Publications by authors named "Sunil K Srivastava"

180 Publications

Corneal epithelial defects following vitreoretinal surgery: incidence and outcomes from the DISCOVER study.

Int J Ophthalmol 2022 18;15(1):83-88. Epub 2022 Jan 18.

The Tony and Leona Campane Center for Excellence in Image-Guided Surgery and Advanced Imaging Research, Cole Eye Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

Aim: To investigate the incidence, risk factors, clinical course, and outcomes of corneal epithelial defects (CED) following vitreoretinal surgery in a prospective study setting.

Methods: This was a post-hoc analysis of all participants in DISCOVER intraoperative optical coherence tomography study. Subjects with CED 1d after surgery without intraoperative corneal debridement was defined as the postoperative CED group. Subjects who underwent intraoperative debridement were defined as intraoperative debridement group. Eyes were matched 2:1 with controls (eyes without postoperative CED) for comparative assessment. The primary outcomes were the incidence of CED on postoperative day one and the incidence of required intraoperative debridement. Secondary outcomes included time to defect closure, delayed healing (>2wk), visual acuity (VA) and presence of scarring at one year and cornea consult.

Results: This study included 856 eyes that underwent vitreoretinal surgery. Intraoperative corneal debridement was performed to 61 (7.1%) subjects and postoperative CED developed spontaneously in 94 (11.0%) subjects. Significant factors associated with postoperative CED included prolonged surgical duration (=0.003), diabetes mellitus (=0.04), postoperative ocular hypotension (<0.001). Prolonged surgical duration was associated with intraoperative debridement. Delayed defect closure time (>2wk) was associated with corneal scar formation at the end of the 1y in all epithelial defect subjects (<0.001). The overall rate of corneal scarring for all eyes undergoing vitrectomy was 1.8%.

Conclusion: Prolonged duration of surgery is the strongest factor associated with both intraoperative debridement and spontaneous postoperative CED. Delayed defect closure is associated with a greater risk of corneal scarring at one year. The overall rate of corneal scarring following vitrectomy is low at <2%.
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http://dx.doi.org/10.18240/ijo.2022.01.13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8720351PMC
January 2022

Risk Classification for Progression to Subfoveal Geographic Atrophy in Dry Age-Related Macular Degeneration Using Machine Learning-Enabled Outer Retinal Feature Extraction.

Ophthalmic Surg Lasers Imaging Retina 2022 Jan 1;53(1):31-39. Epub 2022 Jan 1.

Background And Objective: To evaluate the utility of spectral-domain optical coherence tomography biomarkers to predict the development of subfoveal geographic atrophy (sfGA).

Patients And Methods: This was a retrospective cohort analysis including 137 individuals with dry age-related macular degeneration without sfGA with 5 years of follow-up. Multiple spectral-domain optical coherence tomography quantitative metrics were generated, including ellipsoid zone (EZ) integrity and subretinal pigment epithelium (sub-RPE) compartment features.

Results: Reduced mean EZ-RPE central subfield thickness and increased sub-RPE compartment thickness were significantly different between sfGA convertors and nonconvertors at baseline in both 2-year and 5-year sfGA risk assessment. Longitudinal change assessment showed a significantly higher degradation of EZ integrity in sfGA convertors. The predictive performance of a machine learning classification model based on 5-year and 2-year risk conversion to sfGA demonstrated an area under the receiver operating characteristic curve of 0.92 ± 0.06 and 0.96 ± 0.04, respectively.

Conclusions: Quantitative outer retinal and sub-RPE feature assessment using a machine learning-enabled retinal segmentation platform provides multiple parameters that are associated with progression to sfGA. .
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http://dx.doi.org/10.3928/23258160-20211210-01DOI Listing
January 2022

Quantitative Imaging Biomarkers in Age-Related Macular Degeneration and Diabetic Eye Disease: A Step Closer to Precision Medicine.

J Pers Med 2021 Nov 8;11(11). Epub 2021 Nov 8.

Cole Eye Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

The management of retinal diseases relies heavily on digital imaging data, including optical coherence tomography (OCT) and fluorescein angiography (FA). Targeted feature extraction and the objective quantification of features provide important opportunities in biomarker discovery, disease burden assessment, and predicting treatment response. Additional important advantages include increased objectivity in interpretation, longitudinal tracking, and ability to incorporate computational models to create automated diagnostic and clinical decision support systems. Advances in computational technology, including deep learning and radiomics, open new doors for developing an imaging phenotype that may provide in-depth personalized disease characterization and enhance opportunities in precision medicine. In this review, we summarize current quantitative and radiomic imaging biomarkers described in the literature for age-related macular degeneration and diabetic eye disease using imaging modalities such as OCT, FA, and OCT angiography (OCTA). Various approaches used to identify and extract these biomarkers that utilize artificial intelligence and deep learning are also summarized in this review. These quantifiable biomarkers and automated approaches have unleashed new frontiers of personalized medicine where treatments are tailored, based on patient-specific longitudinally trackable biomarkers, and response monitoring can be achieved with a high degree of accuracy.
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http://dx.doi.org/10.3390/jpm11111161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8622761PMC
November 2021

The 2-Year Leakage Index and Quantitative Microaneurysm Results of the RECOVERY Study: Quantitative Ultra-Widefield Findings in Proliferative Diabetic Retinopathy Treated with Intravitreal Aflibercept.

