Neuropathy target esterase activity defines phenotypes among PNPLA6 disorders.

Biallelic pathogenic variants in the PNPLA6 gene cause a broad spectrum of disorders leading to gait disturbance, visual impairment, anterior hypopituitarism and hair anomalies. PNPLA6 encodes neuropathy target esterase (NTE), yet the role of NTE dysfunction on affected tissues in the large spectrum of associated disease remains unclear. We present a systematic evidence-based review of a novel cohort of 23 new patients along with 95 reported individuals with PNPLA6 variants that implicate missense variants as a driver of disease pathogenesis. Measuring esterase activity of 46 disease-associated and 20 common variants observed across PNPLA6-associated clinical diagnoses unambiguously reclassified 36 variants as pathogenic and 10 variants as likely pathogenic, establishing a robust functional assay for classifying PNPLA6 variants of unknown significance. Estimating the overall NTE activity of affected individuals revealed a striking inverse relationship between NTE activity and the presence of retinopathy and endocrinopathy. This phenomenon was recaptured in vivo in an allelic mouse series, where a similar NTE threshold for retinopathy exists. Thus, PNPLA6 disorders, previously considered allelic, are a continuous spectrum of pleiotropic phenotypes defined by an NTE genotype:activity:phenotype relationship. This relationship, and the generation of a preclinical animal model, pave the way for therapeutic trials, using NTE as a biomarker.

Deciphering the genetic architecture and ethnographic distribution of IRD in three ethnic populations by whole genome sequence analysis.

Patients with inherited retinal dystrophies (IRDs) were recruited from two understudied populations: Mexico and Pakistan as well as a third well-studied population of European Americans to define the genetic architecture of IRD by performing whole-genome sequencing (WGS). Whole-genome analysis was performed on 409 individuals from 108 unrelated pedigrees with IRDs. All patients underwent an ophthalmic evaluation to establish the retinal phenotype. Although the 108 pedigrees in this study had previously been examined for mutations in known IRD genes using a wide range of methodologies including targeted gene(s) or mutation(s) screening, linkage analysis and exome sequencing, the gene mutations responsible for IRD in these 108 pedigrees were not determined. WGS was performed on these pedigrees using Illumina X10 at a minimum of 30X depth. The sequence reads were mapped against hg19 followed by variant calling using GATK. The genome variants were annotated using SnpEff, PolyPhen2, and CADD score; the structural variants (SVs) were called using GenomeSTRiP and LUMPY. We identified potential causative sequence alterations in 61 pedigrees (57%), including 39 novel and 54 reported variants in IRD genes. For 57 of these pedigrees the observed genotype was consistent with the initial clinical diagnosis, the remaining 4 had the clinical diagnosis reclassified based on our findings. In seven pedigrees (12%) we observed atypical causal variants, i.e. unexpected genotype(s), including 4 pedigrees with causal variants in more than one IRD gene within all affected family members, one pedigree with intrafamilial genetic heterogeneity (different affected family members carrying causal variants in different IRD genes), one pedigree carrying a dominant causative variant present in pseudo-recessive form due to consanguinity and one pedigree with a de-novo variant in the affected family member. Combined atypical and large structural variants contributed to about 20% of cases. Among the novel mutations, 75% were detected in Mexican and 50% found in European American pedigrees and have not been reported in any other population while only 20% were detected in Pakistani pedigrees and were not previously reported. The remaining novel IRD causative variants were listed in gnomAD but were found to be very rare and population specific. Mutations in known IRD associated genes contributed to pathology in 63% Mexican, 60% Pakistani and 45% European American pedigrees analyzed. Overall, contribution of known IRD gene variants to disease pathology in these three populations was similar to that observed in other populations worldwide. This study revealed a spectrum of mutations contributing to IRD in three populations, identified a large proportion of novel potentially causative variants that are specific to the corresponding population or not reported in gnomAD and shed light on the genetic architecture of IRD in these diverse global populations.

Enhanced S-cone Syndrome, a Mini-review.

