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To assess safety of gene therapy in G11778A Leber hereditary optic neuropathy (LHON).Phase 1 clinical trial.Setting: single institution.Patients with G11778A LHON and chronic bilateral visual loss12 months (group 1, n = 11), acute bilateral visual loss12 months (group 2, n = 9), or unilateral visual loss (group 3, n = 8).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.Best-corrected visual acuity (BCVA), adverse events, and vector antibody responses. Mean follow-up was 24 months (range, 12-36 months); BCVAs were compared with a published prospective natural history cohort with designated surrogate study and fellow eyes.Incident uveitis (8 of 28, 29%), the only vector-related adverse event, resulted in no attributable vision sequelae and was related to vector dose: 5 of 7 (71%) higher-dose eyes vs 3 of 21 (14%) low-, medium-, or high-dose eyes (P.001). Incident uveitis requiring treatment was associated with increased serum AAV2 neutralizing antibody titers (p=0.007) but not serum AAV2 polymerase chain reaction. Improvements of ≥15-letter BCVA occurred in some treated and fellow eyes of groups 1 and 2 and some surrogate study and fellow eyes of natural history subjects. All study eyes (BCVA ≥20/40) in group 3 lost ≥15 letters within the first year despite treatment.G11778A LHON gene therapy has a favorable safety profile. Our results suggest that if there is an efficacy effect, it is likely small and not dose related. Demonstration of efficacy requires randomization of patients to a group not receiving vector in either eye.

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

Purpose To evaluate the efficacy of motion discrimination training as a potential therapy for stroke-induced hemianopic visual field defects. Design Clinical trial. Participants Forty-eight patients with stroke-induced homonymous hemianopia (HH) were randomized into 2 training arms: intervention and control. Patients were between 21 and 75 years of age and showed no ocular issues at presentation. Methods Patients were trained on a motion discrimination task previously evidenced to reduce visual field deficits, but not in a randomized clinical trial. Patients were randomized with equal allocation to receive training in either their sighted or deficit visual fields. Training was performed at home for 6 months, consisting of repeated visual discriminations at a single location for 20 to 30 minutes daily. Study staff and patients were masked to training type. Testing before and after training was identical, consisting of Humphrey visual fields (Carl Zeiss Meditech), macular integrity assessment perimetry, OCT, motion discrimination performance, and visual quality-of-life questionnaires. Main Outcome Measures Primary outcome measures were changes in perimetric mean deviation (PMD) on Humphrey Visual Field Analyzer in both eyes. Results Mean PMDs improved over 6 months in deficit-trained patients (mean change in the right eye, 0.58 dB; 95% confidence interval, 0.07–1.08 dB; mean change in the left eye 0.84 dB; 95% confidence interval, 0.22–1.47 dB). No improvement was observed in sighted-trained patients (mean change in the right eye, 0.12 dB; 95% confidence interval, –0.38 to 0.62 dB; mean change in the left eye, 0.10 dB; 95% confidence interval, –0.52 to 0.72 dB). However, no significant differences were found between the alternative training methods (right eye, P = 0.19; left eye, P = 0.10). Conclusions To date, no widely accepted therapy is available to treat HH. This study evaluated the efficacy of a promising potential treatment, visual perceptual training. We failed to find a difference between treatment training within the deficit field and control training within the sighted field when performed in a home environment.

Background Cavernous malformations (CMs) of the optic nerve and chiasm are extremely rare, accounting for less than 1% of all intracranial CMs. Acute, subacute, or progressive visual loss from CM may occur with or without hemorrhage. Prompt surgical excision of the CM offers the best hope to improve or stabilize vision. Given its rarity, optic nerve and chiasm CMs may not be readily suspected. We provide 3 cases of optic nerve and chiasm CM, highlighting key neuroimaging features and the importance of expedited intervention. Methods Case records of the neuro-ophthalmology clinics of the Bascom Palmer Eye Institute and the University of Colorado, and literature review of reported cases of optic CM. Results A 49-year-old woman reported acute progressive painless vision loss in the right eye. MRI showed a suprasellar mass with heterogeneity in signal involving the right prechiasmatic optic nerve. Surgical excision of the CM 5 days after onset of visual loss improved vision from 20/300 to 20/30. A 29-year-old woman with acute painless blurred vision in the right eye had anterior chiasmal junctional visual field defects corresponding to a heterogeneously minimally enhancing mass with blood products enlarging the optic chiasm and proximal right optic nerve. Surgical excision of the CM 8 weeks after onset of visual loss improved vision from 20/40 to 20/15 with improved visual fields. A 33-year-old woman with a history of familial multiple CMs, diagnosed at age 18, reported new-onset severe headache followed by blurred vision. MRI showed a hemorrhagic lesion of the optic chiasm and right optic tract. She was 20/20 in each eye with a reported left superior homonymous hemianopia. No intervention was recommended. Vision of the right eye worsened to 20/400 2 months later. The patient was followed over 13 years, and the MRI and visual function remained unchanged. Literature review yielded 87 optic CM cases occurring across gender and nearly all ages with visual loss and headache as the most common presenting symptoms. Optic chiasm is the most common site of involvement (79%). Nearly 95% of reported CM cases were treated with surgery with 81% with improved vision and 1% with worsened vision. Conclusion MRI features are critical to the diagnosis of optic nerve and chiasm CM and may mimic other lesions. A high index of suspicion by the neuro-ophthalmologist and neuroradiologist leads to early recognition and intervention. Given optic CM displaces and does not infiltrate neural tissue, expedited surgical resection by a neurosurgeon after consideration of other diagnostic possibilities improves visual function in most cases.

