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Parastou Pakravan, Shahnaz Miri, Byron L Lam Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USACorrespondence: Byron L Lam, Bascom Palmer Eye Institute, 900 NW 17th St, Miami, FL, 33136, USA, Email blam@med.miami.eduObjective: To describe a case of optic neuropathy after prolonged sirolimus therapy in the setting of cardiac transplant.Background: Sirolimus is an immunosuppressant that inhibits Mechanistic Target of Rapamycin (mTOR) and blocks T-cell activation and B-cell differentiation by preventing response to Interleukin-2 (IL-2). Tacrolimus is another immunosuppressive agent, one of the known but uncommon side effects of which is bilateral optic neuropathy years after taking the medication. To the best of our knowledge, this is the first report of sequential optic neuropathy after years of treatment with sirolimus.Case Presentation: A 69-year-old male with a history of cardiac transplantation presented with progressive, sequential, and painless vision loss. Visual acuity was 20/150 OD and 20/80 OS, with impaired color vision in both eyes (Ishihara 0/10) and bilateral disc pallor and mild optic disc edema in the left eye. Visual field was constricted in both eyes. The patient was on prolonged sirolimus therapy for over 7 years. Orbital MRI revealed bilateral chiasmatic thickness and FLAIR hyperintensity, without optic nerve enhancement post gadolinium. After extensive work up, other etiologies such as infectious, inflammatory, and neoplastic lesions were ruled out. Subsequently, sirolimus was substituted with cyclosporin that led to gradual improvement of vision and visual fields bilaterally.Conclusion: Optic neuropathy is a rare side effect of tacrolimus, which has been seen as sudden, painless, and bilateral vision loss in post-transplant patients. Other concurrent medications influencing the cytochrome P4503A enzyme complexes may alter the pharmacokinetics of tacrolimus and increase the likelihood of toxicity. Discontinuation of offending agent has been shown to improve visual defects. We presented a rare case of optic neuropathy in a patient on sirolimus, whose visual defects improved upon discontinuation of sirolimus and switching to cyclosporin.Keywords: sirolimus, optic neuropathy, vision loss, immunosuppressant

Patrick C Staropoli, 1 Richard K Lee, 1 Zachary A Kroger, 2 Karina Somohano, 3 Matthew Feldman, 4 Jennifer D Verriotto, 1 Adam Aldahan, 5 Potyra R Rosa, 1 William J Feuer, 1 D Diane Zheng, 6 David J Lee, 1, 6 Byron L Lam 1 1Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA; 2Ophthalmology Department, Baylor College of Medicine, Houston, TX, USA; 3Ophthalmology Department, New York Presbyterian Hospital, New York, NY, USA; 4Neurology Department, University of Miami Miller School of Medicine, Miami, FL, USA; 5Dermatology Department, University of Minnesota, Minneapolis, MN, USA; 6Department of Public Health Sciences, University Miami School of Medicine, Miami, FL, USACorrespondence: Byron L LamBascom Palmer Eye Institute, 900 NW 17 Street, Miami, FL, 33136, USATel +1 305-326-6021Fax +1 305 326 6114Email blam@med.miami.eduPurpose: To determine what socioeconomic factors affect follow-up in a glaucoma screening program.Patients and Methods: This was a retrospective cohort study of six health fairs in South Florida from October 2012 to March 2013 among socially and economically disadvantaged populations. Visual acuity (VA), intraocular pressure (IOP), cup-to-disc ratio (CDR), and visual field testing were obtained to identify glaucoma suspects. Glaucoma suspects were defined as having intraocular pressure ≥ 24 mm Hg, cup-to-disc ratio of ≥ 0.6 in either eye, or glaucomatous defects on visual field testing. In July 2015, telephone surveys were administered to assess follow up and socioeconomic factors.Results: Seventy-two out of 144 (50%) glaucoma suspects responded to the survey and were included in the analysis. Of the 72 respondents, average age was 52.8 years old and 65% were female. The most common race was African American (69%) and ethnicity was Haitian (51%). Glaucoma suspects who followed up were significantly more likely to have health insurance compared to those who did not follow up (74% vs 43%, p = 0.014). No significant difference in follow-up based on age (p = 0.125), education (p = 0.151), gender (p = 0.48), or ethnicity (p = 0.707) was identified. Of the 30 respondents, who did not follow up, the most common reasons were “no insurance” (57%, 17/30) and “not worried” (33%, 10/30).Conclusion: Insurance was the main socioeconomic factor in determining whether glaucoma suspects followed up after community health screenings. Streamlining social services could increase clinical access of glaucoma suspects.Keywords: epidemiology, follow-up, glaucoma, socioeconomics

Jia Tan,1,2,* Ye Yang,2,3,* Hong Jiang,2,4 Che Liu,2 Zhihong Deng,1,2 Byron L Lam,2 Liang Hu,3 Jonathan Oakley,5 Jianhua Wang2 1Department of Ophthalmology, Xiangya Hospital, Changsha, Hunan, People’s Republic of China; 2Bascom Palmer Eye Institute, University of Miami, Miami, FL, USA; 3School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 4Department of Neurology, University of Miami, Miami, FL, 5Voxeleron LLC, Pleasanton, CA, USA *These authors contributed equally to this work Purpose: To determine the repeatability and profiles with different partition methods in intraretinal thickness layers in healthy human subjects, using optical coherence tomography (OCT). Methods: A custom-built ultrahigh-resolution OCT was used to acquire three-dimensional volume of the macula in 20 healthy subjects. The dataset was acquired twice using the macular cube 512×128 protocol in an area of 6×6 mm2 centered on the fovea. Commercially available segmentation software (Orion™) was used to segment the dataset into thickness maps of six intraretinal layers. The coefficient of repeatability and intraclass coefficient of correlation (ICC) were analyzed using hemispheric zoning and sectors defined by the Early Treatment Diabetic Retinopathy Study (ETDRS). Results: All datasets were successfully segmented to create six thickness maps of individual intraretinal layers. Coefficients of repeatabilities of these layers in hemispheric zones ranged from 0.9 to 6.6 µm, with an average of 3.6 µm (standard deviation [SD] 1.4), which was not significantly different compared to ETDRS sectors (P>0.05). ICCs of these layers in hemispheric zones ranged from 0.68 to 0.99, with an average of 0.91 (SD 0.07). There were no significant differences in ICCs between two zoning methods (P>0.05). Significant variations of tomographic intraretinal thicknesses were found between the inner and outer annuli and among the quadrantal sectors within the inner and outer annuli (P

Angela M Herro, Byron L Lam Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL, USA Background: The aim of this study was to demonstrate the relationship between topographic reduction in macular ganglion cell complex (GCC) thickness as detected with spectral-domain optical coherence tomography and visual field defects caused by ischemic occipital cortical injury.Methods: This study was a retrospective review of all patients who presented to our eye institution between January 2012 and July 2014 with visual field defects secondary to ischemic cortical injury. The visual field defect pattern and mean deviation were analyzed. Retinal nerve fiber layer (RNFL) and macular GCC were both assessed with spectral-domain optical coherence tomography. Patients with any ocular pathology that could affect these measurements were excluded. The topographic relationship of visual field defect to reduction in GCC was specifically analyzed. Results: Nine patients met the inclusion criteria. Their average age was 65 (57–73) years; eight were men and six had right hemianopsias. The laterality of the visual field defect was used to assign an affected and unaffected side of analysis for RNFL and GCC layer thickness. A right hemianopsia meant that the nasal fibers of the right eye and temporal fibers of the left eye were assigned as the “affected side”, and the temporal fibers of the right eye and nasal fibers of the left eye were assigned as “unaffected”. There was no statistically significant difference between affected and unaffected RNFL. However, there was a significant difference in GCC layer reduction between the affected and unaffected sides (P=0.029).Conclusion: There is evidence of retrograde trans-synaptic retinal ganglion cell loss in patients with homonymous hemianopsias from cortical visual impairment. This relationship is reflected in thinning of the GCC and maintains the topographic relationship of the visual field defect. Keywords: homonymous hemianopsia, ganglion cell complex, occipital lobe