J Pers Med 2021 Nov 1;11(11). Epub 2021 Nov 1.

Cole Eye Institute, Cleveland Clinic, Cleveland, OH 44106, USA.

Eyes with proliferative diabetic retinopathy (PDR) have been shown to improve in the leakage index and microaneurysm (MA) count after intravitreal aflibercept (IAI) treatment. The authors investigated these changes via automatic segmentation on ultra-widefield fluorescein angiography (UWFA). Forty subjects with PDR were randomized to receive either 2 mg IAI every 4 weeks (Arm 1) or every 12 weeks (Arm 2) through Year 1. After Year 1, Arm 1 switched to quarterly IAI and Arm 2 to monthly IAI through Year 2. By Year 2, the Arm 1 leakage index decreased by 43% from Baseline ( = 0.03) but increased by 59% from Year 1 ( = 0.04). Arm 2 decreased by 61% from Baseline ( = 0.008) and by 31% from Year 1 ( = 0.12). Both cohorts exhibited a significant decline in MAs from Baseline to Year 2 (871 to 410; < 0.001; 776 to 207; < 0.001, respectively). Subjects with an improved leakage and MA count showed a more significant improvement in the Diabetic Retinopathy Severity Scale (DRSS) score. Moreover, central subfield thickness (CST) was positively associated with changes in the leakage index. In conclusion, the leakage index and MA counts significantly improved from Baseline following IAI treatment, and monthly injections provided a more rapid and sustained reduction in these parameters compared with quarterly injections.
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http://dx.doi.org/10.3390/jpm11111126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8619795PMC
November 2021

Vitreomacular Traction Surgery from the DISCOVER Study: Intraoperative OCT Utility, Ellipsoid Zone Dynamics, and Outcomes.

Ophthalmic Surg Lasers Imaging Retina 2021 10 1;52(10):544-550. Epub 2021 Oct 1.

Background And Objectives: To characterize the clinical and ellipsoid zone (EZ) integrity outcomes in surgical intervention for symptomatic vitreomacular traction (VMT), and to evaluate the utility of intraoperative optical coherence tomography (OCT) during VMT surgery.

Patients And Methods: This was a post-hoc analysis of eyes in the DISCOVER study undergoing pars plana vitrectomy (PPV) with intraoperative OCT for VMT-related macular disease. Data were collected prospectively on feasibility and utility of intraoperative OCT, with follow-up lasting 12 months.

Results: Forty-three eyes of 41 patients were included and mean visual acuity improved from 20/96 to 20/45 ( < .001). Intraoperative OCT provided information that impacted surgical decision-making in eight patients (18.6%). EZ integrity metrics significantly improved from baseline to 12 months and directly correlated with functional outcomes ( < .001).

Conclusions: Retinal function and morphology improved significantly following PPV for VMT. Intraoperative OCT provided surgeon-perceived valuable information in select cases. Further research is needed to determine whether this information impacts overall surgical outcomes. .
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http://dx.doi.org/10.3928/23258160-20210913-01DOI Listing
October 2021

Real-Time Diabetic Retinopathy Severity Score Level versus Ultra-Widefield Leakage Index-Guided Management of Diabetic Retinopathy: Two-Year Outcomes from the Randomized PRIME Trial.

J Pers Med 2021 Sep 4;11(9). Epub 2021 Sep 4.

Retina Consultants of Texas, Retina Consultants of America, Houston, TX 77030, USA.

The prospective PRIME trial applied real-time, objective imaging biomarkers to determine individualized retreatment needs with intravitreal aflibercept injections (IAI) among eyes with diabetic retinopathy (DR). 40 eyes with nonproliferative or proliferative DR without diabetic macular edema received monthly IAI until a DR severity scale (DRSS) level improvement of ≥2 steps was achieved. Eyes were randomized 1:1 to DRSS- or PLI- guided management. At the final 2-year visit, DRSS level was stable or improved compared to baseline in all eyes, and mean PLI decreased by 11% ( = 0.73) and 23.6% ( = 0.25) in the DRSS- and PLI-guided arms. In both arms, the percent of (PRN) visits requiring IAI was significantly higher in year 2 versus 1 ( < 0.0001). The percent of PRN visits receiving IAI during year 1 was significantly correlated with the percent of PRN visits with IAI during year 2 ( < 0.0001). Through week 104, 77.4% of instances of DRSS level worsening in the DRSS-guided arm were preceded by or occurred alongside an increase of PLI. Overall, consistent IAI re-treatment interval requirements were observed longitudinally among individual patients. Additionally, PLI increases appeared to precede DRSS level worsening, highlighting PLI as a valuable biomarker in the management of DR.
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http://dx.doi.org/10.3390/jpm11090885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8465170PMC
September 2021

LONGITUDINAL ELLIPSOID ZONE AND OUTER RETINAL INTEGRITY DYNAMICS AFTER EPIRETINAL MEMBRANE SURGERY.

