Purpose:Hydroxychloroquine (HCQ) retinopathy is detectable through multimodal ophthalmic screening, yet individual diagnostic tests each have inherent limitations. Machine learning may simplify monitoring, but few HCQ screening algorithms have undergone rigorous external validation. This study evaluated the clinical utility of the Multifocal Electroretinogram Classification Interface (MERCI) algorithm by assessing its ability to predict HCQ retinopathy compared with diagnoses derived from American Academy of Ophthalmology (AAO) guidelines. Methods:Patients referred for HCQ toxicity screening underwent perimetry, spectral-domain optical coherence tomography, fundus autofluorescence photography, and multifocal electroretinogram (mfERG) testing. Performance was assessed in a temporal dataset (participants overlapping with the development dataset) and a novel dataset (newly enrolled participants). Reference diagnoses were assigned using AAO guideline-based decision trees informed by ancillary tests results. MERCI generated corresponding mfERG-based predictions, which were compared with reference diagnoses to compute performance metrics for each dataset. Results:Using the decision trees, the temporal (n = 145) and novel (n = 300) datasets showed retinopathy prevalences of 12.4% and 9.7%, respectively. MERCI yielded 63/145 (43.4%) and 115/300 (38.3%) false-positive cases, respectively. MERCI achieved strong sensitivity (1.000 temporal; 0.931 novel) and negative predictive value (NPV) (1.000 temporal; 0.987 novel), with comparable area under the curve between datasets (0.759 temporal; 0.805 novel). Conclusions:MERCI retained high sensitivity and NPV when validated against temporally distinct cohorts using a clinical definition of HCQ toxicity. This suggests MERCI's potential as a screening tool for HCQ retinopathy. Translational Relevance:The mfERG-based machine learning models may improve screening efficiency and clinical decision-making for HCQ users.

Significance:During their early stages of development, neurological and neurodegenerative diseases cause changes to the biological tissue's morphology, physiology and metabolism at the cellular level, and acute, transient changes in the local blood flow. The development of optical methods that can image and quantify such changes simultaneously and investigate the relationship among them (neurovascular coupling) in neural tissues can have a profound effect on furthering our understanding of neurodegeneration. Aim:Our aim is to develop an optical imaging platform for imaging and characterization of neurovascular coupling in the human retina with high spatial and temporal resolutions. Approach:A compact, clinically viable optical coherence tomography technology was developed for in vivo, simultaneous structural, functional, and vascular imaging of the human retina and was integrated with a clinical electroretinography system. Image processing algorithms were developed to measure visually evoked physiological and blood flow changes in the living retina and explore neurovascular coupling in the healthy human retina. Results:Both intensity and optical path length changes were measured with optical coherence tomography from most major retinal layers (nerve fiber layer, plexiform layers, inner and outer segments of the photoreceptors, and the retinal pigmented epithelium) in response to a visual stimulation with a 4-ms single white light flash. The visual stimulus also caused fast transient changes in the retinal blood flow in the local blood vessels. The time courses of these changes were similar, and their magnitude was proportional to the intensity of the visual stimulus. Conclusions:We have developed an optical imaging modality for non-invasive probing of neurovascular coupling in the living human retina and demonstrated its utility and clinical potential in a pilot study on healthy subjects. This imaging platform could serve as a useful clinical research tool for investigation of potentially blinding retinal diseases, as well as neurodegenerative brain diseases that are expressed in the retina such as Alzheimer's and Parkinson's diseases.

Neurodegenerative retinal diseases, such as glaucoma, age-related macular degeneration and diabetic retinopathy, cause gradual damage to the retinal morphology, blood vasculature, and neuronal function, and ultimately lead to blindness. In this study, a retinal OCT system was combined with a clinical electroretinography (ERG) system to investigate visually-evoked transient changes in the retinal blood flow (RBF) and blood vessel diameter (BVD) in the healthy human retina. The OCT system offered 2.7 µm axial resolution in retinal tissue and 98 dB sensitivity for 1.1 mW imaging power and 250 kHz image acquisition rate. Doppler OCT (double circular scans around the optic nerve head) and ERG traces were acquired from healthy subjects in response to 10 Hz, white light flicker stimuli and different stimulus intensities. The ERG system was used to generate visual stimuli of precise timing, duration, luminance, and flicker frequency, as well as to confirm the retinal neuronal response to the visual stimulation. MATLAB-based custom algorithms were developed to track time-dependent changes in the RBF and BVD from the OCT images. Results from this study revealed a rapid transient increase in the RBF accompanied by transient vasoconstriction and vasodilation of the retinal blood vessels in response to the flicker stimulation. The amplitude and latency of the RBF and BVD responses were dependent on the stimulus intensity as well as the blood vessel type (arteries or veins).