Supplemental Digital Content is Available in the Text. In this article, we review the clinical characteristics of Leber congenital amaurosis due to CEP290 mutations (LCA10) and its impact on patients and society. We discuss the challenges associated with differential diagnosis of LCA10, the significant burden of childhood visual impairment, and the investigational treatment strategies currently in development., Purpose: Leber congenital amaurosis due to CEP290 mutations (LCA10) is an inherited retinal disease that often results in severe visual impairment or blindness in early childhood. Currently, there are no approved treatments, highlighting the considerable unmet medical need associated with LCA10. We aimed to review the clinical characteristics of LCA10, its impact on patients and society, and the investigational treatment strategies currently in development. Methods: Review of the current literature. Results: LCA10 is an autosomal recessive ciliopathy, for which the CEP290 intronic variant c.2991+1655A>G (p.Cys998X) is the most common mutation. Usually diagnosed in early childhood, most patients with LCA10 have severe visual impairment during their first decade of life, which significantly affects the quality of life and development. LCA10 also has a significant societal burden (direct and indirect costs). RNA editing using antisense oligonucleotides or Staphylococcus aureus CRISPR-associated protein-9 nuclease is currently under investigation for treatment of p.Cys998X LCA10. Specifically, the antisense oligonucleotide therapy QR-110 (sepofarsen) has demonstrated encouraging safety and efficacy data in a first-in-human trial; a phase 3 clinical trial is ongoing. Conclusion: Interventions that can preserve or improve vision in patients with LCA10 have considerable potential to improve the patient quality of life and reduce burden of disease.

Background Cholangiocarcinoma is a locally invasive, poorly treatable malignancy of the biliary tract that uncommonly metastasizes to the brain and rarely causes neuro-ophthalmologic complications. Case presentation A 34-year-old woman with an isolated sixth cranial nerve palsy underwent brain neuroimaging and was found to have a large sellar/suprasellar mass invading the cavernous sinus. Gross total resection was performed with improvement in the sixth cranial nerve nerve palsy. Next-generation sequencing and histology studies revealed an adenocarcinoma with a fibroblast growth factor receptor (FGFR)2-BICC1 gene mutation. Positron emission tomography/computed tomography scan demonstrated a large hypermetabolic partially necrotic hepatic mass with local invasion, and liver biopsy confirmed a diagnosis of cholangiocarcinoma. At three weeks after resection, the brain lesion recurred and the patient developed worsening diplopia. The patient then received stereotactic radiotherapy applied to the brain lesion and began treatment with gemcitabine and cisplatin. The patient was transitioned to FGFR-targeted therapy with pemigatinib, and the patient was alive at last follow-up, 49 weeks after diagnosis. Conclusion To our knowledge, this is the first report of cholangiocarcinoma presenting as a neuro-ophthalmologic finding, consisting of an isolated sixth cranial nerve palsy, which was the harbinger of a brain metastatic sellar/suprasellar mass. The case highlights the importance of prompt neuroimaging in isolated cranial nerve palsies, particularly in younger patients, and consideration of rare aggressive metastasis to the sellar region, where prompt surgery and pathology are critical in identifying the primary carcinoma and to instituting expedited therapy.

In pleiotropic diseases, multiple organ systems are affected causing a variety of clinical manifestations. Here, we report a pleiotropic disorder with a unique constellation of neurological, endocrine, exocrine, and haematological findings that is caused by biallelic MADD variants. MADD, the mitogen-activated protein kinase (MAPK) activating death domain protein, regulates various cellular functions, such as vesicle trafficking, activity of the Rab3 and Rab27 small GTPases, tumour necrosis factor-α (TNF-α)-induced signalling and prevention of cell death. Through national collaboration and GeneMatcher, we collected 23 patients with 21 different pathogenic MADD variants identified by next-generation sequencing. We clinically evaluated the series of patients and categorized the phenotypes in two groups. Group 1 consists of 14 patients with severe developmental delay, endo- and exocrine dysfunction, impairment of the sensory and autonomic nervous system, and haematological anomalies. The clinical course during the first years of life can be potentially fatal. The nine patients in Group 2 have a predominant neurological phenotype comprising mild-to-severe developmental delay, hypotonia, speech impairment, and seizures. Analysis of mRNA revealed multiple aberrant MADD transcripts in two patient-derived fibroblast cell lines. Relative quantification of MADD mRNA and protein in fibroblasts of five affected individuals showed a drastic reduction or loss of MADD. We conducted functional tests to determine the impact of the variants on different pathways. Treatment of patient-derived fibroblasts with TNF-α resulted in reduced phosphorylation of the extracellular signal-regulated kinases 1 and 2, enhanced activation of the pro-apoptotic enzymes caspase-3 and -7 and increased apoptosis compared to control cells. We analysed internalization of epidermal growth factor in patient cells and identified a defect in endocytosis of epidermal growth factor. We conclude that MADD deficiency underlies multiple cellular defects that can be attributed to alterations of TNF-α-dependent signalling pathways and defects in vesicular trafficking. Our data highlight the multifaceted role of MADD as a signalling molecule in different organs and reveal its physiological role in regulating the function of the sensory and autonomic nervous system and endo- and exocrine glands.