Retina 2022 Feb;42(2):265-273

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

Purpose: To quantify ellipsoid zone (EZ) changes in integrity after epiretinal membrane (ERM) surgery, correlate findings to visual acuity, and determine predictors for prognosis.

Methods: A post hoc analysis of eyes undergoing ERM surgery pooled from the prospective DISCOVER intraoperative optical coherence tomography study and eyes undergoing conventional ERM surgery without intraoperative optical coherence tomography. Quantitative EZ features were extracted using a multilayer machine learning enabled automated segmentation platform after image analyst review/correction for segmentation accuracy. Visual acuity and EZ integrity were quantitatively assessed and correlated before and after ERM surgery. Multiple linear regression was performed to assess preoperative visual acuity and EZ features as predictors for improvement in visual acuity or EZ integrity.

Results: There were 177 eyes from 177 subjects that underwent ERM surgery from the DISCOVER and conventional arms. Improvement in visual acuity and multiple EZ integrity features was noted after ERM surgery, including EZ partial attenuation and EZ-retinal pigment epithelium (RPE) volume (P < 0.05). A reduction in EZ partial attenuation and increase in EZ-RPE central subfield thickness (EZ-RPE CST) was significantly correlated with improved visual acuity after ERM surgery (P < 0.05). More robust EZ-RPE CST at baseline predicted visual acuity improvement after ERM peel in regression modeling (β = 0.005, P < 0.05).

Conclusions: Longitudinal assessment of EZ features demonstrates significant postoperative improvement in multiple EZ integrity metrics after ERM surgery. Improving EZ integrity was correlated to improving the visual acuity. Ellipsoid zone integrity and visual acuity were significant predictors in regression modeling and may have value in clinical prognostication.
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http://dx.doi.org/10.1097/IAE.0000000000003306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8776576PMC
February 2022

Deep learning-enabled ultra-widefield retinal vessel segmentation with an automated quality-optimized angiographic phase selection tool.

Eye (Lond) 2021 Aug 9. Epub 2021 Aug 9.

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

Objectives: To demonstrate the feasibility of a deep learning-based vascular segmentation tool for UWFA and evaluate its ability to automatically identify quality-optimized phase-specific images.

Methods: Cumulative retinal vessel areas (RVA) were extracted from all available UWFA frames. Cubic splines were fitted for serial vascular assessment throughout the angiographic phases of eyes with diabetic retinopathy (DR), sickle cell retinopathy (SCR), or normal retinal vasculature. The image with maximum RVA was selected as the optimum early phase. A late phase frame was selected at a minimum of 4 min that most closely mirrored the RVA from the selected early image. Trained image analysts evaluated the selected pairs.

Results: A total of 13,980 UWFA sequences from 462 sessions were used to evaluate the performance and 1578 UWFA sequences from 66 sessions were used to create cubic splines. Maximum RVA was detected at a mean of 41 ± 15, 47 ± 27, 38 ± 8 s for DR, SCR, and normals respectively. In 85.2% of the sessions, appropriate images for both phases were successfully identified. The individual success rate was 90.7% for early and 94.6% for late frames.

Conclusions: Retinal vascular characteristics are highly phased and field-of-view sensitive. Vascular parameters extracted by deep learning algorithms can be used for quality assessment of angiographic images and quality optimized phase selection. Clinical applications of a deep learning-based vascular segmentation and phase selection system might significantly improve the speed, consistency, and objectivity of UWFA evaluation.
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http://dx.doi.org/10.1038/s41433-021-01661-4DOI Listing
August 2021

Genome-Wide Expression Profiling of Small RNAs in Indian Strain of AG1-1A Reveals Differential Regulation of milRNAs during Pathogenesis and Crosstalk of Gene Regulation.

J Fungi (Basel) 2021 Jul 14;7(7). Epub 2021 Jul 14.

Indian Council of Agricultural Research (ICAR)-Indian Institute of Rice Research, Hyderabad 500030, India.

AG1-1A is a necrotrophic fungus that causes sheath blight disease in rice. The reliable resistant source against this phytopathogenic fungus is not available in the gene pool of rice. Better understanding of pathogen genomics and gene regulatory networks are critical to devise alternate strategies for developing resistance against this noxious pathogen. In this study, miRNA-like RNAs (milRNAs) of an Indian strain of were identified by deep sequencing of small RNAs. We identified 128 known and 22 novel milRNAs from 20,963,123 sequence reads. These milRNAs showed 1725 target genes in the fungal genome which include genes associated with growth, development, pathogenesis and virulence of Notably, these fungal milRNAs showed their target genes in host (rice) genome also which were later verified by qRT-PCR. The host target genes are associated with auxin metabolism, hypersensitive response, defense genes, and genes related to growth and development of rice. Osa-vacuolar-sorting receptor precursor: Rhi-milR-13, Osa-KANADI1:Rhi-milR-124, Osa-isoflavone reductase: Rhi-milR-135, Osa-nuclear transcription factor Y:Rhi-milR-131, Osa-NB-ARC domain containing protein: Rhi-milR-18, and Osa-OsFBX438: Rhi-milR-142 are notable potential regulons of host target genes: fungal milRNAs that need to be investigated for better understanding of the crosstalk of RNAi pathways between and rice. The detailed expression analysis of 17 milRNAs by qRT-PCR was analysed during infection at different time points of inoculation, at different growth stages of the host, in four different genotypes of the host, and also in four different strains of fungi which revealed differential regulation of milRNAs associated with pathogenesis and virulence. This study highlights several important findings on fungal milRNAs which need to be further studied and characterized to decipher the gene expression and regulation of this economically important phytopathogen.
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http://dx.doi.org/10.3390/jof7070561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8304579PMC
July 2021