Enhanced S-cone Syndrome (ESCS) is an autosomal recessive inherited retinal disease mostly associated with disease-causing variants in the NR2E3 gene. During retinal development in ESCS, rod photoreceptor precursors are misdirected to form photoreceptors similar to short-wavelength cones, or S-cones. Compared to a normal human retina, patients with ESCS have no rods and significantly increased numbers of S-cones. Night blindness is the main visual symptom, and visual acuity and color vision can be normal at early disease stages. Histology of donor eyes and adaptive optics imaging revealed increased S-cone density outside of the fovea compared to normal. Visual function testing reveals absent rod function and abnormally enhanced sensitivity to short-wavelength light. Unlike most retinal degenerative diseases, ESCS results in a gain in S-cone photoreceptor function. Research involving ESCS could improve understanding of this rare retinal condition and also shed light on the role of NR2E3 expression in photoreceptor survival.

Tissue-specific genotype-phenotype correlations among USH2A-related disorders in the RUSH2A study.

We assessed genotype-phenotype correlations among the visual, auditory, and olfactory phenotypes of 127 participants with Usher syndrome (USH2) (n =80) or nonsyndromic autosomal recessive retinitis pigmentosa (ARRP) (n = 47) due to USH2A variants, using clinical data and molecular diagnostics from the Rate of Progression in USH2A Related Retinal Degeneration (RUSH2A) study. USH2A truncating alleles were associated with USH2 and had a dose-dependent effect on hearing loss severity with no effect on visual loss severity within the USH2 subgroup. A group of missense alleles in an interfibronectin domain appeared to be hypomorphic in ARRP. These alleles were associated with later age of onset, larger visual field area, better sensitivity thresholds, and better electroretinographic responses. No effect of genotype on the severity of olfactory deficits was observed. This study unveils a unique, tissue-specific USH2A allelic hierarchy with important prognostic implications for patient counseling and treatment trial endpoints. These findings may inform clinical care or research approaches in others with allelic disorders or pleiotropic phenotypes.

Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness.

The RNA exosome is an essential ribonuclease complex required for processing and/or degradation of both coding and non-coding RNAs. We identified five patients with biallelic variants in EXOSC5, which encodes a structural subunit of the RNA exosome. The clinical features of these patients include failure to thrive, short stature, feeding difficulties, developmental delays that affect motor skills, hypotonia and esotropia. Brain MRI revealed cerebellar hypoplasia and ventriculomegaly. While we ascertained five patients, three patients with distinct variants of EXOSC5 were studied in detail. The first patient had a deletion involving exons 5-6 of EXOSC5 and a missense variant, p.Thr114Ile, that were inherited in trans, the second patient was homozygous for p.Leu206His and the third patient had paternal isodisomy for chromosome 19 and was homozygous for p.Met148Thr. The additional two patients ascertained are siblings who had an early frameshift mutation in EXOSC5 and the p.Thr114Ile missense variant that were inherited in trans. We employed three complementary approaches to explore the requirement for EXOSC5 in brain development and assess consequences of pathogenic EXOSC5 variants. Loss of function for exosc5 in zebrafish results in shortened and curved tails/bodies, reduced eye/head size and edema. We modeled pathogenic EXOSC5 variants in both budding yeast and mammalian cells. Some of these variants cause defects in RNA exosome function as well as altered interactions with other RNA exosome subunits. These findings expand the number of genes encoding RNA exosome subunits linked to human disease while also suggesting that disease mechanism varies depending on the specific pathogenic variant.

VALIDATION OF A DEEP LEARNING-BASED ALGORITHM FOR SEGMENTATION OF THE ELLIPSOID ZONE ON OPTICAL COHERENCE TOMOGRAPHY IMAGES OF AN USH2A-RELATED RETINAL DEGENERATION CLINICAL TRIAL.

