Internal Carotid Artery Stenosis and Ipsilateral Subretinal Drusenoid Deposits.

Purpose: Subretinal drusenoid deposits (SDDs) in age-related macular degeneration (AMD) are strongly associated with vasculopathies such as myocardial infarction and ischemic stroke. This study evaluates ischemic stroke subjects for SDDs to determine whether ocular hypoperfusion from internal carotid artery (ICA) stenosis is associated with ipsilateral SDDs. Methods: A cross-sectional study at Mount Sinai Hospital recruited 39 subjects with ischemic stroke (aged 52-90; 18 women, 21 men); 28 completed all study procedures. Computed tomography (CT) of the head and neck evaluated 54/56 ICAs for stenosis criteria: none (n = 33), mild (n = 12), moderate (n = 3), severe (n = 3), and complete (n = 3). Spectral-domain optical coherence tomography (SD-OCT) scans were read to consensus by two masked graders for soft drusen, SDDs and choroidal thickness (CTh; choroidal thinning = CTh < 250 µm). Univariate testing was done with Fisher's exact test. Multivariate logistic regression models tested age, gender, and ICA stenosis as covariates. Results: Moderate or more ICA stenosis (≥50%-69%) was significantly associated with ipsilateral choroidal thinning (P = 0.021) and ipsilateral SDDs (P = 0.005); the latter were present distal to six of nine stenosed ICAs versus five of 33 normal ICAs. Mild ICA stenosis (≥1%-49%) was not significantly associated with ipsilateral SDDs. Multivariate regression found that older age (P = 0.015) and moderate or more ICA stenosis (P = 0.011) remained significant independent risks for ipsilateral SDDs. Conclusions: At least moderate ICA stenosis (≥50%-69%) is strongly associated with ipsilateral SDDs and choroidal thinning, supporting downstream ophthalmic artery and choroidal hypoperfusion from ICA stenosis as the mechanism for SDD formation. SDDs may thus serve as sensitive biomarkers for ischemic stroke and other vascular diseases.

Subretinal drusenoid deposits, age-related macular degeneration, and cardiovascular disease.

Decades of studies on age-related macular degeneration (AMD), cardiovascular disease and stroke have not found consistent associations between AMD and systemic vascular disease. This study suggests that there is in fact no general relationship, but instead a strong, specific association between only the subretinal drusenoid deposit (SDD) phenotype of AMD on retinal imaging and certain co-existent vascular diseases that are high risk for compromised cardiac output or internal carotid artery stenosis. Future screening initiatives for these high -risk vascular diseases (HRVDs) with fast, inexpensive retinal imaging could make a significant contribution to public health and save lives. Likewise, screening patients with known HRVDs for unrecognized AMD of the SDD form could enable needed treatment and save vision.

Coded aperture snapshot spectral imaging fundus camera.

Spectral imaging holds great promise for the non-invasive diagnosis of retinal diseases. However, to acquire a spectral datacube, conventional spectral cameras require extensive scanning, leading to a prolonged acquisition. Therefore, they are inapplicable to retinal imaging because of the rapid eye movement. To address this problem, we built a coded aperture snapshot spectral imaging fundus camera, which captures a large-sized spectral datacube in a single exposure. Moreover, to reconstruct a high-resolution image, we developed a robust deep unfolding algorithm using a state-of-the-art spectral transformer in the denoising network. We demonstrated the performance of the system through various experiments, including imaging standard targets, utilizing an eye phantom, and conducting in vivo imaging of the human retina.

Treatment of old submacular hemorrhage by subretinal endoscopic surgery and intraoperative subretinal endoscopic findings.