Multi-Compartment Spatially-Derived Radiomics From Optical Coherence Tomography Predict Anti-VEGF Treatment Durability in Macular Edema Secondary to Retinal Vascular Disease: Preliminary Findings.

IEEE J Transl Eng Health Med 2021 12;9:1000113. Epub 2021 Jul 12.

The Tony and Leona Campane Center for Excellence in Image-Guided Surgery and Advancing Imaging ResearchCleveland Clinic Cole Eye InstituteClevelandOH44106USA.

Objective: Diabetic macular edema (DME) and retinal vein occlusion (RVO) are the leading causes of visual impairments across the world. Vascular endothelial growth factor (VEGF) stimulates breakdown of blood-retinal barrier that causes accumulation of fluid within macula. Anti-VEGF therapy is the first-line treatment for both the diseases; however, the degree of response varies for individual patients. The main objective of this work was to identify the (i) texture-based radiomics features within individual fluid and retinal tissue compartments of baseline spectral-domain optical coherence tomography (SD-OCT) images and (ii) the specific spatial compartments that contribute most pertinent features for predicting therapeutic response.

Methods: A total of 962 texture-based radiomics features were extracted from each of the fluid and retinal tissue compartments of OCT images, obtained from the PERMEATE study. Top-performing features selected from the consensus of different feature selection methods were evaluated in conjunction with four different machine learning classifiers: Linear Discriminant Analysis (LDA), Quadratic Discriminant Analysis (QDA), Random Forest (RF), and Support Vector Machine (SVM) in a cross-validated approach to distinguish eyes tolerating extended interval dosing (non-rebounders) and those requiring more frequent dosing (rebounders).

Results: Combination of fluid and retinal tissue features yielded a cross-validated area under receiver operating characteristic curve (AUC) of 0.78±0.08 in distinguishing rebounders from non-rebounders.

Conclusions: This study revealed that the texture-based radiomics features pertaining to IRF subcompartment were most discriminating between rebounders and non-rebounders to anti-VEGF therapy. Clinical Impact: With further validation, OCT-based imaging biomarkers could be used for treatment management of DME patients.
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http://dx.doi.org/10.1109/JTEHM.2021.3096378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328398PMC
December 2021

Bilateral infectious scleritis from in an immunosuppressed uveitis patient.

Am J Ophthalmol Case Rep 2021 Sep 1;23:101156. Epub 2021 Jul 1.

Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA.

Purpose: To describe a case of bilateral infectious scleritis secondary to in the setting of a locally and systemically immunosuppressed patient.

Observations: A 45-year-old man with HLA-B27 associated ankylosing spondylitis and anterior uveitis on systemic secokinumab, underwent bilateral cataract extraction which required extensive peri-operative steroids, including intravitreal triamcinolone, topical prednisolone, and oral prednisone. Six weeks after cataract surgery, the patient presented with mild eye irritation and was found to have bilateral subconjunctival purulence and necrosis. was identified on fungal cultures and confirmed by DNA probe. The patient was treated with fortified amphotericin drops and oral itraconazole with complete resolution of scleritis.

Conclusion And Importance: is a rare cause of infectious scleritis that must be considered in our immunosuppressed and post-surgical patients.
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http://dx.doi.org/10.1016/j.ajoc.2021.101156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261536PMC
September 2021

Exploring the angiographic-biologic phenotype in the IMAGINE study: quantitative UWFA and cytokine expression.

Br J Ophthalmol 2021 Jun 7. Epub 2021 Jun 7.

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

Background: This study investigates the association of intraocular cytokine expression and ultrawide-field fluorescein angiography (UWFA) quantitative imaging biomarkers and their association with angiographical feature response after antivascular endothelial growth factor (VEGF) therapy in diabetic macular oedema (DME).

Methods: The IMAGINE DME study is a post hoc imaging biomarker and intraocular cytokine assessment from the DAVE study, a prospective DME clinical trial that included aqueous humour sampling and UWFA imaging. Fifty-four cytokines associated with inflammation and angiogenesis were evaluated through multiplex arrays. UWFA parameters were assessed using an automated feature analysis platform to determine ischaemic and leakage indices and microaneurysm (MA) count. Eyes were classified into UWFA responder or non-responder groups based on longitudinal quantitative UWFA parameter improvement. Cytokine expression was correlated with UWFA metrics and evaluated in the context of therapeutic response.

