Long-Term Visual Outcomes for a Treat-and-Extend Antivascular Endothelial Growth Factor Regimen in Eyes with Neovascular Age-Related Macular Degeneration: Up to Seven-Year Follow-Up
J Ophthalmol. 2020 Jul 31;2020:3207614.
Simon Javidi, Ali Dirani, Fares Antaki, Marc Saab, Sofiane Rahali, Ghassan Cordahi
PMID: 32802487 PMCID: PMC7415083 DOI: 10.1155/2020/3207614
Purpose: To report long-term visual and anatomical outcomes in eyes with neovascular age-related macular degeneration (nAMD) treated with a treat-and-extend regimen (TER) of intravitreal antivascular endothelial growth factor (anti-VEGF) injections in real-world settings.
Methods: Retrospective cohort study of consecutive patients with nAMD treated with a TER of anti-VEGF intravitreal injections by a single retina specialist (GC). Patients with nAMD who had at least one year of follow-up were identified using an electronic database. Best-corrected visual acuity (BCVA), comprehensive ophthalmologic examination, and macular OCT were performed at each visit. Patients received a loading dose of three monthly intravitreal injections and then were treated according to a TER of bevacizumab, ranibizumab, and/or aflibercept. The number of injections, BCVA, and central retinal thickness (CRT) were evaluated during the follow-up period.
Results: 180 eyes from 180 patients were included in the study. Mean age was 75 ± 9 (range: 51-96). Mean BCVA was 0.77 ± 0.64 LogMAR at baseline, 0.69 ± 0.58 LogMAR (p = 0.0057) after loading phase, 0.64 ± 0.55 LogMAR (p = 0.0001) after 6 months of TER, and 0.76 ± 0.71 LogMAR after 6 years of treatment (n = 32 at year 6). CRT decreased significantly after the loading phase (p = 0.0002). The mean number of intravitreal injections per year was 7.6 during the first three years of treatment and then decreased to 5.9 during year 4 to 7.
Conclusions: This retrospective study of 180 nAMD patients treated with a TER of intravitreal anti-VEGF demonstrates an initial improvement of BCVA after loading phase, followed by long-term visual stabilization for at least six years. These results were obtained with a high number of injections, averaging close to six injections per year during long-term follow-up. In light of the natural evolution of nAMD, these data support the long-term efficacy of this treatment under real-world conditions of heterogeneity of patients and type of anti-VEGF used.
Microstructural Changes in Cystoid Macular Edema in Retinitis Pigmentosa after Intravitreal Dexamethasone Implant Injection
Retina. 2020 Aug 7.
Un Chul Park, Jung Hyun Park, Chang Ki Yoon, Hyeong Gon Yu
PMID: 32796442 DOI: 10.1097/IAE.0000000000002944
Purpose: To evaluate microstructural changes in cystoid macular edema (CME) in retinitis pigmentosa (RP) after intravitreal dexamethasone implant injection.
Methods: In an extended cohort of a randomized trial of intravitreal dexamethasone implant for the management of RP-CME, microstructural changes during six months after treatment were evaluated using spectral domain optical coherence tomography.
Results: Forty-two eyes were included, and all had cystoid space in the inner nuclear layer (INL) at baseline. No eyes showed subretinal fluid, and 28.6% showed hyperreflective foci. Among 38 eyes with cystoid space both in the INL and outer nuclear layer/Henle's layer (ONL/HL), 13 (34.2%) showed complete resolution and 12 (31.6%) showed cystoid space only in the INL at 2 months after injection, while others showed persistent cystoid space in both layers. After complete resolution, cystoid space recurrence was earlier in the INL than in the ONL/HL. Multivariable analysis showed that greater cystoid space area in the INL and ONL/HL, presence of macular leakage, and longer intact external limiting membrane at baseline were associated with greater cystoid space area decrease after treatment.
Conclusion: Resolution and recurrence pattern of RP-CME after dexamethasone treatment showed that the INL is the primary layer of cystic change, and this suggests its pathogenesis is most likely due to Müller cell dysfunction.
DIAGNOSIS & IMAGING
Polypoidal Choroidal Vasculopathy: Consensus Nomenclature and Non-ICGA Diagnostic Criteria from the Asia-Pacific Ocular Imaging Society (APOIS) PCV Workgroup
Ophthalmology. 2020 Aug 11;S0161-6420(20)30784-3.
Chui M Gemmy Cheung, Timothy Y Y Lai, Kelvin Teo, Paisan Ruamviboonsuk, Shih-Jen Chen, Judy E Kim, Fumi Gomi, Adrian H Koh, Gregg Kokame, Janice Marie Jordan-Yu, Federico Corvi, Alessandro Invernizzi, Yuichiro Ogura, Colin Tan, Paul Mitchell, Vishali Gupta, Jay Chhablani, Usha Chakravarthy, Srinivas R Sadda, Tien Y Wong, Giovanni Saturenghi, Won Ki Lee
PMID: 32795496 DOI: 10.1016/j.ophtha.2020.08.006
Purpose: To develop consensus terminology in the setting of polypoidal choroidal vasculopathy (PCV), and to develop and validate a set of diagnostic criteria not requiring indocyanine green angiograph (ICGA) for differentiating PCV from typical neovascular age-related macular degeneration (nAMD) based on a combination of OCT and color fundus photograph findings.
Design: Evaluation of diagnostic test PARTICIPANTS: Panel of retina specialists.