Sapir Z Karli, Sophie D Liao, Andrew R Carey, Byron L Lam, Sara T Wester Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA Abstract: This case report details an association of the use of over-the-counter sexual enhancement supplements with atypical optic neuropathy. A 42-year-old man presented with right-sided headache and vision loss of the right eye, which deteriorated to a single quadrant of hand motion over 11 days. Serial orbital magnetic resonance imaging scans demonstrated progressive orbital optic nerve enhancement extending into the optic canal despite high-dose steroid treatment. The patient eventually admitted to using several over-the-counter sexual enhancement supplements prior to the onset of symptoms and throughout the course of his steroid treatment, which he subsequently discontinued. His vision improved to 20/200 with an expanded visual field. Anterior ischemic optic neuropathy has been reported in association with phosphodiesterase (PDE)-5 inhibitor use, but visual loss in association with unregulated sexual enhancement supplements has not been studied. While one case cannot establish association, our case is suggestive of potential dangers of over-the-counter sexual enhancement supplements, which may contain PDE-5 inhibitors, “male hormones,” and “substances that enhance blood production.” The case also underscores the importance of obtaining a careful history of supplements in patients with optic neuropathies. Keywords: optic neuropathy, PDE-5 inhibitor, sildenafil

Sean M Gratton, Byron L LamBascom Palmer Eye Institute, University of Miami, Miller School of Medicine, Miami, FL, USAAbstract: Visual loss due to optic neuropathy is a rare manifestation of thiamine deficiency. We report a case of a 39-year-old woman with a body mass index (BMI) of 29 kg/m2 who developed visual loss and bilateral optic nerve head swelling after a short, self-limited gastrointestinal illness. She was disoriented and inattentive and had absent ankle jerk reflexes, diminished sensation in both legs below the knees, and marked truncal ataxia. Magnetic resonance imaging (MRI) showed increased T2-signal in the medial thalami and mammillary bodies. The serum thiamine level was 8 nmol/L (normal 8–30). The diagnosis of thiamine deficiency was made, and the patient’s vision and neurologic symptoms improved significantly with intramuscular thiamine treatment. Thiamine deficiency can occur in the absence of an obvious predisposing factor such as alcoholism or low body weight. The clinician must be aware of the factors that govern vitamin availability and maintain a high index of suspicion to make the diagnosis in such cases.Keywords: optic neuropathy, nutritional deficiency

Veeral Shah, Leonid Zlotcavitch, Angela M Herro, Sander R Dubovy, Zohar Yehoshua, Byron L LamBascom Palmer Eye Institute, University of Miami, Miller School of Medicine, Miami, FL, USAAbstract: A 7-year-old girl presented with decreased vision in both eyes for 1 month. Examination showed visual acuity of 20/50 and 20/60, no afferent pupillary defect, cecocentral scotomas, and bilateral optic disc edema with extensive peripapillary and macular exudates. Magnetic resonance imaging showed multiple cortical and subcortical white matter lesions. Both the laboratory workup and the systemic examination were unrevealing. However, on follow-up, the patient showed episodic elevations of blood pressure as high as 240/160. Further workup revealed elevated urine catecholamines and a right supra-adrenal mass proven to be a pheochromocytoma by histopathologic analysis. The paroxysmal hypertension resolved, and the visual acuity, visual fields, fundus exam, and neuroimaging improved. The patient was lost to follow-up until age 18 when she developed shortness of breath and was found to have multiple pulmonary metastases identified as pheochromocytoma by biopsy. Genetic testing identified a 3p25-26 (c.482 G>A) VHL gene chromosomal mutation consistent with von Hippel–Lindau disease genotype. Multiple peripheral retinal vascular dilations and small retinal capillary hemangioblastomas were also found. This case highlights the importance of recognizing the lability of blood pressure often seen with pheochromocytomas, which may mask the underlying cause of hypertensive papillopathy and retinopathy, a diagnosis of low clinical suspicion in the pediatric population. The case also underscores the importance of thorough systemic workup, including genotyping to detect conditions where pheochromocytoma may be the presenting sign of the disease, such as multiple endocrine neoplasia 2A and 2B, von Hippel–Lindau disease, von Recklinghausen disease, tuberous sclerosis, and Sturge–Weber syndrome.Keywords: hypertensive encephalopathy, VHL, pheochromocytoma, paroxysmal hypertension

Ajay E Kuriyan, Byron L Lam Bascom Palmer Eye Institute, University of Miami, Miami, FL, USA Purpose: To describe a case of non-arteritic ischemic optic neuropathy (NAION) secondary to acute primary-angle closure (APAC). Methods: Case report. Results: A 50-year-old woman with painful visual loss in the right eye was found to be in APAC with a right afferent pupillary defect. Laser peripheral iridotomy relieved pain but did not improve vision. Diffuse optic disc edema in the right eye and a small cup-to-disc ratio in the left eye were evident. Magnetic resonance imaging was normal. The patient was diagnosed with non-arteritic ischemic optic neuropathy (NAION) secondary to APAC, a rare clinical entity which can result in markedly decreased visual acuity. Conclusion: NAION secondary to APAC is a rare clinical entity that can result in severe vision loss. Keywords: acute angle closure glaucoma, perfusion pressure, NAION, optic nerve

Yufeng Ye,1,2 Hong Jiang,2,3 Meixiao Shen,4 Byron L Lam,2 Delia Cabrera DeBuc,2 Lili Ge,2,4 Mitra Sehi,2 Jianhua Wang21Hangzhou First People’s Hospital, Hangzhou, China; 2Bascom Palmer Eye Institute, 3Neurology, University of Miami, Miami, FL, USA; 4School of Ophthalmology and Optometry, Wenzhou Medical College, Wenzhou, Zhejiang, ChinaBackground: The purpose of this study was to investigate the repeatability of retinal oximetry using slit-lamp adapted ultrahigh-resolution optical coherence tomography (SL-UHR-OCT).Methods: SL-UHR-OCT was developed and fringe patterns were obtained for a major retinal artery and a major retinal vein. A-scans at the central wavelengths of 805 nm and 855 nm were analyzed for calculating optical density ratios (ODRs), from which the percentage oxygen saturation was calculated. Measurements were made on two occasions for each person. Repeatability and coefficients of repeatability were calculated.Results: The mean ODRs of the artery were 0.79 ± 0.86 and 0.88 ± 0.97 in sessions 1 and 2, respectively. The mean ODRs of the vein were −0.08 ± 0.69 and 0.14 ± 0.77 between the two sessions, and were significantly lower than that of the artery (P < 0.05). The coefficients of repeatability were 1.44 and 1.81 for the artery and vein, respectively. The mean oxygen saturation of the major retinal artery was 94% ± 45% and 98% ± 51% in sessions 1 and 2, respectively, and the mean oxygen saturation of the major retinal vein was 48% ± 36% and 60% ± 40% between sessions.Conclusion: Optical coherence tomographic oximetry for evaluating retinal oxygen saturation was subject to variation, although the averaged measurements in repeated sessions were matched. Further work on reducing variation will be needed.Keywords: ultrahigh-resolution optical coherence tomography, oximetry

OBJECTIVE: To examine the association between the presence and severity of concurrent hearing and visual impairment (HI+VI) and morbidity. METHODS: Data for adults 45 years and older were obtained from the National Health Interview Survey, 1986 to 1996 (n = 60,997). Covariate-adjusted logistic regression analyses were used to examine associations between HI+VI and five morbidity indicators: restricted activity days, bed rest days, doctor visits, hospitalizations and self-rated health. RESULTS: Associations with morbidity indicators tended to be stronger in adults with HI+VI, and in particular, among adults with more severe HI+VI, relative to adults reporting no impairment. These associations were somewhat stronger in adults 45 to 64 years versus older adults. DISCUSSION: HI+VI is associated with morbidity, although the strength of these associations varies across subgroups. Findings indicate that an increased focus on the provision of hearing and eye care services is required. Insurance coverage for these services should also be pursued by health policy makers. [ABSTRACT FROM AUTHOR]

