Early diagnosis and treatment by newborn screening (NBS) or family history is associated with improved visual outcomes for long-chain 3-hydroxyacylCoA dehydrogenase deficiency (LCHADD) chorioretinopathy.

Long chain 3-hydroxyacyl-CoA dehydrogenase (LCHADD) is the only fatty acid oxidation disorder to develop a progressive chorioretinopathy resulting in vision loss; newborn screening (NBS) for this disorder began in the United States around 2004. We compared visual outcomes among 40 participants with LCHADD or trifunctional protein deficiency diagnosed symptomatically to those who were diagnosed via NBS or a family history. Participants completed ophthalmologic testing including measures of visual acuity, electroretinograms (ERG), fundal imaging, contrast sensitivity, and visual fields. Records were reviewed to document medical and treatment history. Twelve participants presented symptomatically with hypoglycemia, failure to thrive, liver dysfunction, cardiac arrest, or rhabdomyolysis. Twenty eight were diagnosed by NBS or due to a family history of LCHADD. Participants diagnosed symptomatically were older but had similar percent males and genotypes as those diagnosed by NBS. Treatment consisted of fasting avoidance, dietary long-chain fat restriction, MCT, C7, and/or carnitine supplementation. Visual acuity, rod- and cone-driven amplitudes on ERG, contrast sensitivity scores, and visual fields were all significantly worse among participants diagnosed symptomatically compared to NBS. In mixed-effects models, both age and presentation (symptomatic vs. NBS) were significant independent factors associated with visual outcomes. This suggests that visual outcomes were improved by NBS, but there was still lower visual function with advancing age in both groups. Early diagnosis and treatment by NBS is associated with improved visual outcomes and retinal function compared to participants who presented symptomatically. Despite the impact of early intervention, chorioretinopathy was greater with advancing age, highlighting the need for novel treatments.

Optical Coherence Tomography Split-Spectrum Amplitude-Decorrelation Optoretinography Detects Early Central Cone Photoreceptor Dysfunction in Retinal Dystrophies.

Purpose: To investigate if split-spectrum amplitude-decorrelation optoretinography (SSADOR) can detect and measure macular cone dysfunction in inherited retinal dystrophies (IRDs). Methods: This study was a case series of participants presenting with various IRD pathologies. Participants were recruited from the Ophthalmic Genetics clinic at the Casey Eye Institute from February to August 2023. Multimodal and SSADOR imaging was obtained in all cases. Results: We recruited nine participants, including four with macular dystrophy, one with fundus flavimaculatus, one with cone dystrophy, and three with retinitis pigmentosa. SSADOR decorrelation maps identified areas of cone functional impairment consistent with disease phenotypes. A correlation between the SSADOR signal and retinal sensitivity measured by microperimetry within the central 20° diameter area was observed. Additionally, SSADOR was able to demonstrate a decreased signal in mild cases when microperimetry measurements were still normal but subtle changes were also apparent on structural OCT. Conclusions: SSADOR is sensitive at detecting functional changes in macular cones, even prior to abnormalities in perimetry testing. We highlight the potential benefits of this innovative technology for the early detection of cone dysfunction and their potential contributions to earlier diagnosis and more accurate monitoring of progression. Translational Relevance: SSADOR is an innovative technology that detects early macular cone function changes, allowing for early diagnosis and precise monitoring of cone dysfunction progression. By serving as a potential clinical trial endpoint, SSADOR facilitates the translation of scientific findings into practical applications, ultimately improving patient care and outcomes.

Detection of macular neovascularization in eyes presenting with macular edema using optical coherence tomography angiography and a deep-learning model.

PURPOSE: To test the diagnostic performance of an artificial intelligence algorithm for detecting and segmenting macular neovascularization (MNV) with optical coherence tomography (OCT) and OCT angiography(OCTA) in eyes with macular edema from various diagnoses. DESIGN: Prospective cross-sectional study. PARTICIPANTS: Study participants with macular edema due to either treatment-naïve exudative age-related macular degeneration (AMD), diabetic macular edema (DME), or retinal vein occlusion (RVO). METHODS: Study participants were imaged with macular 3x3-mm and 6x6-mm spectral-domain OCTA. Eyes with exudative AMD were required to have MNV in the central 3x3-mm area. A previously developed hybrid multi-task convolutional neural network for MNV detection (aiMNV) and segmentation was applied to all images, regardless of image quality. MAIN OUTCOME MEASURES: Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of detecting MNV; and intersection over union(IoU) score and F1 score for segmentation. RESULTS: Of 114 eyes from 112 study participants, 56 eyes had MNV due to exudative AMD and 58 eyes with macular edema due to either DME or RVO. 3x3-mm OCTA scans with aiMNV detected MNV with 96.4% sensitivity, 98.3% specificity, 98.2% PPV, and 96.6% NPV. For segmentation, the average IoU score was 0.947 and the F1 score was 0.973. 6x6-mm scans performed well; however, sensitivity for MNV detection was lower than 3x3-mm scans due to lower scan sampling density. CONCLUSION: This novel aiMNV algorithm can accurately detect and segment MNV in eyes with exudative AMD from a control group of eyes that present with macular edema from either DME or RVO. Higher scan sampling density improved the aiMNV sensitivity for MNV detection.

