Multinational External Validation of Autonomous Retinopathy of Prematurity Screening.

Importance: Retinopathy of prematurity (ROP) is a leading cause of blindness in children, with significant disparities in outcomes between high-income and low-income countries, due in part to insufficient access to ROP screening. Objective: To evaluate how well autonomous artificial intelligence (AI)-based ROP screening can detect more-than-mild ROP (mtmROP) and type 1 ROP. Design, Setting, and Participants: This diagnostic study evaluated the performance of an AI algorithm, trained and calibrated using 2530 examinations from 843 infants in the Imaging and Informatics in Retinopathy of Prematurity (i-ROP) study, on 2 external datasets (6245 examinations from 1545 infants in the Stanford University Network for Diagnosis of ROP [SUNDROP] and 5635 examinations from 2699 infants in the Aravind Eye Care Systems [AECS] telemedicine programs). Data were taken from 11 and 48 neonatal care units in the US and India, respectively. Data were collected from January 2012 to July 2021, and data were analyzed from July to December 2023. Exposures: An imaging processing pipeline was created using deep learning to autonomously identify mtmROP and type 1 ROP in eye examinations performed via telemedicine. Main Outcomes and Measures: The area under the receiver operating characteristics curve (AUROC) as well as sensitivity and specificity for detection of mtmROP and type 1 ROP at the eye examination and patient levels. Results: The prevalence of mtmROP and type 1 ROP were 5.9% (91 of 1545) and 1.2% (18 of 1545), respectively, in the SUNDROP dataset and 6.2% (168 of 2699) and 2.5% (68 of 2699) in the AECS dataset. Examination-level AUROCs for mtmROP and type 1 ROP were 0.896 and 0.985, respectively, in the SUNDROP dataset and 0.920 and 0.982 in the AECS dataset. At the cross-sectional examination level, mtmROP detection had high sensitivity (SUNDROP: mtmROP, 83.5%; 95% CI, 76.6-87.7; type 1 ROP, 82.2%; 95% CI, 81.2-83.1; AECS: mtmROP, 80.8%; 95% CI, 76.2-84.9; type 1 ROP, 87.8%; 95% CI, 86.8-88.7). At the patient level, all infants who developed type 1 ROP screened positive (SUNDROP: 100%; 95% CI, 81.4-100; AECS: 100%; 95% CI, 94.7-100) prior to diagnosis. Conclusions and Relevance: Where and when ROP telemedicine programs can be implemented, autonomous ROP screening may be an effective force multiplier for secondary prevention of ROP.

Unilateral Retinopathy in a Preterm Infant With 4q Duplication: Description and Management.

A 33-5/7, 1570 g dichorionic diamniotic twin presented with cryptorchidism, failed hearing examination (both ears), poor feeding, profound hypoglycemia, coagulopathy, conjugated hyper-bilirubinemia, hydronephrosis, and hypotension. Microarray sent with results of whole genome SNP microgray analysis detected an interstitial duplication of the chromosomal segment 4q35 1q35.2. On this basis, telemedicine screening was performed to evaluate for ocular abnormalities in association with abnormal gene testing. Unilateral advanced retinopathy was noted affecting the right eye, with mature vascularization in the left eye. This infant was managed in concordance with retinopathy of prematurity guidelines, despite not making screening criteria. Off-label intravitreal bevacizumab injection (0.625 mg in 0.025 mL) resulted in full vascular maturation assessed by fluorescein angiography 6 months later. This represents the first description and management of retinopathy in 4q duplication syndrome. [Ophthalmic Surg Lasers Imaging Retina 2024;55:228-230.].

Management of Icteric Vitreous, Retinal Opacification, and Atypical Retinopathy of Prematurity.