Sociodemographic correlates of visual impairment were examined in 6- to 19-year-old Hispanic children and adolescents using data from the Hispanic Health and Nutrition Examination Survey. Mexican American and Puerto Rican children whose parents had 0 to 6 years of education were more likely to remain visually impaired even when tested with their glasses or contact lenses, if any (i.e., with usual correction) than children whose parents reported 12 to 17 years of education. Mexican Americans residing below versus at or above the poverty line were more likely to remain visually impaired even with the usual correction. Mexican Americans enrolled in the Medicaid program or who were without health insurance were more likely to remain visually impaired than Mexican Americans with private health insurance. When tested without glasses or contact lenses, Cuban Americans and Mexican Americans born outside of the mainland United States had lower rates of visual impairment compared to those born in the United States; however, children in this latter group were more likely to remain visually impaired with usual correction than U.S.-born Mexican Americans. These findings suggest that Hispanic children from economically disadvantaged households and those born outside the United States may not be receiving optimal eye care that could improve visual function. [ABSTRACT FROM AUTHOR]

Objective: Compare differences in health-related quality of life among blacks and whites to examine if race, diabetes, and visual impairment (VI) present a triple disadvantage in terms of quality-adjusted life expectancy.Research Design and Methods: Data were analyzed from the 2000-2003 Medical Expenditure Panel Survey, a nationally representative survey that contains the EuroQol 5D (EQ-5D). The EQ-5D generates health utility values that provide a measure of the morbidity associated with various health states, such as having moderate or severe problems with mobility. The EQ-5D score can be linked with life expectancy data to calculate quality-adjusted life-years (QALYs), the number of years of optimal health an individual is expected to live. Multivariate analyses were conducted to estimate and compare differences in QALYs by diabetes status, VI status, and race.Results: Whites had a higher quality-adjusted life expectancy across all diabetes/VI comparisons. Overall, blacks with diabetes and VI had the fewest number of QALYs remaining (19.6 years), and whites with no impairment had the greatest number of QALYs remaining (31.6 years). Blacks with diabetes only had 1.7 fewer years of optimal health (fewer QALYs) than whites with diabetes. Within individuals with both diabetes and VI, however, this gap more than doubled, with blacks experiencing 3.5 fewer QALYs than whites.Conclusions: Although efforts to target and reduce racial health disparities associated with diabetes appear to be effective, black communities may be contributing to a greater overall burden of illness given poorer infrastructure and less accommodation for disabilities such as VI. [ABSTRACT FROM AUTHOR]

Introduction: Usher syndrome (USH) is a rare, autosomal-recessive genetic disorder and a leading cause of early onset deaf-blindness. A clinical diagnosis is made by the presence of retinitis pigmentosa (RP) with sensorineural hearing loss (SNHL). Subtype (USH1, USH2, USH3) is determined by severity and age of onset. Molecular testing is able to further distinguish USH subtypes by causative gene. As gene therapy strategies continue to be explored for USH, it is important to know the underlying genetic cause and to coordinate care among an interdisciplinary team., Methods: We reviewed charts of 198 individuals presenting to the RP clinic at Bascom Palmer Eye Institute (BPEI) for suspected USH. Demographic information, USH clinical diagnosis, molecular testing, molecular diagnosis, and audiological data were collected., Results: Of the 198 patients reviewed, 190 (96%) met clinical criteria for USH and received a clinical diagnosis. There were 67 (35%) that had a genetic test with a pathogenic molecular diagnosis. The average ages at molecular diagnosis were USH1B, 20 years old; USH2A, 37 years old; USH2C, 50 years old. Of the 67 with a molecular diagnosis, 23 (34%) established ophthalmic care and 8 of these (11%) established audiological care., Discussion/conclusion: Molecular testing and diagnosis should be part of the routine care of USH individuals to facilitate earlier interventions and coordinated care between ophthalmology and audiology., Level of Evidence: 4 Laryngoscope, 2024., (© 2024 The Author(s). The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

The silver nanoparticles-sodium alginate-chitosan (AgNPs-Alg-Chi) nanocomposite film is a compelling material with demonstrated antibacterial efficacy against various pure bacterial strains. However, its potential cytotoxicity at elevated Ag doses warrants investigation. There is a notable dearth of studies assessing its antibacterial effectiveness against clinically relevant bacterial strains, notably Cutibacterium acnes . This study aims to assess the antibacterial efficacy of the low-dose AgNPs-Alg-Chi nanocomposite films on both pure bacterial strains and strains isolated from clinical samples obtained from 65 acne patients. The films were synthesized using green methods, incorporating kumquat ( Citrus japonica ) extract as a silver ion-reducing agent. The material characterization methods include UV-Vis and FTIR spectroscopies, SEM-EDS, XPS, cell culture, and MTT assay. We successfully fabricated the AgNPs-Alg-Chi nanocomposite films with a low-loading dose of Ag NPs (≤11 μg mL -1 , and 37.8 ± 11.5 nm in size). The AgNPs-Alg-Chi nanocomposite film demonstrated comparable antibacterial efficacy to the AgNPs-Chi solution, with MIC values ranging from 3.67 to 5.50 μg mL -1 ( p > 0.05) across all strains. Importantly, the AgNPs-Alg-Chi films demonstrated excellent biocompatibility with human keratinocytes (HaCaT cells), maintaining cell viability above 70%. The present AgNPs-Alg-Chi nanocomposite films synthesized by a green approach demonstrated potent antibacterial activity, making them promising for further development into suitable products for human use., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Purpose: To report a case series of 4 patients with poor visual outcomes from concurrent fulminant idiopathic intracranial hypertension (IIH) and malignant arterial hypertension with bilateral optic disc edema. The diagnosis of fulminant IIH was delayed given the bilateral optic disc edema was attributed initially to hypertensive optic neuropathy., Observation: All 4 patients (3 males, 3 African Americans, mean BMI 27.6 kg/m 2 (range 19.5-36 kg/m 2 ) presented to the emergency department with bilateral vision loss, optic disc edema, and blood pressure (BP) of greater than 180/120. The patients were treated initially to control BP and the optic disc edema was either attributed to the hypertension or the ophthalmic examination was not performed. The patients were subsequently diagnosed with IIH with Brain MRI, MR venogram, and lumber puncture (mean cerebrospinal fluid (CSF) opening pressure 42 cm, range 40-43 cm). The mean time from presentation to diagnosis of IIH was 3.2 months (range 1-6 months). The final visual acuity ranged from 20/400 to hand motions in the better eye and count fingers to hand motions in the worse eye despite bilateral optic nerve sheath fenestrations (3 patients), ventriculoperitoneal shunts (3 patients), and treatments with acetazolamide (3 patients) and furosemide (1 patient)., Conclusion: Our case series underscores the need to promptly include IIH in the differential diagnosis in patients with bilateral optic disc edema including patients with malignant hypertension, particularly in those experiencing progressive visual loss, regardless of gender or BMI. Prompt work-up with brain MRI with contrast and MR or CT venogram to detect neuroimaging signs of intracranial hypertension followed by a lumbar puncture with CSF opening pressure are essential to initiate rapid treatment of fulminant IIH to avoid poor outcome., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors have no conflict of interest., (© 2024 The Authors. Published by Elsevier Inc.)