A proposal for an updated staging system for LCHADD retinopathy.

OBJECTIVE: To develop an updated staging system for long-chain 3-hydroxyacyl coenzyme A dehydrogenase deficiency (LCHADD) chorioretinopathy based on contemporary multimodal imaging and electrophysiology. METHODS: We evaluated forty cases of patients with genetically confirmed LCHADD or trifunctional protein deficiency (TFPD) enrolled in a prospective natural history study. Wide-field fundus photographs, fundus autofluorescence (FAF), optical coherence tomography (OCT), and full-field electroretinogram (ffERG) were reviewed and graded for severity. RESULTS: Two independent experts first graded fundus photos and electrophysiology to classify the stage of chorioretinopathy based upon an existing published system. With newer imaging modalities and improved electrophysiology, many patients did not fit cleanly into a single traditional staging group. Therefore, we developed a novel staging system that better delineated the progression of LCHADD retinopathy. We maintained the four previous delineated stages but created substages A and B in stages 2 to 3 to achieve better differentiation. DISCUSSION: Previous staging systems of LCHADD chorioretinopathy relied on only on the assessment of standard 30 to 45-degree fundus photographs, visual acuity, fluorescein angiography (FA), and ffERG. Advances in recordings of ffERG and multimodal imaging with wider fields of view, allow better assessment of retinal changes. Following these advanced assessments, seven patients did not fit neatly into the original classification system and were therefore recategorized under the new proposed system. CONCLUSION: The new proposed staging system improves the classification of LCHADD chorioretinopathy, with the potential to lead to a deeper understanding of the disease's progression and serve as a more reliable reference point for future therapeutic research.

Practice Patterns and Challenges in Managing Inherited Retinal Diseases Across Asia-Pacific: A Survey from the APIED Network.

PURPOSE: The objective of this paper is to shed light on the current landscape of genotyping practices, phenotyping practices and availability of essential vision rehabilitation management for inherited retinal diseases (IRD) in the Asia-Pacific (APAC) Region. METHODS: The 62-item questionnaire was distributed electronically via email. The questions covered five domains: (1) structure of the IRD service and registry/database; (2) genotyping practices; (3) genetic counselling; (4) deep phenotyping practices; (5) low-vision rehabilitation services. RESULTS: The survey was completed by 36 of 45 centres in twelve countries and regions in APAC. Among these centres, 42 % reported managing more than 1000 patients. Notably, 39 % of centres lack an IRD database or registry, and 44 % of centres have tested less than one-quarter of their IRD patients. The majority of centres (67 %) do not have genetic counsellors. While there was consistency in the imaging-based investigations, there was marked heterogeneity for functional testing using electrophysiology and formal perimetry. Only 34 % of centres confirmed the availability of access to low-vision assistive devices. CONCLUSIONS: This study reveals several critical gaps in managing IRDs in the APAC region. These include the lack of IRD database/registry in one-third of centres, a substantial proportion of patients remaining genetically undiagnosed, and limited availability of genetic counsellors. The findings also underscore a need to harmonise investigations for evaluating retinal function and identify areas for improvement in the provision of low-vision rehabilitation services.

Klebsiella pneumoniae Endophthalmitis with Subretinal Abscess: A Case Series and Review of the Literature.

This study assessed prognostic factors and the role of vitrectomy in patients with subretinal abscesses secondary to K. pneumoniae endophthalmitis. We reviewed published studies, including three cases from our cohort. Among 50 eyes, 26 had poor visual outcomes (final visual acuity <20/800, eyeball removal, or phthisis bulbi). Poor outcomes correlated with delayed ocular symptom-to-diagnosis time, initial visual acuity <20/800, severe vitritis, and macular involvement of abscesses (p < 0.001, p = 0.008, p < 0.001, and p = 0.033, respectively). Vitrectomy had a trend towards reducing eyeball removal and phthisis bulbi rates compared with non-vitrectomy (10.8% vs 30.8%, p = 0.181). However, the final visual acuity was not different and the rate of retinal detachment tended to be higher in vitrectomized eyes (45.9% vs 15.4%, p = 0.095). The study suggested that vitrectomy and drainage of K. pneumoniae subretinal abscesses could be avoided in patients with a mild degree of vitritis.

Gene therapy in bestrophinopathies: Insights from preclinical studies in preparation for clinical trials.