A dichorionic, diamniotic twin born at 24-0/7 weeks and 740 g developed hyperbilirubinemia, necrotizing enterocolitis, and sepsis. Photographic imaging documented vitreous opacification, which was absent in the fellow twin. Retinal opacification was presumed secondary to embolic sepsis and responded to systemic antibiotics. Subsequent dropout of vascularized retina corresponded to areas of retinal opacification. Type 1 retinopathy of prematurity (ROP)-Zone I, Stage 3 ROP bilateral-demonstrated a rapid and durable response to off-label intravitreal bevacizumab 0.625 mg. Retinal opacification resolved between 39 and 40 weeks postmenstrual age. Systemic comorbidities may alter the appearance, course, and management of ROP. [Ophthalmic Surg Lasers Imaging Retina 2024;55:164-167.].

The Incidence and Timing of Treatment-Requiring Retinopathy of Prematurity in Nanopremature and Micropremature Infants in the United States: A National Multicenter Retrospective Cohort Study.

PARTICIPANTS: This article includes 7293 infants (14 586 eyes) screened for ROP across 5 centers in the United States (Austin Retina Associates, Austin, TX; Bascom Palmer Eye Institute, Miami, FL; Beaumont Eye Institute, Royal Oak, MI; Massachusetts Eye and Ear, Boston, MA; and Stanford Byers Eye Institute, Stanford, CA). PURPOSE: To analyze the incidence and timing of treatment requiring retinopathy of prematurity (ROP) in extremely small premature infants. We hypothesize that the smaller the infant by gestational age and birthweight, the higher their likelihood of requiring treatment for ROP. DESIGN: Premature infants screened for Retinopathy of Prematurity from 2002-2022 were divided into cohorts based on the following criteria based on gestational age (GA) and birth weight (BW). "Micropremature infants" are infants born between 24-26 weeks GA and between 600-799 g BW. "Nanopremature infants" are born ≤ 24 weeks GA and ≤ 600 g BW. METHODS: Retrospective chart review. MAIN OUTCOME MEASURES: The incidence and timing of treatment-requiring ROP. RESULTS: We found that infants defined as nanopremature had a ∼63% chance of requiring treatment at an average postmenstrual age (PMA) of 36.6 weeks, whereas those defined as micropremature had a 30% chance of requiring treatment at an average PMA of 36.3 weeks. This significantly contrasts with the risk of all screened babies for ROP where the risk of requiring treatment was 8.5%. CONCLUSION: Micropremature and nanopremature infants are significantly more likely to require treatment for ROP. With demographic data matched to all 5 major US regions spanning the last decade, these results have the potential to inform neonatologists, pediatricians, and ophthalmologists of an important shift in the landscape of prematurity in the United States. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

A Literary Pediatric Retina Fellowship With Michael T. Trese, MD.

Michael T. Trese, MD (1946-2022), a vitreoretinal surgeon, made significant contributions to the field of retina. Although most known for his work in pediatric retina surgery, he was a pioneer in areas such as medical retina, translational research, and telemedicine. This article reviews his major contributions to spread his knowledge more widely to vitreoretinal trainees and specialists. We discuss six areas where Trese made a lasting impact: lens-sparing vitrectomy, familial exudative vitreoretinopathy, congenital X-linked retinoschisis, autologous plasmin enzyme, regenerative medicine, and telemedicine. [Ophthalmic Surg Lasers Imaging Retina 2023;54:701-712.].

Telemedicine retinopathy of prematurity severity score (TeleROP-SS) versus modified activity score (mROP-ActS) retrospective comparison in SUNDROP cohort.