Purpose: Assessment of Ocular Perfusion Pressure (OPP) requires estimation of the Mean Central Retinal Artery Pressure (MCRAP) [OPP = MCRAP-IOP]. In a seated position, MCRAP is currently estimated as 2/3 of the Mean Arterial Pressure (MAP) to account for the hydrostatic reduction of MAP at eye level. We tested a surrogate method for direct MCRAP assessment by measuring MAP with Arm-Up and cuff at eye level (AUMAP) at different postures and ages. Methods: MAP and AUMAP were assessed in a mixed population of 136 subjects (mean age 44 ± 17.39 years) including healthy participants (N = 30) and patients with optic neuropathies (Glaucoma suspects, N = 14; Open-Angle Glaucoma, N = 26, LHON, N = 19; MS, N = 47) not expected to alter systemic blood pressure. None of the subjects had history of carotid stenosis or pharmacological treatment to regulate blood pressure. AUMAP was also tested in two subgroups in supine (N = 42) and -10° Head Down body Tilt position (HDT, N = 46). Results: In the seated position, both 2/3MAP and AUMAP increased with increasing age, however with steeper (2x) slope for AUMAP (P

Background: Juvenile X-linked Retinoschisis (JXLRS) is a hereditary retinopathy that commonly presents with macular retinoschisis. In this study, we describe a group of patients who presented with peripheral retinoschisis with no macular schisis.Materials and Methods: A retrospective case series of three JXLRS patients with genetically confirmed RS1 genotypes was identified. Presence of macular and/or peripheral retinoschisis as assessed by optical coherence tomography (OCT), wide-field fluorescein angiography, clinical ophthalmoscopy, and color fundus photography.Results: The eyes of the three JXLRS patients with peripheral retinoschisis had no macular schisis or atrophy on OCT. ERG was available in one patient and showed no reduced b-waves on scotopic combined rod-cone response.Conclusions: RS1 mutations can cause a macular-sparing JXLRS phenotype. The diagnosis of JXLRS should be considered for young males presenting with peripheral retinoschisis even if there is no evidence of macular schisis.

IMPORTANCE: Recent studies suggest that maintenance intravenous immunoglobulin (IVIG) may be an effective treatment to prevent relapses in myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD); however, most of these studies had pediatric cohorts, and few studies have evaluated IVIG in adult patients. OBJECTIVE: To determine the association of maintenance IVIG with the prevention of disease relapse in a large adult cohort of patients with MOGAD. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective cohort study conducted from January 1, 2010, to October 31, 2021. Patients were recruited from 14 hospitals in 9 countries and were included in the analysis if they (1) had a history of 1 or more central nervous system demyelinating attacks consistent with MOGAD, (2) had MOG-IgG seropositivity tested by cell-based assay, and (3) were age 18 years or older when starting IVIG treatment. These patients were retrospectively evaluated for a history of maintenance IVIG treatment. EXPOSURES: Maintenance IVIG. MAIN OUTCOMES AND MEASURES: Relapse rates while receiving maintenance IVIG compared with before initiation of therapy. RESULTS: Of the 876 adult patients initially identified with MOGAD, 59 (median [range] age, 36 [18-69] years; 33 women [56%]) were treated with maintenance IVIG. IVIG was initiated as first-line immunotherapy in 15 patients (25%) and as second-line therapy in 37 patients (63%) owing to failure of prior immunotherapy and in 7 patients (12%) owing to intolerance to prior immunotherapy. The median (range) annualized relapse rate before IVIG treatment was 1.4 (0-6.1), compared with a median (range) annualized relapse rate while receiving IVIG of 0 (0-3) (t(108) = 7.14; P

BACKGROUND: Atypical Usher syndrome (USH) is poorly defined with a broad clinical spectrum. Here we characterize the clinical phenotypic of disease caused by variants in CEP78, CEP250, ARSG, and ABHD12. MATERIALS AND METHODS: Chart review evaluating demographic, clinical, imaging, and genetic findings of 19 patients from 18 families with a clinical diagnosis of retinal disease and confirmed disease causing variants in CEP78, CEP250, ARSG, or ABHD12. RESULTS: CEP78-related disease included sensorineural hearing loss (SNHL) in 6/7 patients and demonstrated a broad phenotypic spectrum including: vascular attenuation, pallor of the optic disc, intraretinal pigment, retinal pigment epithelium mottling, areas of mid-peripheral hypo-autofluorescence, outer retinal atrophy, mild pigmentary changes in the macula, foveal hypo-autofluorescence, and granularity of the ellipsoid zone. Nonsense and frameshift variants in CEP250 showed mild retinal disease with progressive, non-congenital SNHL. ARSG variants resulted in a characteristic pericentral pattern of hypo-autofluorescence with one patient reporting non-congenital SNHL. ABHD12 related disease showed rod-cone dystrophy with macular involvement, early and severe decreased best corrected visual acuity, and non-congenital SNHL ranging from unreported to severe. CONCLUSIONS: This study serves to expand the clinical phenotypes of atypical USH. Given the variable findings, atypical USH should be considered in patients with peripheral and macular retinal disease even without the typical RP phenotype especially when SNHL is noted. Additionally, genetic screening may be useful in patients that have clinical symptoms and retinal findings even in the absence of known SNHL given the variability of atypical USH.