The BEST1 gene encodes bestrophin-1, a homopentameric ion channel expressed in the retinal pigment epithelium (RPE), where it localizes to the basolateral plasma membrane. Pathogenic variants in this gene can cause different autosomal dominant and recessive inherited retinal diseases (IRDs), collectively named "bestrophinopathies." These disorders share a number of clinical and molecular features that make them an appealing target for gene therapy. Clinically, bestrophinopathies are often slowly progressive with a wide window of opportunity, and the presence of subretinal material (vitelliform deposits and/or fluid) as a hallmark of these conditions provides an easily quantifiable endpoint in view of future clinical trials. From a molecular standpoint, most BEST1 pathogenic variants have been shown to cause either loss of function (LOF) of the protein or a dominant-negative (DN) effect, with a smaller subset causing a toxic gain of function (GOF). Both LOF and DN mutations may be amenable to gene augmentation alone. On the other hand, individuals harboring GOF variants would require a combination of gene silencing and gene augmentation, which has been shown to be effective in RPE cells derived from patients with Best disease. In this article, we review the current knowledge of BEST1-related IRDs and we discuss how their molecular and clinical features are being used to design novel and promising therapeutic strategies.

Retinitis pigmentosa GTPase regulator-related retinopathy and gene therapy.

Retinitis pigmentosa GTPase regulator (RPGR)-related retinopathy is a retinal dystrophy inherited in a X-linked recessive manner that typically causes progressive visual loss starting in childhood with severe visual impairment by the fourth decade of life. It manifests as an early onset and severe form of retinitis pigmentosa. There are currently no effective treatments for RPGR-related retinopathy; however, there are multiple clinical trials in progress exploring gene augmentation therapy aimed at slowing down or halting the progression of disease and possibly restoring visual function. This review focuses on the molecular biology, clinical manifestations, and the recent progress of gene therapy clinical trials.

Optical coherence tomography angiography of choroidal neovascularization in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD).

Purpose: To report the clinical utility of optical coherence tomography angiography (OCTA) for demonstrating choroidal neovascularization (CNV) associated with Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency (LCHADD) retinopathy. Methods: Thirty-three participants with LCHADD (age 7-36 years; median 17) were imaged with OCTA and the Center for Ophthalmic Optics & Lasers Angiography Reading Toolkit (COOL-ART) software was implemented to process OCTA scans. Results: Seven participants (21 %; age 17-36 years; median 25) with LCHADD retinopathy demonstrated evidence of CNV by retinal examination or presence of CNV within outer retinal tissue on OCTA scans covering 3 × 3 and/or 6 × 6-mm. These sub-clinical CNVs are adjacent to hyperpigmented areas in the posterior pole. CNV presented at stage 2 or later of LCHADD retinopathy prior to the disappearance of RPE pigment in the macula. Conclusion: OCTA can be applied as a non-invasive method to evaluate the retinal and choroidal microvasculature. OCTA can reveal CNV in LCHADD even when the clinical exam is inconclusive. These data suggest that the incidence of CNV is greater than expected and can occur even in the early stages of LCHADD retinopathy.

Application of Deep Learning for Automated Detection of Polypoidal Choroidal Vasculopathy in Spectral Domain Optical Coherence Tomography.

Objective: To develop an automated polypoidal choroidal vasculopathy (PCV) screening model to distinguish PCV from wet age-related macular degeneration (wet AMD). Methods: A retrospective review of spectral domain optical coherence tomography (SD-OCT) images was undertaken. The included SD-OCT images were classified into two distinct categories (PCV or wet AMD) prior to the development of the PCV screening model. The automated detection of PCV using the developed model was compared with the results of gold-standard fundus fluorescein angiography and indocyanine green (FFA + ICG) angiography. A framework of SHapley Additive exPlanations was used to interpret the results from the model. Results: A total of 2334 SD-OCT images were enrolled for training purposes, and an additional 1171 SD-OCT images were used for external validation. The ResNet attention model yielded superior performance with average area under the curve values of 0.8 and 0.81 for the training and external validation data sets, respectively. The sensitivity/specificity calculated at a patient level was 100%/60% and 85%/71% for the training and external validation data sets, respectively. Conclusions: A conventional FFA + ICG investigation to differentiate PCV from wet AMD requires intense health care resources and adversely affects patients. A deep learning algorithm is proposed to automatically distinguish PCV from wet AMD. The developed algorithm exhibited promising performance for further development into an alternative PCV screening tool. Enhancement of the model's performance with additional data is needed prior to implementation of this diagnostic tool in real-world clinical practice. The invisibility of disease signs within SD-OCT images is the main limitation of the proposed model. Translational Relevance: Basic research of deep learning algorithms was applied to differentiate PCV from wet AMD based on OCT images, benefiting a diagnosis process and minimizing a risk of ICG angiogram.

