ultra-widefield fluorescein angiography in proliferative diabetic retinopathy treated with intravitreal aflibercept.

Methods: Prospective study enrolling subjects for treatment of proliferative diabetic retinopathy randomized 1:1 to receive 2-mg intravitreal aflibercept every 4 weeks (2q4) or every 12 weeks (2q12). Ultra-widefield fluorescein angiography images obtained at baseline, 24, and 48 weeks were analyzed using a semiautomated leakage segmentation platform. Panretinal and zonal leakage indices were calculated.

Results: Forty eyes of 40 subjects were included, and mean age was 48 ± 12.1 years. Mean number of injections was 11 ± 1.7 in the 2q4 arm and 4 ± 0.4 in the 2q12 arm. Median baseline leakage index in the 2q4 and 2q12 groups was 5.1% and 4.3%, respectively (P = 0.28). At 24 and 48 weeks, the 2q4 group significantly improved to 1.1% (-79%, P < 0.0001). At Week 24, the 2q12 group demonstrated nonsignificant improvement (3.4%; -21%, P = 0.47); by Week 48, improvement was significant (1.4%; -68%, P = 0.02). The 2q4 group resulted in lower leakage index compared with the 2q12 group at 24 weeks (1.1% vs. 3.4%, respectively; P = 0.008), but by 48 weeks, leakage index was similar between both groups (1.1% vs. 1.4%, respectively; P = 0.34).

Conclusion: Proliferative diabetic retinopathy treated with intravitreal aflibercept demonstrated significant leakage index reductions at 1 year. Monthly dosing provided more rapid reduction in leakage index compared with quarterly dosing.

Trial Registration: RECOVERY study (NCT02863354); https://clinicaltrials.gov/ct2/show/NCT02863354.
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http://dx.doi.org/10.1097/IAE.0000000000002727DOI Listing
November 2020

Longitudinal Panretinal Leakage and Ischemic Indices in Retinal Vascular Disease after Aflibercept Therapy: The PERMEATE Study.

Ophthalmol Retina 2020 02 10;4(2):154-163. Epub 2019 Sep 10.

The Tony and Leona Campane Center for Excellence in Image-Guided Surgery and Advanced Imaging Research, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio; Vitreoretinal Service, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio. Electronic address:

Purpose: To characterize the longitudinal panretinal retinal vascular dynamics in diabetic macular edema (DME) and retinal vein occlusion (RVO) over a 12-month period while being treated with intravitreal aflibercept injections (IAIs).

Design: Prospective open-label study (clinicaltrials.gov identifier, NCT02503540).

Participants: Thirty-one treatment-naive eyes with foveal-involving retinal edema secondary to DME and RVO.

Methods: Participants received 2 mg IAI every 4 weeks for the first 6 months, followed by 2 mg every 8 weeks. Ultra-widefield fluorescein angiography (UWFA; California Optos [Optos, Dunfermline, United Kingdom]) and spectral-domain OCT (Cirrus; Zeiss, Oberkochen, Germany) scans were obtained and analyzed using a novel quantitative assessment platform. Visual acuity, central subfield thickness, and adverse events also were collected.

Main Outcome Measures: The primary end point was the mean change in panretinal leakage index at month 12 from baseline as measured by UWFA.

Results: Mean age was 67.1 years. At month 12, visual acuity significantly improved by a mean of 18.4±21.4 letters (P < 0.0001), and central subfield thickness also improved significantly, with a mean reduction of 301.3±250.3 μm (P < 0.0001). Mean panretinal leakage index improved significantly, decreasing from 3.4% at baseline to 0.5% at month 6 (P <0.0001) and 0.4% at month 12 (P < 0.0001). Panretinal ischemic index did not demonstrate any significant change but showed a nonsignificant increase from 5.5% at baseline to 6.1% at month 6 (P = 0.315) and 8.7% at month 12 (P = 0.193). Eyes with DME showed a decrease in leakage index from 3.5±2.7% at baseline to 1.6±0.8% at month 12 (P = 0.018) and overall stability in ischemic index from 5.0±4.1% at baseline to 4.7±3.5% at month 12 (P = 0.689). Participants with RVO showed a decrease in leakage index from 3.3±1.1% at baseline to 0.02±0.03% at 12 months (P < 0.0001) and a nonsignificant increase in ischemic index from 5.9±4.5% at baseline to 12.6±9.8% at month 12 (P = 0.172).

