PEDF-derived peptide protects against Amyloid-ß toxicity in vitro and prevents retinal dysfunction in rats.

Amyloid-beta (Aß), a family of aggregation-prone and neurotoxic peptides, has been implicated in the pathophysiology of age-related macular degeneration (AMD). We have previously shown that oligomeric and fibrillar species of Aß42 exerted retinal toxicity in rats, but while the consequences of exposure to amyloid were related to intracellular effects, the mechanism of Aß42 internalization in the retina is not well characterized. In the brain, the 67 kDa laminin receptor (67LR) participates in Aß-related neuronal cell death. A short peptide derived from pigment epithelium-derived factor (PEDF), formerly designated PEDF-335, was found to mitigate experimental models of ischemic retinopathy via targeting of 67LR. In the present study, we hypothesized that 67LR mediates the uptake of pathogenic Aß42 assemblies in the retina, and that targeting of this receptor by PEDF-335 may limit the internalization of Aß, thereby ameliorating its retinotoxicity. To test this assumption ARPE-19 cells in culture were incubated with PEDF-335 before treatment with fibrillar or oligomeric structures of Aß42. Immunostaining confirmed that PEDF-335 treatment substantially prevented amyloid internalization into ARPE-19 cells and maintained their viability in the presence of toxic oligomeric and fibrillar Aß42 entities in vitro. FRET competition assay was performed and confirmed the binding of PEDF-335 to 67LR in RPE-like cells. Wild-type rats were treated with intravitreal PEDF-335 in the experimental eye 2 days prior to administration of retinotoxic Aß42 oligomers or fibrils to both eyes. Retinal function was assessed by electroretinography through 6 weeks post injection. The ERG responses in rats treated with oligomeric or fibrillar Aß42 assemblies were near-normal in eyes previously treated with intravitreal PEDF-335, whereas those measured in the control eyes treated with injection of the Aß42 assemblies alone showed pathologic attenuation of the retinal function through 6 weeks. The retinal presence of 67LR was determined ex vivo by immunostaining and western blotting. Retinal staining demonstrated the constitutional expression of 67LR mainly in the retinal nuclear layers. In the presence of Aß42, the levels of 67LR were increased, although its retinal distribution remained largely unaltered. In contrast, no apparent differences in the retinal expression level of 67LR were noted following exposure to PEDF-335 alone, and its pattern of localization in the retina remained similarly concentrated primarily in the inner and outer nuclear layers. In summary, we found that PEDF-335 confers protection against Aß42-mediated retinal toxicity, with significant effects noted in cells as well as in vivo in rats. The effects of PEDF-335 in the retina are potentially mediated via binding to 67LR and by at least partial inhibition of Aß42 internalization. These results suggest that PEDF-335 may merit further consideration in the development of targeted inhibition of amyloid-related toxicity in the retina. More broadly, our observations provide evidence on the importance of extracellular versus intracellular Aß42 in the retina and suggest concepts on the molecular mechanism of Aß retinal pathogenicity.

Accelerated hydroxychloroquine toxic retinopathy.

PURPOSE: To report a case series of patients with retinal toxicity due to hydroxychloroquine (HCQ) within a short span of treatment. METHODS: A retrospective review of case records of patients with accelerated HCQ toxicity within 1 year of starting the treatment was done. Systemic co-morbidities, details of HCQ treatment, details of ocular examination, and results of multimodal investigations were noted. RESULTS: Nine patients (1 male, 8 females) with age ranging from 40 to 73 years (mean 54.2 ± 13.4 years) who showed accelerated HCQ toxicity were included. None had systemic conditions or drug history predisposing to early HCQ toxicity. The treatment duration ranged from 2 to 11 months and the cumulative HCQ dose ranged from 18 to 120 g (mean 45.0 ± 33.0 g). The visual acuity was normal in 8 (88.9%) patients and retinal evaluation was normal in 4 (44.4%). Optical coherence tomography was abnormal in 4 (44.4%). Six (66.6%) cases had reduced sensitivity in the parafoveal point on visual field testing. All 9 cases had multifocal electroretinographic changes diagnostic of HCQ toxicity. The HCQ treatment was stopped in 8 and continued with reduced dose in 1 patient. The mean duration of follow-up was 11.2 ± 9.6 months during which 5 patients showed improved mfERG and 1 patient had a stable mfERG. Visual fields improvement was noted in 2 cases. CONCLUSIONS: Patients on HCQ need to be kept on regular monitoring with more frequent follow-ups to detect signs of early onset toxicity and prevent permanent visual impairment. mfERG is an important diagnostic tool for HCQ toxicity.