Purpose: Invasive fungal sinusitis (IFS) is associated with high rates of morbidity and mortality and often presents with orbital apex syndrome. Prompt diagnosis and management are crucial to prevent irreversible visual loss. We report a case of an immunosuppressed patient with rapidly progressive severe visual loss associated with frontal lobe cerebritis and leptomeningitis related to IFS, causing an adjacent compressive inflammatory optic neuropathy, which was treated successfully by large-dose corticosteroids., Observations: A 29-year-old woman with acute myeloid leukemia status post chemotherapy presented with right-sided headaches and periorbital swelling. Her examination was significant for subjective red desaturation and trace right eyelid edema and ptosis. The remainder of her initial ocular examination was normal. Her labs demonstrated neutropenia and thrombocytopenia. Imaging of the brain and orbits was concerning for extensive sinus disease with intracranial extension. An urgent multi-sinus and optic nerve decompression was performed given concern for compressive optic neuropathy, and the biopsy was consistent with invasive fungal infection. Despite aggressive antifungal treatment, vision in her right eye decreased rapidly to counting fingers. No optic nerve abnormalities were observed on serial MRIs, but adjacent inferior frontal lobe enhancement was present. After a vigorous debate in a multidisciplinary meeting, her severe vision loss was attributed to cerebritis causing an adjacent compressive inflammatory optic neuropathy, and large-dose intravenous (IV) steroid treatment was initiated while maintaining systemic antifungal therapy. Remarkably, she had a full recovery of her vision., Conclusions and Importance: Severe vision loss in IFS can occur due to compressive inflammatory optic neuropathy without direct fungal invasion as a contributing factor. Timely and effective intervention is crucial in preventing vision loss. Large-dose steroid therapy may be a potential treatment option for immunocompromised patients with invasive fungal sinusitis and intracranial invasion, provided strict fungal infection control measures are in place., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors have no conflict of interest., (© 2024 The Authors. Published by Elsevier Inc.)

Inherited retinal diseases (IRDs) encompass a wide spectrum of rare conditions characterized by diverse phenotypes associated with hundreds of genetic variations, often leading to progressive visual impairment and profound vision loss. Multiple natural history studies and clinical trials exploring gene therapy for various IRDs are ongoing. Outcomes for ophthalmic trials measure visual changes in three main categories-structural, functional, and patient-focused outcomes. Since IRDs may range from congenital with poor central vision from birth to affecting the peripheral retina initially and progressing insidiously with visual acuity affected late in the disease course, typical outcome measures such as central visual acuity and ocular coherence tomography (OCT) imaging of the macula may not provide adequate representation of therapeutic outcomes including alterations in disease course. Thus, alternative unique outcome measures are necessary to assess loss of peripheral vision, color vision, night vision, and contrast sensitivity in IRDs. These differences have complicated the assessment of clinical outcomes for IRD therapies, and the clinical trials for IRDs have had to design novel specialized endpoints to demonstrate treatment efficacy. As genetic engineering and gene therapy techniques continue to advance with growing investment from industry and accelerated approval tracks for orphan conditions, the clinical trials must continue to improve their assessments to demonstrate safety and efficacy of new gene therapies that aim to come to market. Here, we will provide an overview of the current gene therapy approaches, review various endpoints for measuring visual function, highlight those that are utilized in recent gene therapy trials, and provide an overview of stage 2 and 3 IRD trials through the second quarter of 2024.

Purpose: Cotoretigene toliparvovec (BIIB112/AAV8-RPGR) is an investigational vector-based gene therapy designed to provide a full-length, codon-optimized retinitis pigmentosa GTPase regulator (RPGR) protein to individuals with RPGR-associated X-linked retinitis pigmentosa (XLRP). We assessed efficacy and tolerability of cotoretigene toliparvovec subretinal gene therapy., Design: Part 2 of the XIRIUS trial (ClinicalTrials.gov identifier, NCT03116113) was a phase 2/3, 12-month, randomized (1:1:1) dose-expansion study., Participants: Male patients ≥10 years of age with RPGR-associated XLRP were included., Methods: Participants were randomized 1:1:1 to receive low-dose subretinal cotoretigene toliparvovec (5 × 10 10 vector genomes/eye), high-dose cotoretigene toliparvovec (2.5 × 10 11 vector genomes/eye) or to be an untreated control participant., Main Outcome Measures: The primary end point was the percentage of participants meeting microperimetry responder criteria (≥ 7-dB improvement at ≥ 5 of 16 central loci). Secondary end points included change from baseline in retinal sensitivity at the central 16 loci and the entire 68 loci at 12 months and change from baseline in low-luminance visual acuity (LLVA) at 12 months, as well as the proportion of eyes with a ≥ 15-Early Treatment Diabetic Retinopathy Study ETDRS letter LLVA and ≥ 10-ETDRS letter LLVA change from baseline at month 12., Results: Because of the impact of the COVID-19 pandemic, enrollment ended before reaching the initial target, leaving the trial underpowered. Twenty-nine participants were included (low-dose group, n = 10; high-dose group, n = 10; control group, n = 9). At month 12, the percentage of participants meeting microperimetry responder criteria was not significantly different between either cotoretigene toliparvovec group (low dose, 37.5% [P = 0.3181]; high dose, 25.0% [P = 0.5177]) and the control group (22.2%). However, the mean change from baseline in microperimetry sensitivity improved significantly with the low-dose group versus the control group at month 12 (P = 0.0350). Significant improvement in LLVA occurred in the low-dose group versus the control group at month 12 (33.3% difference [80% confidence interval, 14.7%-55.2%]; P = 0.0498). Three ocular-related serious adverse events (SAEs) occurred in the low-dose group versus 7 SAEs in the high-dose group., Conclusions: The primary microperimetry end point was not met. Significant improvements in LLVA and mean microperimetry were observed compared with controls and fewer SAEs occured with low-dose compared with high dose cotoretigene toliparvovec., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2024. Published by Elsevier Inc.)

Objective: To improve the understanding of the natural disease progression of retinitis pigmentosa GTPase regulator ( RPGR ) - associated X-linked retinitis pigmentosa (XLRP)., Design: A multicenter, prospective, observational natural history study over 24 months., Participants: Male participants aged ≥7 years with a pathogenic variant in the RPGR gene, a best-corrected visual acuity (BCVA) score of ≥34 ETDRS letters, and a mean 68-loci retinal sensitivity (assessed by microperimetry) of 0.1 to 20 decibels (dB)., Methods: Participants were divided into subgroups based on their BCVA score at baseline: 34 to 73 (lower BCVA) or ≥74 (higher BCVA) ETDRS letters. There were 7 visits over 24 months., Main Outcome Measures: Change from baseline in BCVA, retinal sensitivity, low luminance visual acuity (LLVA), fixation stability, contrast sensitivity, visual field, anatomical measures, 25-item Visual Function Questionnaire (VFQ-25), intraocular pressure, and adverse events (AEs)., Results: Overall, 201 participants were included. The mean (standard deviation [SD]) age was 30.3 (11.9) years in the lower BCVA subgroup (n = 170) and 27.7 (10.1) years in the higher BCVA subgroup (n = 31). The study eye baseline mean (SD) BCVA scores were 59.4 (10.30) and 77.3 (3.95) in the lower and higher BCVA subgroups, respectively; the lower BCVA subgroup had lower retinal sensitivity in the study eye at baseline than the higher BCVA subgroup. Over 24 months, there were small observed changes in BCVA, retinal sensitivity, LLVA, fixation, contrast sensitivity, and fundus photography findings. There were observed mean (SD) changes at 24 months in the lower and higher BCVA subgroups of -1.01 (4.67) and 0.03 (5.83) dB-steradians in the volume of full-field hill of vision, -330.6 (869.51) and -122.7 (22.01) μm in distance from foveal center to the nearest border of preserved fundus autofluorescence, -104.3 (277.80) and -207.1 (171.01) μm in central ellipsoid width, and -2.8 (9.7) and -0.6 (7.6) in VFQ-25 composite score, respectively. There was 1 death from completed suicide. There were no ocular serious adverse events, and most AEs were mild/moderate., Conclusions: This study provides evidence of the slow natural progression of XLRP over 24 months in both subgroups and provides important functional, anatomical, and safety data., Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (© 2024 by the American Academy of Ophthalmology.)