Identifying and planning treatment for retinopathy of prematurity (ROP) using telemedicine is becoming increasingly ubiquitous, necessitating a grading system to help caretakers of at-risk infants gauge disease severity. The modified ROP Activity Scale (mROP-ActS) factors zone, stage, and plus disease into its scoring system, addressing the need for assessing ROP's totality of binocular burden via indirect ophthalmoscopy. However, there is an unmet need for an alternative score which could facilitate ROP identification and gauge disease improvement or deterioration specifically on photographic telemedicine exams. Here, we propose such a system (Telemedicine ROP Severity Score [TeleROP-SS]), which we have compared against the mROP-ActS. In our statistical analysis of 1568 exams, we saw that TeleROP-SS was able to return a score in all instances based on the gradings available from the retrospective SUNDROP cohort, while mROP-ActS obtained a score of 80.8% in right eyes and 81.1% in left eyes. For treatment-warranted ROP (TW-ROP), TeleROP-SS obtained a score of 100% and 95% in the right and left eyes respectively, while mROP-ActS obtained a score of 70% and 63% respectively. The TeleROP-SS score can identify disease improvement or deterioration on telemedicine exams, distinguish timepoints at which treatments can be given, and it has the adaptability to be modified as needed.

Photographic Gel Artifact Simulating International Classification of Retinopathy of Prematurity Notch: Stanford University Network for Diagnosis of Retinopathy of Prematurity (SUNDROP) Report no. 16.

PURPOSE: To report a series of fundus photographs taken for retinopathy of prematurity (ROP) screening that contain artifacts with imaging characteristics mimicking a notch, a recently refined classification metric in the International Classification of Retinopathy of Prematurity, third edition. DESIGN: Retrospective case series. PARTICIPANTS: Infants requiring ROP screening in neonatal intensive care units from the Stanford University Network for Diagnosis of Retinopathy of Prematurity (SUNDROP) and TeleROP telemedicine screening programs. METHODS: Preterm infants meeting ROP examination criteria were screened with 130° wide-angle imaging systems. The images were taken by a trained nurse in the neonatal intensive care unit and transferred to an ROP specialist using a Health Insurance Portability and Accountability Act-compliant picture archiving and communication system for interpretation. MAIN OUTCOME MEASURES: Presence of an artifact that appeared consistent with a notch. RESULTS: We identified a total of 17 cases in ROP screening with artifact findings that had imaging characteristics similar to a notch. The artifactual appearance of the pseudo-notch was created by the camera illumination system within the gel-lens interface when the lens was not well apposed to the cornea. In telemedicine screening for ROP, we present fundus images of eyes with a pseudo-notch appearance; review of overlapping images can help differentiate between notch and artifact. CONCLUSIONS: Pediatric retinal specialists need to be aware that artifacts play a confounding role in screening for ROP, that can be mitigated through the use of overlapping and redundant images. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

AI-Human Hybrid Workflow Enhances Teleophthalmology for the Detection of Diabetic Retinopathy.

Objective: Detection of diabetic retinopathy (DR) outside of specialized eye care settings is an important means of access to vision-preserving health maintenance. Remote interpretation of fundus photographs acquired in a primary care or other nonophthalmic setting in a store-and-forward manner is a predominant paradigm of teleophthalmology screening programs. Artificial intelligence (AI)-based image interpretation offers an alternative means of DR detection. IDx-DR (Digital Diagnostics Inc) is a Food and Drug Administration-authorized autonomous testing device for DR. We evaluated the diagnostic performance of IDx-DR compared with human-based teleophthalmology over 2 and a half years. Additionally, we evaluated an AI-human hybrid workflow that combines AI-system evaluation with human expert-based assessment for referable cases. Design: Prospective cohort study and retrospective analysis. Participants: Diabetic patients ≥ 18 years old without a prior DR diagnosis or DR examination in the past year presenting for routine DR screening in a primary care clinic. Methods: Macula-centered and optic nerve-centered fundus photographs were evaluated by an AI algorithm followed by consensus-based overreading by retina specialists at the Stanford Ophthalmic Reading Center. Detection of more-than-mild diabetic retinopathy (MTMDR) was compared with in-person examination by a retina specialist. Main Outcome Measures: Sensitivity, specificity, accuracy, positive predictive value, and gradability achieved by the AI algorithm and retina specialists. Results: The AI algorithm had higher sensitivity (95.5% sensitivity; 95% confidence interval [CI], 86.7%-100%) but lower specificity (60.3% specificity; 95% CI, 47.7%-72.9%) for detection of MTMDR compared with remote image interpretation by retina specialists (69.5% sensitivity; 95% CI, 50.7%-88.3%; 96.9% specificity; 95% CI, 93.5%-100%). Gradability of encounters was also lower for the AI algorithm (62.5%) compared with retina specialists (93.1%). A 2-step AI-human hybrid workflow in which the AI algorithm initially rendered an assessment followed by overread by a retina specialist of MTMDR-positive encounters resulted in a sensitivity of 95.5% (95% CI, 86.7%-100%) and a specificity of 98.2% (95% CI, 94.6%-100%). Similarly, a 2-step overread by retina specialists of AI-ungradable encounters improved gradability from 63.5% to 95.6% of encounters. Conclusions: Implementation of an AI-human hybrid teleophthalmology workflow may both decrease reliance on human specialist effort and improve diagnostic accuracy. Financial Disclosures: Proprietary or commercial disclosure may be found after the references.