PURPOSE:To provide a comprehensive overview of quantitative adaptive optics imaging (AOI) photoreceptor parameters in retinitis pigmentosa (RP). METHODS:A systematic literature search was conducted on Ovid Medline, Embase, and Cochrane Library from January 2000 to June 2023 for articles reporting on quantitative photoreceptor measurements from AOI systems in RP. Our primary outcomes were cone density, regularity, and spacing measurements at various eccentricities. RESULTS:Twenty-six studies reporting on 299 eyes with various forms of RP that underwent AOI were included. Seventeen studies reported on cone density parameters in RP, which mostly decreased with increasing eccentricity from the fovea and were reduced in RP eyes relative to normal control eyes. Four studies reported on cone regularity in RP, which was reduced relative to normal control eyes. Twelve studies reported on cone spacing parameters in RP, which were often increased relative to normal control eyes. CONCLUSION:RP eyes showed a reduced cone density, reduced cone regularity, and increased cone spacing relative to control eyes. There is considerable variability in the reporting of AOI parameters in this setting, a paucity of data comparing AOI parameters in RP eyes to age-matched controls, and best practices of AOI use have yet to be established.

Purpose: To our knowledge, we present the first case series investigating the relationship between adaptive optics (AO) imaging and intravenous fluorescein angiography (IVFA) parameters in patients with diabetic retinopathy (DR). Methods: Consecutive patients with DR over the age of 18 years presenting to a single centre in Toronto, Canada from 2020-2021 were recruited. AO was performed with the RTX1 camera (Imagine Eyes, Orsay, France) at retinal eccentricities of 2° and 4°. IVFA was assessed with the artificial intelligence-based RETICAD system to extract blood flow, perfusion, and blood-retinal barrier (BRB) permeability at the same retinal locations. Correlations between AO and IVFA parameters were calculated using Pearson’s correlation coefficient. Results: Across nine cases, a significant positive correlation existed between photoreceptor spacing on AO and BRB permeability (r=0.303, p=0.027), as well as perfusion (r=0.272, p=0.049) on IVFA. When stratified by location, a significant positive correlation between photoreceptor dispersion and both BRB permeability and perfusion (r=0.770, p=0.043; r=0.846, p=0.034, respectively) was observed. Cone density was also negatively correlated with BRB permeability (r=-0.819, p=0.046). Conclusion: Photoreceptor spacing on AO was significantly correlated with BRB permeability and perfusion on IVFA in patients with DR. Future studies with larger sample sizes are needed to understand the relationship between AO and IVFA parameters in diverse patient populations.

BACKGROUND AND OBJECTIVE: This study aimed to investigate correlations between photoreceptor and vascular parameters in varying stages of diabetic retinopathy (DR) using adaptive optics (AO) imaging. PATIENTS AND METHODS: In this single-center, prospective cohort study, 29 participants (46 eyes) were classified into control/mild non-proliferative DR (NPDR), moderate/severe NPDR, and proliferative DR. AO images of photoreceptors and retinal vasculature were analyzed, and Spearman's correlation (rho) was used to assess relationships between photoreceptor density and vascular parameters. RESULTS: Higher cone density was inversely associated with total vessel (rho = 0.22, P = 0.03) and lumen diameters (rho = -0.24, P = 0.01), while higher dispersion was associated with total vessel (rho = 0.19, P = 0.06) and lumen diameters (rho = 0.21, P = 0.04). These associations were primarily significant in mild NPDR. No significant correlations were found in advanced DR stages. CONCLUSION: This study underscores intricate neurovascular correlations in early-stage DR, suggesting these parameters may aid in early disease detection. Further research is needed to understand whether similar correlations exist in advanced DR.