Results: Twenty-one eyes were included with a mean age of 55±10 years. Increased panretinal leakage index correlated with VEGF (r=0.70, p=0.0005), angiopoietin-like 4 (r=0.77, p=4.6E-5) and interleukin (IL)-6 (r=0.64, p=0.002). Panretinal ischaemic index was associated with tissue inhibitor of metalloproteinases 1 (TIMP-1, r=0.49, p=0.03) and peripheral ischaemia correlated with VEGF (r=0.45, p=0.05). MA count correlated with increased monocyte chemotactic protein-4 (MCP-4, r=0.60, p=0.004) and platelet and endothelial cell adhesion molecule 1 (PECAM-1, r=0.58, p=0.005). Longitudinal MA reduction was associated with decreased baseline VEGF and urokinase receptor (uPAR) (p<0.05). High baseline VEGF and IL-6 were associated with dramatic reduction in macular leakage (p<0.05).

Conclusions: Baseline and longitudinal quantitative UWFA imaging parameters correlated with multiple aqueous humour cytokine concentrations, including VEGF and IL-6. Further research is needed to assess the possible implications of using these findings for evaluating treatment response.
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http://dx.doi.org/10.1136/bjophthalmol-2020-318726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8761372PMC
June 2021

Panuveitis Presumed Secondary to Ibrutinib Therapy.

Ophthalmic Surg Lasers Imaging Retina 2021 03 1;52(3):160-164. Epub 2021 Mar 1.

Although a small number of cases of secondary uveitis have been documented in the setting of ibrutinib therapy, panuveitis has not previously been described with this medication. The authors describe a presumed case of panuveitis in a patient on ibrutinib for chronic lymphocytic leukemia. The purpose of this report is to document a case of asymmetric, bilateral panuveitis in the setting of ibrutinib use. Panuveitis may develop in the setting of ibrutinib use, and local steroid therapy can be successfully used for treatment without cessation of systemic cancer therapy. .
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http://dx.doi.org/10.3928/23258160-20210302-08DOI Listing
March 2021

Longitudinal Higher-Order OCT Assessment of Quantitative Fluid Dynamics and the Total Retinal Fluid Index in Neovascular AMD.

Transl Vis Sci Technol 2021 03;10(3):29

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

Purpose: The purpose of this study was to evaluate the feasibility of assessing quantitative longitudinal fluid dynamics and total retinal fluid indices (TRFIs) with higher-order optical coherence tomography (OCT) for neovascular age-related macular degeneration (nAMD).

Methods: A post hoc image analysis study was performed using the phase II OSPREY clinical trial comparing brolucizumab and aflibercept in nAMD. Higher-order OCT analysis using a machine learning-enabled fluid feature extraction platform was used to segment intraretinal fluid (IRF) and subretinal fluid (SRF) volumetric components. TRFI, the proportion of fluid volume against total retinal volume, was calculated. Longitudinal fluid metrics were evaluated for the following groups: all subjects (i.e. treatment agnostic), brolucizumab, and aflibercept.

Results: Mean IRF and SRF volumes were significantly reduced from baseline at each timepoint for all groups. Fluid feature extraction allowed high-resolution assessment of quantitative fluid burden. A greater proportion of brolucizumab participants achieved true zero and minimal fluid (total fluid volume between 0.0001 and 0.001mm3) versus aflibercept participants at week 40. True zero fluid during q12 brolucizumab dosing was achieved in 36.6% to 38.5%, similar to the 25.6% to 38.5% during the corresponding q8 aflibercept cycles. TRFI was significantly reduced from baseline in all groups.

Conclusions: Higher-order OCT analysis demonstrates the feasibility of fluid feature extraction and longitudinal volumetric fluid burden and TRFI characterization in nAMD, supporting a unique opportunity for fluid burden assessment and the impact on outcomes.

Translational Relevance: Detection and characterization of disease activity is vital for optimal treatment of nAMD. Longitudinal assessment of fluid dynamics and the TRFI provide important proof of concept for future automated tools in characterizing disease activity.
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http://dx.doi.org/10.1167/tvst.10.3.29DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995350PMC
March 2021

Multimodal Imaging Findings in Acute West Nile Virus Chorioretinitis.

Retin Cases Brief Rep 2021 May 12. Epub 2021 May 12.

Department of Ophthalmology, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, United States.

Purpose: To describe multimodal imaging findings of acute West Nile virus (WNV) chorioretinitis.

Methods: Observational case report. Fundus photographs, fluorescein angiography, indocyanine green angiography, and swept-source optical coherence tomography angiography were used to characterize and describe the clinical findings.

