Use of the Medmont Dark-Adapted Chromatic Perimeter for Assessing Rod Function in Retinitis Pigmentosa.

Medmont Dark-Adapted Chromatic (DAC) Perimeter enables efficient and quantifiable evaluation of rod-mediated (scotopic) vision. DAC tests rod function at multiple retinal locations, creating a topographical map of rod-mediated vision. These dynamic rod responses can be used as a functional marker to monitor disease progression and functional alterations in inherited retinal dystrophies, such as retinitis pigmentosa, Stargardt disease, cone-rod dystrophy, and choroideremia. In this chapter, we describe a protocol for the operation and analysis of the Medmont DAC in monitoring and assessing various retinal disorders.

A mutation in CRX causing pigmented paravenous retinochoroidal atrophy.

INTRODUCTION: Mutations in the cone-rod homeobox (CRX) gene, a known cause of inherited retinal dystrophy, are characterized by extensive phenotypic heterogeneity. We describe a novel presentation of rod-cone dystrophy (RCD) phenocopying pigmented paravenous retinochoroidal atrophy associated with a mutation in CRX. CASE DESCRIPTION: A 53-year-old man and his 48-year-old brother presented with a history of progressive vision loss and nyctalopia. Fundus examination revealed a bull's eye lesion with chorioretinal atrophy and intraretinal pigment migration, while spectral-domain optical coherence tomography (SD-OCT) demonstrated retinal thinning with outer retinal atrophy. On short-wavelength autofluorescence (SW-AF) imaging, an atypical paravenous pattern of atrophy with a surrounding hyperautofluorescent border was observed. Full-field electroretinogram (ffERG) revealed a rod-cone pattern of dysfunction. A heterozygous pathogenic variant, c.119G>A:p.(Arg40Gln), in the CRX gene was identified in both brothers and segregated in their family. CONCLUSION: This case report broadens the currently known phenotypic presentations of CRX-associated retinopathy and suggests that mutations in CRX may be associated with pigmented paravenous retinochoroidal atrophy.

Gene therapy for inherited retinal diseases.

Inherited retinal diseases (IRDs) are a genetically variable collection of devastating disorders that lead to significant visual impairment. Advances in genetic characterization over the past two decades have allowed identification of over 260 causative mutations associated with inherited retinal disorders. Thought to be incurable, gene supplementation therapy offers great promise in treating various forms of these blinding conditions. In gene replacement therapy, a disease-causing gene is replaced with a functional copy of the gene. These therapies are designed to slow disease progression and hopefully restore visual function. Gene therapies are typically delivered to target retinal cells by subretinal (SR) or intravitreal (IVT) injection. The historic Food and Drug Administration (FDA) approval of voretigene neparvovec for RPE65-associated Leber's congenital amaurosis (LCA) spurred tremendous optimism surrounding retinal gene therapy for various other monogenic IRDs. Novel disease-causing mutations continue to be discovered annually, and targeted genetic therapy is now under development in clinical and preclinical models for many IRDs. Numerous clinical trials for other IRDs are ongoing or have recently completed. Disorders being targeted for genetic therapy include retinitis pigmentosa (RP), choroideremia (CHM), achromatopsia (ACHM), Leber's hereditary optic neuropathy, usher syndrome (USH), X-linked retinoschisis, and Stargardt disease. Here, we provide an update of completed, ongoing, and planned clinical trials using gene supplementation strategies for retinal degenerative disorders.

Stage-dependent choriocapillaris impairment in Best vitelliform macular dystrophy characterized by optical coherence tomography angiography.

Characterization of vascular impairment in Best vitelliform macular dystrophy (BVMD) is essential for the development of treatment modalities and therapy trials. As such, we seek to characterize the choriocapillaris (CC) at each stage of the disease process in 22 patients (44 eyes) with a diagnosis of BVMD confirmed by genetic sequencing. We utilize optical coherence tomography angiography (OCTA) images to characterize the CC and correlate our findings to the status of the retinal pigment epithelium (RPE) as observed on short-wavelength fundus autofluorescence (SW-AF) images. We observed that in the vitelliruptive stage, the CC appeared as bright and granular in the area where the vitelliform lesion was present. In the atrophic stage, varying degrees of CC atrophy were observed within the lesion area, with the regions of CC atrophy appearing as hypoautofluorescent on SW-AF images. Our results suggest that the CC impairment observed in the vitelliruptive stage of BVMD progressively culminates in the CC atrophy observed at the atrophic stage. As such, OCTA imaging can be used to characterize CC impairment in BVMD patients as part of diagnosis and tracking of disease progression. Our findings suggest that the best window of opportunity for therapeutic approaches is before the atrophic stage, as it is during this stage that CC atrophy is observed.