Conclusions: Intravitreal aflibercept injections resulted in a dramatic reduction in panretinal leakage index. Panretinal ischemic index did not improve and trended toward worsening.
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http://dx.doi.org/10.1016/j.oret.2019.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024601PMC
February 2020

Quantitative Ultra-Widefield Angiographic Features and Associations with Diabetic Macular Edema.

Ophthalmol Retina 2020 01 28;4(1):49-56. Epub 2019 Aug 28.

The Tony and Leona Campane Center for Excellence in Image-Guided Surgery and Advanced Imaging Research, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio; Vitreoretinal Service, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio. Electronic address:

Purpose: To examine the relationship between diabetic macular edema (DME) and quantitative ultra-widefield fluorescein angiography (UWFA) metrics of ischemia, leakage, and microaneurysms.

Design: Retrospective image analysis study.

Participants: Eyes with diabetic retinopathy that had undergone spectral-domain OCT, UWFA, and ultra-widefield fundus photography.

Methods: OCT images were analyzed to determine the presence or absence of DME, central subfield thickness (CST), and subretinal fluid. Using a semiautomated analysis platform, UWFA images were segmented for ischemia, leakage, and microaneurysms with manual correction as needed. Clinical variables, including age, gender, race, hemoglobin A1C levels, blood pressure, cholesterol levels, use of blood thinners, smoking status, and lens status also were evaluated.

Main Outcome Measures: Factors associated with the presence and severity of DME.

Results: A total of 304 eyes (156 right eyes, 148 left eyes) from 178 diabetic patients were analyzed in the study. Panretinal leakage index, microaneurysm count, and ischemic index were not significantly different between eyes with and without DME in univariate assessment. Zonal assessments of macular microaneurysms and macular leakage index values revealed that eyes with DME showed a significantly higher microaneurysm count (P = 0.001) and leakage index (P < 0.0001) in the posterior pole compared with eyes without DME. Severity of macular thickening (i.e., CST) was associated significantly with macular leakage index and posterior pole microaneurysm count (P = 0.0002 and P = 0.03, respectively). In addition to posterior pole leakage index and microaneurysm count, DME was associated with older age (P < 0.01), higher systolic blood pressure (P < 0.001), and white race (P = 0.03). Multivariate assessment confirmed the independent association of presence of DME with macular leakage index and macular microaneurysm count (P < 0.01).

Conclusions: Quantitative measures of leakage index and microaneurysm count in the posterior pole on UWFA images were associated with the presence and severity of DME. Panretinal analyses were not linked to DME as strongly. Additional research is needed to determine the role of quantitative UWFA in predicting DME development and characterizing patient prognosis.
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http://dx.doi.org/10.1016/j.oret.2019.08.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944750PMC
January 2020

Detection of Choroidal Neovascular Membrane Beneath Pigment Epithelial Detachment Using SD-OCTA.

Ophthalmic Surg Lasers Imaging Retina 2019 10;50(10):620-626

Background And Objective: To identify choroidal neovascular membrane (CNVM) associated with spectral-domain optical coherence tomography (SD-OCT)-defined pigment epithelial detachment (PED) using SD-OCT angiography (SD-OCTA).

Patients And Methods: Sixty-nine patients with same-day OCT and OCTA imaging were reviewed, and 41 eyes of 29 patients with PEDs were included. OCTs were analyzed for PED type, fluid, and subretinal hyperreflective material (SHRM).