Methods: As part of the Asia-Pacific Ocular Imaging Society (APOIS), an international group of experts surveyed and discussed the published literature regarding the current nomenclature and lesion components for PCV and proposed an updated consensus nomenclature, which reflects our latest understanding based on imaging and histology reports. The workgroup evaluated a set of diagnostic features based on OCT and color fundus photographs for PCV that may distinguish it from typical nAMD and assessed the performance of individual and combinations of these non-ICGA features, aiming to propose a new set of diagnostic criteria which does not require the use of ICGA. The final recommendation was validated in 80 eyes from 2 additional cohorts.
Main outcome measures: A consensus nomenclature system for PCV lesion components and non-ICGA-based criteria to differentiate PCV from typical nAMD.
Results: The workgroup recommended the terms 'polypoidal lesion' and 'branching neovascular network' for the two key lesion components in PCV. For the diagnosis of PCV, the combination of 3 OCT-based 'major criteria' (sub-RPE ring-like lesion, enface OCT complex RPE elevation, and sharp-peaked PED) achieved an area under the receiver operating characteristic curve of 0.90. Validation of this new scheme in a separate subset 110 eyes achieved an accuracy of 82%.
Conclusions: We propose updated terminology for PCV lesion components which better reflect the nature of these lesions which was based on international consensus. A set of practical diagnostic criteria that are easily applied to SD-OCT can be used for diagnosing PCV with high accuracy in clinical settings in which ICGA is not routinely performed.
Relationship Between Rod-Mediated Sensitivity, Low-Luminance Visual Acuity, and Night Vision Questionnaire in Age-Related Macular Degeneration
Transl Vis Sci Technol. 2020 May 28;9(6):30.
Myra B McGuinness, Rogan G Fraser, Rose Tan, Chi D Luu, Robyn H Guymer
PMID: 32821527 PMCID: PMC7409161 DOI: 10.1167/tvst.9.6.30
Purpose: To quantify the association between dark adaptation parameters and other clinical measures of visual function among people with and without early and intermediate age-related macular degeneration (AMD).
Methods: In this cross-sectional study, participants underwent multimodal imaging and visual function testing, including best-corrected visual acuity (BCVA), low-luminance visual acuity (LLVA), low-luminance deficit (LLD = BCVA - LLVA) and the 10-item Night Vision Questionnaire (NVQ-10). Dynamic and static dark-adapted chromatic perimetry (DACP) was performed. Sensitivity difference was defined as the difference in sensitivity between the 505-nm and 625-nm stimuli. Rod intercept time (RIT) was estimated as the time required to reach a threshold of -3 log candelas/meter2 with the 505-nm stimulus following bleaching. The magnitude of association between the DACP parameters and other clinical tests was estimated via mixed-effects regression.
Results: A total of 51 participants (aged 51-88 years, 65% female, 39% with AMD) were included. RIT was found to be negatively associated with BCVA (P < 0.001), LLVA (P = 0.005), and NVQ-10 score (P = 0.028) but not LLD (P = 0.763). There was no evidence of an association between sensitivity difference and any of the clinical measures (P ≥ 0.081).
Conclusions: Reduced rod function, as determined by RIT, was associated with lower NVQ-10 scores (designed to interrogate rod-mediated function) and with worse BCVA and LLVA (measures of cone function).
Translational relevance: Decreasing rod function maybe indicative of more generalized photoreceptor dysfunction involving cones. Further development of questionnaires to target function in scotopic conditions may provide an easier to administer test without the need to perform perimetric tests of rod function.
Quantifying the Separation Between the Retinal Pigment Epithelium and Bruch's Membrane using Optical Coherence Tomography in Patients with Inherited Macular Degeneration
Transl Vis Sci Technol. 2020 May 23;9(6):26.
Kamron N Khan, Shyamanga Borooah, Leonardo Lando, Kunny Dans, Omar A Mahroo, Amit Meshi, Angelos Kalitzeos, Georgios Agorogiannis, Sasan Moghimi, William R Freeman, Andrew R Webster, Anthony T Moore, Martin McKibbin, Michel Michaelides
PMID: 32821523 PMCID: PMC7409156 DOI: 10.1167/tvst.9.6.26
Purpose: To describe and quantify Bruch's membrane (BM) and retinal pigment epithelium (RPE) separation using spectral-domain (SD) optical coherence tomography (OCT) in patients affected by inherited macular degenerations associated with BM thickening.
Methods: Patients with molecularly confirmed Sorsby fundus dystrophy (SFD), dominant drusen (DD), and late-onset retinal degeneration (L-ORD) were included in this retrospective study. Each disease was classed as early stage if subjects were asymptomatic, intermediate stage if they had nyctalopia alone, and late stage if they described loss of central vision. The main outcome was measurement of BM-RPE separation on SD-OCT. The BM-RPE separation measurements were compared against those in normal age-matched controls.
Results: Seventeen patients with SFD, 22 with DD, and eight with L-ORD were included. BM-RPE separation on SD-OCT demonstrated a high test-retest and interobserver reproducibility (intraclass correlation coefficients >0.9). BM-RPE separation was not identified in normal subjects. In SFD, there was greater BM-RPE separation in late-stage disease compared with intermediate-stage patients both at subfoveal (P < 0.05) and juxtafoveal (P < 0.01) locations. In DD, there was increased BM-RPE separation in late-stage disease compared with early stage at subfoveal (P < 0.001) and juxtafoveal (P < 0.05) topographies. There was no significant difference in BM-RPE separation between disease stages in L-ORD.