Choroideremia, an incurable, progressive retinal degeneration primarily affecting young men, leads to sight loss. GEMINI was a multicenter, open-label, prospective, two-period, interventional Phase II study assessing the safety of bilateral sequential administration of timrepigene emparvovec, a gene therapy, in adult males with genetically confirmed choroideremia (NCT03507686, ClinicalTrials.gov). Timrepigene emparvovec is an adeno-associated virus serotype 2 vector encoding the cDNA of Rab escort protein 1, augmented by a downstream woodchuck hepatitis virus post-transcriptional regulatory element. Up to 0.1 mL of timrepigene emparvovec, containing 1 × 10 11 vector genomes, was administered by subretinal injection following vitrectomy and retinal detachment. The second eye was treated after an intrasurgery window of <6, 6-12, or >12 months. Each eye was followed at up to nine visits over 12 months. Overall, 66 participants received timrepigene emparvovec, and 53 completed the study. Visual acuity (VA) was generally maintained in both eyes, independent of intrasurgery window duration, even after bilateral retinal detachment and subretinal injection. Bilateral treatment was well tolerated, with predominantly mild or moderate treatment-emergent adverse events (TEAEs) and a low rate of serious surgical complications (7.6%). Retinal inflammation TEAEs were reported in 45.5% of participants, with similar rates in both eyes; post hoc analyses found that these were not associated with clinically significant vision loss at month 12 versus baseline. Two participants (3.0%) reported serious noninfective retinitis. Prior timrepigene emparvovec exposure did not increase the risk of serious TEAEs or serious ocular TEAEs upon injection of the second eye; furthermore, no systemic immune reaction or inoculation effect was observed. Presence of antivector neutralizing antibodies at baseline was potentially associated with a higher percentage of TEAEs related to ocular inflammation or reduced VA after injection of the first eye. The GEMINI study results may inform decisions regarding bilateral sequential administration of other gene therapies for retinal diseases.

Background/objectives: Stroke damage to the primary visual cortex induces large, homonymous visual field defects that impair daily living. Here, we asked if vision-related quality of life (VR-QoL) is impacted by time since stroke., Subjects/methods: We conducted a retrospective meta-analysis of 95 occipital stroke patients (female/male = 26/69, 27-78 years old, 0.5-373.5 months poststroke) in whom VR-QoL was estimated using the National Eye Institute Visual Functioning Questionnaire (NEI-VFQ) and its 10-item neuro-ophthalmic supplement (Neuro10). Visual deficit severity was represented by the perimetric mean deviation (PMD) calculated from 24-2 Humphrey visual fields. Data were compared with published cohorts of visually intact controls. The relationship between VR-QoL and time poststroke was assessed across participants, adjusting for deficit severity and age with a multiple linear regression analysis., Results: Occipital stroke patients had significantly lower NEI-VFQ and Neuro10 composite scores than controls. All subscale scores describing specific aspects of visual ability and functioning were impaired except for ocular pain and general health, which did not differ significantly from controls. Surprisingly, visual deficit severity was not correlated with either composite score, both of which increased with time poststroke, even when adjusting for PMD and age., Conclusions: VR-QoL appears to improve with time postoccipital stroke, irrespective of visual deficit size or patient age at insult. This may reflect the natural development of compensatory strategies and lifestyle adjustments. Thus, future studies examining the impact of rehabilitation on daily living in this patient population should consider the possibility that their VR-QoL may change gradually over time, even without therapeutic intervention., (© 2024 The Author(s). Brain and Behavior published by Wiley Periodicals LLC.)

Purpose: The NIGHT study aimed to assess the natural history of choroideremia (CHM), an X-linked inherited chorioretinal degenerative disease leading to blindness, and determine which outcomes would be the most sensitive for monitoring disease progression., Design: A prospective, observational, multicenter cohort study., Methods: Males aged ≥18 years with genetically confirmed CHM, visible active disease within the macular region, and best-corrected visual acuity (BCVA) ≥34 Early Treatment Diabetic Retinopathy Study (ETDRS) letters at baseline were assessed for 20 months. The primary outcome was the change in BCVA over time at Months 4, 8, 12, 16, and 20. A range of functional and anatomical secondary outcome measures were assessed up to Month 12, including retinal sensitivity, central ellipsoid zone (EZ) area, and total area of fundus autofluorescence (FAF). Additional ocular assessments for safety were performed., Results: A total of 220 participants completed the study. The mean BCVA was stable over 20 months. Most participants (81.4% in the worse eye and 77.8% in the better eye) had change from baseline > -5 ETDRS letters at Month 20. Interocular symmetry was low overall. Reductions from baseline to Month 12 were observed (worse eye, better eye) for retinal sensitivity (functional outcome; -0.68 dB, -0.48 dB), central EZ area (anatomical outcome; -0.276 mm 2 , -0.290 mm 2 ), and total area of FAF (anatomical outcome; -0.605 mm 2 , -0.533 mm 2 ). No assessment-related serious adverse events occurred., Conclusions: Retinal sensitivity, central EZ area, and total area of FAF are more sensitive than BCVA in measuring the natural progression of CHM., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: CEP290 -associated inherited retinal degeneration causes severe early-onset vision loss due to pathogenic variants in CEP290 . EDIT-101 is a clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) gene-editing complex designed to treat inherited retinal degeneration caused by a specific damaging variant in intron 26 of CEP290 (IVS26 variant)., Methods: We performed a phase 1-2, open-label, single-ascending-dose study in which persons 3 years of age or older with CEP290 -associated inherited retinal degeneration caused by a homozygous or compound heterozygous IVS26 variant received a subretinal injection of EDIT-101 in the worse (study) eye. The primary outcome was safety, which included adverse events and dose-limiting toxic effects. Key secondary efficacy outcomes were the change from baseline in the best corrected visual acuity, the retinal sensitivity detected with the use of full-field stimulus testing (FST), the score on the Ora-Visual Navigation Challenge mobility test, and the vision-related quality-of-life score on the National Eye Institute Visual Function Questionnaire-25 (in adults) or the Children's Visual Function Questionnaire (in children)., Results: EDIT-101 was injected in 12 adults 17 to 63 years of age (median, 37 years) at a low dose (in 2 participants), an intermediate dose (in 5), or a high dose (in 5) and in 2 children 9 and 14 years of age at the intermediate dose. At baseline, the median best corrected visual acuity in the study eye was 2.4 log 10 of the minimum angle of resolution (range, 3.9 to 0.6). No serious adverse events related to the treatment or procedure and no dose-limiting toxic effects were recorded. Six participants had a meaningful improvement from baseline in cone-mediated vision as assessed with the use of FST, of whom 5 had improvement in at least one other key secondary outcome. Nine participants (64%) had a meaningful improvement from baseline in the best corrected visual acuity, the sensitivity to red light as measured with FST, or the score on the mobility test. Six participants had a meaningful improvement from baseline in the vision-related quality-of-life score., Conclusions: The safety profile and improvements in photoreceptor function after EDIT-101 treatment in this small phase 1-2 study support further research of in vivo CRISPR-Cas9 gene editing to treat inherited retinal degenerations due to the IVS26 variant of CEP290 and other genetic causes. (Funded by Editas Medicine and others; BRILLIANCE ClinicalTrials.gov number, NCT03872479.)., (Copyright © 2024 Massachusetts Medical Society.)

Competing Interests: The authors report no conflicts of interest.