PURPOSE: To assess the generalizability of a deep learning-based algorithm to segment the ellipsoid zone (EZ). METHODS: The dataset consisted of 127 spectral-domain optical coherence tomography volumes from eyes of participants with USH2A-related retinal degeneration enrolled in the RUSH2A clinical trial (NCT03146078). The EZ was segmented manually by trained readers and automatically by deep OCT atrophy detection, a deep learning-based algorithm originally developed for macular telangiectasia Type 2. Performance was evaluated using the Dice similarity coefficient between the segmentations, and the absolute difference and Pearson's correlation of measurements of interest obtained from the segmentations. RESULTS: With deep OCT atrophy detection, the average (mean ± SD, median) Dice similarity coefficient was 0.79 ± 0.27, 0.90. The average absolute difference in total EZ area was 0.62 ± 1.41, 0.22 mm2 with a correlation of 0.97. The average absolute difference in the maximum EZ length was 222 ± 288, 126 µm with a correlation of 0.97. CONCLUSION: Deep OCT atrophy detection segmented EZ in USH2A-related retinal degeneration with good performance. The algorithm is potentially generalizable to other diseases and other biomarkers of interest as well, which is an important aspect of clinical applicability.

Auditory and olfactory findings in patients with USH2A-related retinal degeneration-Findings at baseline from the rate of progression in USH2A-related retinal degeneration natural history study (RUSH2A).

Sensorineural hearing loss (SNHL) is characteristic of Usher syndrome type 2 (USH2), but less is known about SNHL in nonsyndromic autosomal recessive retinitis pigmentosa (ARRP) and olfaction in USH2A-associated retinal degeneration. The Rate of Progression of USH2A-related Retinal Degeneration (RUSH2A) is a natural history study that enrolled 127 participants, 80 with USH2 and 47 with ARRP. Hearing was measured by pure-tone thresholds and word recognition scores, and olfaction by the University of Pennsylvania Smell Identification Test (UPSIT). SNHL was moderate in 72% of USH2 participants and severe or profound in 25%, while 9% of ARRP participants had moderate adult-onset SNHL. Pure-tone thresholds worsened with age in ARRP but not in USH2 participants. The degree of SNHL was not associated with other participant characteristics in either USH2 or ARRP. Median pure-tone thresholds in ARRP participants were significantly higher than the normative population (p < 0.001). Among 14 USH2 participants reporting newborn hearing screening results, 7 reported passing. Among RUSH2A participants, 7% had mild microsmia and 5% had moderate or severe microsmia. Their mean (±SD) UPSIT score was 35 (±3), similar to healthy controls (34 [±3]; p = 0.39). Olfaction differed by country (p = 0.02), but was not significantly associated with clinical diagnosis, age, gender, race/ethnicity, smoking status, visual measures, or hearing. Hearing loss in USH2A-related USH2 did not progress with age. ARRP patients had higher pure-tone thresholds than normal. Newborn hearing screening did not identify all USH2A-related hearing loss. Olfaction was not significantly worse than normal in participants with USH2A-related retinal degeneration.

LEBER CONGENITAL AMAUROSIS DUE TO CEP290 MUTATIONS-SEVERE VISION IMPAIRMENT WITH A HIGH UNMET MEDICAL NEED: A Review.

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.

ABUNDANCE AND MULTIMODAL VISIBILITY OF SOFT DRUSEN IN EARLY AGE-RELATED MACULAR DEGENERATION: A Clinicopathologic Correlation.

PURPOSE: To determine the abundance and multimodal visibility of drusen and basal linear deposit (BLinD) in early age-related macular degeneration. METHODS: A 69-year-old white man was imaged by color fundus photography and red free photography, fundus autofluorescence, and optical coherence tomography. From en face images, we determined the drusen field, drusen area, and equivalent diameters of individual drusen. From high-resolution light-microscopic histology (6 months after the last clinic visit), we determined the area of drusen, BLinD, and pre-BLinD in a subretinal pigment epithelium-basal lamina lipid field. RESULTS: In right and left eyes, respectively, BLinD covered 40% and 46% of the lipid field, versus 21% and 14% covered by drusen. The lipid field was covered 60% to 61% by Drusen + BLinD and 65% to 72% by BLinD + pre-BLinD. In the left eye, the drusen area on color fundus photography (0.18 mm) and red free (0.28 mm) was smaller than the drusen area on histology (1.16 mm). Among drusen confirmed by optical coherence tomography, 55.1% and 56.6% were observed on red free and fundus autofluorescence, respectively. CONCLUSION: Basal linear deposit covered 1.9 and 3.4-fold more fundus area than soft drusen, silently increasing progression risk. Improved visualization of BLinD and readouts of the retinal pigment epithelium health over lipid will assist population surveillance, early detection, and trial outcome measures.