Purpose: To report a unique case of metastatic paraganglioma presenting as a junctional scotoma. Observations: A 38-year-old Caucasian man with a history of abdominal paraganglioma presented with minimally blurred vision 20/25 visual acuity in the left eye. The patient was found to have a junctional scotoma upon visual field testing. Cranial MRI revealed a large peri-clival mass compressing the pre-chiasmal optic nerves and other loci of metastatic disease. Intracranial masses, including metastases, can present with a relatively intact central acuity and nonspecific visual symptoms. Conclusions and Importance: To the best of our knowledge, this is the first report of metastatic paraganglioma causing a junctional scotoma. In cases with junctional scotoma, careful neuro-ophthalmic assessment and imaging are of paramount importance, even in patients with excellent visual acuity.

Retinal gene therapy has shown great promise in treating retinitis pigmentosa (RP), a primary photoreceptor degeneration that leads to severe sight loss in young people. In the present study, we report the first-in-human phase 1/2, dose-escalation clinical trial for X-linked RP caused by mutations in the RP GTPase regulator (RPGR) gene in 18 patients over up to 6 months of follow-up (https://clinicaltrials.gov/: NCT03116113). The primary outcome of the study was safety, and secondary outcomes included visual acuity, microperimetry and central retinal thickness. Apart from steroid-responsive subretinal inflammation in patients at the higher doses, there were no notable safety concerns after subretinal delivery of an adeno-associated viral vector encoding codon-optimized human RPGR (AAV8-coRPGR), meeting the pre-specified primary endpoint. Visual field improvements beginning at 1 month and maintained to the last point of follow-up were observed in six patients.

Purpose The purpose of this study was to characterize the phenotypic spectrum of ophthalmic findings in patients with Alagille syndrome. Methods We conducted a retrospective, observational, multicenter, study on 46 eyes of 23 subjects with Alagille syndrome. We reviewed systemic and ophthalmologic data extracted from medical records, color fundus photography, fundus autofluorescence, optical coherence tomography, visual fields, electrophysiological assessments, and molecular genetic findings. Results Cardiovascular abnormalities were found in 83% of all cases (of those, 74% had cardiac murmur), whereas 61% had a positive history of hepatobiliary issues, and musculoskeletal anomalies were present in 61% of all patients. Dysmorphic facies were present in 16 patients, with a broad forehead being the most frequent feature. Ocular symptoms were found in 91%, with peripheral vision loss being the most frequent complaint. Median (range) Snellen visual acuity of all eyes was 20/25 (20/20 to hand motion [HM]). Anterior segment abnormalities were present in 74% of the patients; of those, posterior embryotoxon was the most frequent finding. Abnormalities of the optic disc were found in 52%, and peripheral retinal abnormalities were the most frequent ocular finding in this series, found in 96% of all patients. Fifteen JAG1 mutations were identified in 16 individuals; of those, 6 were novel. Conclusions This study reports a cohort of patients with Alagille syndrome in which peripheral chorioretinal changes were more frequent than posterior embryotoxon, the most frequent ocular finding according to a number of previous studies. We propose that these peripheral chorioretinal changes are a new hallmark to help diagnose this syndrome.

Background/AimsTo better understand the pattern of degeneration progression in cases with choroideremia.MethodsA cohort of genotypically confirmed choroideremia cases who underwent optical coherence tomography (OCT) and fundus autofluorescence (FAF) imaging was studied. Using HEYEX review software, the foveal centre was marked on FAF images under guidance of corresponding OCT images, followed by application of an ETDRS grid. The boundaries of preserved autofluorescence (AF) were manually segmented in each individual ETDRS subfield. The regional distribution of preserved AF was assessed by comparing its area among the various subfields.ResultsA total of 168 eyes from 84 choroideremia cases were enrolled. There was a statistically significant difference in the amount of preserved AF area between inner subfields as determined by one-way analysis of variance (F (3,668)=9.997, pConclusionThe asymmetric spatial distribution of preserved AF in choroideremia (corresponding to the stellate shaped nature of these regions) suggests that the progression of degeneration has directional preference.

International audience; Usher syndrome (USH) encompasses a group of clinically and genetically heterogenous disorders defined by the triad of sensorineural hearing loss (SNHL), vestibular dysfunction, and vision loss. USH is the most common cause of deaf blindness. USH is divided clinically into three subtypes—USH1, USH2, and USH3—based on symptom severity, progression, and age of onset. The underlying genetics of these USH forms are, however, significantly more complex, with over a dozen genes linked to the three primary clinical subtypes and other atypical USH phenotypes. Several of these genes are associated with other deaf-blindness syndromes that share significant clinical overlap with USH, pointing to the limits of a clinically based classification system. The genotype-phenotype relationships among USH forms also may vary significantly based on the location and type of mutation in the gene of interest. Understanding these genotype-phenotype relationships and associated natural disease histories is necessary for the successful development and application of gene-based therapies and precision medicine approaches to USH. Currently, the state of knowledge varies widely depending on the gene of interest. Recent studies utilizing next-generation sequencing technology have expanded the list of known pathogenic mutations in USH genes, identified new genes associated with USH-like phenotypes, and proposed algorithms to predict the phenotypic effects of specific categories of allelic variants. Further work is required to validate USH gene causality, and better define USH genotype-phenotype relationships and disease natural histories—particularly for rare mutations—to lay the groundwork for the future of USH treatment.