Results: Twenty-seven eyes (66%) demonstrated CNVM on OCTA beneath all subtypes of PED. Twenty-two eyes (75.9%) with fluid or SHRM demonstrated CNVM on OCTA (P = .036). Fluid corresponded in a statistically significant manner with treatment (P = .0032), whereas SHRM did not (P = .613). OCTA-defined CNVM showed borderline statistically significant correlation to treatment (P = .05). Increased choroidal flow signal seen in 50% of eyes did not demonstrate statistically significant correlation to the presence of fluid on SD-OCT (P = .2798) or treatment decision (P = .678). A subset of 14 untreated eyes with CNVM was analyzed, 21% of which required treatment at subsequent visits.

Conclusions: OCTA-defined CNVM was seen in all subtypes of PED in clinically active and inactive disease. The role of OCTA in predicting need for treatment remains to be established. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:620-626.].
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http://dx.doi.org/10.3928/23258160-20191009-04DOI Listing
October 2019

Intraoperative Optical Coherence Tomography-Assisted Descemet Membrane Endothelial Keratoplasty in the DISCOVER Study: First 100 Cases.

Am J Ophthalmol 2020 02 25;210:167-173. Epub 2019 Sep 25.

Department of Ophthalmology, Cleveland Clinic Cole Eye Institute, Cleveland, Ohio, USA; Tony and Leona Campane Center for Excellence in Image-Guided Surgery and Advanced Imaging Research, Cleveland Clinic, Cleveland, Ohio, USA. Electronic address:

Purpose: Intraoperative optical coherence tomography (iOCT) may facilitate successful transition to Descemet membrane endothelial keratoplasty (DMEK) surgery via improved efficiency of tissue orientation. The purpose of this study is to report a large consecutive series of iOCT-assisted DMEK, inclusive of all learning curve cases.

Design: Prospective consecutive case series.

Methods: The Determination of Feasibility of Intraoperative Spectral Domain Microscope Combined/Integrated OCT Visualization During En Face Retinal and Ophthalmic Surgery (DISCOVER) study is a single-site, multisurgeon, IRB-approved investigational device prospective study. The first 100 consecutive iOCT-assisted DMEK surgeries performed by 1 attending corneal surgeon (JMG) and 6 novice surgeons (cornea fellows under supervision) were reviewed. iOCT was utilized for tissue orientation. Patient demographics, tissue characteristics, intraoperative parameters, and postoperative complications are reported.

Outcomes: (1) Utility of iOCT based on surgeon reporting during surgery, (2) intraoperative graft unscrolling efficiency, and (3) frequency of postoperative complications.

Results: One hundred eyes of 76 patients were enrolled. Forty-three cases were performed by 1 staff physician and 57 cases were performed by 6 cornea fellows. Concurrent phacoemulsification with lens implantation was performed in 52 cases (52%). Nine eyes (9%) required rebubbling. Two eyes (2.0%) experienced primary graft failure. One graft failure resulted from surgeon error in interpreting the iOCT. Average unscrolling time was 4.4 ± 4.1 minutes (range: 0.7-27.6 minutes).

Conclusions: iOCT facilitates DMEK orientation without the need for external markings. For novice DMEK surgeons, complication rates and unscrolling times compare favorably with alternative tissue orientation methods.
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http://dx.doi.org/10.1016/j.ajo.2019.09.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002191PMC
February 2020

Intravitreal Aflibercept for Retinal Nonperfusion in Proliferative Diabetic Retinopathy: Outcomes from the Randomized RECOVERY Trial.

Ophthalmol Retina 2019 12 24;3(12):1076-1086. Epub 2019 Jul 24.

Doheny Image Reading Center, Doheny Eye Institute, Los Angeles, California; Department of Ophthalmology, David Geffen School of Medicine at UCLA, Los Angeles, California.

Purpose: Evaluate the impact of intravitreal aflibercept (Eylea; Regeneron, Tarrytown, NY) on retinal nonperfusion (RNP) in eyes with proliferative diabetic retinopathy (PDR).