PURPOSE: We report a case of old submacular hemorrhage (SMH) due to polypoidal choroidal vasculopathy (PCV). Subretinal endoscopic surgery (SES) was performed, which improved visual function. In addition, we show the intraoperative findings of subretinal aberrant PCV vessels as seen under endoscopic observation, which cannot be observed by microscopic surgery. OBSERVATIONS: A 71-year-old Japanese man presented with an old dehemoglobinized SMH due to PCV in his left eye. At the time of presentation, three weeks had already passed after the onset of the patient's symptoms, and the best-corrected visual acuity (BCVA) was 20/200. SES was performed to remove the SMH and treat the subretinal PCV lesions. After creating retinal detachment using a 38-gauge cannula, three subretinal 25-gauge trocars were inserted from the sclera to the subretinal space. Then, SES was performed under ophthalmic endoscopic observation with continued subretinal irrigation for maintaining the retinal detachment. After removal of the SMH, subretinal polyp-shaped nodular vascular lesions (polyps) and a branching vascular network, which is located inside the retinal pigmented epithelium, were identified. The sites that presumably originated from the aberrant vessels of the PCV and the associated polyps were coagulated using endodiathermy. After the subretinal procedure, the retina was flattened with fluid/air exchange, and silicone oil (SO) was injected into the vitreous cavity. The SMH completely disappeared after surgery. Although at one-month follow-up BCVA (20/250) was slightly worse than that before surgery, there was an improvement in postoperative retinal sensitivity in the macula compared to that before surgery. At the three-month follow-up, the SO was removed. The BCVA was 20/200 one month after SO removal. No postoperative complications occurred. Additional treatment was not required, including anti-vascular endothelial growth factor therapy, for PCV progression or SMH recurrence in the left eye till the final visit two years after surgery. CONCLUSION AND IMPORTANCE: SES could effectively remove the old SMH, and the activity of PCV was suppressed by intraoperative subretinal coagulation. The retinal sensitivity of the macula improved after the SES. In addition, we observed subretinal polyps and a branching vascular network located internal to the retinal pigmented epithelium under intraoperative subretinal endoscopic observation. SES is a good surgical option for the removal of old SMH or treatment of subretinal lesions.

SUBRETINAL DRUSENOID DEPOSITS AND SOFT DRUSEN: Are They Markers for Distinct Retinal Diseases?

PURPOSE: Soft drusen and subretinal drusenoid deposits (SDDs) characterize two pathways to advanced age-related macular degeneration (AMD), with distinct genetic risks, serum risks, and associated systemic diseases. METHODS: One hundred and twenty-six subjects with AMD were classified as SDD (with or without soft drusen) or non-SDD (drusen only) by retinal imaging, with serum risks, genetic testing, and histories of cardiovascular disease (CVD) and stroke. RESULTS: There were 62 subjects with SDD and 64 non-SDD subjects, of whom 51 had CVD or stroke. SDD correlated significantly with lower mean serum high-density lipoprotein (61 ± 18 vs. 69 ± 22 mg/dL, P = 0.038, t-test), CVD and stroke (34 of 51 SDD, P = 0.001, chi square), ARMS2 risk allele (P = 0.019, chi square), but not with CFH risk allele (P = 0.66). Non-SDD (drusen only) correlated/trended with APOE2 (P = 0.032) and CETP (P = 0.072) risk alleles (chi square). Multivariate independent risks for SDD were CVD and stroke (P = 0.008) and ARMS2 homozygous risk (P = 0.038). CONCLUSION: Subjects with subretinal drusenoid deposits and non-SDD subjects have distinct systemic associations and serum and genetic risks. Subretinal drusenoid deposits are associated with CVD and stroke, ARMS2 risk, and lower high-density lipoprotein; non-SDDs are associated with higher high-density lipoprotein, CFH risk, and two lipid risk genes. These and other distinct associations suggest that these lesions are markers for distinct diseases.

Optimized Prediction Models from Fundus Imaging and Genetics for Late Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is a leading cause of blindness in the developed world. In this study, we compare the performance of retinal fundus images and genetic-information-based machine learning models for the prediction of late AMD. Using data from the Age-related Eye Disease Study, we built machine learning models with various combinations of genetic, socio-demographic/clinical, and retinal image data to predict late AMD using its severity and category in a single visit, in 2, 5, and 10 years. We compared their performance in sensitivity, specificity, accuracy, and unweighted kappa. The 2-year model based on retinal image and socio-demographic (S-D) parameters achieved a sensitivity of 91.34%, specificity of 84.49% while the same for genetic and S-D-parameters-based model was 79.79% and 66.84%. For the 5-year model, the retinal image and S-D-parameters-based model also outperformed the genetic and S-D parameters-based model. The two 10-year models achieved similar sensitivities of 74.24% and 75.79%, respectively, but the retinal image and S-D-parameters-based model was otherwise superior. The retinal-image-based models were not further improved by adding genetic data. Retinal imaging and S-D data can build an excellent machine learning predictor of developing late AMD over 2-5 years; the retinal imaging model appears to be the preferred prognostic tool for efficient patient management.

Combined automated screening for age-related macular degeneration and diabetic retinopathy in primary care settings.