Factors associated with early hydroxychloroquine-induced retinal toxicity in patients with systemic lupus erythematosus.

PURPOSE: Hydroxychloroquine is currently recommended for the treatment of systemic lupus erythematosus (SLE), but it can cause irreversible retinal toxicity. This study aimed to identify factors associated with early hydroxychloroquine-induced retinal toxicity in patients with SLE from a single centre for 20 years. METHODS: SLE patients diagnosed between 1998 and 2017 and followed up for at least 1 year were included. Demographic, clinical, laboratory and therapeutic data were collected from the electronic medical records and retrospectively analysed. Early hydroxychloroquine-induced retinal toxicity was defined as the development of macular toxicity within the first 5 years of hydroxychloroquine treatment. RESULTS: A total of 345 patients followed for a median of 15 years were analysed; 337 (97.7%) patients received hydroxychloroquine, 38 (11.3%) of them presented with retinal toxicity, and 10 (3%) developed early retinal toxicity. These patients had a mean treatment duration of 3.3 years with a mean cumulative dose of 241 g. Patients were diagnosed by visual field (VF) and fundoscopy, and two were also assessed using spectral domain optical coherence tomography (SD-OCT). The median (IQR) age of patients with early toxicity was 56 (51-66) years, and 80% were female. Factors independently associated with early hydroxychloroquine-induced retinal toxicity were lupus anticoagulant positivity (OR 4.2; 95% CI 1.2-15.5) and hypercholesterolaemia (OR 5.6; 95% CI 1.5-21.5). CONCLUSION: Our results suggest that lupus anticoagulant positivity and hypercholesterolaemia among SLE patients may be risk factors for early hydroxychloroquine-induced retinal toxicity, regardless of the dose or duration of treatment.

SCREENING PRACTICES AND LATE DIAGNOSIS OF HYDROXYCHLOROQUINE RETINOPATHY IN ASIAN PATIENTS.

PURPOSE: To investigate the associations between screening practices and late diagnosis in Asian patients with hydroxychloroquine retinopathy. METHODS: In total, 92 Korean patients with hydroxychloroquine retinopathy were included and separated into late diagnosis and earlier diagnosis groups according to the retinopathy stage at the time of diagnosis. Details of screening practices regarding timing and modalities for baseline and annual monitoring examinations were compared between the two groups. Adherence to the current American Academy of Ophthalmology guidelines was compared between the two groups. RESULTS: Timing of baseline and initial monitoring examinations was appropriate as per the Academy of Ophthalmology guidelines in only 5.3% of patients with late diagnosis. There were significant differences in the proportions of patients receiving initial monitoring at 5 years of use and those receiving annual monitoring between the late and earlier diagnosis groups ( P = 0.003 and <0.001, respectively). The duration from the start date of hydroxychloroquine therapy to the first monitoring examination was significantly prolonged in the late diagnosis group ( P < 0.001). Multivariate logistic regression revealed significant association of the time duration with the first monitoring examination ( P = 0.042) and age ( P = 0.028) with late diagnosis. CONCLUSION: Results of this study suggest that poor adherence to the Academy of Ophthalmology guideline, particularly delayed initial monitoring, may be associated with late diagnosis of hydroxychloroquine retinopathy.

OPTICAL COHERENCE TOMOGRAPHY FINDINGS IN PRESUMED VETERINARY ANTHELMINTIC DRUG-INDUCED RETINAL TOXICITY: A Glimpse into Underlying Mechanism.