A mutation in IFT43 causes non-syndromic recessive retinal degeneration.

The aim of this work is to identify the molecular cause of autosomal recessive early onset retinal degeneration in a consanguineous pedigree. Seventeen members of a four-generation Pakistani family were recruited and underwent a detailed ophthalmic examination. Exomes of four affected and two unaffected individuals were sequenced. Variants were filtered using exomeSuite to identify rare potentially pathogenic variants in genes expressed in the retina and/or brain and consistent with the pattern of inheritance. Effect of the variant observed in the gene Intraflagellar Transport Protein 43 (IFT43) was studied by heterologous expression in mIMCD3 and MDCK cells. Expression and sub-cellular localization of IFT43 in the retina and transiently transfected cells was examined by RT-PCR, western blot analysis, and immunohistochemistry. Affected members were diagnosed with early onset non-syndromic progressive retinal degeneration and the presence of bone spicules distributed throughout the retina at younger ages while the older affected members showed severe central choroidal atrophy. Whole-exome sequencing analysis identified a novel homozygous c.100 G > A change in IFT43 segregating with retinal degeneration and not present in ethnicity-matched controls. Immunostaining showed IFT43 localized in the photoreceptors, and to the tip of the cilia in transfected mIMCD3 and MDCK cells. The cilia in mIMCD3 and MDCK cells expressing mutant IFT43 were found to be significantly shorter (P < 0.001) than cells expressing wild-type IFT43. Our studies identified a novel homozygous mutation in the ciliary protein IFT43 as the underlying cause of recessive inherited retinal degeneration. This is the first report demonstrating the involvement of IFT43 in retinal degeneration.

Influence of eye pigmentation on retinal degeneration in P23H and S334ter mutant rhodopsin transgenic rats.

Dark-rearing has been found to slow the rate of retinal degeneration in albino P23H but not S334ter mutant rhodopsin transgenic (Tg) rats. Since eye pigmentation has the same protective slowing effect as dark-rearing in RCS rats, we examined whether eye pigmentation has a comparable slowing effect in the different mutant rhodopsin Tg rats. Different lines of albino P23H and S334ter Tg rats on the Sprague-Dawley (SD) background were bred to Long-Evans (LE) rats to produce pigmented Tg rats. These were compared to albino Tg rats at postnatal days of different ages using the outer nuclear layer (ONL) as a morphological measure of photoreceptor number and electroretinogram (ERG) a- and b-wave amplitudes as a measure of retinal function. When compared to albino P23H rats, pigmented P23H rats had a slower rate of degeneration as measured by greater ONL thicknesses and greater ERG a- and b-wave amplitudes. By contrast, pigmented S334ter rats showed no difference in ONL thicknesses or ERG a- and b-wave amplitudes when compared to their albino equivalents. Thus, degeneration of photoreceptors in P23H Tg rats is slowed by eye pigmentation as measured by ONL thickness, while it is not in the S334ter Tg rats. Eye pigmentation also protects functional changes in ERG a- and b-waves for the P23H lines, but not for the S334ter lines.

CHOROIDEREMIA: Retinal Degeneration With an Unmet Need.

PURPOSE: Choroideremia is an incurable, X-linked, recessive retinal dystrophy caused by loss of function mutations in the CHM gene. It is estimated to affect approximately 1 in 50,000 male patients. It is characterized by progressive degeneration of the retinal pigment epithelium, choroid, and photoreceptors, resulting in visual impairment and blindness. There is an unmet need in choroideremia, because currently, there are no approved treatments available for patients with the disease. METHODS: We review the patient journey, societal impact, and emerging treatments for patients with choroideremia. RESULTS: Its relative rarity and similarities with other retinal diseases in early years mean that diagnosis of choroideremia can often be delayed. Furthermore, its impact on affected individuals, and wider society, is also likely underestimated. AAV2-mediated gene therapy is an investigational treatment that aims to replace the faulty CHM gene. Early-phase studies reported potentially important visual acuity gains and maintenance of vision in some patients, and a large Phase 3 program is now underway. CONCLUSION: Choroideremia is a disease with a significant unmet need. Interventions that can treat progression of the disease and improve visual and functional outcomes have the potential to reduce health care costs and enhance patient quality of life.