Results: A 58-year-old man presented with acute painless vision loss in the right eye.Multimodal imaging demonstrated multifocal pinpoint early phase hyperfluoresence with late expanding leakage on fluorescein angiography (FA) and late hyperfluorescence on indocyanine green angiography (ICGA). Swept-source optical coherence tomography angiography (SS-OCTA) en face imaging of the ellipsoid zone layer revealed target-like lesions with central hyperreflectivity with surrounding hyporeflectivity. At 4-week follow-up, the chorioretinal lesions now demonstrated greater demarcation of borders with increased pigmentation. At 8-week follow-up, fundus exam revealed multiple target-like lesions with hyperpigmentation centrally surrounded by a hypopigmented rim. Repeat FA demonstrated central hypofluorescence with surrounding hyperfluoresent staining rim prompting work-up for WNV, which was later confirmed by laboratory testing. The patient's visual acuity and clinical exam remained stable on subsequent follow-up visits.

Conclusion: Our case highlights multimodal imaging findings in the acute phase of WNV chorioretinitis which may be crucial to early diagnosis and identification.
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http://dx.doi.org/10.1097/ICB.0000000000001162DOI Listing
May 2021

LONGITUDINAL ELLIPSOID ZONE DYNAMICS AFTER MACULAR HOLE REPAIR IN THE DISCOVER STUDY: Structure-Function Assessment.

Retina 2021 May;41(5):915-920

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

Purpose: To evaluate association of the baseline macular hole (MH) geometric features and longitudinal ellipsoid zone integrity with the visual acuity outcome after surgical repair.

Methods: This was a post-hoc analysis of eyes in the DISCOVER study undergoing vitrectomy repair for MH. Anatomical and functional data were collected through one year postoperatively. An automated retinal layer segmentation platform was used for the assessment of outer retinal metrics and volumetric reconstruction of MH. Association of longitudinal ellipsoid zone features and baseline MH height, width, and volume with VA outcomes were investigated.

Results: Eighty-four eyes with MH were included. The mean baseline VA was 20 of 114 and increased to 20 of 45 (P < 0.001) at postoperative Month 12 (N = 45). Successful MH closure was achieved in 98.8% of cases. Ellipsoid zone integrity metrics significantly improved from baseline (P = 0.002) and postoperative Month 1 (P < 0.001) to post-operative Month 12. Ellipsoid zone metrics independently correlated with VA at all follow-up visits (P < 0.05). Increased baseline MH width and volume negatively correlated with the VA at postoperative Month 12 (P < 0.001). Preoperative VA and EZ integrity on optical coherence tomography were predictors for postoperative VA.

Conclusion: Baseline MH volumetric parameters and EZ parameters were associated with VA outcomes after repair.
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http://dx.doi.org/10.1097/IAE.0000000000002983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074992PMC
May 2021

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

Ophthalmol Retina 2021 Dec 27;5(12):1254-1262. Epub 2021 Feb 27.

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 provide a comparative assessment of clinical outcomes between patients undergoing intraoperative OCT (iOCT) and conventional surgery for pars plana vitrectomy (PPV) with epiretinal membrane (ERM) peel.

Design: Case-control retrospective, comparative assessment.

Participants: Patients undergoing PPV with membrane peel for ERM with eyes pooled from the prospective Determination of Feasibility of Intraoperative Spectral Domain Microscope Combined/Integrated OCT Visualization During En Face Retinal and Ophthalmic Surgery (DISCOVER) iOCT study and eyes undergoing conventional ERM surgery without iOCT.

Methods: Visual acuity and OCT assessment before ERM surgery and at 1-, 3-, 6-, and 12-month follow-up after standard small-gauge PPV with iOCT feedback (iOCT DISCOVER group) or PPV with compulsory internal limiting membrane (ILM) peeling (conventional group). Visual acuity, central subfield thickness (CST), reoperation 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 11.9 letters in the iOCT group (P < 0.0001) and 12.1 letters in the conventional group (P < 0.0001) at 12 months after ERM surgery. Visual acuity improvement did not differ between the iOCT and conventional groups at 1, 3, 6, or 12 months after surgery (P > 0.05 for each time point). Preoperative mean 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). No reoperations or visually significant recurrent ERMs occurred in either cohort.

Conclusions: Intraoperative OCT-guided ERM removal without mandated ILM peeling provided similar VA and anatomic results to conventional ILM peeling for ERM. Future randomized prospective studies are needed to assess fully the possible role of iOCT in ERM surgery and to evaluate the potential impact of nonfoveal ERM persistence or recurrence in comparison with conventional surgery.
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http://dx.doi.org/10.1016/j.oret.2021.02.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8390556PMC
December 2021

Longitudinal Assessment of Ellipsoid Zone Integrity, Subretinal Hyperreflective Material, and Subretinal Pigment Epithelium Disease in Neovascular Age-Related Macular Degeneration.

Ophthalmol Retina 2021 Dec 26;5(12):1204-1213. Epub 2021 Feb 26.

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

Purpose: To assess longitudinally 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: 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 OCT at 4-week intervals in the OSPREY trial (n = 81). Spectral-domain OCT scans collected from each visit were segmented automatically 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 patients evaluated with the Cirrus (Zeiss) platform (n = 28).