Purpose of Review: To discuss relevant clinical outcomes, challenges, and future opportunities of gene therapy in Leber hereditary optic neuropathy (LHON)., Recent Findings: Results of G11778A LHON Phase 3 randomized clinical trials with unilateral intravitreal rAAV2/2-ND4 allotopic gene therapy show good safety and unexpected bilateral partial improvements of BCVA (best-corrected visual acuity) with mean logMAR BCVA improvements of up to near ∼0.3 logMAR (3 lines) in the treated eyes and ∼0.25 logMAR (2.5 lines) in the sham-treated or placebo-treated fellow eyes. Final mean BCVA levels after gene therapy were in the range of ∼1.3 logMAR (20/400) bilaterally., Summary: Bilateral partial improvement with unilateral LHON gene therapy was unanticipated and may be due to treatment efficacy, natural history, learning effect, and other mediators. The overall efficacy is limited given the final BCVA levels. The sequential progressive visual loss and varied occurrence of spontaneous partial improvement in LHON confound trial results. Future clinical trials with randomization of patients to a group not receiving gene therapy in either eye would help to assess treatment effect. Promising future LHON gene therapy strategies include mitochondrially-targeted-sequence adeno-associated virus ('MTS-AAV') for direct delivery of the wild-type mitochondrial DNA into the mitochondria and CRISPR-free, RNA-free mitochondrial base editing systems. Signs of anatomical optic nerve damage and objective retinal ganglion cell dysfunction are evident in the asymptomatic eyes of LHON patients experiencing unilateral visual loss, indicating the therapeutic window is narrowing before onset of visual symptoms. Future treatment strategies utilizing mitochondrial base editing in LHON carriers without optic neuropathy holds the promise of a more advantageous approach to achieve optimal visual outcome by reducing disease penetrance and mitigating retinal ganglion cell loss when optic neuropathy develops., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Choroidal neovascularization (CNV) is a rare complication of choroideremia that occurs secondary to relative atrophy of the retinal pigment epithelium and eventual rupture of Bruch's membrane. The ideal management of CNV in choroideremia is unclear., Materials and Methods: Case report., Observations: A 14-year-old male with no known ocular history presented to the eye emergency department complaining of a central scotoma in the right eye for 4 days. He had no past medical history and family history was unremarkable for known ocular disease. Visual acuity was 20/70 in the right eye and 20/30 in the left eye. Posterior segment exam revealed chorioretinal atrophy extending from the outer macula to the midperiphery in both eyes. There was CNV with associated subretinal hemorrhage in the right eye. Optical coherence tomography demonstrated the presence of CNV with subretinal fluid in the right eye and parafoveal outer retinal atrophy in both eyes. Genetic testing revealed a hemizygous exon 2 deletion on the CHM gene, pathogenic for choroideremia. The patient received a total of 3 injections 4 weeks apart followed by 1 injection 6 weeks later with resolution of the subretinal hemorrhage and reduction in CNV size with improvement in visual acuity to 20/20 at last follow-up exam., Conclusions and Importance: Choroidal neovascularization is a rare cause of central vision loss in patients with choroideremia. In this report, we demonstrate a good functional and anatomic response to intravitreal bevacizumab in a 14-year-old patient with undiagnosed choroideremia who presented with CNV-induced central vision loss.

Purpose: Damage to the adult primary visual cortex (V1) causes vision loss in the contralateral hemifield, initiating a process of transsynaptic retrograde degeneration (TRD). Here, we examined retinal correlates of TRD using a new metric to account for global changes in inner retinal thickness and asked if perceptual training in the intact or blind field impacts its progression., Methods: We performed a meta-analysis of optical coherence tomography data in 48 participants with unilateral V1 stroke and homonymous visual defects who completed clinical trial NCT03350919. After measuring the thickness of the macular ganglion cell and inner plexiform layer (GCL-IPL) and the peripapillary retinal nerve fiber layer (RNFL), we computed individual laterality indices (LI) at baseline and after ∼6 months of daily motion discrimination training in the intact or blind field. Increasingly positive LI denoted greater layer thinning in retinal regions affected versus unaffected by the cortical damage., Results: Pretraining, the affected GCL-IPL and RNFL were thinner than their unaffected counterparts, generating LI values positively correlated with time since stroke. Participants trained in their intact field exhibited increased LIGCL-IPL. Those trained in their blind field had no significant change in LIGCL-IPL. LIRNFL did not change in either group., Conclusions: Relative shrinkage of the affected versus unaffected macular GCL-IPL can be reliably measured at an individual level and increases with time post-V1 stroke. Relative thinning progressed during intact-field training but appeared to be halted by training within the blind field, suggesting a potentially neuroprotective effect of this simple behavioral intervention.

Competing Interests: The authors report no conflicts of interest.

Development of high yielding cowpea varieties coupled with good taste and rich in essential minerals can promote consumption and thus nutrition and profitability. The sweet taste of cowpea grain is determined by its sugar content, which comprises mainly sucrose and galacto-oligosaccharides (GOS) including raffinose and stachyose. However, GOS are indigestible and their fermentation in the colon can produce excess intestinal gas, causing undesirable bloating and flatulence. In this study, we aimed to examine variation in grain sugar and mineral concentrations, then map quantitative trait loci (QTLs) and estimate genomic-prediction (GP) accuracies for possible application in breeding. Grain samples were collected from a multi-parent advanced generation intercross (MAGIC) population grown in California during 2016-2017. Grain sugars were assayed using high-performance liquid chromatography. Grain minerals were determined by inductively coupled plasma-optical emission spectrometry and combustion. Considerable variation was observed for sucrose (0.6-6.9%) and stachyose (2.3-8.4%). Major QTLs for sucrose (QSuc.vu-1.1), stachyose (QSta.vu-7.1), copper (QCu.vu-1.1) and manganese (QMn.vu-5.1) were identified. Allelic effects of major sugar QTLs were validated using the MAGIC grain samples grown in West Africa in 2017. GP accuracies for minerals were moderate (0.4-0.58). These findings help guide future breeding efforts to develop mineral-rich cowpea varieties with desirable sugar content., (© 2024. The Author(s).)

Purpose: To define the clinical characteristics of centrosomal protein 290 ( CEP290 )-associated inherited retinal degeneration (IRD) and determine which assessments may provide reliable endpoints in future interventional trials., Design: Participants in this natural history study were enrolled into 2 best-corrected visual acuity (BCVA) cohorts: light perception to > 1.0 logarithm of the minimum angle of resolution (logMAR) and 1.0 logMAR to 0.4 logMAR. Each comprised 4 age cohorts (3-5, 6-11, 12-17, and ≥ 18 years)., Participants: Patients with CEP290 -associated IRD caused by the intron 26 c.2991+1655A>G mutation and BCVA ranging from light perception to 0.4 logMAR., Methods: Best-corrected visual acuity, full-field stimulus threshold (FST) sensitivity, Ora-Visual Navigation Challenge (Ora-VNC) composite score, and OCT-outer nuclear layer (OCT-ONL) average thickness were assessed at screening, baseline, 3 months, 6 months, and 12 months., Main Outcome Measures: Best-corrected visual acuity, FST sensitivity, Ora-VNC composite score, and OCT-ONL average thickness., Results: Twenty-six participants were included in this analysis. Nineteen were female. All participants were White and 4 reported Hispanic ethnicity. At screening, 13 of 16 adult and 9 of 10 pediatric participants had BCVA > 1.0 logMAR. Baseline BCVA was variable (median [range] = 2.0 [0.5, 3.9] logMAR) and was uncorrelated with age, as were VNC composite score, FST sensitivity, and OCT-ONL average thickness. Mean (95% confidence interval [CI]) test-retest variability was -0.04 (-0.09, 0.01) logMAR for BCVA (n = 25); 0.6 (-0.1, 1.3) for VNC composite score (n = 18); and 0.10 (-0.07, 0.27) log cd.s/m 2 for red FST (n = 14). A greater than expected test-retest variability (5 [0, 10] μm, n = 14) was observed for OCT-ONL average thickness as nystagmus impacted ability to repeat measures at the same retinal location. Functional assessments were stable over 12 months. Mean (95% CI) change from baseline was 0.06 (-0.17, 0.29) logMAR for BCVA (n = 23); -0.1 (-1.2, 1.0) for VNC composite score (n = 21); and -0.15 (-0.43, 0.14) log cd.s/m 2 for red FST (n = 16)., Conclusions: Vision was stable over 12 months. Best-corrected visual acuity, FST, and VNC composite score are potentially viable endpoints for future studies in CEP290-associated IRD. Repeatability of OCT measures poses challenges for quantifying anatomical changes in this population., Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (© 2024 by the American Academy of Ophthalmology.)