Retinal Pigment Epithelium Atrophy in Recessive Stargardt Disease as Measured by Short-Wavelength and Near-Infrared Autofluorescence.

Purpose: To compare the detection of retinal pigment epithelium (RPE) atrophy in short-wavelength (SW-AF) and near-infrared autofluorescence (NIR-AF) images in Stargardt disease (STGD1) patients. Methods: SW-AF and NIR-AF images (115 eyes from 115 patients) were analyzed by two independent graders. Hypoautofluorescent (hypoAF) areas, indicative of RPE atrophy, were measured, and the two modalities were compared. Results: Patients were segregated into four groups: nascent (6 [5%]), widespread (21 [18%]), discrete (55 [48%]), and chorioretinal atrophy (33 [29%]). The areas of hypoAF were larger in NIR-AF compared to SW-AF images in discrete (3.9 vs. 2.2 mm2, P < 0.001) and chorioretinal atrophy (12.7 vs. 11.4 mm2, P = 0.015). Similar findings were observed qualitatively in nascent and widespread atrophy patients. Using the area linear model (ALM), lesion area increased at similar rates in SW-AF and NIR-AF images of discrete atrophy (0.20 vs. 0.32 mm2/y, P = 0.275) and chorioretinal atrophy (1.30 vs. 1.74 mm2/y, P = 0.671). Using the radius linear model (RLM), the lesion effective radius also increased similarly in SW-AF and NIR-AF images in discrete (0.03 vs. 0.05 mm2/y, P = 0.221) and chorioretinal atrophy (0.08 vs. 0.10 mm2/y, P = 0.754) patients. Conclusions: NIR-AF reveals a larger area of RPE atrophy in STGD1 patients compared to SW-AF images, but rates of lesion enlargement in the two modalities are similar. Translational Relevance: Measurements of RPE atrophy by AF imaging are crucial for monitoring STGD1 disease progression and given our findings we advocate greater use of NIR-AF for patients.

Efficacy of 3D digital visualization in minimizing coaxial illumination and phototoxic potential in cataract surgery: pilot study.

PURPOSE: To compare the coaxial light intensity required during cataract surgery and rate of postoperative visual recovery, with surgical visualization achieved with a traditional analog operating microscope compared with a 3D digital visualization system. SETTING: Weill Cornell Medical Center, New York Presbyterian Hospital, New York, New York. DESIGN: Retrospective, consecutive, single-surgeon series. METHODS: Patients undergoing femtosecond laser-assisted cataract surgery were retrospectively grouped into either: (1) visualization using the binoculars of a standard operating microscope (traditional group) or (2) visualization using a 3D digital visualization system affixed to the same operating microscope (digital group). Note was made in each case of light intensity used, light exposure time, intraoperative and/or postoperative complications, and postoperative visual acuities. RESULTS: The study comprised 24 eyes in the traditional group and 27 eyes in the digital group. There were no intraoperative or postoperative complications in either group and no difference in mean light exposure time, but the mean light intensity used in the digital group was significantly less (18.5% ± 1.5%) than that in the traditional group (43.3% ± 3.7%; P < .001). Furthermore, the digital group achieved a postoperative day 1 visual acuity that was within 2 lines of the postoperative month 1 visual acuity a greater percentage of time than that in the traditional group (81.5% of eyes vs 54.2% of eyes; P = .04). CONCLUSIONS: Light intensity was significantly decreased in patients who underwent cataract surgery assisted by the 3D digital visualization platform without an increase in complications or surgical time and possibly with a faster postoperative visual recovery.

Retinal Manifestations of Mitochondrial Oxidative Phosphorylation Disorders.

Purpose: The purpose of this paper was to discuss manifestations of primary mitochondrial dysfunctions and whether the retinal pigment epithelium or the photoreceptors are preferentially affected. Methods: A retrospective analysis was performed of patients with clinically and laboratory confirmed diagnoses of maternally inherited diabetes and deafness (MIDD) or Kearns-Sayre syndrome (KSS). Patients underwent full ophthalmic examination, full-field electroretinogram, and multimodal imaging studies, including short-wavelength autofluorescence, spectral domain-optical coherence tomography, and color fundus photography. Results: A total of five patients with MIDD and four patients with KSS were evaluated at two tertiary referral centers. Mean age at initial evaluation was 50.3 years old. Nascent outer retinal tubulations corresponding with faint foci of autofluorescence were observed in two patients with MIDD. Characteristic features of this cohort included a foveal sparing phenotype observed in 13 of 18 eyes (72%), global absence of intraretinal pigment migration, and preserved retinal function on full-field electroretinogram testing in 12 of 16 eyes (75%). One patient diagnosed with MIDD presented with an unusual pattern of atrophy surrounding the parapapillary region and one patient with KSS presented with an atypical choroideremia-like phenotype. Conclusions: MIDD and KSS are phenotypically heterogeneous disorders. Several features of disease suggest that primary mitochondrial dysfunction may first affect the retinal pigment epithelium followed by secondary photoreceptor loss. Similarities between primary mitochondrial degenerations and retinal disorders, such as age-related macular degeneration may suggest a primary role of mitochondria in the pathogenesis of these oligogenic disorders.