Conclusions: BM-RPE separation is a novel, quantifiable phenotype in the three monogenic macular dystrophies studied, and may be an optical correlate of the histopathological thickening in BM that is known to occur. BM-RPE separation, as measured by OCT, varies with stage of disease in SFD and DD, but not in L-ORD.
Translational relevance: SFD, DD, and L-ORD are associated with BM thickening. In this group of patients, OCT assessment of macular structure identifies a separation of the usually single, hyperreflective line thought to represent BM and the overlying RPE. This separation is a novel and quantifiable feature of disease staging in SFD and DD.
Sensitivity and specificity of high-resolution wide field fundus imaging for detecting neovascular age-related macular degeneration
PLoS One. 2020 Aug 21;15(8):e0238072.
Maiko Maruyama-Inoue, Yoko Kitajima, Shaheeda Mohamed, Tatsuya Inoue, Shimpei Sato, Arisa Ito, Shin Yamane, Kazuaki Kadonosono
PMID: 32822418 DOI: 10.1371/journal.pone.0238072
Purpose: Early detection and treatment are important management strategies for neovascular age-related macular degeneration (AMD). The purpose of this study was to determine the sensitivity and specificity in detecting neovascular AMD using two wide-field imaging systems: ClarusTM (CLARUS 500™, Carl Zeiss Meditec AG, Jena, Germany) and Optos®(Optos California®, Optos PLC, Dunfermline, United Kingdom), compared to conventional digital fundus photographs.
Methods: We retrospectively analyzed 109 eyes of 73 consecutive patients with neovascular AMD, who underwent standard examination and multimodal imaging, including fundus photography, and optical coherence tomography (OCT). Unmasked graders utilized slit-lamp biomicroscopy and OCT to diagnose neovascular AMD. Masked graders evaluated ClarusTM, Optos®, and digital fundus photograph methods to determine the presence of choroidal neovascularization associated with AMD. Sensitivity and specificity analyses were performed using combined fundoscopy and OCT as the reference standard.
Results: Ninety eyes were diagnosed with neovascular AMD and the remaining 19 eyes were normal based on the reference standard. Of these, neovascular AMD was detected using ClarusTM in 94.4% (85/90). The sensitivities of Optos® and digital fundus photographs were 81.1% (73/90) and 87.8% (79/90), respectively. The specificities using ClarusTM, Optos®, and digital fundus photographs were 89.5% (17/19), 94.7% (18/19), and 89.5% (17/19), respectively.
Conclusion: ClarusTM, with its ability to image high-resolution wide field fundus, was considered superior for diagnosing neovascular AMD with high sensitivity and specificity. It may be a useful screening tool for early detection of neovascular AMD, facilitating prompt referral and treatment.
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. 2020 Aug 21;PP.
Azam Moosavi, Natalia Figueiredo, Prateek Prasanna, Sunil K Srivastava, Sumit Sharma, Anant Madabhushi, Justis Ehlers
PMID: 32822291 DOI: 10.1109/TBME.2020.3018464
Diabetic Macular Edema (DME) and macular edema secondary to retinal occlusion (RVO) are the 2 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.
Fundus Autofluorescence Lifetimes and Spectral Features of Soft Drusen and Hyperpigmentation in Age-Related Macular Degeneration
Transl Vis Sci Technol. 2020 Apr 24;9(5):20.
Martin Hammer, Rowena Schultz, Somar Hasan, Lydia Sauer, Matthias Klemm, Lukas Kreilkamp, Lynn Zweifel, Regine Augsten, Daniel Meller
PMID: 32821492 PMCID: PMC7401897 DOI: 10.1167/tvst.9.5.20
Purpose: To investigate the autofluorescence lifetimes as well as spectral characteristics of soft drusen and retinal hyperpigmentation in age-related macular degeneration (AMD).
Methods: Forty-three eyes with nonexudative AMD were included in this study. Fluorescence lifetime imaging ophthalmoscopy (FLIO), which detects autofluorescence decay over time in the short (SSC) and long (LSC) wavelength channel, was performed. The mean autofluorescence lifetime (τm) and the spectral ratio (sr) of autofluorescence emission in the SSC and LSC were recorded and analyzed. In total, 2760 soft drusen and 265 hyperpigmented areas were identified from color fundus photographs and spectral domain optical coherence tomography (SD-OCT) images and superimposed onto their respective AF images. τm and sr of these lesions were compared with fundus areas without drusen. For clearly hyperfluorescent drusen, the local differences compared to fundus areas without drusen were determined for lifetimes and sr.
Results: Hyperpigmentation showed significantly longer τm (SSC: 341 ± 81 vs. 289 ± 70 ps, P < 0.001; LSC: 406 ± 42 vs. 343 ± 42 ps, P < 0.001) and higher sr (0.621 ± 0.077 vs. 0.539 ± 0.083, P < 0.001) compared to fundus areas without hyperpigmentation or drusen. No significant difference in τm was found between soft drusen and fundus areas without drusen. However, the sr was significantly higher in soft drusen (0.555 ± 0.077 vs. 0.539 ± 0.081, P < 0.0005). Hyperfluorescent drusen showed longer τm than surrounding fundus areas without drusen (SSC: 18 ± 42 ps, P = 0.074; LSC: 16 ± 29 ps, P = 0.020).
Conclusions: FLIO can quantitatively characterize the autofluorescence of the fundus, drusen, and hyperpigmentation in AMD.