Design: Prospective, randomized clinical trial.

Participants: Eyes with treatment-naïve PDR and extensive RNP without diabetic macular edema.

Methods: Patients were randomized 1:1 to intravitreal 2 mg aflibercept every 4 weeks (monthly) or every 12 weeks (quarterly).

Main Outcome Measures: The primary outcome measure was change in total RNP area (in square millimeters) from baseline to year 1. Secondary outcomes included ischemic index (ISI), diabetic retinopathy severity scale (DRSS) scores, visual acuity, central retinal thickness, and adverse events. The mean and 95% confidence interval were calculated for each outcome.

Results: Through 1 year, the monthly (n = 20) and quarterly (n = 20) cohorts received 11.0 and 3.95 mean aflibercept injections, and DRSS scores improved 2 steps or more in 74% and 67% of patients, respectively. Among all patients through 1 year, mean total area of RNP increased from 235 mm to 266 mm (P = 0.18) and ISI increased from 25.8% to 31.9% (P = 0.004). Retinal nonperfusion outcomes favored monthly dosing. Mean total RNP increased from 207 mm at baseline to 268 mm (P = 0.01) at 1 year in the quarterly cohort and remained stable at 264 mm at baseline and 1 year (P = 0.70) in the monthly cohort (P = 0.05, monthly vs. quarterly cohorts). Although many eyes demonstrated increased areas of RNP longitudinally (n = 24 [66.7%]), this was more common with quarterly dosing (n = 14 [77.8%]), and a proportion of eyes (n = 12 [33.3%]) demonstrated localized areas of apparent reperfusion of nonperfused retina, more commonly in the monthly cohort (n = 8 [44.4%]).

Conclusions: Widespread evidence of retinal reperfusion with aflibercept dosing of PDR eyes with extensive RNP was not identified, and therefore the primary outcome of the current study was not met. Nevertheless, zones of apparent reperfusion were detected in some patients, and a dose response was identified with a reduction of RNP progression with monthly compared to quarterly dosing.
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http://dx.doi.org/10.1016/j.oret.2019.07.011DOI Listing
December 2019

Higher-Order Assessment of OCT in Diabetic Macular Edema from the VISTA Study: Ellipsoid Zone Dynamics and the Retinal Fluid Index.

Ophthalmol Retina 2019 12 6;3(12):1056-1066. Epub 2019 Jul 6.

The Tony and Leona Campane Center for Excellence in Image-Guided Surgery and Advanced Imaging Research, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio; Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio.

Purpose: To investigate retinal fluid features and ellipsoid zone (EZ) integrity dynamics on spectral-domain OCT (SD-OCT) in eyes with diabetic macular edema (DME) treated with intravitreal aflibercept injection (IAI) in the VISTA-DME study.

Design: A post hoc subanalysis of a phase III, prospective clinical trial.

Participants: Eyes received either IAI 2 mg every 4 weeks (2q4) or every 8 weeks after 5 initial monthly doses (2q8).

Methods: All eyes from the VISTA Phase III study in the IAI groups imaged with the Cirrus HD-OCT system (Zeiss, Oberkochen, Germany) were included. The OCT macular cube datasets were evaluated using a novel software platform to generate retinal layer and fluid boundary lines that were manually corrected for assessment of change in EZ parameters and volumetric fluid parameters from baseline. The retinal fluid index (i.e., proportion of the retinal volume consisting of cystic fluid) was also calculated at each time point.

Main Outcome Measures: The feasibility of volumetric assessment of higher-order OCT-based retinal parameters and its correlation with best-corrected visual acuity (BCVA).