PURPOSE: To report optical coherence tomography findings of presumed veterinary anthelmintic drugs (VADs)-induced retinal toxicity that may aid in understanding potential pathogenic mechanisms. METHODS: This is a retrospective observational case series analysis of patients with vision abnormalities following the accidental or intentional consumption of veterinary anthelmintic drugs. All cases underwent a thorough ophthalmological examination. Moreover, medical records, as well as the initial and follow-up optical coherence tomography images, were thoroughly scrutinized. RESULTS: Four patients were identified (3 men; mean [range] age, 36.5 [22-52] years). Each patient overdosed on one or two of the following VADs: closantel, triclabendazole, praziquantel, pyrantel pamoate, and niclofolan. The most characteristic optical coherence tomography finding was diffuse, granular, hyperreflective lesions throughout the outer retina, which were initially identified in the ellipsoid zone in two cases. At follow-up, optical coherence tomography exhibited regression of hyperreflective lesions and extensive loss of the outer retinal elements in two patients. In addition, the subfoveal outer retinal layers may be partially preserved. CONCLUSION: Some veterinary anthelmintic drugs could be detrimental to the human retina if overdosed, resulting in visual disturbances. Optical coherence tomography revealed the mitochondria-enriched ellipsoid zone where outer retinal damage first appeared on, implying that these medications may harm the retina by inhibiting mitochondrial energy metabolism, as they do to eliminate parasites.

PREVALENCE OF DIDANOSINE-RELATED RETINAL TOXICITY AT AN URBAN ACADEMIC CENTER AS DIAGNOSED WITH ULTRA-WIDEFIELD IMAGING.

PURPOSE: Antiretroviral therapy has revolutionized HIV treatment with didanosine (DDI) as a pioneering drug. However, DDI has been associated with retinal toxicity, characterized by peripheral chorioretinal degeneration with macular sparing. Despite its clinical recognition, the prevalence and risk factors for didanosine-induced retinopathy are not well described. METHODS: This retrospective case series analyzed 127 DDI-treated patients at Weill Cornell Medicine Department of Ophthalmology. Inclusion criteria included at least 6 months of DDI use and available ultra-widefield imaging. Patients were categorized as affected or unaffected based on retinal imaging assessed by two reviewers. The affected group was further divided into "probable" or "possible" retinopathy. Patient demographics, DDI usage characteristics, and imaging findings were analyzed with statistical comparisons drawn between affected and unaffected cohorts. RESULTS: Of the 127 patients, 9 (7%) showed signs of didanosine-induced retinal toxicity. On average, the affected group was older compared with the unaffected group (65.1 vs. 56.5 years, P = 0.025), with lower BMI (23.2 vs. 27.4, P = 0.04), and older at the start of the treatment (51.6 vs. 40.8 years, P = 0.026). Mild phenotypes with peripheral pigmentary changes were also identified using ultra-widefield imaging. CONCLUSION: This pioneering academic study highlighted a notable prevalence of DDI-induced retinal toxicity. Statistical analysis demonstrated age, BMI, and age at treatment initiation as potential risk factors. Ultra-widefield autofluorescence emerged as a valuable tool in detecting and delineating findings. Follow-up studies are needed to determine the necessity of regular screening for individuals on or with a history of didanosine use.

Hydroxychloroquine Dose and Risk for Incident Retinopathy : A Cohort Study.

BACKGROUND: Hydroxychloroquine is recommended for all patients with systemic lupus erythematosus and is often used for other inflammatory conditions, but a critical long-term adverse effect is vision-threatening retinopathy. OBJECTIVE: To characterize the long-term risk for incident hydroxychloroquine retinopathy and examine the degree to which average hydroxychloroquine dose within the first 5 years of treatment predicts this risk. DESIGN: Cohort study. SETTING: U.S. integrated health network. PARTICIPANTS: All patients aged 18 years or older who received hydroxychloroquine for 5 or more years between 2004 and 2020 and had guideline-recommended serial retinopathy screening. MEASUREMENTS: Hydroxychloroquine dose was assessed from pharmacy dispensing records. Incident hydroxychloroquine retinopathy was assessed by central adjudication of spectral domain optical coherence tomography with severity assessment (mild, moderate, or severe). Risk for hydroxychloroquine retinopathy was estimated over 15 years of use according to hydroxychloroquine weight-based dose (>6, 5 to 6, or ≤5 mg/kg per day) using the Kaplan-Meier estimator. RESULTS: Among 3325 patients in the primary study population, 81 developed hydroxychloroquine retinopathy (56 mild, 17 moderate, and 8 severe), with overall cumulative incidences of 2.5% and 8.6% at 10 and 15 years, respectively. The cumulative incidences of retinopathy at 15 years were 21.6% for higher than 6 mg/kg per day, 11.4% for 5 to 6 mg/kg per day, and 2.7% for 5 mg/kg per day or lower. The corresponding risks for moderate to severe retinopathy at 15 years were 5.9%, 2.4%, and 1.1%, respectively. LIMITATION: Possible misclassifications of dose due to nonadherence to filled prescriptions. CONCLUSION: In this large, contemporary cohort with active surveillance retinopathy screening, the overall risk for hydroxychloroquine retinopathy was 8.6% after 15 years, and most cases were mild. Higher hydroxychloroquine dose was associated with progressively greater risk for incident retinopathy. PRIMARY FUNDING SOURCE: National Institutes of Health.