Translational relevance: The experimental FLIO technique was applied in a clinical investigation. As FLIO yields information on molecular changes in AMD, it might support future diagnostics.
Identification of Novel Serum MicroRNAs in Age-Related Macular Degeneration
Transl Vis Sci Technol. 2020 Mar 30;9(4):28.
Hanan ElShelmani, Michael A Wride, Tahira Saad, Sweta Rani, David J Kelly, David Keegan
PMID: 32818115 PMCID: PMC7396178 DOI: 10.1167/tvst.9.4.28
Purpose: To identify circulating microRNAs (miRNA) associated with age-related macular degeneration (AMD). Thus differentially expressed serum miRNA could be used as AMD biomarkers.
Methods: This study involved total RNA isolation from sera from patients with atrophic AMD (n = 10), neovascular AMD (n = 10), and age- and sex-matched controls (n = 10). A total of 377 miRNAs were coanalyzed using array technologies, and differentially regulated miRNAs were determined. Extensive validation studies (n = 90) of serum from AMD patients and controls confirmed initial results. Total RNA isolation was carried out from sera from patients with atrophic AMD (n = 30), neovascular AMD (n = 30), and controls (n = 30). Fourteen miRNAs from the discovery dataset were coanalyzed using quantitative real-time polymerase chain reaction (qRT-PCR) to validate their presence.
Results: Unsupervised hierarchical clustering indicated that AMD serum specimens have a different miRNA profile to healthy controls. We successfully identified and validated the differentially regulated miRNAs in serum from AMD patients versus controls. The biomarker potential of three miRNAs (miR-126, miR-19a, and miR-410) was confirmed by qRT-PCR, with significantly increased quantities in serum of AMD patients compared with healthy controls.
Conclusions: Increased quantities of miR-126, miR-410, and miR-19a in serum from AMD patients indicate that these miRNAs could potentially serve as diagnostic AMD biomarkers. All three miRNAs significantly correlated with AMD pathogenesis.
Translational relevance: The discovery of new AMD miRNA may act as biomarkers in evaluating AMD diagnosis and prognosis.
Performance of Classification Systems for Age-Related Macular Degeneration in the Rotterdam Study
Transl Vis Sci Technol. 2020 Apr 24;9(2):26.
Eric F Thee, Magda A Meester-Smoor, Daniel T Luttikhuizen, Johanna M Colijn, Clair A Enthoven, Annechien E G Haarman, Dimitris Rizopoulos, Caroline C W Klaver, EyeNED Reading Center
PMID: 32818087 PMCID: PMC7396180 DOI: 10.1167/tvst.9.2.26
Purpose: To compare frequently used classification systems for age-related macular degeneration (AMD) in their abilty to predict late AMD.
Methods: In total, 9066 participants from the population-based Rotterdam Study were followed up for progression of AMD during a study period up to 30 years. AMD lesions were graded on color fundus photographs after confirmation on other image modalities and grouped at baseline according to six classification systems. Late AMD was defined as geographic atrophy or choroidal neovascularization. Incidence rate (IR) and cumulative incidence (CuI) of late AMD were calculated, and Kaplan-Meier plots and area under the operating characteristics curves (AUCs) were constructed.
Results: A total of 186 persons developed incident late AMD during a mean follow-up time of 8.7 years. The AREDS simplified scale showed the highest IR for late AMD at 104 cases/1000 py for ages <75 years. The Rotterdam classification showed the highest IR at 89 cases/1000 py >75 years. The 3-Continent harmonization classification provided the most stable progression. Drusen area >10% ETDRS grid (hazard ratio 30.05, 95% confidence interval [CI] 19.25-46.91) was most prognostic of progression. The highest AUC of late AMD (0.8372, 95% CI: 0.8070-0.8673) was achieved when all AMD features present at baseline were included.
Conclusions: Highest turnover rates from intermediate to late AMD were provided by the AREDS simplified scale and the Rotterdam classification. The 3-Continent harmonization classification showed the most stable progression. All features, especially drusen area, contribute to late AMD prediction.
Translational relevance: Findings will help stakeholders select appropriate classification systems for screening, deep learning algorithms, or trials.
Artificial Intelligence to Stratify Severity of Age-Related Macular Degeneration (AMD) and Predict Risk of Progression to Late AMD
Transl Vis Sci Technol. 2020 Apr 24;9(2):25.
Alauddin Bhuiyan, Tien Yin Wong, Daniel Shu Wei Ting, Arun Govindaiah, Eric H Souied, R Theodore Smith
PMID: 32818086 PMCID: PMC7396183 DOI: 10.1167/tvst.9.2.25
Purpose: To build and validate artificial intelligence (AI)-based models for AMD screening and for predicting late dry and wet AMD progression within 1 and 2 years.
Methods: The dataset of the Age-related Eye Disease Study (AREDS) was used to train and validate our prediction model. External validation was performed on the Nutritional AMD Treatment-2 (NAT-2) study.
First step: An ensemble of deep learning screening methods was trained and validated on 116,875 color fundus photos from 4139 participants in the AREDS study to classify them as no, early, intermediate, or advanced AMD and further stratified them along the AREDS 12 level severity scale. Second step: the resulting AMD scores were combined with sociodemographic clinical data and other automatically extracted imaging data by a logistic model tree machine learning technique to predict risk for progression to late AMD within 1 or 2 years, with training and validation performed on 923 AREDS participants who progressed within 2 years, 901 who progressed within 1 year, and 2840 who did not progress within 2 years. For those found at risk of progression to late AMD, we further predicted the type (dry or wet) of the progression of late AMD.