Rapid Improvement in Lipid Maculopathy Following Faricimab Therapy in Recalcitrant Familial Exudative Vitreoretinopathy.

A monocular 22-year-old man with recalcitrant familial exudative vitreoretinopathy presented with progressive subretinal lipid exudation and lipid maculopathy that responded poorly to repeated aflibercept injections. The subretinal exudation started temporally and gradually progressed, involving the macula and the retinal periphery in all 4 quadrants. At the 22-month follow-up visit, macular and peripheral subretinal exudation persisted despite a total of 29 injections. Faricimab was then injected once every 2 weeks for a total of 3 injections, which resulted in rapid dramatic resolution of the macular and most of the peripheral subretinal exudation. No ocular or systemic adverse events were noted. [Ophthalmic Surg Lasers Imaging Retina 2023;54:426-428.].

Epidemiology of rhegmatogenous retinal detachment in commercially insured myopes in the United States.

Myopia is a known risk factor for rhegmatogenous retinal detachment (RRD). Given global trends of increasing myopia, we aimed to determine the absolute risk (incidence rate) of RRD in non-myopes, myopes and high myopes in the United States over ten years. We performed a retrospective cohort study of 85,476,781 commercially insured patients enrolled in the Merative™ Marketscan® Research Database. The incidence rate of RRD in phakic patients in the United States was 39-fold higher in high myopes than non-myopes (868.83 per 100,000 person-years versus 22.44 per 100,000 person-years) and three-fold higher in myopes than non-myopes (67.51 per 100,000 person-years versus 22.44 per 100,000 person-years). The incidence rate was significantly higher in males in each category (P < 0.01). Combined, the incidence rate of RRD in phakic patients in the United States from 2007 to 2016 was 25.27 RRDs per 100,000 person-years, a rate higher than those in prior published studies in North America, South America, Europe, Asia, and Australia. The absolute risk of myopia and high myopia increased from 2007 to 2016. The risk of RRD in phakic high myopes rose with increasing age. Notably, the magnitude of increased risk of RRD in myopes varied substantially according to the minimum follow-up period in our models and should be accounted for when interpreting data analyses.

Causes of Childhood Blindness in the United States Using the IRIS® Registry (Intelligent Research in Sight).

PURPOSE: To investigate causes of childhood blindness in the United States using the IRIS® Registry (Intelligent Research in Sight). DESIGN: Cross-sectional study. PARTICIPANTS: Patients ≤ 18 years of age with visual acuity (VA) 20/200 or worse in their better-seeing eye in the IRIS Registry during 2018. METHODS: Causes of blindness were classified by anatomic site and specific diagnoses. MAIN OUTCOME MEASURES: Percentages of causes of blindness. RESULTS: Of 81 164 children with 2018 VA data in the IRIS Registry, 961 (1.18%) had VA 20/200 or worse in their better-seeing eye. Leading causes of blindness were retinopathy of prematurity (ROP) in 301 patients (31.3%), nystagmus in 78 patients (8.1%), and cataract in 64 patients (6.7%). The retina was the leading anatomic site (47.7%) followed by optic nerve (11.6%) and lens (10.0%). A total of 52.4% of patients had treatable causes of blindness. CONCLUSIONS: This analysis offers a unique cross-sectional view of childhood blindness in the United States using a clinical data registry. More than one-half of blind patients had a treatable cause of blindness. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Cellular and subcellular optogenetic approaches towards neuroprotection and vision restoration.