Quality of hydroxychloroquine retinopathy screening at a Canadian teaching hospital.

PURPOSE: To assess the quality of hydroxychloroquine (HCQ)-induced retinopathy screening at a Canadian tertiary center, we concentrate on risk factor documentation within the electronic health record, in accordance with the 2016 AAO guidelines. METHODS: We performed a retrospective quality assessment study based on chart review of patients who underwent screening for HCQ-induced retinopathy at the Centre Hospitalier de l'Université de Montréal (CHUM) from 2016 to 2019. We evaluated four key risk factors for HCQ-induced retinopathy: daily dose, duration of use, renal disease, and tamoxifen use, using a three-tier grading system (ideal, adequate, inadequate) for documentation assessment. Pareto and root cause analyses were conducted to identify potential improvement solutions. RESULTS: Documentation quality varied in our study: daily dosage was 33% ideal, 31% appropriate, and 36% inappropriate. Duration of use documentation was 75% ideal, 2% adequate, and 24% inadequate. Renal disease documentation was only 6% ideal, with 62% adequate and 32% of charts lacking any past medical history. Among women's charts, tamoxifen use wasn't documented at all, with 65% adequately documenting medication lists. Pareto analysis indicated that improving renal disease and tamoxifen documentation could reduce 64% of non-ideal records, and enhancing daily dose documentation could decrease this by up to 90%. CONCLUSION: Accurate documentation of key risk factors is critical for HCQ-induced retinopathy screening, impacting both exam initiation and frequency. Our study identifies potential improvements in the screening process at the hospital, referring physician, and ophthalmologist levels. Implementing integrated pathways could enhance patient experience and screening effectiveness.

The assessment of structural and functional test results for early detection of hydroxychloroquine macular toxicity.

PURPOSE: To assess structural (optical coherence tomography, fundus autofluorescence) and functional (contrast sensitivity and visual field) test results which were used for detecting early retinal changes in patients using oral hydroxychloroquine. METHODS: Patients using oral hydroxychloroquine for at least one year were divided into two groups according to the duration of drug use. Groups 1 and 2 consisted of patients with drug use for more than 5 years and 1-5 years, respectively. The drug-using groups were compared with the control group. The mean retinal nerve fiber layer (RNFL), central macular thickness (CMT), ganglion cell-inner plexiform layer (GC-IPL), static 10-2 visual field, fundus autofluorescence (FAF) imaging, and contrast sensitivity tests were performed and statistically compared between groups. RESULTS: Median and temporal quadrant RNFL thicknesses were found to be statistically significantly lower in the drug groups. In the drug groups, the GC-IPL sectoral and mean thicknesses were found to be statistically lower in all quadrants. Central macular thickness was also found to be similar in all three groups. There was no significant difference between the groups in visual field parameters. Macular FAF images were significantly higher in the drug users, but there was no significant difference between the three groups in foveal FAF images. Contrast sensitivity measurements were significantly lower in the drug groups than in the control group at all spatial frequencies except 6 and 18 cycles/degree. CONCLUSIONS: The combined use of structural and functional tests in patients using hydroxychloroquine provides useful information in detecting early retinal changes.

A case of successful treatment of a rare retinal disease presented by interferon-induced retinopathy.