In-Person Verification of Deep Learning Algorithm for Diabetic Retinopathy Screening Using Different Techniques Across Fundus Image Devices.

Purpose: To evaluate the clinical performance of an automated diabetic retinopathy (DR) screening model to detect referable cases at Siriraj Hospital, Bangkok, Thailand. Methods: A retrospective review of two sets of fundus photographs (Eidon and Nidek) was undertaken. The images were classified by DR staging prior to the development of a DR screening model. In a prospective cross-sectional enrollment of patients with diabetes, automated detection of referable DR was compared with the results of the gold standard, a dilated fundus examination. Results: The study analyzed 2533 Nidek fundus images and 1989 Eidon images. The sensitivities calculated for the Nidek and Eidon images were 0.93 and 0.88 and the specificities were 0.91 and 0.85, respectively. In a clinical verification phase using 982 Nidek and 674 Eidon photographs, the calculated sensitivities and specificities were 0.86 and 0.92 for Nidek along with 0.92 and 0.84 for Eidon, respectively. The 60°-field images from the Eidon yielded a more desirable performance in differentiating referable DR than did the corresponding images from the Nidek. Conclusions: A conventional fundus examination requires intense healthcare resources. It is time consuming and possibly leads to unavoidable human errors. The deep learning algorithm for the detection of referable DR exhibited a favorable performance and is a promising alternative for DR screening. However, variations in the color and pixels of photographs can cause differences in sensitivity and specificity. The image angle and poor quality of fundus photographs were the main limitations of the automated method. Translational Relevance: The deep learning algorithm, developed from basic research of image processing, was applied to detect referable DR in a real-word clinical care setting.

Extralesional microvascular and structural macular abnormalities in cytomegalovirus retinitis.

To evaluate extralesional microvascular and structural changes of the macula using optical coherence tomography angiography (OCTA) and structural OCT in cytomegalovirus retinitis (CMVR). An observational study of CMVR patients were performed. Complete ophthalmic examination, serial color fundus photography, structural OCT and OCTA were performed at baseline and follow-up visits for up to 12 months. The structural OCT was analyzed to evaluate macular areas within, bordering and beyond the CMVR lesions. Extralesional retinal capillary plexus of the macula were evaluated by OCT angiography and compared with the unaffected fellow eyes. Thirteen eyes from 13 patients were enrolled. At baseline, macular areas without CMVR lesions showed decreased vessel density (VD) of both the superficial (P = 0.0002) and deep (P < 0.0001) retinal capillary plexus in eyes with CMVR as compared with the corresponding macular areas of the unaffected fellow eyes. The decrease of VD persisted through the follow-up period for up to 12 months after adjusting for degree of vitreous haze. Structural macular OCT characteristics at the borders and beyond the lesions included intraretinal hyperreflective dots, cystoid macular edema, subretinal fluid and selective ellipsoid zone (EZ) loss. The selective EZ loss found in 6 of 12 eyes showed recovery in 4 eyes after receiving anti-viral treatment. In CMVR eyes, there were microvascular and microstructural abnormalities in the macular area without clinically visible CMVR lesions. Our results provided interesting insights into CMV infection of the retina.

Comparison of central corneal thickness measurements in corneal edema using ultrasound pachymetry, Visante anterior-segment optical coherence tomography, Cirrus optical coherence tomography, and Pentacam Scheimpflug camera tomography.

PURPOSE: To compare the central corneal thickness (CCT) measurements in subjects with corneal edema using ultrasound pachymetry, Visante anterior-segment optical coherence tomography (OCT), Cirrus OCT, and Pentacam Scheimpflug camera tomography. METHODS: This prospective cross-sectional study included 46 eyes of 33 patients with corneal edema and a CCT exceeding 550 µm evaluated by ultrasound pachymetry, Visante OCT, Cirrus OCT, and Pentacam. Two observers measured each eye twice. Intraobserver and interobserver reproducibility were determined and agreement among the devices calculated. RESULTS: CCT was measured in 40 eyes of 29 patients. Regardless of the CCT, the measurements obtained using Visante OCT, Cirrus CCT, and ultrasound pachymetry were well correlated. Interobserver and intraobserver reproducibility were high among the three devices. Pentacam overestimated the results compared with the other devices, and ultrasound pachymetry was unmeasurable in six (13%) eyes with very thick and opaque corneas. In eyes with mild corneal edema (CCT 551-650 µm), measurements from the four devices were comparable. CONCLUSION: All devices reliably measured the CCT <650 µm. In eyes with edema exceeding 650 µm, CCT measurements from the Visante OCT, Cirrus OCT, and ultrasound pachymetry devices showed good reproducibility and were well correlated, while the Pentacam overestimated the values compared to the other devices. Pentacam and ultrasound pachymetry should not be used in eyes with extreme corneal edema and opacity.