Results: For identification of early/none vs. intermediate/late (i.e., referral level) AMD, we achieved 99.2% accuracy. The prediction model for a 2-year incident late AMD (any) achieved 86.36% accuracy, with 66.88% for late dry and 67.15% for late wet AMD. For the NAT-2 dataset, the 2-year late AMD prediction accuracy was 84%.
Conclusions: Validated color fundus photo-based models for AMD screening and risk prediction for late AMD are now ready for clinical testing and potential telemedical deployment.
Translational relevance: Noninvasive, highly accurate, and fast AI methods to screen for referral level AMD and to predict late AMD progression offer significant potential improvements in our care of this prevalent blinding disease.
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;bjophthalmol-2020-317182.
Prateek Prasanna, Vishal Bobba, Natalia Figueiredo, Duriye Damla Sevgi, Cheng Lu, Nathaniel Braman, Mehdi Alilou, Sumit Sharma, Sunil K Srivastava, Anant Madabhushi, Justis P Ehlers
PMID: 32816791 DOI: 10.1136/bjophthalmol-2020-317182
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.
Associations of Variation in Retinal Thickness With Visual Acuity and Anatomic Outcomes in Eyes With Neovascular Age-Related Macular Degeneration Lesions Treated With Anti-Vascular Endothelial Growth Factor Agents
JAMA Ophthalmol. 2020 Aug 20.
Rebecca N Evans, Barnaby C Reeves, Maureen G Maguire, Daniel F Martin, Alyson Muldrew, Tunde Peto, Chris Rogers, Usha Chakravarthy
PMID: 32816002 DOI: 10.1001/jamaophthalmol.2020.3001
Importance: When initiating anti-vascular endothelial growth factor (VEGF) treatment for patients with neovascular age-related macular degeneration (nAMD), knowledge of prognostic factors is important for advising patients and guiding treatment. We hypothesized that eyes with greater fluctuation in retinal thickness over time have worse outcomes than eyes with less variation.
Objective: To investigate whether visual and anatomic outcomes in eyes with nAMD initiating anti-VEGF treatment are associated with fluctuations in retinal thickness.
Design, setting, and participants: In this study using data from the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) and the Inhibition of VEGF in Age-Related Choroidal Neovascularization (IVAN) randomized clinical trial, people with previously untreated nAMD were included. Data were collected from February 2008 to November 2012, and data were analyzed from April 2017 to April 2020.
Main outcomes and measures: Foveal center point thicknesses (FCPTs) were extracted from 1165 study eyes from CATT and 566 study eyes from the IVAN trial, excluding those with 3 measurements or less. For each eye, the SD of FCPT was calculated. Eyes were grouped by FCPT SD quartile. Associations of FCPT SD quartile with outcomes were quantified at month 24 or the last available visit by linear or logistic regression, adjusting for baseline best-corrected visual acuity (BCVA) and randomized allocations to drug and treatment regimen, for BCVA, development of fibrosis, and development of macular atrophy.
Results: Of the 1731 included patients, 1058 (61.1%) were female, and the mean (SD) age was 78.6 (7.4) years. The median (interquartile range) FCPT SD was 40.2 (27.1-61.2) in the IVAN cohort and 59.0 (38.3-89.4) in the CATT cohort. After adjustment for baseline BCVA and trial allocations, BCVA worsened significantly across the quartiles of FCPT SD; the difference between the first and fourth quartiles was -6.27 Early Treatment Diabetic Retinopathy Study letters (95% CI, -8.45 to -4.09). The risk of developing fibrosis and macular atrophy also increased across FCPT SD quartiles. Odds ratios ranged from 1.40 (95% CI, 1.03 to 1.91) for quartile 2 to 1.95 (95% CI, 1.42 to 2.68) for quartile 4 for fibrosis and from 1.32 (95% CI, 0.90 to 1.92) for quartile 2 to 2.10 (95% CI, 1.45 to 3.05) for quartile 4 for macular atrophy.
Conclusions and relevance: Greater variation in retinal thickness in eyes with nAMD during treatment with anti-VEGF was associated with worse BCVA and development of fibrosis and macular atrophy in these post hoc analyses, despite protocol-directed treatment frequency. Practitioners may want to consider variation in retinal thickness when advising patients about their prognosis.
The spectrum of polypoidal choroidal vasculopathy in Caucasians: clinical characteristics and proposal of a classification
Graefes Arch Clin Exp Ophthalmol. 2020 Aug 18.
Elon H C van Dijk, Danial Mohabati, Simona Veselinovic, Wing H Chung, Greet Dijkman, Camiel J F Boon
PMID: 32812132 DOI: 10.1007/s00417-020-04844-z
Purpose: To describe the clinical characteristics and outcome of polypoidal choroidal vasculopathy (PCV), also known as aneurysmal type 1 (sub-retinal pigment epithelium (RPE)) neovascularization, in Caucasian patients.
Methods: Single-centre study in 66 Caucasian patients with a diagnosis of PCV based on optical coherence tomography scan and indocyanine green angiography. Clinical characteristics and multimodal imaging were collected and assessed by an experienced retina specialist.