BACKGROUND: Age-related macular degeneration (AMD) and diabetic retinopathy (DR) are among the leading causes of blindness in the United States and other developed countries. Early detection is the key to prevention and effective treatment. We have built an artificial intelligence-based screening system which utilizes a cloud-based platform for combined large scale screening through primary care settings for early diagnosis of these diseases. METHODS: iHealthScreen Inc., an independent medical software company, has developed automated AMD and DR screening systems utilizing a telemedicine platform based on deep machine learning techniques. For both diseases, we prospectively imaged both eyes of 340 unselected non-dilated subjects over 50 years of age. For DR specifically, 152 diabetic patients at New York Eye and Ear faculty retina practices, ophthalmic and primary care clinics in New York city with color fundus cameras. Following the initial review of the images, 308 images with other confounding conditions like high myopia and vascular occlusion, and poor quality were excluded, leaving 676 eligible images for AMD and DR evaluation. Three ophthalmologists evaluated each of the images, and after adjudication, the patients were determined referrable or non-referable for AMD DR. Concerning AMD, 172 were labeled referable (intermediate or late), and 504 were non-referable (no or early). Concurrently, regarding DR, 33 were referable (moderate or worse), and 643 were non-referable (none or mild). All images were uploaded to iHealthScreen's telemedicine platform and analyzed by the automated systems for both diseases. The system performances are tested on per eye basis with sensitivity, specificity, accuracy, and kappa scores with respect to the professional graders. RESULTS: In identifying referable DR, the system achieved a sensitivity of 97.0% and a specificity of 96.3%, and a kappa score of 0.70 on this prospective dataset. For AMD, the sensitivity was 86.6%, the specificity of 92.1%, and a kappa score of 0.76. CONCLUSIONS: The AMD and DR screening tools achieved excellent performance operating together to identify two retinal diseases prospectively in mixed datasets, demonstrating the feasibility of such tools in the early diagnosis of eye diseases. These early screening tools will help create an even more comprehensive system capable of being trained on other retinal pathologies, a goal within reach for public health deployment.

An Artificial-Intelligence- and Telemedicine-Based Screening Tool to Identify Glaucoma Suspects from Color Fundus Imaging.

RESULTS: The system achieved an accuracy of 89.67% (sensitivity, 83.33%; specificity, 93.89%; and AUC, 0.93). For external validation, the Retinal Fundus Image Database for Glaucoma Analysis dataset, which has 638 gradable quality images, was used. Here, the model achieved an accuracy of 83.54% (sensitivity, 80.11%; specificity, 84.96%; and AUC, 0.85). CONCLUSIONS: Having demonstrated an accurate and fully automated glaucoma-suspect screening system that can be deployed on telemedicine platforms, we plan prospective trials to determine the feasibility of the system in primary-care settings.

Hyperspectral autofluorescence characterization of drusen and sub-RPE deposits in age-related macular degeneration.

BACKGROUND: Soft drusen and basal linear deposit (BLinD) are two forms of the same extracellular lipid rich material that together make up an Oil Spill on Bruch's membrane (BrM). Drusen are focal and can be recognized clinically. In contrast BLinD is thin and diffusely distributed, and invisible clinically, even on highest resolution OCT, but has been detected on en face hyperspectral autofluorescence (AF) imaging ex vivo. We sought to optimize histologic hyperspectral AF imaging and image analysis for recognition of drusen and sub-RPE deposits (including BLinD and basal laminar deposit), for potential clinical application. METHODS: Twenty locations specifically with drusen and 12 additional locations specifically from fovea, perifovea and mid-periphery from RPE/BrM flatmounts from 4 AMD donors underwent hyperspectral AF imaging with 4 excitation wavelengths (λex 436, 450, 480 and 505 nm), and the resulting image cubes were simultaneously decomposed with our published non-negative matrix factorization (NMF). Rank 4 recovery of 4 emission spectra was chosen for each excitation wavelength. RESULTS: A composite emission spectrum, sensitive and specific for drusen and presumed sub-RPE deposits (the SDr spectrum) was recovered with peak at 510-520 nm in all tissues with drusen, with greatest amplitudes at excitations λex 436, 450 and 480 nm. The RPE spectra of combined sources Lipofuscin (LF)/Melanolipofuscin (MLF) were of comparable amplitude and consistently recapitulated the spectra S1, S2 and S3 previously reported from all tissues: tissues with drusen, foveal and extra-foveal locations. CONCLUSIONS: A clinical hyperspectral AF camera, with properly chosen excitation wavelengths in the blue range and a hyperspectral AF detector, should be capable of detecting and quantifying drusen and sub-RPE deposits, the earliest known lesions of AMD, before any other currently available imaging modality.

The Change in Color Vision with Normal Aging Evaluated on Standard Pseudoisochromatic Plates Part-3.