Vitamin A is a lipid-soluble compound that is critical in maintaining phototransduction. Ocular manifestations of hypovitaminosis A may present with anterior segment signs of xeropthalmia, with advanced cases also causing classic retinal and electrophysiologic changes of vitamin A deficiency retinopathy. We present a case of vitamin A deficiency retinopathy, with corresponding retinal imaging and electrophysiology, in an adult patient with celiac disease and liver fibrosis. A single case report was conducted in Toronto, Canada. A 77-year-old male with known celiac disease and liver fibrosis presented progressively worsening vision noticed primarily when driving. Vision was 20/50 OD and 20/200 OS. Bitot spots were noted on anterior segment examination. Fundus photography demonstrated bilateral peripheral macular hypopigmentation and far-peripheral granular retinal hypopigmentation with focal yellow dots and hyper-pigmented deposits. Optical coherence tomography (OCT) imaging demonstrated indistinct outer retinal banding with mild outer nuclear layer thinning, focal hyper-reflective deposits, and a thin choroid bilaterally. Full-field electroretinography (ERG) testing demonstrated reduced rod-isolated and combined rod-cone response amplitudes, and multifocal ERG testing demonstrated blunted individual responses throughout the field. The patient was treated with pulse vitamin A therapy. After 6 months of therapy, ERG responses were back within reference range, and the outer retinal changes reversed; visual acuity improved to 20/30 OD and 20/40 OS. This case represents the classic findings of vitamin A deficiency retinopathy on fundus examination and electrophysiologic testing secondary to gastrointestinal pathology. Prompt treatment of high dose vitamin A supplementation led to improvement of full-field and multifocal ERG results, as well as reconstitution of outer retinal architecture.

Visual stimulation-induced increase in the metabolic activity of retinal neurons leads to temporary vasodilation of retinal blood vessels and an increase in the retinal blood flow, which is often referred to as functional hyperaemia. Neurodegenerative retinal diseases such as glaucoma, age-related macular degeneration, and diabetic retinopathy have been known to cause progressive damage to the retinal morphology, blood perfusion and retinal blood flow, and eventually lead to blindness. In this study, we utilize a combined OCT+ERG system to investigate functional hyperemia in the human retina.

Purpose: To investigate the correlation between diabetic retinopathy (DR) severity and microscopic retinal and vascular alterations using adaptive optics imaging (AOI). Methods: In this single-center, prospective cohort study, adult participants with healthy eyes or DR underwent AOI. Participants were classified into control/mild non-proliferative DR (NPDR), moderate/severe NPDR, and proliferative DR. AOI using the RTX1 camera was obtained from 48 participants (87 eyes) for photoreceptor data, and from 36 participants (62 eyes) for vascular data. Results: Photoreceptor parameters significantly differed between DR groups at 2° and 4° of retinal eccentricity. Wall-to-lumen ratio varied significantly at 2° eccentricity, while other vascular parameters remained non-significant. Cone density and dispersion were the strongest predictors for DR severity (p<0.001) in multivariable generalized estimating equation (GEE) modeling, while other vascular parameters remained non-significant between DR severity groups. All photoreceptor parameters showed significant correlations with visual acuity overall and across most DR severity groups. Conclusion: To date, this is one of the largest studies evaluating the use of AOI in DR. AOI was demonstrated to differentiate between various levels of disease severity in DR. These results support the potential role in diagnostic and therapeutic microstructural evaluation in research and clinical practice.

Hydroxychloroquine (HCQ) is a disease-modifying antirheumatic drug. HCQ retinopathy is an adverse effect associated with prolonged treatment and increased dosage.1,2 Patients with HCQ retinopathy are initially asymptomatic, and the disease progresses slowly with poor visual recovery after therapy is stopped, making early detection difficult but essential.