Results: This study involved 74 eyes of 66 patients with PCV, with a mean age at onset of 73 years and a female preponderance of 66%. The mean number of polypoidal lesions per eye was 1 (range: 1-5 lesions), out of which 75% was located in the macula and 19% in the peripapillary region. Of the 74 eyes, 37 eyes (50%) had PCV associated with a drusenoidal neovascular age-related macular degeneration (AMD) phenotype (PCV-AMD) and 18 eyes (24%) had PCV associated with non-polypoidal type 1 choroidal neovascularization/branching vascular network (PCV-BVN) without signs of drusenoidal AMD, while 19 eyes (26%) had idiopathic, isolated PCV (iPCV). The mean subfoveal choroidal thickness measured in 22 patients was 245 μm (range: 71-420 μm). In 51% of patients, the initially performed therapy showed good anatomical recovery (resolution of intra- and subretinal fluid).
Conclusions: A spectrum of PCV (aneurysmal type 1/sub-RPE neovascularization) can be seen in Caucasian patients. PCV associated with a drusenoidal neovascular AMD phenotype in Caucasians is phenotypically and presumably pathophysiologically more associated with neovascular AMD (PCV-AMD: type A PCV). However, this may not be the case for patients with PCV with non-polypoidal type 1 choroidal neovascularization or BVN and no signs of drusenoidal AMD (PCV-BVN: type B PCV), and for patients with idiopathic PCV without associated drusen or BVN (iPCV; type C PCV). Most patients have a thin choroid, even when drusen are absent. For the entire patient group, a moderate anatomical recovery was observed after treatment.
Home Monitoring of Age-Related Macular Degeneration: Real-World Utility of the ForeseeHome Device for Detection of Neovascularization
Ophthalmol Retina. 2020 Aug 15;S2468-6530(20)30331-6.
Hannah J Yu, Daniel F Kiernan, David Eichenbaum, Veeral S Sheth, Charles C Wykoff
PMID: 32810682 PMCID: PMC7428765 DOI: 10.1016/j.oret.2020.08.003
Purpose: To evaluate real-world utility of the ForeseeHome monitoring device for the detection of conversion from intermediate age-related macular degeneration (iAMD) to neovascular AMD (nAMD) and compare with results published by the HOME study.
Design: Retrospective analysis of electronic health records.
Subjects: Eyes prescribed use of the ForeseeHome device across 4 retinal practices in the USA.
Methods: Usage information was collected from the online ForeseeHome portal for all eyes prescribed. For a pre-determined subset of eyes, additional clinical information was collected through chart review and analyzed for clinical utility.
Main outcome measures: Outcome measures include frequency and length of use, number of eyes that used the device, established baseline and converted to nAMD, and number of alerts.
Results: 775 eyes of 448 patients were prescribed use of the ForeseeHome device. 649 eyes (83.7%) used the device at least once; among this population, 478 (73.7%) established baseline. Patients who established baseline were significantly younger than those who did not establish baseline (p<0.001). Among eyes that established baseline, 126 (26.4%) had an overall inadequate frequency of use (≥2 tests per week), and 250 (52.3%) did not use the device as frequently as instructed by the manufacturer (≥3 tests per week); 112 (24.7%) discontinued use within one year. Over a mean of 20.35 months, 106 patients had 152 alerts, indicating possible conversions to nAMD. Out of the 136 eyes that established baseline among 211 eyes prescribed the device at one clinical site, 52 alerts were recorded, 3 (6.8%) correctly identified conversion to nAMD and 47 (93.2%) represented false-positive alerts.
Conclusions: Compared to the prospective HOME study, utility of the ForeseeHome device in the current analysis of real-world clinical-practice application was limited. A meaningful proportion of eyes never used the device or could not establish baseline. Overall frequency of use was low and continuous usage of the device decreased over time. There is a need for improvement in home monitoring technology for eyes with iAMD at risk of conversion to nAMD.
Neovascular age-related macular degeneration presenting at extremities of age: a comparative study
Graefes Arch Clin Exp Ophthalmol. 2020 Aug 19.
Alexander Rubowitz, Saleh Esa, Maayan Fradkin, Elad Moisseiev
PMID: 32813106 DOI: 10.1007/s00417-020-04893-4
Purpose: To compare the characteristics and response to treatment between patients with NVAMD presenting at the extremities of the AMD age spectrum.
Methods: Fifty-four eyes of 47 patients were included in this retrospective study, divided by age at NVAMD presentation under 65 (n = 15) or over 85 (n = 39) years. All patients were initially treated with 3 monthly bevacizumab injections, followed by a PRN protocol. Clinical parameters and OCT characteristics were recorded and analyzed at presentation, after the initial 3 monthly injections and at 1 year.
Results: At presentation, patients in the young group had significantly higher rates of subretinal fluid (p = 0.005), a polypoidal choroidal vasculopathy-like pattern (p < 0.01) and a history of smoking (p = 0.004). Submacular hemorrhage and pigment epithelial detachments were more common in young patients, and intraretinal fluid was more common in elderly patients (all with borderline statistical significance). VA improved significantly more in the younger patients at 3 months and 1 year (p = 0.001 and 0.002, respectively), despite similar treatment protocols and mean number of injections. Bilateral involvement at baseline was more common in elderly patients (p = 0.008). The differences in OCT characteristics between groups remained throughout the study period.
Conclusion: There are considerable differences in the clinical manifestations and response to treatment between NVAMD patients at the extremities of the AMD age spectrum. Different pathophysiological, systemic, and genetic factors may play a role in such patients.