OBJECTIVE: Aim: To showcase a rare retinal lesion and the results of contemporary diagnostic and treatment of interferon-induced retinopathy. PATIENTS AND METHODS: Materials and Methods: We describe a case of a 36-year-old patient with interferon-induced retinopathy, with hepatitis C, that received prolonged interferon treatment. Clinical signs, examination and combined laser and pharmacologic treatment were showcased in the study. RESULTS: Results: As a result of pharmacologic and laser treatment, the patient's visual acuity increased from 0.1 to 1.0 through the duration of 3 months after treatment. The patients` condition remained stable under dynamic observation. CONCLUSION: Conclusions: Because interferon-induced retinopathy is a rare occurrence in routine ophthalmologic practice, combined laser therapy can be used for treatment of preretinal hemorrhage, which leads to improvement of visual functions and stabilization of the retinal processes. This case is an addition to the few described cases of interferon-induced retinopathy.

A corneo-retinal hypercitrullination axis underlies ocular injury to nitrogen mustard.

The vesicant sulfur mustard (SM) is a chemical warfare agent that causes acute and chronic injury to the cornea and proximal anterior segment structures. Despite clinical evidence of SM-exposure causing unexplained retinal deficits, there have been no animal studies conducted to examine the retinal toxicity of this vesciant. The cardinal hallmark of retinal response to stressors or injury is the activation of reactive gliosis, a cellular process largely governed by Müller glia. Previously we showed that corneal exposure to sodium hydroxide elicits rapid induction of reactive gliosis and results in retinal degeneration in a dose-related manner. Based on this evidence, we hypothesized that the vesicant nitrogen mustard (NM), an analog of SM, may also elicit reactive gliosis. To test this idea, we developed a mouse model of NM ocular injury and investigated corneal and retinal effects focusing on citrullination, a posttranslational modification (PTM) of proteins. This PTM was recently linked to alkali injury and has also been shown to occur in retinal degenerative conditions. Here, we demonstrate that corneal exposure to 1% NM causes a synchronous activation of citrullination in both the cornea and retina with hypercitrullination becoming apparent temporally and manifesting with altered cellular expression characteristics. A key finding is that ocular citrullination occurs acutely as early as 1-h post-injury in both the cornea and retina, which underscores a need for expeditious interception of this acute corneal and retinal response. Moreover, exploiting dose response and temporal studies, we uncoupled NM-induced retinal citrullination from its induction of retinal gliosis. Our findings demonstrate that hypercitrullination is a common corneo-retinal mechanism that sensitizes the eye to NM injury and suggests that counteracting hypercitrullination may provide a suitable countermeasure to vesicant injury.

Fundus autofluorescence, optical coherence tomography and electroretinography abnormalities in a patient with digoxin retinopathy that resemble those in KCNV2-associated retinopathy.

BACKGROUND: Digoxin related retinal toxicity causes blurred vision, photophobia, central scotoma, color vision abnormality, and electroretinography (ERG) abnormalities. Here, we report a case with transient abnormalities in vison, in which fundus autofluorescence (FAF), optical coherence tomography (OCT), and ERG findings resembled those in KCNV2 (potassium voltage-gated channel modifier subfamily V member 2)-associated retinopathy. CASE REPORT: An 89-year-old woman presented with complaints of acute blurred vision, nyctalopia, photophobia, and color vision abnormality. She received digoxin for tachycardia induced by atrial fibrillation for a month. The fundi showed a faint white ring at the fovea, which showed hyperfluorescence in FAF. OCT showed a thickened EZ in the macula. A dark-adapted (DA)-30 ERG showed a reduced and "squaring (trough-flattened)" a-wave, and a delayed, supernormal b-wave, resulting in a high b/a-wave amplitude ratio. The digoxin dose was reduced following an elevation in serum levels. Five weeks later, her visual acuities improved, and abnormal hyperfluorescence on FAF disappeared. After 6 months, no visual symptoms were reported. The ellipsoid-zone thickening in OCT improved; however, the b/a-wave amplitude ratio on DA-30 ERG remained high. The b-wave in LA-long-flash ERG was initially reduced, which improved after correction of serum level of digoxin. CONCLUSIONS: The patient's clinical findings resembled those of patients with KCNV2-associated retinopathy or temporal hyperkalemia. These disorders appear to have a common pathogenesis, which may be related to abnormal extracellular potassium levels in the retina. The on-bipolar cells seemed to be more affected than the off-bipolar cells in digoxin related retinal toxicity.