Dysflective Cones.

Retinal imaging has advanced to enable noninvasive in vivo visualization of macular photoreceptors with cellular resolution. Images of retinal structure are best interpreted in the context of visual function, but clinical measures of visual function lack resolution on the scale of individual cells. Combined with cross-sectional measures of retinal structure acquired with optical coherence tomography (OCT), macular photoreceptor function can be evaluated using visual acuity and fundus-guided microperimetry, but the resolution of these measures is limited to relatively large retinal areas. By incorporating adaptive optics correction of aberrations in light entering and exiting the pupil, individual photoreceptors can be visualized and stimulated to assess structure and function. Discrepancy between structural images and visual function can shed light on the origin of visible features and their relation to visual function. Dysflective cones, cones with abnormal waveguiding properties on confocal adaptive optics scanning laser ophthalmoscopy (AOSLO) images and measurable function, provide insight into the visual significance of features in retinal images and may facilitate identification of patients who could benefit from therapies.

Multimodal Imaging in Choroideremia.

Choroideremia (CHM) is associated with progressive degeneration of the retinal pigment epithelium (RPE), choriocapillaris (CC), and photoreceptors. As animal models of CHM are lacking, most information about cell survival has come from imaging affected patients. This chapter discusses a combination of imaging techniques, including fundus-guided microperimetry, confocal and non-confocal adaptive optics scanning laser ophthalmoscopy (AOSLO), fundus autofluorescence (FAF), and swept-source optical coherence tomography angiography (SS-OCTA) to analyze macular sensitivity, cone photoreceptor outer and inner segment structure, RPE structure, and CC perfusion, respectively. Combined imaging modalities such as those described here can provide sensitive measures of monitoring retinal structure and function in patients with CHM.

A missense mutation in ASRGL1 is involved in causing autosomal recessive retinal degeneration.

Inherited retinal dystrophies are a group of genetically heterogeneous conditions with broad phenotypic heterogeneity. We analyzed a large five-generation pedigree with early-onset recessive retinal degeneration to identify the causative mutation. Linkage analysis and homozygosity mapping combined with exome sequencing were carried out to map the disease locus and identify the p.G178R mutation in the asparaginase like-1 gene (ASRGL1), segregating with the retinal dystrophy phenotype in the study pedigree. ASRGL1 encodes an enzyme that catalyzes the hydrolysis of L-asparagine and isoaspartyl-peptides. Studies on the ASRGL1 expressed in Escherichia coli and transiently transfected mammalian cells indicated that the p.G178R mutation impairs the autocatalytic processing of this enzyme resulting in the loss of functional ASRGL1 and leaving the inactive precursor protein as a destabilized and aggregation-prone protein. A zebrafish model overexpressing the mutant hASRGL1 developed retinal abnormalities and loss of cone photoreceptors. Our studies suggest that the p.G178R mutation in ASRGL1 leads to photoreceptor degeneration resulting in progressive vision loss.

Phenotypic characterization of P23H and S334ter rhodopsin transgenic rat models of inherited retinal degeneration.