Purpose: To evaluate the influence of aging on color vision in a large normal population using Standard Pseudoisochromatic Plates part-3 (SPP-3), which is a pseudoisochromatic plate test used to detect congenital or acquired color vision deficiency (CVD).Materials and methods: We retrospectively reviewed SPP-3 test results of 23,565 normal eyes of 23,565 subjects (women: 12,035; men: 11,530), who were examined between July 1993 and December 2010. The subjects had a mean age of 46.9 ± 18.5 years, ranging from 5 to 89 years, and they were evaluated following categorization into age groups with five-year increments. Subjects whose best-corrected visual acuity (BCVA) was 20/20 or better, with no history of ocular diseases, were included. Subjects with congenital CVD were excluded.Results: We found a negative correlation between age and the total number of correct answers in SPP-3 (Spearman's correlation coefficient, r = -0.5743; p < .0001). The total number of correct answers was the highest in subjects aged 10-14, 15-19, and 20-24 years (17.2 ± 0.9 [mean ±SD]). The total number of correct answers of these groups had significant differences from those in the 5-9 years age group and those aged >30 years (Dunn's post-hoc test: p < .0001). Among the 19 detection numerals in SPP-3, we found that the correct answer rates of six numerals decreased with aging, and the colors of the numerals and their backgrounds all located parallel to the tritanopic confusion line.Conclusions: Using SPP-3, we confirmed that aging influenced color vision, even in normal eyes with a good BCVA (20/20 or better). The total number of correct answers of SPP-3 was the highest in subjects aged 10-24 years and had already begun to decline in those in their 30s.

Subretinal Deposits in Pre-eclampsia and Malignant Hypertension: Implications for Age-Related Macular Degeneration.

PURPOSE: To describe the incidence of subretinal deposits that are similar in structure and stage on OCT imaging to subretinal drusenoid deposits (SDDs) in age-related macular degeneration (AMD) in patients with hypertensive choroidopathy secondary to severe pre-eclampsia and malignant hypertension (MHT) and the implications of this ischemic choroidopathy for the pathophysiologic characteristics of SDDs in AMD. DESIGN: Retrospective cross-sectional study. PARTICIPANTS: Thirty-three pre-eclampsia patients and 25 MHT patients with serous retinal detachment (SRD) in at least 1 eye were included. METHODS: Serial multimodal images, including enhanced depth imaging spectral-domain OCT of eyes with hypertensive choroidopathy secondary to pre-eclampsia and MHT, were reviewed at 2 time points, the acute phase (within 4 weeks of initial hypertensive insult) and the recovery phase (beyond 4 weeks). MAIN OUTCOME MEASURES: Incidence of SDD-like lesions in patients with hypertensive choroidopathy secondary to pre-eclampsia and MHT. RESULTS: Subretinal drusenoid deposit-like lesions were observed exclusively in eyes with SRD. Serous retinal detachment occurred in 87.87% of eyes of pre-eclampsia patients and in 94% of eyes of MHT patients. Subretinal drusenoid deposit-like lesions occurred in 28.57% of all eyes with SRD, in 32.76% of eyes with SRD from the pre-eclampsia group, and in 23.40% of eyes with SRD from the MHT group. Vascular imaging suggested underlying choroidal ischemia in all patients (12 eyes) in which it was performed. CONCLUSIONS: Choroidal ischemia may be the underlying mechanism of SDD-like lesions in patients with pre-eclampsia and MHT choroidopathy. These findings potentially are of utmost importance in understanding the mechanism of the reticular macular disease subtype of AMD. Reticular macular disease is characterized by the known association of choroidal insufficiency and SDD, with choroidal insufficiency postulated, but not proven, to be causative. Pre-eclampsia and MHT choroidopathy seems to be a model for lesions similar to SDD in AMD developing based on choroidal insufficiency and, as such, may offer further insights into the pathoetiologic features of SDD in AMD.

Not cat-scratch disease: Bartonella henselae neuroretinitis associated with non-feline pet mammals.

To describe the ocurrence of Bartonella-associated neuroretinitis secondary to non-feline pet exposure, we retrospectively reviewed medical records and imaging from patients with a clinical and serologic diagnosis of Bartonella henselae (BH). Retinal imaging included color fundus photography, optical coherence tomography (OCT) and fluorescein angiography (FA). Four eyes of two patients with cat-scratch disease were included in this study, with a mean age of 35 years. The mean follow-up was 13 months, after presentation of infectious neuroretinitis. Both patients suffered from bilateral neuroretinitis after direct contact with family pets (ferret and guinea pig). All patients were treated with a long-term systemic antimicrobial therapy. Visual acuity in all improved to 20/30 or better at six months. In conclusion, humans may develop cat-scratch disease when they are exposed to Bartonella henselae (BH) in the saliva of infected cats or BH-containing flea feces reaching the systemic circulation through scratches or mucous membranes. As the cat flea (Ctenocephalides felis) may reside on non-feline mammals, Bartonella-associated neuroretinitis may result from contact with other furred family pets.