Optogenetics is defined as the combination of genetic and optical methods to induce or inhibit well-defined events in isolated cells, tissues, or animals. While optogenetics within ophthalmology has been primarily applied towards treating inherited retinal disease, there are a myriad of other applications that hold great promise for a variety of eye diseases including cellular regeneration, modulation of mitochondria and metabolism, regulation of intraocular pressure, and pain control. Supported by primary data from the authors' work with in vitro and in vivo applications, we introduce a novel approach to metabolic regulation, Opsins to Restore Cellular ATP (ORCA). We review the fundamental constructs for ophthalmic optogenetics, present current therapeutic approaches and clinical trials, and discuss the future of subcellular and signaling pathway applications for neuroprotection and vision restoration.

Retinal arterial tortuosity in Ehlers-Danlos syndromes.

PURPOSE: To report a novel finding of retinal arterial tortuosity (RAT) associated with Ehlers-Danlos syndromes (EDS). METHODS: We queried the STAnford Research Repository (STARR) database to identify patients diagnosed with EDS. We included patients with a confirmed diagnosis of any subtype of EDS who had any form of readable retinal imaging including colour fundus photos, autofluorescence, red-free photos, red-free optical coherence tomography photos and fluorescein angiography. Patients who had no retinal imaging and those with no confirmed EDS diagnosis were excluded. Retinal images were reviewed for RAT and were graded into no, possible and definite RAT. Eyes with definite RAT were further graded into mild, moderate and severe. Eyes with definite RAT were again subclassified according to the type of involved vessels into first-order arteriolar, macular and arteriovenous. RESULTS: A total of 307 patients were identified using the STARR tool and 142 patients were included. Mean age was 40.9 ± 18.1 years and 87% were female. Underlying EDS subtypes were hypermobile EDS (69.7%), classical EDS (2.8%), vascular EDS (2.1%), myopathic EDS (0.7%) and not specified (24.6%). We graded 37.3% of patients with definite RAT, 10.6% with possible RAT and 52.1% with no RAT. In patients with definite RAT, we graded 39.2% of eyes with mild RAT, 40.2% with moderate RAT and 20.6% with severe RAT. In all, 84.9% showed involvement of first-order retinal arterioles, 35.8% showed involvement of macular arterioles and 1.9% showed arteriovenous involvement. CONCLUSIONS: Variable degrees of RAT are associated with EDS.

Biometric Variations in High Myopia Associated with Different Underlying Ocular and Genetic Conditions.

Purpose: To report different biometric measurements in high myopia associated with different underlying ocular and genetic conditions. Design: Retrospective study. Subjects: Patients with high myopia. Methods: We searched the Stanford Research Repository tool to identify patients with the diagnosis of high myopia who were seen by a single provider at Byers Eye Institute at Stanford from January 2019 to March 2022. We performed a chart review and included eyes that had high myopia and ocular biometric measurements at any time point after January 2019. We divided our cohort into 5 different groups: (1) isolated high myopia (IHM) (control group); (2) retinopathy of prematurity (ROP); (3) familial exudative vitreoretinopathy; (4) Marfan syndrome; and (5) Stickler syndrome. Main Outcome Measures: Biometric measurements. Results: A total of 246 patients (432 eyes) were included as follows: 202 patients (359 eyes) in the IHM group, 17 patients (27 eyes) in the ROP group, 7 patients (12 eyes) in the familial exudative vitreoretinopathy group, 8 patients (14 eyes) in the Marfan group, and 12 patients (20 eyes) in the Stickler group. The ROP group showed significantly shorter axial lengths, shallower anterior chambers, and thicker lenses compared with the IHM group. The Marfan group showed significantly flatter corneas and thicker lenses compared with the IHM group. The Stickler group showed significantly longer axial lengths compared with the IHM group. Conclusions: High myopia is associated with variable biometric measurements according to underlying ocular or genetic conditions. Retinopathy of prematurity-associated high myopia is primarily lenticular, while Stickler syndrome-associated high myopia is axial. Marfan syndrome-associated high myopia is derived from both axial and lenticular mechanisms.