Results: Overall, 106 eyes of 106 patients were included. Specifically, 52 eyes of 52 patients were included in the IAI 2q4 arm, and 54 eyes of 54 patients were included in the IAI 2q8 arm. Ellipsoid zone integrity metrics significantly improved from baseline to week 100, including central macular mean EZ to retinal pigment epithelium (RPE) thickness (2q4: 26.6 μm to 31.6 μm, P < 0.001; 2q8: 25.2 μm to 31.4 μm, P < 0.001). At week 100, central macular intraretinal fluid volume was reduced by >65% (P < 0.001) and central macular subretinal fluid volume was reduced by >99% in both arms (P < 0.001). Central macular retinal fluid index (RFI) significantly improved in both arms (2q4: 17.9% to 7.2%, P < 0.001; 2q8: 19.8% to 4.2%, P < 0.001). Central macular mean EZ-RPE thickness (i.e., a surrogate for photoreceptor outer segment length) and central RFI were independently correlated with BCVA at multiple follow-up visits.

Conclusions: Intravitreal aflibercept injection resulted in significant improvement in EZ integrity and quantitative fluid metrics in both 2q4 and 2q8 arms and correlated with visual function.
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http://dx.doi.org/10.1016/j.oret.2019.06.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899163PMC
December 2019

Local therapy for cancer therapy-associated uveitis: a case series and review of the literature.

Br J Ophthalmol 2020 05 13;104(5):703-711. Epub 2019 Aug 13.

Retina and Uveitis, Cleveland Clinic Foundation, Cleveland, Ohio, USA.

Background/aims: Immunotherapy and targeted therapy for metastatic cancer may cause immune-related adverse events (irAEs) such as uveitis. If irAEs are severe or require systemic steroids, cancer therapy is often held or discontinued. Local steroid therapy for cancer therapy-associated uveitis allows the continuation of cancer therapy. This series demonstrates successful management of cancer therapy-associated uveitis with local therapy based on uveitis subtype.

Methods: This is an Institutional Review Board-approved retrospective case series of patients with uveitis secondary to immunotherapy or targeted therapy managed with local treatment, and focused literature review.

Results: Five patients (median age: 54, range 31 to 75) were included. Time to uveitis onset following cancer therapy initiation was 3 to 12 months. All patients received checkpoint inhibitor therapy; one patient additionally received targeted therapy. Two patients presented with anterior uveitis, two with panuveitis and one with posterior uveitis. Four of five patients demonstrated evidence of posterior segment inflammation on multimodal imaging. Anterior uveitis was successfully treated with topical prednisolone acetate 1% (PA 1%) alone, and posterior segment involvement recalcitrant to topical PA 1% was treated successfully with topical difluprednate, intravitreal triamcinolone acetonide or a combination. Patients with isolated anterior uveitis did not require maintenance topical therapy; those with posterior and panuveitis required chronic low-dose topical therapy.

Conclusion: Based on our series as well as the existing literature demonstrating the use of local therapy for irAEs, we propose an approach to local therapy for cancer therapy-associated uveitis starting with topical steroids and initiating injectable steroids in cases of recalcitrant panuveitis or posterior uveitis. Subclinical inflammation on posterior segment imaging responds robustly to difluprednate or intravitreal steroid therapy, and patients with posterior segment involvement may require more aggressive management and long-term maintenance.
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http://dx.doi.org/10.1136/bjophthalmol-2019-314403DOI Listing
May 2020

Quantitative Ultra-Widefield Angiography and Diabetic Retinopathy Severity: An Assessment of Panretinal Leakage Index, Ischemic Index and Microaneurysm Count.

Ophthalmology 2019 11 8;126(11):1527-1532. Epub 2019 Jun 8.

The Tony and Leona Campane Center for Excellence in Image-Guided Surgery and Advanced Imaging Research, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio; Vitreoretinal Service, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio.

Purpose: To investigate the relationship between the diabetic retinopathy (DR) severity and quantitative ultra-widefield angiographic metrics, including leakage index, ischemic index, and microaneurysm count.

Design: Retrospective image analysis study.