Purpose To assess the photoreceptor mosaic in patients with idiopathic full thickness macular hole (MH) before and after pars plana vitrectomy (PPV) with adaptive optics enhanced retinal imaging (AO). Design Prospective case series. Methods Prospective cohort study of patients who presented at the Kensington Eye Institute, Toronto, Canada with a diagnosis of macular hole treated with PPV. Exclusion criteria: secondary MH, high myopia (axial length >26.5 mm), media opacity precluding OCT or AO imaging, previous intraocular surgery except for cataract extraction. Imaging using an AO fundus camera (Imagine Eyes, RTX1) was performed preoperatively and 3-months following successful MH repair in both eyes. Cone density (CD), regularity, dispersion, regularity, dispersion, and spacing were measured at 2° and 4° of eccentricity in 4 quadrants (superior, inferior, nasal, and temporal) with pre- and postoperative values compared. Results We included 18 eyes of 9 patients. At 2° there was significant reduction in CD and increase in spacing and dispersion and a non-significant change in regularity post-operatively. Comparison between preoperative and postoperative measurements at 2° mean (Standard Error= SE) were: CD: 14612 ± 3003 and 12280 ± 4632 photoreceptors/mm2 [95%CIs= -2413 to -702] p=0.0004, regularity: 88 ± 7% and 84 ± 12% [95%CIs= -4.67 to 0.04] p=0.054, dispersion: 19 ± 6% and 23 ± 10% [95%CIs= 0.5 to 4.24] p=0.013, spacing: 9 ± 1 microns and 10 ± 2microns [95%CIs= 0.40 to 1.27] p=0.0002; at 4° was: CD: 13377 ± 4339 and 12770 ± 4391 photoreceptors/mm2 [95%CIs= -1368 to 252] p=0.176, regularity:87 ± 9% and 86 ± 12% [95%CIs= -4.65 to 0.08] p=0.74, dispersion: 20 ± 8% and 20 ±9 % [95%CIs= -2.11 to 1.5] p=0.74, spacing:10 ± 2 microns and 10 ± 3 microns [95%CIs= -0.23 to 0.58] p=0.39. Conclusion Adaptive optics imaging allows quantitative assessment of the photoreceptor mosaic pre- and post-PPV in patients with MH. There was a significant change to the photoreceptor mosaic related to the MH at 2° pre- and post-operatively. AO imaging enables high-resolution investigation of the photoreceptor remodeling process following surgery, which may allow for a more thorough assessment of surgical outcomes.

PURPOSE:Hydroxychloroquine (HCQ) is an anti-inflammatory drug in widespread use for the treatment of systemic auto-immune diseases. Vision loss caused by retinal toxicity is a significant risk associated with long term HCQ therapy. Identifying patients at risk of developing retinal toxicity can help prevent vision loss and improve the quality of life for patients. This paper presents updated reference thresholds and examines the diagnostic accuracy of a machine learning approach for identifying retinal toxicity using the multifocal Electroretinogram (mfERG).METHODS:A retrospective study of patients referred for mfERG testing to detect HCQ retinopathy. A consecutive series of all patients referred to Kensington Vision and Research Centre between August 2017 and July 2020 were considered eligible. Eyes suspect for other ocular pathology including widespread retinal disease and advanced macular pathology unrelated to HCQ or with poor quality mfERG recordings were excluded. All patients received mfERG testing and Ocular Coherence Tomography (OCT) imaging. Presence of HCQ retinopathy was based on ring ratio analysis using clinical reference thresholds established at KVRC coupled with structural features observed on OCT, the clinical reference standard. A Support Vector Machine (SVM) using selected features of the mfERG was trained. Accuracy, sensitivity and specificity are reported.RESULTS:1463 eyes of 748 patients were included in the study. SVM model performance was assessed on 293 eyes from 265 patients. 55 eyes from 54 patients were identified as demonstrating HCQ retinopathy based on the clinical reference standard, 50 eyes from 49 patients were identified by the SVM. Our SVM achieves an accuracy of 85.3% with a sensitivity of 90.9% and specificity of 84.0%.CONCLUSIONS:Machine learning approaches can be applied to mfERG analysis to identify patients at risk of retinopathy caused by HCQ therapy.

Purpose To provide an overview of the effect that the COVID-19 pandemic has had on visual electrophysiology referral patterns and the subsequent effect this may have on patients. Methods All electrodiagnostic tests performed at Kensington Vision and Research Centre, Toronto Canada, in a 3-month period prior to the COVID-19 pandemic (1 September 2019 to 30 November 2019) were compared to a 3-month period after the start of the COVID-19 pandemic (1 September 2021 to 30 November 2021). Results A total of 502 patients had electrodiagnostic testing carried out in the designated time periods: 292 in the time period prior to the COVID-19 pandemic and 210 patients after. There was a significant change in the reason for referral in patients pre-COVID compared to post-COVID (p = 0.004). There was a 43% reduction in referrals for drug monitoring, 25% reduction for hereditary pathology and a 27% increase in acquired pathology after the start of the COVID-19 pandemic compared to before. Conclusions There was a substantial decrease in the total number of patients referred after the start of the COVID-19 pandemic compared to pre-COVID with inherited retinal pathology and drug monitoring patients being 2 populations most affected by the disruption to healthcare services.