Purpose Adaptive optics scanning light ophthalmoscopy (AOSLO) imaging in patients with achromatopsia (ACHM) and albinism is not always successful. Here, we tested whether optical coherence tomography (OCT) measures of foveal structure differed between patients for whom AOSLO images were either quantifiable or unquantifiable. Methods The study included 166 subjects (84 with ACHM; 82 with albinism) with previously acquired OCT scans, AOSLO images, and best-corrected visual acuity (BCVA, if available). Foveal OCT scans were assessed for outer retinal structure, outer nuclear layer thickness, and hypoplasia. AOSLO images were graded as quantifiable if a peak cone density could be measured and/or usable if the location of peak density could be identified and the parafoveal mosaic was quantifiable. Results Forty-nine percent of subjects with ACHM and 57% of subjects with albinism had quantifiable AOSLO images. Older age and better BCVA were found in subjects with quantifiable AOSLO images for both ACHM (P = 0.0214 and P = 0.0276, respectively) and albinism (P = 0.0073 and P < 0.0004, respectively). There was a significant trend between ellipsoid zone appearance and ability to quantify AOSLO (P = 0.0028). In albinism, OCT metrics of cone structure did not differ between groups. Conclusions Previously reported AOSLO-based cone density measures in ACHM may not necessarily reflect the degree of remnant cone structure in these patients. Translational Relevance Until AOSLO is successful in all patients with ACHM and albinism, the possibility of the reported data from a particular cohort not being representative of the entire population remains an important issue to consider when interpreting results from AOSLO studies.

To explore the effect of patients' age, baseline visual acuity (VA), and intraoperative foveal detachment on outcomes of subretinal voretigene neparvovec-rzyl (Luxturna) therapy and to assess patients' perceptions of the treatment effect.Multicenter, retrospective, consecutive case series, and cross-sectional prospective survey.All 41 consecutive patients treated with voretigene neparvovec-rzyl after Food and Drug Administration approval at 3 institutions between January 2018 and May 2020.A retrospective chart review of operative reports, clinical notes, ancillary testing, and complications, comparing data at baseline and at 1, 2 to 3, 6 to 9, and 10 to 15 months after subretinal surgery was conducted. A survey was administered to adult patients and parents of pediatric patients.Changes in best-corrected VA and retinal morphology and in patients' perceptions.Seventy-seven eyes of 41 patients (16 adults and 25 pediatric patients; age range, 2-44 years; mean follow-up, 10 months [range, 1 week to 18.5 months]) were analyzed. There was no statistically significant vision change for the adults, whereas there was a trend of improvement for pediatric patients, which reached statistical significance for some time points. The baseline VA did not affect the posttherapy VA (P = 0.23). The central foveal thickness decreased mildly in both pediatric patients and adults, without significant differences between the populations. The fovea was detached by voretigene neparvovec-rzyl in 62 (81%) eyes. The inner segment-outer segment junction remained unchanged in 91% of 54 eyes with gradable OCT, with or without foveal detachment. Thirty-two (78%) patients were reached for the survey an average of 1.15 ± 0.50 years (range, 0.31 to 2.31) after the surgery in the first eye. Improvement in night, day, or color vision was reported by 23 (72%), 22 (69%), and 18 (56%) patients, respectively.This study is limited by the large variability in follow-up time. There were no persistent statistically significant vision changes. A decrease in foveal thickness was noted in most eyes, but the long-term significance of this remains to be determined.

Purpose: To determine whether artifacts in optical coherence tomography (OCT) images are associated with the success or failure of adaptive optics scanning light ophthalmoscopy (AOSLO) imaging in subjects with achromatopsia (ACHM). / Methods: Previously acquired OCT and non-confocal, split-detector AOSLO images from one eye of 66 subjects with genetically confirmed achromatopsia (15 CNGA3 and 51 CNGB3) were reviewed along with best-corrected visual acuity (BCVA) and axial length. OCT artifacts in interpolated vertical volumes from CIRRUS macular cubes were divided into four categories: (1) none or minimal, (2) clear and low frequency, (3) low amplitude and high frequency, and (4) high amplitude and high frequency. Each vertical volume was assessed once by two observers. AOSLO success was defined as sufficient image quality in split-detector images at the fovea to assess cone quantity. / Results: There was excellent agreement between the two observers for assessing OCT artifact severity category (weighted kappa = 0.88). Overall, AOSLO success was 47%. For subjects with OCT artifact severity category 1, AOSLO success was 65%; for category 2, 47%; for category 3, 11%; and for category 4, 0%. There was a significant association between OCT artifact severity category and AOSLO success (P = 0.0002). Neither BCVA nor axial length was associated with AOSLO success (P = 0.07 and P = 0.75, respectively). / Conclusions: Artifacts in OCT volumes are associated with AOSLO success in ACHM. Subjects with less severe OCT artifacts are more likely to be good candidates for AOSLO imaging, whereas AOSLO was successful in only 7% of subjects with category 3 or 4 OCT artifacts. These results may be useful in guiding patient selection for AOSLO imaging. / Translational Relevance: Using OCT to prescreen patients could be a valuable tool for clinical trials that utilize AOSLO to reduce costs and decrease patient testing burden.