We produced 8 lines of transgenic (Tg) rats expressing one of two different rhodopsin mutations in albino Sprague-Dawley (SD) rats. Three lines were generated with a proline to histidine substitution at codon 23 (P23H), the most common autosomal dominant form of retinitis pigmentosa in the United States. Five lines were generated with a termination codon at position 334 (S334ter), resulting in a C-terminal truncated opsin protein lacking the last 15 amino acid residues and containing all of the phosphorylation sites involved in rhodopsin deactivation, as well as the terminal QVAPA residues important for rhodopsin deactivation and trafficking. The rates of photoreceptor (PR) degeneration in these models vary in proportion to the ratio of mutant to wild-type rhodopsin. The models have been widely studied, but many aspects of their phenotypes have not been described. Here we present a comprehensive study of the 8 Tg lines, including the time course of PR degeneration from the onset to one year of age, retinal structure by light and electron microscopy (EM), hemispheric asymmetry and gradients of rod and cone degeneration, rhodopsin content, gene dosage effect, rapid activation and invasion of the outer retina by presumptive microglia, rod outer segment disc shedding and phagocytosis by the retinal pigmented epithelium (RPE), and retinal function by the electroretinogram (ERG). The biphasic nature of PR cell death was noted, as was the lack of an injury-induced protective response in the rat models. EM analysis revealed the accumulation of submicron vesicular structures in the interphotoreceptor space during the peak period of PR outer segment degeneration in the S334ter lines. This is likely due to the elimination of the trafficking consensus domain as seen before as with other rhodopsin mutants lacking the C-terminal QVAPA. The 8 rhodopsin Tg lines have been, and will continue to be, extremely useful models for the experimental study of inherited retinal degenerations.

Genetic analysis of 10 pedigrees with inherited retinal degeneration by exome sequencing and phenotype-genotype association.

Our purpose was to identify causative mutations and characterize the phenotype associated with the genotype in 10 unrelated families with autosomal recessive retinal degeneration. Ophthalmic evaluation and DNA isolation were carried out in 10 pedigrees with inherited retinal degenerations (IRD). Exomes of probands from eight pedigrees were captured using Nimblegen V2/V3 or Agilent V5+UTR kits, and sequencing was performed on Illumina HiSeq. The DHDDS gene was screened for mutations in the remaining two pedigrees with Ashkenazi Jewish ancestry. Exome variants were filtered to detect candidate causal variants using exomeSuite software. Segregation and ethnicity-matched control sample analysis were performed by dideoxy sequencing. Retinal histology of a patient with DHDDS mutation was studied by microscopy. Genetic analysis identified six known mutations in ABCA4 (p.Gly1961Glu, p.Ala1773Val, c.5461-10T>C), RPE65 (p.Tyr249Cys, p.Gly484Asp), PDE6B (p.Lys706Ter) and DHDDS (p.Lys42Glu) and ten novel potentially pathogenic variants in CERKL (p.Met323Val fsX20), RPE65 (p.Phe252Ser, Thr454Leu fsX31), ARL6 (p.Arg121His), USH2A (p.Gly3142Ter, p.Cys3294Trp), PDE6B (p.Gln652Ter), and DHDDS (p.Thr206Ala) genes. Among these, variants/mutations in two separate genes were observed to segregate with IRD in two pedigrees. Retinal histopathology of a patient with a DHDDS mutation showed severe degeneration of retinal layers with relative preservation of the retinal pigment epithelium. Analysis of exome variants in ten pedigrees revealed nine novel potential disease-causing variants and nine previously reported homozygous or compound heterozygous mutations in the CERKL, ABCA4, RPE65, ARL6, USH2A, PDE6B, and DHDDS genes. Mutations that could be sufficient to cause pathology were observed in more than one gene in one pedigree.

Performance of real-world functional vision tasks by blind subjects improves after implantation with the Argus® II retinal prosthesis system.

BACKGROUND: The main objective of this study was to test Argus II subjects on three real-world functional vision tasks. DESIGN: The study was designed to be randomized and prospective. Testing was conducted in a hospital/research laboratory setting at the various participating centres. PARTICIPANTS: Twenty eight Argus II subjects, all profoundly blind, participated in this study. METHODS: Subjects were tested on the three real-world functional vision tasks: Sock Sorting, Sidewalk Tracking and Walking Direction Discrimination task MAIN OUTCOME MEASURES: For the Sock Sorting task, percentage correct was computed based on how accurately subjects sorted the piles on a cloth-covered table and on a bare table. In the Sidewalk Tracking task, an 'out of bounds' count was recorded, signifying how often the subject veered away from the test course. During the Walking Direction Discrimination task, subjects were tested on the number of times they correctly identified the direction of testers walking across their field of view. RESULTS: The mean percentage correct OFF versus ON for the Sock Sorting task was found to be significantly different for both testing conditions (t-test, P < 0.01). On the Sidewalk Tracking task, subjects performed significantly better with the system ON than they did with the system OFF (t-test, P < 0.05). Eighteen (18) of 27 subjects (67%) performed above chance with the system ON, and 6 (22%) did so with system OFF on the Walking Direction Discrimination task. CONCLUSIONS: Argus II subjects performed better on all three tasks with their systems ON than they did with their systems OFF.