Optical coherence tomography and color fundus photography in the screening of age-related macular degeneration: A comparative, population-based study
PLoS One. 2020 Aug 14;15(8):e0237352.
Edoardo Midena, Luisa Frizziero, Tommaso Torresin, Paolo Boscolo Todaro, Giacomo Miglionico, Elisabetta Pilotto
PMID: 32797085 PMCID: PMC7428158 DOI: 10.1371/journal.pone.0237352
Purpose: To analyze the individual value and the contribution of color fundus photography (CFP) and optical coherence tomography (OCT) in the screening of age-related macular degeneration (AMD) of an unselected population.
Methods: CFP and OCT images of 15957 eyes of 8069 subjects older than 55 years, obtained during a population-based screening for AMD using a single diagnostic non-mydriatic imaging device, were analyzed by a blinded examiner. The two techniques were preliminary evaluated considering the dichotomous parameter "gradable/ungradable", then gradable images were classified. CFP were graded according to the standardized classification of AMD lesions. OCT images were also categorized considering the presence of signs of early/intermediate AMD, late AMD, or other retinal diseases. Another blinded operator re-graded 1978 randomly selected images (for both CFP and OCT), to assess test reproducibility.
Results: Of the 15957 eyes, 8356 CFP (52.4%) and 15594 (97.7%) OCT scans were gradable. Moreover, most of the eyes with ungradable CFP (7339, 96.6%) were gradable at OCT. AMD signs were revealed in 7.4% of gradable CFP and in 10.4% of gradable OCT images. Moreover, at OCT, AMD signs were found in 1110 (6.9%) eyes whose CFP were ungradable or without AMD (847 and 263 eyes, respectively). The inter-operator agreement was good for the gradable versus ungradable parameter, and optimal for the AMD grading parameter of CFP. The agreement was optimal for all OCT parameters.
Conclusions: OCT provided gradable images in almost all examined eyes, compared to limited CFP efficiency. Moreover, OCT images allowed to detect more AMD eyes compared to gradable photos. OCT imaging appears to significantly improve the power of AMD screening in a general, unselected population, compared to CFP alone.
Central geographic atrophy vs. neovascular age-related macular degeneration: differences in longitudinal vision-related quality of life
Graefes Arch Clin Exp Ophthalmol. 2020 Aug 19.
Aneesha Ahluwalia, Liangbo L Shen, Lucian V Del Priore
PMID: 32813108 DOI: 10.1007/s00417-020-04892-5
Objective: Prior studies of vision-related quality of life (VRQoL) have examined advanced age-related macular degeneration (AMD) as a single group or focused on neovascular AMD (nAMD), even though advanced AMD can refer to either central geographic atrophy (GA) or nAMD. We compared the natural progression of VRQoL in central GA versus nAMD.
Methods: We included Age-Related Eye Disease Study (AREDS) participants with central GA (n = 206) or nAMD (n = 198) who completed the National Eye Institute Visual Function Questionnaire (NEI-VFQ) between 1997 and 2005. The rate of change of VRQoL was calculated as the slopes of linear models fit to longitudinal individual-level NEI-VFQ scores. Multivariable regressions identified factors associated with experiencing a decline in VRQoL during the study period and cross-sectional VRQoL score.
Results: There was a minor decline in VRQoL prior to the development of nAMD but a significantly steeper decline after progression to nAMD (0.49 ± 2.91 vs. 3.30 ± 5.58 NEI-VFQ units/year; p < 0.001). The rates of VRQoL decline were similar before and after the development of central GA (1.99 ± 4.97 vs. 1.68 ± 4.65 NEI-VFQ units/year; p = 0.66). Prior to the development of advanced AMD, the rate of VRQoL decline was greater for participants destined to develop central GA versus nAMD (p = 0.007), while postprogression to advanced disease, the rate was greater in nAMD compared with central GA (p = 0.012). Female gender (odds ratio [OR] 2.61, 95% confidence interval [CI] 1.38-5.06; p = 0.003) and higher baseline VRQoL score (OR 1.03, 95% CI 1.01-1.06; p = 0.006) were independently associated with experiencing a longitudinal decline in VRQoL.
Conclusion: The natural progression of VRQoL differed in central GA versus nAMD, both before and after the development of advanced disease, suggesting that future studies should consider separating these phenotypes. Females and those with a higher baseline VRQoL were more likely to experience a longitudinal decline in VRQoL following progression to advanced AMD.
High-resolution photoreceptor imaging analysis of patients with autosomal dominant retinitis pigmentosa (adRP) caused by HK1 mutation
Ophthalmic Genet. 2020 Aug 20;1-10.
Daiki Kubota, Kaori Matsumoto, Mika Hayashi, Noriko Oishi, Kiyoko Gocho, Kunihiko Yamaki, Shinichiro Kobayakawa, Tsutomu Igarashi, Hiroshi Takahashi, Shuhei Kameya
PMID: 32814480 DOI: 10.1080/13816810.2020.1810284
Purpose: The hexokinase 1 (HK1) gene encodes one of the four human hexokinases that play essential roles in glucose metabolism. Recently, several cases of E847K mutation in the HK1 gene were reported to cause inherited retinal dystrophy. The purpose of this study was to identify the phenotypical characteristics of patients with a recurrent E847K mutation in the HK1 gene.
Methods: Three generations of one family with autosomal dominant retinitis pigmentosa were examined. Whole exome sequencing was performed on the DNA. Fundus imaging by an adaptive optics fundus camera was used to obtain high-resolution photoreceptor images.