The purpose of this study was to compare the baseline steady-state pattern electroretinogram (SS-PERG) of patients with G11778A Leber hereditary optic neuropathy (LHON) with different stages of visual acuity (VA) loss before allotopic gene therapy (GT).Patients (n = 28) were enrolled into groups (GT I: chronic bilateral VA ≤35 Early Treatment Diabetic Retinopathy Study [ETDRS]; GT II: acute bilateral VA ≤35 ETDRS; GT III: acute unilateral, VA ≤35 ETDRS, and better eye VA ≥70 ETDRS) and tested with SS-PERG together with 210 age-matched normal controls (NCs). SS-PERG amplitude (nV) and latency (ms) of each eye were averaged for groups GT I, GT II, and NC. Symptomatic eyes (GT III-S) and asymptomatic eyes (GT III-A) of group GT III were included separately and accounted for by using generalized estimating equation (GEE) methods.Compared to NC, SS-PERG amplitudes were reduced similarly by approximately 50% (P0.001) among all GT groups (NCGT I, GT II, GT III-S, and GT III-A). SS-PERG latencies were shorter by ≥3.5 ms in all LHON groups and differed by disease stage (G III-ANC, P = 0.002; GT III-SGT III-A, P = 0.01; GT IIGT III-S, P = 0.03; GT INC, P0.001, but not different from other GT groups, all P0.1).Although SS-PERG amplitude reduction did not distinguish between disease stages, SS-PERG latency shortening occurred in asymptomatic eyes and symptomatic eyes and distinguished between disease stages.SS-PERG latency shortening is consistent with primary damage of smaller/slower axons and sparing of larger/faster axons and may provide an objective staging of LHON, which may be helpful to determine efficacy in LHON trials.

To evaluate the efficacy of motion discrimination training as a potential therapy for stroke-induced hemianopic visual field defects.Clinical trial.Forty-eight patients with stroke-induced homonymous hemianopia (HH) were randomized into 2 training arms: intervention and control. Patients were between 21 and 75 years of age and showed no ocular issues at presentation.Patients were trained on a motion discrimination task previously evidenced to reduce visual field deficits, but not in a randomized clinical trial. Patients were randomized with equal allocation to receive training in either their sighted or deficit visual fields. Training was performed at home for 6 months, consisting of repeated visual discriminations at a single location for 20 to 30 minutes daily. Study staff and patients were masked to training type. Testing before and after training was identical, consisting of Humphrey visual fields (Carl Zeiss Meditech), macular integrity assessment perimetry, OCT, motion discrimination performance, and visual quality-of-life questionnaires.Primary outcome measures were changes in perimetric mean deviation (PMD) on Humphrey Visual Field Analyzer in both eyes.Mean PMDs improved over 6 months in deficit-trained patients (mean change in the right eye, 0.58 dB; 95% confidence interval, 0.07-1.08 dB; mean change in the left eye 0.84 dB; 95% confidence interval, 0.22-1.47 dB). No improvement was observed in sighted-trained patients (mean change in the right eye, 0.12 dB; 95% confidence interval, -0.38 to 0.62 dB; mean change in the left eye, 0.10 dB; 95% confidence interval, -0.52 to 0.72 dB). However, no significant differences were found between the alternative training methods (right eye, P = 0.19; left eye, P = 0.10).To date, no widely accepted therapy is available to treat HH. This study evaluated the efficacy of a promising potential treatment, visual perceptual training. We failed to find a difference between treatment training within the deficit field and control training within the sighted field when performed in a home environment.

Electroretinogram (ERG) is the only clinical objective test available to assess retinal function. Full-field ERG (ffERG) measures the panretinal rod and cone photoreceptor function as well as inner retinal function and is an important measure in the diagnosis and management of inherited retinal diseases as well as inflammatory, toxic, and nutritional retinopathies. Adhering to international standards and maintaining retinal dark adaptation are critical to acquire valid and reliable dark-adapted (scotopic) and light-adapted (photopic) ffERG responses. Performing ffERG in infants and children is challenging and often requires general anesthesia in the operating room. However, maintaining retinal dark adaptation in the operating room is becoming increasingly difficult given the numerous light sources from anesthesiology monitoring systems and other equipment. A practical and widely applicable method for ffERG testing is described in the operating room that optimizes retinal dark adaptation. The method reduces operating room time by dark-adapting the patient before general anesthesiology is instituted. The operating room is modified for dark adaptation and any remaining light source in the darkened operating room is minimized with the use of a modified portable foldable darkroom that encloses the patient's head and the ERG examiner during ffERG scotopic recordings. The simple method adheres to ffERG international standards and provides valid reliable scotopic and photopic ffERG recordings that are critical to assess objective retinal function in this young age group where subjective assessment of visual function such as visual acuity and visual fields are not possible. Furthermore, the ffERG is the gold standard clinical test in detecting early onset inherited retinal diseases including Leber congenital amaurosis where approved gene therapy has become available. In sedated conditions, very low amplitude ffERG signals can be detected due to minimal orbicularis muscle activity interference, which is particularly relevant in patients after gene therapy to detect improved amplitude responses.

A2E (N-retinylidene-N-retinylethanolamine) is a major fluorophore in the RPE (retinal pigment epithelium). To identify and characterize A2E-rich RPE lipofuscin, we fractionated RPE granules from human donor eyes into five fractions (F1&ndash, F5 in ascending order of density) by discontinuous sucrose density gradient centrifugation. The dry weight of each fraction was measured and A2E was quantified by liquid chromatography/mass spectrometry (LC/MS) using a synthetic A2E homolog as a standard. Autofluorescence emission was characterized by a customer-built spectro-fluorometer system. A significant A2E level was detected in every fraction, and the highest level was found in F1, a low-density fraction that makes up half of the total weight of all RPE granules, contains 67% of all A2E, and emits 75% of projected autofluorescence by all RPE granules. This group of RPE granules, not described previously, is therefore the most abundant RPE lipofuscin granule population. A progressive decrease in autofluorescence was observed from F2 to F4, whereas no autofluorescence emission was detected from the heavily pigmented F5. The identification of a novel and major RPE lipofuscin population could have significant implications in our understanding of A2E and lipofuscin in human RPE.