Methods: Eyes with DR that had undergone ultra-widefield fluorescein angiography (UWFA) with associated color photography were identified. All eyes were laser-naive and had not received any intravitreal pharmacotherapy within 6 months of UWFA. Each eye was graded for DR severity. Quantitative angiographic parameters were evaluated with a semiautomated analysis platform with expert reader correction, as needed. Angiographic parameters included panretinal leakage index, ischemic index, and microaneurysm count. Clinical characteristics analyzed included age, gender, race, hemoglobin A1C level, hypertension, systolic blood pressure, diastolic blood pressure, and smoking history.

Main Outcome Measures: Association of DR severity with panretinal leakage index, ischemic index, and microaneurysm count.

Results: Three hundred thirty-nine eyes were included with mean age of 62±13 years. Forty-two percent of eyes were from women and 57.5% were from men. Distribution of DR severity was as follows: mild NPDR in 11.2%, moderate NPDR in 23.9%, severe NPDR in 40.1%, and PDR with 24.8%. Panretinal leakage index [mild NPDR (mean = 0.51%), moderate NPDR mean = 1.20%, severe NPDR (mean = 2.75%), and PDR (mean = 5.84%); P<2×10], panretinal ischemic index [mild NPDR (mean = 0.95%, moderate NPDR (mean = 1.37%), severe NPDR (mean = 2.80%), and PDR (mean = 9.53%); P<2×10], and panretinal microaneurysm count [mild NPDR (mean = 36), moderate NPDR (mean = 129), severe NPDR (mean = 203), and PDR (mean = 254); P<5×10] were strongly associated with DR severity. Multivariate analysis demonstrated that ischemic index and leakage index were the parameters associated most strongly with level of DR severity.

Conclusions: Panretinal leakage index, panretinal ischemic index, and panretinal microaneurysm count are associated with DR severity. Additional research is needed to understand the clinical implications of these parameters related to progression risk, prognosis, and implications for therapeutic response.
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http://dx.doi.org/10.1016/j.ophtha.2019.05.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6810836PMC
November 2019

Repeatability of automated leakage quantification and microaneurysm identification utilising an analysis platform for ultra-widefield fluorescein angiography.

Br J Ophthalmol 2020 04 18;104(4):500-503. Epub 2019 Jul 18.

The Tony and Leona Campane Center for Excellence in Image-Guided Surgery and Advanced Imaging Research, Cole Eye Instute, Cleveland, Ohio, USA

Background/aimsUltra-widefield fluorescein angiography (UWFA) provides unique opportunities for panretinal assessment of retinal diseases. The objective quantification of UWFA features is a labour-intensive manual process, limiting its utility. The present study assesses the consistency/repeatability of an automated assessment platform for the characterisation of retinal vascular features, quantification of microaneurysms (MA) and leakage foci in UWFA images.

Methods: An Institutional Review Board-approved retrospective image analysis study was performed on UWFA images. For each eye, two arteriovenous-phase images and two late-phase images were selected. Automated assessment was performed for retinal vascular features, MA identification and leakage segmentation. Panretinal and zonal assessment of metrics was performed.

Results: There was a significant correlation between paired time points for retinal vessel area and vessel length on early images (Pearson r=0.92, p<0.0001; Pearson r=0.94, p<0.0001) and late images (Pearson r=0.92, p<0.0001; Pearson r=0.92, p<0.0001, respectively). Panretinal and zonal MA counts demonstrated high repeatability between images (all p<0.0001). Similarly, panretinal leakage area and zonal leakage areas were highly correlated (all p<0.001).

Conclusion: This automated algorithm demonstrated very strong intrastudy correlation between paired time points in the same phases of the angiogram for quantifying retinal vascular characteristics, MA count and leakage parameters in UWFA images. These findings suggest significant flexibility in the platform for consistency in evaluating metrics over time and is encouraging for longitudinal assessment opportunities.
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http://dx.doi.org/10.1136/bjophthalmol-2019-314416DOI Listing
April 2020