Spectral-Domain Optical Coherence Tomography Is More Sensitive for Hydroxychloroquine-Related Structural Abnormalities Than Short-Wavelength and Near-Infrared Autofluorescence.

Purpose: To analyze the appearance of structural abnormalities due to hydroxychloroquine (HCQ) toxicity by spectral-domain optical coherence tomography (SD-OCT) and short-wavelength autofluorescence (SW-AF) and near-infrared fundus autofluorescence (NIR-AF) imaging. Methods: This retrospective cohort study included 88 eyes from 44 patients who had a history of or were currently taking HCQ. SD-OCT, SW-AF, and NIR-AF images were analyzed by two independent graders for the detection of HCQ-associated abnormalities. Results: Sixty eyes (30 patients, 68%) presented with no abnormalities for either imaging modality. Twenty eyes (10 patients, 23%) presented with parafoveal abnormalities (ellipsoid zone attenuation and/or interdigitation zone continuity loss) in SD-OCT scans but with qualitatively normal SW-AF and NIR-AF images. Eight eyes (four patients, 9%) presented with bull's-eye maculopathy in SW-AF and NIR-AF images, with corresponding outer retinal structures disrupted parafoveally in SD-OCT scans ("flying saucer" sign). No patients presented with normal SD-OCT scans and concurrent abnormalities in SW-AF or NIR-AF images. Conclusions: SD-OCT was more sensitive in detecting structural abnormalities than either SW-AF or NIR-AF imaging, suggesting its superiority as a screening imaging modality for HCQ toxicity. Maculopathy and abnormalities in the retinal pigment epithelium from HCQ toxicity can be appreciated in both SW-AF and NIR-AF images. Translational Relevance: Although debate exists regarding the best imaging modalities for screening patients for potential HCQ toxicity, our study supports the use of SD-OCT over both SW-AF and NIR-AF imaging as a screening modality.

Treatment-Emergent Adverse Events in Gene Therapy Trials for Inherited Retinal Diseases: A Narrative Review.

Patient safety is a primary priority in the conduction of retinal gene therapy trials. An understanding of risk factors and mitigation strategies for post-procedure complications is crucial for the optimization of gene therapy clinical trial protocols. In this review, we synthesize the literature on ocular delivery methods, vector platforms, and treatment-emergent adverse effects in recent gene therapy clinical trials for inherited retinal diseases.

Optical coherence tomography in the evaluation of retinitis pigmentosa.

BACKGROUND: Optical coherence tomography (OCT) is a non-invasive imaging test that provides easily obtainable and highly reproducible cross-sectional images of the retina. Improved modalities of the OCT that are capable of providing high quality images of not only the retina, but also the deeper structures and vasculature have been developed, including swept-source OCTs and OCT angiography. MATERIALS AND METHODS: Review. RESULTS: The use of OCT in the monitoring of retinitis pigmentosa has been well described and numerous signs of disease progression have been studied. Notably among them are the detection of changes to retinal thickness, the ellipsoid zone, the vasculature on OCT angiography, and cystoid macular edema. CONCLUSION: In this review, we discuss the multiple applications of OCT as a tool in the monitoring of retinitis pigmentosa and its potential use as an outcome measurement in current and future therapeutic endeavors.

Depletion of transglutaminase 2 in neurons alters expression of extracellular matrix and signal transduction genes and compromises cell viability.

The protein transglutaminase 2 (TG2) has been implicated as a modulator of neuronal viability. TG2's role in mediating cell survival processes has been suggested to involve its ability to alter transcriptional events. The goal of this study was to examine the role of TG2 in neuronal survival and to begin to delineate the pathways it regulates. We show that depletion of TG2 significantly compromises the viability of neurons in the absence of any stressors. RNA sequencing revealed that depletion of TG2 dysregulated the expression of 86 genes with 59 of these being upregulated. The genes that were upregulated by TG2 knockdown were primarily involved in extracellular matrix function, cell signaling and cytoskeleton integrity pathways. Finally, depletion of TG2 significantly reduced neurite length. These findings suggest for the first time that TG2 plays a crucial role in mediating neuronal survival through its regulation of genes involved in neurite length and maintenance.