PURPOSE: To determine interocular symmetry of foveal cone topography in achromatopsia (ACHM) using non-confocal split-detection adaptive optics scanning light ophthalmoscopy (AOSLO). METHODS: Split-detector AOSLO images of the foveal cone mosaic were acquired from both eyes of 26 subjects (mean age 24.3 years; range 8 – 44 years, 14 females) with genetically confirmed CNGA3- or CNGB3-associated ACHM. Cones were identified within a manually delineated rod-free zone. Peak cone density (PCD) was determined using an 80 × 80 μm sampling window within the rod-free zone. The mean and standard deviation (SD) of intercell distance (ICD) were calculated to derive the coefficient of variation (CV). Cone density difference maps were generated to compare cone topography between eyes. RESULTS: PCD (mean ± SD) was 17,530 ± 9,614 cones/mm(2) and 17,638 ± 9,753 cones/mm(2) for right and left eyes, respectively (p = 0.677, Wilcoxon test). The mean (± SD) for ICD was 9.05 ± 2.55 μm and 9.24 ± 2.55 μm for right and left eyes, respectively (p = 0.410, paired t test). The mean (± SD) for CV of ICD was 0.16 ± 0.03 μm and 0.16 ± 0.04 μm for right and left eyes, respectively (p = 0.562, paired t test). Cone density maps demonstrated that cone topography of the ACHM fovea is non-uniform with local variations in cone density between eyes. CONCLUSIONS: These results demonstrate interocular symmetry of the foveal cone mosaic (both density and packing) in ACHM. As cone topography can differ between eyes of a subject, PCD does not completely describe the foveal cone mosaic in ACHM. Nonetheless, these findings are of value in longitudinal monitoring of patients during treatment trials and further suggest that both eyes of a given subject may have similar therapeutic potential and non-study eye can be used as a control.

Stargardt macular dystrophy (STGD1) is a hereditary retinal degeneration that lacks effective treatment options. Gene therapy, stem cell therapy, and pharmacotherapy with visual cycle modulators (VCMs) and complement inhibitors are discussed as potential treatments.Investigational therapies for STGD1 aim to reduce toxic bisretinoids and lipofuscin in the retina and retinal pigment epithelium (RPE). These agents include C20-D3-vitamin A (ALK-001), isotretinoin, VM200, emixustat, and A1120. Avacincaptad pegol is a C5 complement inhibitor that may reduce inflammation-related RPE damage. Animal models of STGD1 show promising data for these treatments, though proof of efficacy in humans is lacking. Fenretinide and emixustat are VCMs for dry AMD and STGD1 that failed to halt geographic atrophy progression or improve vision in trials for AMD. A1120 prevents retinol transport into RPE and may spare side effects typically seen with VCMs (nyctalopia and chromatopsia). Stem cell transplantation suggests potential biologic plausibility in a phase I/II trial. Gene therapy aims to augment the mutated ABCA4 gene, though results of a phase I/II trial are pending.Stem cell transplantation, ABCA4 gene therapy, VCMs, and complement inhibitors offer biologically plausible treatment mechanisms for treatment of STGD1. Further trials are warranted to assess efficacy and safety in humans.

PURPOSE: To assess the retinal anatomy and array position in the Argus II Retinal Prosthesis recipients. DESIGN: Prospective, non-comparative cohort study METHODS: Setting: international multicenter study Patients: Argus II recipients enrolled in the Post-Market Surveillance Studies. Procedures: Spectral-domain Optical Coherence Tomography images collected for the Surveillance Studies (NCT01860092 and NCT01490827) were reviewed. Baseline and postoperative macular thickness, electrode-retina distance (gap), optic disc-array overlap, and preretinal membrane presence were recorded at 1, 3, 6, and 12 months. Main Outcome Measures: Axial retinal thickness and axial gap along the array’s long axis (a line between the tack and handle), maximal retinal thickness and maximal gap along a B-scan near the tack, midline, and handle. RESULTS: Thirty-three patients from 16 surgical sites in the United States and Germany were included. Mean axial retinal thickness increased from month 1 through month 12 at each location, but reached statistical significance only at the array midline (p- value=0.007). The rate of maximal thickness increase was highest near the array midline (slope=6.02, p=0.004), compared to the tack (slope=3.60, p

Pharmacotherapy with visual cycle modulators (VCMs) is under investigation for retinitis pigmentosa (RP), Leber congenital amaurosis (LCA), Stargardt macular dystrophy (SMD) and nonexudative age-related macular degeneration (AMD), all blinding diseases that lack effective treatment options.The authors review investigational VCMs, including oral retinoids, 9-cis-retinyl-acetate (zuretinol) and 9-cis-β-carotene, which restore 11-cis-retinal levels in RP and LCA caused by LRAT and RPE65 gene mutations, and may improve visual acuity and visual fields. Therapies for SMD aiming to decrease accumulation of toxic Vitamin A dimers and lipofuscin in the retina and retinal pigment epithelium (RPE) include C20-D3-vitamin A (ALK-001), isotretinoin, VM200, emixustat, and A1120. Mouse models of SMD show promising data for these treatments, though proof of efficacy in humans is currently lacking. Fenretinide and emixustat are investigational VCMs for dry AMD, though neither has been shown to reduce geographic atrophy or improve vision in human trials. A1120 prevents retinol transport into the RPE and may spare the side effects typically seen in VCMs (nyctalopia and chromatopsia) per mouse studies.Oral VCMs may be feasible treatment options for degenerative retinal diseases based on pre-clinical and some early clinical studies. Further trials are warranted to assess their efficacy and safety in humans.