Non-invasive imaging of a choroidal macrovessel.

PURPOSE: To describe novel anatomic findings of an apparent choroidal macrovessel, originally misdiagnosed as a choroidal tumor, using non-invasive imaging tools. OBSERVATIONS: Initial ophthalmic examination revealed an elevated hypopigmented choroidal mass in the macular area, with a serpentine track extending temporally to the equator. Enhanced depth imaging optical coherence tomography (EDI-OCT) revealed an optically hollow lesion just outside the choroid-scleral junction (CSJ), indenting the retina and compressing the choroid from the scleral side. Optical coherence tomography angiography (OCTA) at the choroidal level showed relative low flow within the lesion. En face OCT at the level of the choroid demonstrated similar reflectivity to the physiological adjacent choroidal vessels. CONCLUSION AND IMPORTANCE: Non-invasive imaging can be used to demonstrate the presence and anatomy of a choroidal macrovessel. OCTA is presented as a useful diagnostic imaging test that can distinguish this lesion from alternative diagnoses without the use of dye injection. In addition to the previously published reports of such vessels in the choroid, we suggest a possible anatomic variant infra-choroidal location of a macrovessel and hypothesize its origin.

Artificial Intelligence to Stratify Severity of Age-Related Macular Degeneration (AMD) and Predict Risk of Progression to Late AMD.

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.

Development of a fast calibration method for image mapping spectrometry.

An image mapping spectrometer (IMS) is a snapshot hyperspectral imager that simultaneously captures both the spatial (x, y) and spectral (λ) information of incoming light. The IMS maps a three-dimensional (3D) datacube (x, y, λ) to a two-dimensional (2D) detector array (x, y) for parallel measurement. To reconstruct the original 3D datacube, one must construct a lookup table that connects voxels in the datacube and pixels in the raw image. Previous calibration methods suffer from either low speed or poor image quality. We herein present a slit-scan calibration method that can significantly reduce the calibration time while maintaining high accuracy. Moreover, we quantitatively analyzed the major artifact in the IMS, the striped image, and developed three numerical methods to correct for it.

Translational Retinal Imaging.

The diagnosis and treatment of medical retinal disease is now inseparable from retinal imaging in all its multimodal incarnations. The purpose of this article is to present a selection of very different retinal imaging techniques that are truly translational, in the sense that they are not only new, but can guide us to new understandings of disease processes or interventions that are not accessible by present methods. Quantitative autofluorescence imaging, now available for clinical investigation, has already fundamentally changed our understanding of the role of lipofuscin in age-related macular degeneration. Hyperspectral autofluorescence imaging is bench science poised not only to unravel the molecular basis of retinal pigment epithelium fluorescence, but also to be translated into a clinical camera for earliest detection of age-related macular degeneration. The ophthalmic endoscope for vitreous surgery is a radically new retinal imaging system that enables surgical approaches heretofore impossible while it captures subretinal images of living tissue. Remote retinal imaging coupled with deep learning artificial intelligence will transform the very fabric of future medical care.

MULTIMODAL IMAGING OF ANGIOID STREAKS ASSOCIATED WITH TURNER SYNDROME.

PURPOSE: To report multimodal imaging in a novel case of angioid streaks in a patient with Turner syndrome with 10-year follow-up. METHODS: Case report of a patient with Turner syndrome and angioid streaks followed at Bellevue Hospital Eye Clinic from 2007 to 2017. Fundus photography, fluorescein angiography, and optical coherence tomography angiography were obtained. RESULTS: Angioid streaks with choroidal neovascularization were noted in this patient with Turner syndrome without other systemic conditions previously correlated with angioid streaks. CONCLUSION: We report a case of angioid streaks with choroidal neovascularization in a patient with Turner syndrome. We demonstrate that angioid streaks, previously associated with pseudoxanthoma elasticum, Ehlers-Danlos syndrome, Paget disease of bone, and hemoglobinopathies, may also be associated with Turner syndrome, and may continue to develop choroidal neovascularization, suggesting the need for careful ophthalmic examination in these patients.