Main Outcome Measures: Outcome measures included change from baseline in EZ-RPE (i.e., photoreceptor outer segment) 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 weeks 4 through 56 (P < 0.05 at each visit). Ellipsoid zone integrity measures and SHRM volume correlated significantly with BCVA at most visits (P < 0.05). 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387490PMC
December 2021

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

Am J Ophthalmol 2021 06 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
June 2021

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

Am J Ophthalmol 2021 04 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
April 2021

Risk of Inflammation, Retinal Vasculitis, and Retinal Occlusion-Related Events with Brolucizumab: Post Hoc Review of HAWK and HARRIER.

Ophthalmology 2021 07 15;128(7):1050-1059. Epub 2020 Nov 15.

Ophthalmic Consultants of Boston, Boston, Massachusetts. Electronic address:

Purpose: An independent Safety Review Committee (SRC), supported by Novartis Pharma AG, analyzed investigator-reported cases of intraocular inflammation (IOI), endophthalmitis, and retinal arterial occlusion in the phase 3 HAWK and HARRIER trials of brolucizumab versus aflibercept in neovascular age-related macular degeneration (nAMD).

Design: A post hoc analysis of a subset of data from two 2-year, double-masked, multicenter, active-controlled randomized phase 3 trials (NCT02307682, NCT02434328).

Participants: Patients (N = 1817) with untreated, active choroidal neovascularization due to age-related macular degeneration in the study eye were randomized and treated in HAWK/HARRIER. The SRC reviewed data from cases of investigator-reported IOI (60/1088 brolucizumab-treated eyes; 8/729 aflibercept-treated eyes).

Methods: The SRC received details and images (color fundus photography, fluorescein angiography, and OCT) for all investigator-determined cases of IOI, retinal arterial occlusion, and endophthalmitis. Cases were reviewed in detail by ≥2 readers, then adjudicated by the SRC as a group.

Main Outcome Measures: Within this patient subset: incidence of IOI, signs and incidence of retinal vasculitis and/or retinal vascular occlusion, and visual acuity loss; time since first brolucizumab injection to IOI event onset; and frequency of visual acuity loss after brolucizumab injection by time of first IOI event onset.

Results: Fifty brolucizumab-treated eyes were considered to have definite/probable drug-related events within the spectrum of IOI, retinal vasculitis, and/or vascular occlusion. On the basis of these cases, incidence of definite/probable IOI was 4.6% (IOI + vasculitis, 3.3%; IOI + vasculitis + occlusion, 2.1%). There were 8 cases (incidence 0.74%) of at least moderate visual acuity loss (≥15 ETDRS letters) in eyes with IOI (7 in eyes with IOI + vasculitis + occlusion). Of the 8 cases, 5 experienced their first IOI-related event within 3 months of the first brolucizumab injection (increasing to 7/8 within 6 months). Incidence of IOI in aflibercept-treated eyes was 1.1%, with at least moderate visual acuity loss in 0.14%.

Conclusions: This analysis of IOI cases after brolucizumab injection identified signs of retinal vasculitis with or without retinal vascular occlusion and an associated risk of visual acuity loss. The findings will help physicians to evaluate the risks and benefits of brolucizumab treatment for nAMD.
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http://dx.doi.org/10.1016/j.ophtha.2020.11.011DOI Listing
July 2021

Acute retinal necrosis following recombinant subunit varicella-zoster virus vaccine.

Am J Ophthalmol Case Rep 2020 Dec 8;20:100962. Epub 2020 Oct 8.

Cleveland Clinic Cole Eye Institute, 9500 Euclid Avenue i-32 Cleveland, OH, 44195, USA.

Purpose: Previously, secondary prevention of herpes zoster required live-attenuated vaccination, which is contraindicated in immunocompromised populations. More recently, a recombinant subunit vaccine (Shingrix, GlaxoSmithKline, Research Triangle Park, North Carolina) was approved by the Food and Drug Administration. Iatrogenic varicella-zoster virus (VZV) infection is theoretically impossible as it does not contain a live virus. We present a case of acute retinal necrosis (ARN) and disseminated zoster after receiving the recombinant subunit vaccine.

Observations: A 65-year-old woman with past medical history of multiple myeloma treated with a previous autologous hematopoietic stem cell transplant and now with daratumumab and pomalidomide developed disseminated zoster and subsequently acute retinal necrosis weeks after receiving the zoster subunit vaccine. Molecular testing confirmed the presence of VZV, and the absence of herpes simplex virus, cytomegalovirus, and toxoplasmosis. The VZV was found to be genotypically wildtype and not related to the Oka strain used in the live-attenuated zoster vaccine. She was treated with systemic valacyclovir and intravitreal foscarnet.

Conclusions And Importance: This is the first report of VZV infection following the zoster subunit vaccine. The Advisory Committee on Immunization Practices (ACIP) has recommended the recombinant subunit vaccine over the live-attenuated vaccine due to its superior efficacy. The off-label use of the subunit vaccine in immunocompromised populations has been supported up to this point by studies demonstrating its relative safety. Though post-vaccination VZV infection or reactivation appears to be rare, clinicians should be aware of this potential complication to the recombinant subunit vaccine.
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http://dx.doi.org/10.1016/j.ajoc.2020.100962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599389PMC
December 2020

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

Ophthalmol Retina 2021 07 12;5(7):625-632. 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
July 2021

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

Imaging Features of Vessels and Leakage Patterns Predict Extended Interval Aflibercept Dosing Using Ultra-Widefield Angiography in Retinal Vascular Disease: Findings From the PERMEATE Study.