Background and Objectives: To investigate the associations between self-reported visual functioning (VF) and hearing functioning with cognition in the Hispanic/Latino population., Research Design and Methods: We utilized data from the Miami Ocular Study of Latinos ancillary study to Hispanic Community Health Study/Study of Latinos with 1,056 participants aged 45 and older. The outcomes were cognitive performances assessed by the Digit Symbol Substitution Test (DSST), Word Fluency, Brief-Spanish English Verbal Learning Test-recall (B-SEVLT recall), words recalled over 3 trials, and the Six-Item Screener. VF was measured by National Eye Institute Visual Function Questionnaire (NEI-VFQ), and hearing function was measured by Hearing Handicap Inventory Screening Questionnaire for Adults and Elderly (HHIA/E-S). Multiple regressions were performed for each cognitive outcome while controlling for covariates and complex sampling design., Results: NEI-VFQ was associated with 3 of the 5 cognitive outcomes. A 4-point NEI-VFQ score difference was associated with a 0.56-point difference in DSST (standard error [ SE ] = 0.27, p  < .001), 0.17 in Word fluency ( SE  = 0.16, p  < .01), and 0.08 in B-SEVLT-recall ( SE  = 0.07, p  < .01). HHIA/E-S was not associated with any of the cognitive measures examined., Discussion and Implications: These data suggest that impaired VF is associated with worse cognition in the Hispanic/Latino population. Although previous work in this cohort indicated hearing loss assessed by pure tone audiometry was associated with worse cognition, we found self-perceived hearing function was not associated with cognition, suggesting the potential limitation of self-reported hearing function as a proxy for hearing loss in epidemiological research in Hispanic/Latino populations. Results also imply impaired VF and hearing function may be linked to cognition differently in the Hispanic population, and more research is needed to better understand the underlying linking mechanisms. Visual and hearing impairments are common and treatable and represent important modifiable risk factors that can be treated to preserve cognitive function in Hispanics/Latinos., Competing Interests: None., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Purpose: To assess longitudinal relationships among visual function and anatomical measures of gene therapy in G11778A Leber hereditary optic neuropathy (LHON)., Design: Phase 1 clinical trial., Methods: This was a single-institution study of patients with G11778A LHON. Patients with chronic bilateral visual loss >12 months (group 1, n = 11), acute bilateral visual loss <12 months (group 2, n = 9), or unilateral visual loss (group 3, n = 8) were administered unilateral intravitreal AAV2(Y444,500,730F)-P1ND4v2 injection with low, medium, high, and higher doses to worse eye for groups 1 and 2 and better eye for group 3. Oucome measures were best-corrected visual acuity (BCVA), visual field mean deviation (VF MD), steady-state pattern electroretinogram (SS-PERG), optical coherence tomography (OCT) retinal nerve fiber layer (RNFL) thickness and ganglion cell+inner plexiform layer (GCIPL) thickness, and National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) scores. Mean follow-up was 33.6 months (range = 18-36 months)., Results: Baseline SS-PERG amplitude was much reduced in both eyes of all groups including asymptomatic eyes of group 3, and showed no appreciable changes irrespective of disease stage and treatment. Significant and progressive GCIPL and RNFL thinning occurred in all eyes; BCVA and VF MD fluctuated in treated and fellow eyes, with some eyes having modest improvement that may be related to natural history or to gene therapy. Mean NEI-VFQ-25 scores declined in group 3 subjects (P = .023), CONCLUSION: Asymptomatic eyes in LHON patients with unilateral visual loss may be beyond the window of effective neuroprotection given reduced GCIPL and SS-PERG. Randomization of patients to an untreated control group would help to assess treatment effect by accounting for variable natural history. NOTE: Publication of this article is sponsored by the American Ophthalmological Society., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Choroideremia is a rare, X-linked retinal degeneration resulting in progressive vision loss. A randomized, masked, phase 3 clinical trial evaluated the safety and efficacy over 12 months of follow-up in adult males with choroideremia randomized to receive a high-dose (1.0 × 10 11 vector genomes (vg); n = 69) or low-dose (1.0 × 10 10 vg; n = 34) subretinal injection of the AAV2-vector-based gene therapy timrepigene emparvovec versus non-treated control (n = 66). Most treatment-emergent adverse events were mild or moderate. The trial did not meet its primary endpoint of best-corrected visual acuity (BCVA) improvement. In the primary endpoint analysis, three of 65 participants (5%) in the high-dose group, one of 34 (3%) participants in the low-dose group and zero of 62 (0%) participants in the control group had ≥15-letter Early Treatment Diabetic Retinopathy Study (ETDRS) improvement from baseline BCVA at 12 months (high dose, P = 0.245 versus control; low dose, P = 0.354 versus control). As the primary endpoint was not met, key secondary endpoints were not tested for significance. In a key secondary endpoint, nine of 65 (14%), six of 35 (18%) and one of 62 (2%) participants in the high-dose, low-dose and control groups, respectively, experienced ≥10-letter ETDRS improvement from baseline BCVA at 12 months. Potential opportunities to enhance future gene therapy studies for choroideremia include optimization of entry criteria (more preserved retinal area), surgical techniques and clinical endpoints. EudraCT registration: 2015-003958-41 ., (© 2023. The Author(s).)

Purpose: RPGR-associated X-linked retinitis pigmentosa (RPGR-XLRP) is a rare and severe form of retinitis pigmentosa (RP) resulting in progressive visual impairment; however, disease progression data are limited. A systematic literature review was conducted to assess available data on disease progression in RPGR-XLRP., Methods: PubMed, EMBASE, and select congress abstracts were evaluated through June 2022. Eligible studies included results specific to RPGR-XLRP or populations with ≥80% of RP patients carrying disease-causing RPGR variants. Endpoints of interest included visual acuity (VA), visual field (VF), ellipsoid zone width (EZW), progression to blindness, and patient-reported outcomes (PROs)., Results: Fourteen studies met ≥1 endpoint of interest. Progressive declines in VA, VF, and EZW were reported across studies. Nearly all publications reported annual declines in VA (3.5%-8.2%). Annual VF declines ranged from 4.2% to 13.3%. Changes in retinal structure were also observed (EZW changes: -177 to -830 μm/y). Most studies measured blindness using VA; VF-based definitions resulted in blindness by age ∼25 years. PRO data were limited., Conclusion: Published evidence shows that patients with RPGR-XLRP experience progressive decline in VA, VF, and EZW, eventually resulting in blindness. Additional longitudinal data with standardized endpoints and expanded collection of PROs are needed to assess visual decline in RPGR-XLRP., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Opthalmic Communications Society, Inc.)

Patients with inherited retinal diseases (IRDs) utilize various adaptive techniques and devices designed to assist them with activities of daily living (ADLs). The purpose of this study was to assess the assistive devices used by patients with IRDs, the difficulties they face despite these devices, and their recommendations for a future visual prosthesis. In collaboration with blind patients, an online survey was developed and administered to adults with IRDs and visual acuities of 20/400 to no light perception in the better-seeing eye. We analyzed data from 121 survey respondents (aged 18 to >80 years). Five respondents were Argus II prosthesis recipients. The most commonly used aids were cellular phones/tablets for reading (63.6%) as well as a sighted guide (75.0%) and a cane (71.4%) for mobility. Despite current assistive devices, participants reported continued difficulty with ADLs. Improved navigation, reading, and facial recognition were ranked the most desirable features for future visual prostheses. Argus II recipients suggested technology with improved ability to recognize objects and obstacles, detect movement, and cut out busy backgrounds. These insights are valuable in shaping the design of future prosthetic devices tailored to the needs of IRD patients.