Fall risk in patients with pseudophakic monovision.

OBJECTIVE: Vision changes can precipitate falls in the elderly resulting in significant morbidity and mortality. We hypothesized that pseudophakic monovision and ensuing anisometropia and aniseikonia impact elderly fall risk. This study assessed fall risk in patients with pseudophakic monovision, pseudophakic single vision distance (classic cataract surgery), and cataracts with no surgery. DESIGN: Retrospective single-institution cohort study PARTICIPANTS: Patients with bilateral cataracts diagnosed at 60 years of age or older who underwent bilateral cataract surgery (monovision or single vision distance) or did not undergo any cataract surgery (n = 13 385). Patients with unilateral surgery or a fall prior to cataract diagnosis were excluded. METHODS: Data were obtained from the Stanford Research Repository. Time-to-fall analysis was performed across all 3 groups. Primary outcome was hazard ratio (HR) for fall after second eye cataract surgery or after bilateral cataract diagnosis. RESULTS: Of 13 385 patients (241 pseudophakic monovision, 2809 pseudophakic single vision, 10 335 no surgery), 850 fell after cataract diagnosis. Pseudophakic monovision was not associated with fall risk after controlling for age, sex, and myopia. Pseudophakic single-vision patients had a decreased time to fall compared with no-surgery patients (log rank, p < 0.001). Older age at cataract diagnosis (HR =1.05, 95% confidence interval [CI] 1.04-1.06, p < 0.001) or at time of surgery (HR = 1.05, 95% CI 1.03-1.07, p < 0.001) increased fall risk, as did female sex (HR = 1.29, 95% CI 1.10-1.51, p = 0.002) and preexisting myopia (HR = 1.31, 95% CI 1.01-1.71, p = 0.046) among nonsurgical patients. CONCLUSIONS: Pseudophakic monovision did not impact fall risk, but pseudophakic single vision may increase falls compared with patients without cataract surgery.

Effective field of view of wide-field fundus photography in the Stanford University Network for Diagnosis of Retinopathy of Prematurity (SUNDROP).

Five-field 130° wide-angle imaging is the standard of care for retinopathy of prematurity (ROP) screening with an ideal hypothetical composite field-of-view (FOV) of 180°. We hypothesized that in many real-world scenarios the effective composite FOV is considerably less than ideal. This observational retrospective study analyzed the effective FOV of fundus photos of patients screened for ROP as part of the Stanford University Network for Diagnosis of Retinopathy of Prematurity (SUNDROP) initiative. Five fundus photos were selected from each eye per image session. Effective FOV was defined as the largest circular area centered on the optic disc that encompassed retina in each of the four cardinal views. Seventy-three subjects were analyzed, 35 without ROP and 34 with ROP. Mean effective FOV was 144.55 ± 6.62° ranging from 130.00 to 153.71°. Effective FOV was not correlated with the presence or absence of ROP, gestational age, birth weight, or postmenstrual age. Mean effective FOV was wider in males compared to females. Standard five-field 130° fundus photos yielded an average effective FOV of 144.54° in the SUNDROP cohort. This implies that an imaging FOV during ROP screening considerably less than the hypothetical ideal of 180° is sufficient for detecting treatment warranted ROP.