Occult retinopathy following treatment of Hepatitis C with glecaprevir/pibrentasvir (Mavyret).

BACKGROUND/PURPOSE: Medication-induced ocular toxicity is an important consideration in the differential diagnosis of unexplained visual disturbance. We present a case of visual disturbance after starting treatment with glecaprevir/pibrentasvir (Mavyret), a therapy for Hepatitis C virus approved by the FDA in 2017. METHODS: A 50-year-old male with no significant ocular history experienced bilateral visual disturbance, including visual field and acuity loss, shortly after initiating treatment with Mavyret for Hepatitis C. Examination of the anterior and posterior segments was unremarkable, and no abnormalities could be identified on multimodal imaging of the eye and brain, including MRI, SD-OCT, and fundus autofluorescence. Extensive testing for inflammatory, infectious, nutritional, and genetic etiologies for optic neuropathy and retinopathy was negative. RESULTS: Electrophysiology testing was pursued to narrow the broad differential diagnosis. Full-field electroretinography and multi-focal electroretinography detected deficiencies in the rod and cone visual pathways and attenuated electrophysiologic responses in the fovea. Pattern electroretinography and visually-evoked potentials demonstrated macula dysfunction. Taken together, electrophysiologic data suggested diffuse retinal dysfunction, which was most pronounced in the macula. CONCLUSIONS: Given the temporal relationship between Mavyret administration and vision loss in our patient, and the absence of an underlying cause after extensive evaluation, we propose that Mavyret may be associated with a toxic occult retinopathy characterized by panretinal dysfunction without clinically apparent structural findings.

Retinal microvascular density analysis in patients with rheumatoid arthritis treated with hydroxychloroquine.

PURPOSE: Rheumatoid arthritis (RA) is the most common inflammatory joint disease, and hydroxychloroquine (HCQ) is an established treatment. The extent to which HCQ impacts ocular microvascular vessel density (VD) in patients with RA without evidence of HCQ retinopathy has not yet been conclusively clarified. The main aim of this study was to evaluate VD measured by optical coherence tomography angiography (OCTA) in patients with RA treated with HCQ. METHODS: The VD data of the 3 × 3 mm OCT angiogram (RTVue XR Avanti, Optovue Inc., Fremont, California, USA) as well as the retinal thickness (RT) data of patients with RA (n = 30) and healthy controls (n = 30) were extracted and analyzed. The study group was further divided into patients undergoing HCQ treatment for > 5 years (high-risk-group) and < 5 years (low-risk group). RESULTS: Patients with RA showed no evidence of VD reduction compared to the control group in all obtained regions (p > 0.05). Correlation analysis revealed no dependency between VD, RT, and HCQ therapy duration or cumulative HCQ dose (p > 0.05). High-risk patients showed a decreased VD in the superficial quadrant of the superficial capillary plexus compared to low-risk-patients (p = 0.022). Whole-en-face RT was reduced in the high-risk group compared to the control group (p = 0.019). CONCLUSION: Our study showed no evidence that HCQ diminishes VD in patients with RA without HCQ retinopathy measured by OCTA. However, RA patients with a long duration of therapy showed a significantly reduced RT. Our results suggest that quantitative VD analysis by OCTA may not be suitable for early detection of HCQ retinopathy and that the focus on detecting early HCQ retinopathy should be on intensive and sequential OCT diagnostics.

CHOROIDAL VASCULARITY INDEX IN HYDROXYCHLOROQUINE TOXIC RETINOPATHY: A Quantitative Comparative Analysis Using Enhanced Depth Imaging In Spectral Domain Optical Coherence Tomography.