Results: Fundus examination of the proband showed degeneration of the mid-peripheral retina, and SD-OCT images showed an absence of the ellipsoid zone (EZ) and interdigitation zone (IZ) in the parafovea and more peripherally. SD-OCT images of the mother of the proband showed an absence of the EZ and IZ, and fundus autofluorescence images showed hypo-autofluorescence surrounding the macular region. One daughter of the proband had only mild night blindness, however, the density of the cone photoreceptors was reduced in the parafoveal region. Whole exome sequencing identified a heterozygous variant, E847K, in the HK1 gene. This variant was found to co-segregate with the disease in three family members.
Conclusions: Although the systemic phenotypes were found to be associated with the HK1 mutations, only the E847K mutation can cause a non-syndromic photoreceptor degeneration. Our study strengthened the hypothesis that the amino acid E847 might play a critical role in the maintenance of the morphology and function of the photoreceptors.
The 10q26 Risk Haplotype of Age-Related Macular Degeneration Aggravates Subretinal Inflammation by Impairing Monocyte Elimination
Immunity. 2020 Aug 18;53(2):429-441.e8.
Fanny Beguier, Michael Housset, Christophe Roubeix, Sebastien Augustin, Yvrick Zagar, Caroline Nous, Thibaud Mathis, Chiara Eandi, Mustapha Benchaboune, Adèle Drame-Maigné, Wassila Carpentier, Solenne Chardonnet, Sara Touhami, Guillaume Blot, Jean Baptiste Conart, Hugo Charles-Messance, Anaïs Potey, Jean-François Girmens, Michel Paques, Fréderic Blond, Thierry Leveillard, Elod Koertvely, Jerome E Roger, José-Alain Sahel, Przemyslaw Sapieha, Cécile Delarasse, Xavier Guillonneau, Florian Sennlaub
PMID: 32814029 DOI: 10.1016/j.immuni.2020.07.021
A minor haplotype of the 10q26 locus conveys the strongest genetic risk for age-related macular degeneration (AMD). Here, we examined the mechanisms underlying this susceptibility. We found that monocytes from homozygous carriers of the 10q26 AMD-risk haplotype expressed high amounts of the serine peptidase HTRA1, and HTRA1 located to mononuclear phagocytes (MPs) in eyes of non-carriers with AMD. HTRA1 induced the persistence of monocytes in the subretinal space and exacerbated pathogenic inflammation by hydrolyzing thrombospondin 1 (TSP1), which separated the two CD47-binding sites within TSP1 that are necessary for efficient CD47 activation. This HTRA1-induced inhibition of CD47 signaling induced the expression of pro-inflammatory osteopontin (OPN). OPN expression increased in early monocyte-derived macrophages in 10q26 risk carriers. In models of subretinal inflammation and AMD, OPN deletion or pharmacological inhibition reversed HTRA1-induced pathogenic MP persistence. Our findings argue for the therapeutic potential of CD47 agonists and OPN inhibitors for the treatment of AMD.
Can the Onset of Atrophic Age-Related Macular Degeneration Be an Acceptable Endpoint for Preventative Trials?
Ophthalmologica. 2020 Aug 17.
Zhichao Wu, Robyn H Guymer
PMID: 32805732 DOI: 10.1159/000510887
The slowly progressive nature of age-related macular degeneration (AMD) means that establishing the efficacy of novel preventative treatments aiming to slow progression of disease, remains challenging, and where earlier endpoints are needed to improve their feasibility. This review examines whether the onset of atrophic AMD, as seen as anatomical signs on optical coherence tomography termed nascent geographic atrophy (nGA), could act as a useful surrogate endpoint for early intervention trials.
Review of Ophthalmic and Breastfeeding Medicine Evidence: Real and Theoretical Risks of Intravitreal Anti-VEGF Administration in Lactating Women
Retina. 2020 Aug 7.
Prarthana J Dalal, Aloka L Patel, Michelle Carle, Alekya Rajanala, Manjot K Gill
PMID: 32796446 DOI: 10.1097/IAE.0000000000002946
Importance: There is limited research regarding the consequences of treating lactating mothers with intravitreal anti-VEGF agents. Balancing the need for vision-saving treatment, the benefits of breastfeeding, and the concern for affecting the newborn can present a conflict for both mothers and ophthalmologists. This review summarizes the state of the literature regarding the use of intravitreal anti-VEGF agents during breastfeeding along with details about their pharmacology.
Observations: Bevacizumab and aflibercept have Fc domains subjecting them to FcRn recycling and extending their half-life compared to ranibizumab which is an antibody fragment and lacks the Fc domain. Case reports and small studies have shown that ranibizumab has the lowest serum concentration after intravitreal injection and the least effect on plasma free VEGF concentrations and breastmilk VEGF levels.
Conclusions and relevance: Clinical and pharmacologic data suggest that ranibizumab has less systemic circulation and effect on maternal serum and breastmilk VEGF levels when compared to bevacizumab and aflibercept. However, there is significant need for further research on the degree and duration to which intravitreal agents circulate systemically, what fraction is transferred into breastmilk and is absorbed, and whether this results in any functional adverse effects to the infant. Other factors to consider in the medical decision making of lactating mothers necessitating intravitreal anti-VEGF treatment include the gestational and post-natal age of the child and whether it is feasible to avoid breastfeeding for the half-life duration of the intravitreal agent rather than ceasing breastfeeding altogether.