Hemizygous pathogenic variants in CACNA1F lead to defective signal transmission from retinal photoreceptors to bipolar cells and cause incomplete congenital stationary night blindness in humans. Although the primary defect is at the terminal end of first-order neurons (photoreceptors), there is limited knowledge of higher-order neuronal changes (inner retinal) in this disorder. This study aimed to investigate inner retinal changes in CACNA1F-retinopathy by analyzing macular ganglion cell layer-inner plexiform layer (GCL-IPL) thickness and optic disc pallor in 22 subjects with molecularly confirmed CACNA1F-retinopathy. Detailed ocular phenotypic data including distance and color vision, refraction and electroretinogram (ERG) were collected. Distance vision was universally reduced (mean: 0.42 LogMAR), six had abnormal color vision and myopia was common (n = 15; mean: −6.32 diopters). Mean GCL-IPL thickness was significantly lower in patients (55.00 µm) compared to age-matched controls (n = 87; 84.57 µm; p << 0.001). The GCL-IPL thickness correlated with scotopic standard (p = 0.04) and bright-flash (p = 0.014) ERG b/a ratios and photopic b-wave amplitudes (p = 0.05). Twenty-one patients had some degree of disc pallor (bilateral in 19). Fifteen putative disease-causing, including five novel variants were identified. This study establishes macular inner retinal thinning and optic atrophy as characteristic features of CACNA1F-retinopathy, which are independent of myopia and could impact potential future treatment strategies.

Purpose Vigabatrin-associated retinal toxicity manifests as reduction in the clinical electroretinogram and retinal nerve fiber layer (RNFL) thinning. This observational investigation of RNFL thickness in young vigabatrin-treated children was to identify intravisit and intervisit reliabilities of peripapillary RNFL thickness measurements performed with Envisu (optical coherence tomography) OCT. Secondarily, a longitudinal assessment investigated the presence and extent of RNFL thinning. Methods We measured the handheld OCT in sedated children to evaluate the RNFL thickness using segmentation software. Intraclass correlation coefficient (ICC) statistics identified intravisit and intervisit reliabilities for RNFL thickness. Results Twenty-nine children (10.1 ± 6.0 months old) underwent handheld optical coherence tomography (OCT). Fourteen of these completed follow-up assessments. Intravisit reliability was good for the right eye (ICCs = 0.82−0.98) and the left eye (ICCs = 0.75−0.89) for each of the 4 retinal quadrants. Inter-visit ICCs for each of the 4 retinal quadrants were good (ICC = 0.82−0.98). There was no consistent change in RNFL thickness longitudinally. Conclusions In this pediatric cohort, RNFL thickness measures using handheld OCT provided good reliability within a single visit and between consecutive visits supporting its use as an adjunctive tool in the clinical setting. Further long-term follow-up is required to understand RNFL thickness changes in this specific population and its association with vigabatrin toxicity. Translational Relevance The findings of good reliability and clinical feasibility would provide an opportunity for the handheld OCT to monitor reliably for vigabatrin-associated retinal toxicity in children who often show noncompliance to traditional testing approaches.

A 45-year-old man presented with longstanding poor vision in both eyes. His medical history was significant for a remote overdose of quinine. After the ingestion, he fell into a coma and on awakening was not able to see light out of both eyes. Several days later, his central vision began to gradually recover and continued to improve over the span of several months. Presently, he had 20/20 visual acuity in both eyes with severely constricted peripheral visual fields. There were bilateral iris transillumination defects, and both optic nerves were diffusely pale with attenuated vasculature and inner retinal thinning on ocular coherence tomography. We present a patient with the stereotypical findings and natural history of quinine toxicity, a rare and not widely known cause of toxic optic neuropathy and retinopathy.