IEEE Trans Biomed Eng 2021 06 21;68(6):1777-1786. Epub 2021 May 21.

Diabetic Macular Edema (DME) and macular edema secondary to retinal occlusion (RVO) are the two most common retinal vascular causes of visual impairment and leading cause of worldwide vision loss. The blood-retinal barrier is the key barrier for maintaining fluid balance within the retinal tissue. Vascular Endothelial Growth Factor (VEGF) has a significant role in the permeability of the blood-retinal barrier, which also leads to appearance of leakage foci. Intravitreal anti-VEGF therapy is the current gold standard treatment and has been demonstrated to improve macular thickening, improve vision acuity and reduce vascular leakage. However, treatment response and required dosing interval can vary widely across patients. Given the role of the blood-retinal barrier and vascular leakage in the pathogenesis of these disorders, the goal of this study was to present and evaluate new computer extracted features relating to morphology, spatial architecture and tortuosity of vessels and leakages from baseline ultra-widefield fluorescein angiography (UWFA) images. Specifically, we sought to evaluate the role of these computer extracted features from baseline UWFA images. Notably, these UWFA images were obtained from IRB-approved PERMEATE clinical trial [1], [2] to distinguish eyes tolerating extended dosing intervals (n = 16) who are referred to as non-rebounders and those who require more frequent dosing (n = 12) and are called rebounders based on visual acuity loss with extended dosing challenges. A total of 64 features encapsulating different morphological and geometrical attributes of leakage patches including the anatomical (shape, size, density, area, minor and major axis, orientation, area, extent ratio, perimeter, radii) and geometrical characteristics (the proximity of each leakage foci to main vessels, to other leakage foci and to optical disc) as well as 54 tortuosity features (tortuosity of whole vessel network, local tortuosity of vessels in the vicinity of leakage foci) were extracted. The most significant and predictive biomarkers related to treatment response were proximity of leakage nodes to major and minor eye vessels as well as local vasculature tortuosity in the vicinity of the leakages. The imaging features were then used in conjunction with a Linear Discriminant Analysis (LDA) classifier to distinguish rebounders from non-rebounders. The 3-fold cross-validated Area Under Curve (AUC) was found to be 0.82 for the morphological based features and 0.85 for the tortuosity based features. Our findings suggest higher variation in leakage node proximity to retinal vessels in eyes tolerating extended interval dosing. In contrast, eyes with increased local vascular tortuosity demonstrated less tolerance of increased dosing interval. Moreover, a class activation map generated by a deep learning model identified regions that corresponded to regions of leakages proximal to the vessels, providing confirmation of the validity of predictive image features extracted from these regions in this study.
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http://dx.doi.org/10.1109/TBME.2020.3018464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128650PMC
June 2021

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

Br J Ophthalmol 2021 08 19;105(8):1155-1160. 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8153073PMC
August 2021

Recurrence Rates of Inflammation after Switching from the Originator Infliximab to Biosimilar Infliximab-abda for Noninfectious Uveitis.

Am J Ophthalmol 2021 05 12;225:172-177. Epub 2020 Aug 12.

Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA. Electronic address:

Purpose: To describe the frequency of ocular flares in patients with noninfectious uveitis who were switched from the originator infliximab to a biosimilar infliximab.

Design: Retrospective case series.

Methods: All patients with noninfectious uveitis who were switched from the originator infliximab to biosimilar infliximab-abda for nonmedical reasons were reviewed. Patients were excluded if they had less than 3 months of follow-up on either drug. Data included patient demographics, infliximab dosage information, additional immunosuppression medications, and numbers of and times to flares. The main study outcome was frequency of flares, defined as new or worsening inflammatory activity on examination or imaging.

Results: A total of 17 patients met the inclusion criteria. There were no statistical differences between the duration of follow-up while on the originator and the duration while on the biosimilar infliximab (12.0 vs. 10.1 months, respectively; P = .307). Patients experienced more flares per person-years after switching to infliximab-abda (.92), than on the originator infliximab (0.19; P = .028). Four of the 6 patients (66.7%) who experienced flare after switching to infliximab-abda did so within 90 days. Only 1 patient had flares while on originator infliximab went on to develop a single flare on infliximab-abda. The final normalized dosage for patients who flared and remained on infliximab-abda (1.301 mg/kg/week) was higher than that for those who did not flare (1.186 mg/kg/week) but was not statistically significant (P = .417).

Conclusions: Patients who were switched to biosimilar infliximab-abda experience more flares than when previously treated with the originator infliximab. Providers should closely observe patients who switch to biosimilar infliximab, especially within the first 90 days. Patients who do have flares after switching may achieve quiescence with increased biosimilar dosage.
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http://dx.doi.org/10.1016/j.ajo.2020.08.005DOI Listing
May 2021
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