Purpose To determine the effects of AAV2(Y444,500,730F)-P1ND4v2 in patients with Leber hereditary optic neuropathy (LHON). Design Prospective open-label, unilateral single-dose, intravitreal injection of AAV2(Y444,500,730F)-P1ND4v2 per participant. Participants Fourteen patients with visual loss and mutated G11778A mitochondrial DNA. Methods Intravitreal injection with the gene therapy vector AAV2(Y444,500,730F)-P1ND4v2 into 1 eye. Six participants with chronic bilateral visual loss lasting more than 12 months (group 1), 6 participants with bilateral visual loss lasting less than 12 months (group 2), and 2 participants with unilateral visual loss (group 3) were treated. Nine patients had at least 12 months of follow-up. Clinical testing included visual acuity, visual fields, optical coherence tomography, pattern electroretinography, and neuro-ophthalmic examinations. Generalized estimating equation methods were used for longitudinal analyses. Main Outcome Measure Loss of visual acuity. Results For groups 1 and 2, month 12 average acuity improvements with treatment relative to baseline were 0.24 logarithm of the minimum angle of resolution (logMAR). Fellow eyes had a 0.09-logMAR improvement. A post hoc comparison found that at month 12, the difference between study eye minus fellow eye improvement in group 2 patients of 0.53 logMAR was greater than that observed in our prior acute natural history patients of 0.21 logMAR ( P = 0.053). At month 18, the difference between study eye minus fellow eye improvement in our acute group 2 gene therapy patients of 0.96 was more than that observed in our prior acute natural history patients (0.17 logMAR; P P = 0.013). Generalized estimating equations suggested that PERG amplitudes worsened more in treated eyes than in fellow eyes by approximately 0.05 μV ( P = 0.009 exchangeable). No difference between eyes in outcomes of other visual function measures was evident. Conclusions Allotopic gene therapy for LHON at low and medium doses seems to be safe and does not damage the temporal retinal nerve fiber layer, opening the door next for testing of the high dose.

High-resolution in vivo imaging has provided evidence of residual cone structure in congenital achromatopsia, although the progressive nature of the disease remains unclear. In this study, the authors use optical coherence tomography and adaptive optics scanning light ophthalmoscopy to investigate longitudinal changes in cone structure in achromatopsia., Purpose: Congenital achromatopsia is an autosomal recessive disease causing substantial reduction or complete absence of cone function. Although believed to be a relatively stationary disorder, questions remain regarding the stability of cone structure over time. In this study, the authors sought to assess the repeatability of and examine longitudinal changes in measurements of central cone structure in patients with achromatopsia. Methods: Forty-one subjects with CNGB3-associated achromatopsia were imaged over a period of between 6 and 26 months using optical coherence tomography and adaptive optics scanning light ophthalmoscopy. Outer nuclear layer (ONL) thickness, ellipsoid zone (EZ) disruption, and peak foveal cone density were assessed. Results: ONL thickness increased slightly compared with baseline (0.184 μm/month, P = 0.02). The EZ grade remained unchanged for 34/41 subjects. Peak foveal cone density did not significantly change over time (mean change 1% per 6 months, P = 0.126). Conclusion: Foveal cone structure showed little or no change in this group of subjects with CNGB3-associated achromatopsia. Over the time scales investigated (6–26 months), achromatopsia seems to be a structurally stable condition, although longer-term follow-up is needed. These data will be useful in assessing foveal cone structure after therapeutic intervention.

Background. Smoking causes blindness-related diseases. Eye-care providers are uniquely positioned to help their patients quit smoking. Aims. Using a pre-/postevaluation design, this study evaluated a web-based training in smoking cessation counseling targeting eye-care providers. Method. The training was developed based on the 3A1R protocol: “Ask about smoking, Advise to quit, Assess willingness to quit, and Refer to tobacco quitlines,” and made available in the form of a web-based video presentation. Providers ( n = 654) at four academic centers were invited to participate. Participants completed pretraining, posttraining, and 3-month follow-up surveys. Main outcomes were self-reported improvement in their motivation, confidence, and counseling practices at 3-month follow-up. Generalized linear mixed models for two time-points (pretraining and 3-month) were conducted for these outcomes. Results. A total of 113 providers (54.0% males) participated in the study (17.7% response rate). At the 3-month evaluation, 9.8% of participants reported improvement in their motivation. With respect to the 3A1R, 8% reported improvement in their confidence for Ask, 15.5% for Advise, 28.6% for Assess, and 37.8% for Refer. Similarly, 25.5% reported improvement in their practices for Ask, 25.5% for Advise, 37.2% for Assess, and 39.4% for Refer to tobacco quitlines ( p < .001 for all except for Refer confidence p = .05). Discussion. Although participation rate was low, the program effectively improved providers’ smoking cessation counseling practices. Conclusions. Including training in smoking cessation counseling in ophthalmology curriculums, and integrating the 3A1R protocol into the electronic medical records systems in eye-care settings, might promote smoking cessation practices in these settings.