Five-Year Safety and Performance Results from the Argus II Retinal Prosthesis System Clinical Trial.

PURPOSE: The Argus II Retinal Prosthesis System (Second Sight Medical Products, Inc, Sylmar, CA) was developed to restore some vision to patients blind as a result of retinitis pigmentosa (RP) or outer retinal degeneration. A clinical trial was initiated in 2006 to study the long-term safety and efficacy of the Argus II System in patients with bare or no light perception resulting from end-stage RP. DESIGN: Prospective, multicenter, single-arm clinical trial. Within-patient controls included the nonimplanted fellow eye and patients' native residual vision compared with their vision with the Argus II. PARTICIPANTS: Thirty participants in 10 centers in the United States and Europe. METHODS: The worse-seeing eye of blind patients was implanted with the Argus II. Patients wore glasses mounted with a small camera and a video processor that converted images into stimulation patterns sent to the electrode array on the retina. MAIN OUTCOME MEASURES: The primary outcome measures were safety (the number, seriousness, and relatedness of adverse events) and visual function, as measured by 3 computer-based, objective tests. Secondary measures included functional vision performance on objectively scored real-world tasks. RESULTS: Twenty-four of 30 patients remained implanted with functioning Argus II Systems at 5 years after implantation. Only 1 additional serious adverse event was experienced after the 3-year time point. Patients performed significantly better with the Argus II on than off on all visual function tests and functional vision tasks. CONCLUSIONS: The 5-year results of the Argus II trial support the long-term safety profile and benefit of the Argus II System for patients blind as a result of RP. The Argus II is the first and only retinal implant to have market approval in the European Economic Area, the United States, and Canada.

Correlation of Serial Scleral and Corneal Pneumatonometry.

PURPOSE: To evaluate the usefulness of scleral pneumatonometry as an alternative for corneal measurements of intraocular pressure (IOP) over a broad range of IOPs. DESIGN: Prospective, observational cohort study. PARTICIPANTS: The study was conducted in the University of California, San Francisco, Retina Clinic between August and November 2013 in 33 adult patients (age range, 34-94 years; mean ± standard deviation, 74.1±13.4 years) receiving anti-vascular endothelial growth factor intravitreal injections, which transiently increase IOP. METHODS: Corneal pachymetry and serial corneal and temporal scleral pneumatonometry (baseline, immediately after, and 10, 20, and 30 minutes after injection) were collected. One-time baseline corneal and scleral pneumatonometry readings were obtained in the noninjected eye. MAIN OUTCOME MEASURES: Correlation analysis and a Bland-Altman plot were used to evaluate reliability and agreement between scleral and corneal measurements of IOP. A linear mixed model was used to determine the relationship between measurements and to perform covariate analyses. RESULTS: Scleral and corneal pneumatonometry showed nearly 1:1 linear correlation, although scleral pneumatonometry was biased toward higher values (r = 0.94; P < 0.001). Scleral pneumatonometry averaged 9.0 mmHg higher than corneal pneumatonometry (95% limits of agreement, -1.5 to 19.5 mmHg). A linear mixed model resulted in the following equation: corneal IOP = 1.04 × scleral IOP - 10.37. Age, central corneal thickness, laterality, and glaucoma and lens status did not impact this relationship. The difference between corneal and scleral pneumotonometry was correlated between the two eyes of individual patients (r = 0.75; P < 0.001). CONCLUSIONS: Differences between serial scleral measurements reflect differences between serial corneal measurements. Scleral pneumatonometry should be considered as an alternative to corneal pneumatonometry for following patients in whom corneal measurements are unreliable or unobtainable.