PURPOSE: To investigate choroidal involvement in eyes of patients treated with hydroxychloroquine (HCQ), by quantifying the choroidal vascularity index (CVI) and other choroidal biomarkers. METHODS: Vertical enhanced depth imaging spectral domain optical coherence tomography (SD-OCT) scans were performed in eyes with either advanced-stage or mild HCQ toxic retinopathy, as well as in healthy age-matched and sex-matched controls. Based on SD-OCT scans, the subfoveal and mean choroidal thickness (ChT) was measured. The CVI, total choroidal area (TCA), luminal choroidal area (LCA), and stromal choroidal area (SCA) were calculated based on a binarization image process. These variables were computed and compared between the three groups (i.e., advanced stage, mild toxicity, and healthy controls). RESULTS: Forty-eight eyes of 47 patients under HCQ (26 eyes presented with advanced stage HCQ toxicity and 22 eyes with mild toxicity) and 34 eyes of 31 healthy controls were included. Both CVI and ChT were significantly different between the three groups ( P < 0.001, P < 0.001). When comparing the advanced stage toxicity group to healthy controls, both the subfoveal and the mean ChT were diminished ( P < 0.001). The CVI, TCA, LCA, and SCA were significantly lower in the advanced stage of toxicity group when compared with controls ( P < 0.001, <0.00001, <0.0001, and P = 0.0094, respectively). CONCLUSION: Our study suggests that eyes with HCQ toxic retinopathy, especially at advanced stages, present with choroidal impairment, giving further pathophysiological insights into the unfolding of this retinal toxicity.

REFINING THE RETINAL PHENOTYPE OF PATIENTS WITH SUSPECTED PENTOSAN POLYSULFATE SODIUM RETINOPATHY.

PURPOSE: To refine the retinal phenotypes of suspected pentosan polysulfate sodium toxicity using ultra-widefield imaging. METHODS: Patients with complete dosing profiles who visited the ophthalmology department and with ultra-widefield and optical coherence tomography imaging records were identified using electronic health records at a large academic center. Retinal toxicity was initially identified using previously published imaging criteria, while grading was categorized using both previously reported and new classification systems. RESULTS: One hundred and four patients were included in this study. Twenty-six (25%) were identified as having toxicity from PPS. The mean duration of exposure and cumulative dose between the retinopathy group (162.7 months, 1,803.2 g) were longer and higher compared with the nonretinopathy group (69.7 months, 972.6 g) (both P < 0.001). There was variability of extramacular phenotype in the retinopathy group, with four eyes having only peripapillary involvement and six eyes having far peripheral extension. CONCLUSION: Retinal toxicity in the setting of prolonged exposure and increased cumulative dosing from PPS therapy produces phenotypic variability. Providers should be aware of the extramacular component of toxicity when screening patients. Understanding the different retinal phenotypes may prevent continued exposure and reduce the risk of vision-threatening foveal-involving disease.

"En Face" Spectral-Domain Optical Coherence Tomography versus Multifocal Electroretinogram in Hydroxychloroquine Retinopathy Screening.

INTRODUCTION: The performance of "en face" optical coherence tomography (OCT) in screening for chloroquine (CQ) or hydroxychloroquine (HCQ) retinopathy has not been largely explored. The aim of this study was to determine the concordance of "en face" OCT with multifocal electroretinography (mfERG) in screening for CQ/HCQ retinopathy. METHODS: This is a prospective cohort study conducted at the Rothschild Foundation Hospital, Paris, between August 2016 and February 2021. Patients taking HCQ were followed up over 2 consecutive years and received an "en face" OCT and a mfERG on each visit. RESULTS: A total of 91 patients (182 eyes) were analyzed. mfERG and "en face" OCT were concordant in 147 eyes (86.3%). Cohen's kappa coefficient for concordance between mfERG and "en face" OCT was considered weak with a value 0.61 (95% CI: 0.50-0.72). The sensitivity and specificity of "en face" OCT were 70% (95% CI: 59-79%) and 91% (95% CI: 83-96%), respectively, relatively to mfERG. Proportion of abnormal R2/R5 and R3/R5 ratios did not differ between patients with normal and abnormal "en face" OCT (p = 0.2). DISCUSSION: "En face" OCT and mfERG have low concordance and cannot be used interchangeably as each investigation evaluates a different facet of CQ/HCQ retinopathy. "En face" OCT could be used as a complement in screening for CQ/HCQ retinal toxicity if the anomalies detected on "en face" OCT are confirmed by B-scan OCT sections.