Purpose: To assess the safety and efficacy of a ciliary neurotrophic factor (CNTF) intraocular implant on neuroprotection and neuroenhancement in glaucoma., Design: Open-label, prospective, phase I clinical trial., Participants: A total of 11 participants were diagnosed with primary open-angle glaucoma (POAG). One eye of each patient was assigned as the study (implant) eye., Methods: The study eye was implanted with a high-dose CNTF-secreting NT-501 implant, whereas the other eye served as a control. All patients were followed up for 18 months. Analysis was limited to descriptive statistics., Main Outcome Measures: Primary outcome was safety through 18 months after implantation assessed by serial eye examinations, structural and functional testing, and adverse events (AEs) recording. Parameters measured included visual acuity (VA), Humphrey visual field (HVF), pattern electroretinogram, scanning laser polarimetry with variable corneal compensation (GDx VCC), and OCT. These parameters were also used for secondary analysis of efficacy outcome., Results: All NT-501 implants were well tolerated with no serious AEs associated with the implant. The majority of AEs were related to the implant placement procedure and were resolved by 12 weeks after surgery. Foreign-body sensation was the most commonly reported AE and was self-limited to the postoperative period. The most common implant-related AE was pupil miosis; no patients underwent explant. Visual acuity and contrast sensitivity decreased more in fellow eyes than in study eyes (VA, -5.82 vs. -0.82 letters; and contrast sensitivity, -1.82 vs. -0.37 letters, for fellow vs. study eyes, respectively). The median HVF visual field index and mean deviation measurements worsened (decreased) in fellow eyes (-13.0%, -3.9 dB) and improved (increased) in study eyes (2.7%, 1.2 dB). Implanted eyes showed an increase in retinal nerve fiber layer thickness measured by OCT and by GDx VCC (OCT, 2.66 μm vs. 10.16 μm; and GDx VCC, 1.58 μm vs. 8.36 μm in fellow vs. study eyes, respectively)., Conclusions: The NT-501 CNTF implant was safe and well tolerated in eyes with POAG. Eyes with the implant demonstrated both structural and functional improvements suggesting biological activity, supporting the premise for a randomized phase II clinical trial of single and dual NT-501 CNTF implants in patients with POAG, which is now underway., Financial Disclosures: Proprietary or commercial disclosure may be found after the references.

Inherited retinal diseases (IRDs) are a genetically and phenotypically heterogeneous group of genetic eye disorders. There are more than 300 disease entities, and together this group of disorders affects millions of people globally and is a frequent cause of blindness or low-vision certification. However, each type is rare or ultra-rare. Characteristically, the impaired vision in IRDs is due to retinal photoreceptor dysfunction and loss resulting from mutation in a gene that codes for a retinal protein. Historically, IRDs have been considered incurable and individuals living with these blinding conditions could be offered only supportive care. However, the treatment landscape for IRDs is beginning to evolve. Progress is being made, driven by improvements in understanding of genotype-phenotype relationships, through advances in molecular genetic testing and retinal imaging. Alongside this expanding knowledge of IRDs, the current era of precision medicine is fueling a growth in targeted therapies. This has resulted in the first treatment for an IRD being approved. Several other therapies are currently in development in the IRD space, including RNA-based therapies, gene-based therapies (such as augmentation therapy and gene editing), cell therapy, visual prosthetics, and optogenetics. RNA-based therapies are a novel approach within precision medicine that have demonstrated success, particularly in rare diseases. Three antisense oligonucleotides (AONs) are currently in development for the treatment of specific IRD subtypes. These RNA-based therapies bring several key advantages in the setting of IRDs, and the potential to bring meaningful vision benefit to individuals living with inherited blinding disorders. This review will examine the increasing breadth and relevance of RNA-based therapies in clinical medicine, explore the key features that make AONs suitable for treating genetic eye diseases, and provide an overview of the three-leading investigational AONs in clinical trials., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: K.S., I.A., B.P.L., and M.M. are the members of ERN-EYE (www.ern-eye.eu). A.G. is an employee of ProQR Therapeutics. I.A. is a consultant/advisor for Novartis, Sparing Vision, Janssen, Roche, and ProQR Therapeutics; she is supported by the Foundation Fighting Blindness, Retina France, and UNADEV. D.G.B. reports support from the National Eye Institute EY09076 and Foundation Fighting Blindness; he has served as a consultant for ProQR Therapeutics, AGTC, Nacuity, Editas, and Biogen and has received clinical trial support from AGTC, ProQR Therapeutics, NightstaRx, and 4D Therapeutics. R.M.H. is a consultant for AGTC, Annexon, ProQR, Regeneron, and Vida Ventures and an advisor for Intergalactic Therapeutics; she receives grant funding from FFB and clinical trial support from AGTC, Biogen, MeiraGTx/Janssen, ProQR, and Spark. B.L.L. reports grant funding from ProQR Therapeutics, Biogen, AGTC, Allergan, and Spark Therapeutics; he has served as a consultant for ProQR Therapeutics, Biogen, and Allergan. B.P.L. is a Senior Clinical Investigator of the Research Foundation – Flanders, Belgium (Grant No. 1.8.038.11 N); he reports trial support from Second Sight Medical Products, consultancy fees from Bayer, REGENXBIO, and Vedere Bio, and trial support and consultancy fees and travel support from GenSight Therapeutics, IVERIC Bio, Novartis Pharma, Spark Therapeutics, and ProQR Therapeutics; he reports no personal financial gain, with all consultancy fees paid into Ghent University Hospital research accounts to support research. M.M. is supported by a grant from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology. S.R.R. reports grant funding from Spark Therapeutics and ProQR Therapeutics, is a consultant for Novartis and co-founded an artificial intelligence-based retinal imaging company, Digital Diagnostics Incorporated (formerly IDx, LLC). J.M.F.S. has nothing to disclose. K.S. is or has served as a consultant for ProQR Therapeutics, ViGeneron, Novartis, Santen and Nayan, with consultancy fees paid to the Center for Ophthalmology, University of Tuebingen to support research. S.H.T. receives salary from the National Institute of Health (Health U01 EY030580, U54OD020351, R24EY028758, R24EY027285, R01EY018213, R01EY024698, R01EY026682), New York State (SDHDOH01-C32590GG-3450000), Research to Prevent Blindness and Alcon Research Institute, and serves as a consultant for SAB, EmendoBio, Nanoscope, and Rejuvitas. P.Y. is supported by grant from the Foundation Fighting Blindness TRAP1 Award (TA-NMT-0521-0803-OHSU-TRAP), the National Institutes of Health (Bethesda, MD) (P30 EY010572), and by unrestricted departmental funding from Research to Prevent Blindness (New York, NY); he serves as a consultant for 4D Molecular Therapeutics, Adverum, AGTC, Annexon Bio, EcoR1, ExpertConnect, Guidepoint, Janssen, MeiraGTx, Nanoscope Therapeutics, Otonomy, ProQR and Vedere and receives research support from 4D Molecular Therapeutics, Acucela, AGTC, Biogen, Editas, Foundation Fighting Blindness, Iveric bio, ProQR Therapeutics, Reneuron, Sanofi, and Spark., (© The Author(s), 2022.)

Purpose: Swept-source optical coherence tomography angiography (SS-OCTA) was used to analyze Bruch membrane (BM) and choriocapillaris (CC) abnormalities in undiagnosed family members with Sorsby macular dystrophy (SMD)., Methods: In a family with SMD ( TIMP3 Tyr191Cys), SS-OCTA imaging was performed using the 6 × 6 mm scan patter and previously validated algorithms to detect abnormalities in BM and the CC, as well as the presence of reticular pseudodrusen and macular neovascularization. Genetic analyses were performed for TIMP3 mutations., Results: Of eight family members, two were previously diagnosed with SMD and six were asymptomatic. SS-OCTA imaging of the 33-year-old proband revealed type 1 macular neovascularization in the left eye and bilateral reticular pseudodrusen, thickening of BM, CC thinning, and increases in CC flow deficits. A TIMP3 mutation was confirmed. His niece, despite having no clinical evidence of SMD, showed BM thickening and CC thinning on SS-OCTA. A TIMP3 mutation was confirmed. The proband's younger nephew and niece also carried the TIMP3 mutation without clinical evidence of SMD. Two additional members had normal examinations, unremarkable SS-OCTA findings, and no TIMP3 mutation., Conclusion: Swept-source optical coherence tomography angiography imaging can detect BM and CC abnormalities in vivo in subjects unaware of their TIMP3 status in a family with SMD.