Analysis of the outer retinal thickness pixel maps for the screening of hydroxychloroquine retinopathy.

PURPOSE: To describe the findings and new interpretation methods of retinal thickness maps in the setting of hydroxychloroquine (HCQ) therapy. METHODS: A case series of 27 patients with a history of HCQ intake of more than 5 years and 21 normal subjects as the control group were studied. Patients were tested using swept-source optical coherence tomography (OCT). Custom-made 10 × 10 retinal thickness pixel maps of the 6 mm⨯6 mm area centered on the fovea were created for the full, inner, and outer retina of each eye and normal values obtained from the control group were used to calculate the statistical significance of each pixel and highlight suspicious pixels. A pixel was shown with light or dark gray color if its p value was ≤ 0.05 or ≤ 0.01, respectively. Cross-sectional OCT images and visual fields were examined as well and used to confirm the diagnosis of HCQ retinopathy. RESULTS: The pixel outer retinal thickness maps appeared accurate in detecting lesions even in eyes with unremarkable full retina thickness maps. The size and location of atrophic retinal defects were shown on pixel maps. Outer retinal thickness maps were able in differentiating outer retinal thinning from inner retinal thinning as the hallmark of HCQ retinopathy. CONCLUSION: Outer retinal thickness pixel maps can be used for the screening of HCQ retinopathy.

[Toxic retinopathy caused by veterinary antiparasitic closantel: a case report].

A 32-year-old female patient presented with bilateral vision loss for 2 months following her intake of various antiparasitic drugs, including closantel, a veterinary drug, for a self-perceived intraocular parasitic infection. Swept-source optical coherence tomography revealed diffuse hyperreflectivity between the outer nuclear layer and the retinal pigment epithelium, as well as the largely indistinguishable outer retinal layers. This case was clinically diagnosed with veterinary closantel-induced toxic retinopathy and had a poor visual prognosis after nerve nutrition and circulation improvement therapy due to the long duration of the disease.

[Protective effect of melatonin against oxygen-induced retinopathy: a study based on the HMGB1/NF-κB/NLRP3 axis]. / 基于HMGB1/NF-κB/NLRP3è½´æŽ¢è®¨è¤ªé»‘ç´ å¯¹æ°§è¯±å¯¼è§†ç½‘è†œç— å˜çš„ä¿æŠ¤ä½œç”¨.

OBJECTIVES: To study the protective effect of melatonin (Mel) against oxygen-induced retinopathy (OIR) in neonatal mice and the role of the HMGB1/NF-κB/NLRP3 axis. METHODS: Neonatal C57BL/6J mice, aged 7 days, were randomly divided into a control group, a model group (OIR group), and a Mel treatment group (OIR+Mel group), with 9 mice in each group. The hyperoxia induction method was used to establish a model of OIR. Hematoxylin and eosin staining and retinal flat-mount preparation were used to observe retinal structure and neovascularization. Immunofluorescent staining was used to measure the expression of proteins and inflammatory factors associated with the HMGB1/NF-κB/NLRP3 axis and lymphocyte antigen 6G. Colorimetry was used to measure the activity of myeloperoxidase. RESULTS: The OIR group had destruction of retinal structure with a large perfusion-free area and neovascularization, while the OIR+Mel group had improvement in destruction of retinal structure with reductions in neovascularization and perfusion-free area. Compared with the control group, the OIR group had significant increases in the expression of proteins and inflammatory factors associated with the HMGB1/NF-κB/NLRP3 axis, the expression of lymphocyte antigen 6G, and the activity of myeloperoxidase (P<0.05). Compared with the OIR group, the OIR+Mel group had significant reductions in the above indices (P<0.05). Compared with the control group, the OIR group had significant reductions in the expression of melatonin receptors in the retina (P<0.05). Compared with the OIR group, the OIR+Mel group had significant increases in the expression of melatonin receptors (P<0.05). CONCLUSIONS: Mel can alleviate OIR-induced retinal damage in neonatal mice by inhibiting the HMGB1/NF-κB/NLRP3 axis and may exert an effect through the melatonin receptor pathway.