Longitudinal Retinal Layer Changes and Clinical Outcome in Patients with Multiple Evanescent White Dot Syndrome.

Purpose: To evaluate longitudinal changes in retinal layer thickness and clinical outcome in patients with MEWDS.Methods: In 20 patients with MEWDS, SD-OCT images and BCVA were assessed at baseline, and at months 1, 3, and 12. SD-OCTs were segmented and measurements were performed within the fovea and a MEWDS lesion. Baseline and follow-up values in the affected eye were compared to measurements performed at the corresponding location in the fellow eye.Results: ONL thickness was 4.7% thicker in MEWDS-eyes compared with the baseline, with a significant decrease of 9% at 3 months. Within the lesion, INL thickness was 7.9% increased at baseline and decreased significantly over the follow-up of 12 months. BCVA was decreased at baseline (0.2 ± 0.18logMAR) and at the 3 months but after 12 months had increased to 0.01 ± 0.04 logMAR.Conclusion: MEWDS shows the involvement of different retinal layers and characteristic changes over the disease course.

Ciliary body length revisited by anterior segment optical coherence tomography: implications for safe access to the pars plana for intravitreal injections.

PURPOSE: To investigate the dependence of the ciliary body length (CBL) on the axial length (AL) and to draw conclusions on implications regarding safe pars plana access for intravitreal injections and vitreoretinal surgery. METHODS: A total of 200 individuals (mean age 42 years, SD ± 15.4) were enrolled in the study. Objective refraction and AL were obtained. Spherical equivalent (SE) was calculated. Anterior segment optical coherence tomography (ASOCT) was used to image and measure the CBL. RESULTS: The mean SE was - 1.64 diopters (SD ± 3.15, range - 14.5 to + 9 diopters) and the mean AL was 24.19 mm (SD ± 1.65, range 19.8-32.2 mm). There was a significant correlation between SE and AL (r2 = 0.62, p < 0.0001). Mean CBL correlated significantly with age (r2 = 0.11, p < 0.0001), AL (r2 = 0.23, p < 0.0001) and SE (r2 = 0.25, p < 0.0001). The mean CBL was 3351 µm (SD ± 459, range 2184-4451 µm). Three separate groups were defined by their AL with a normal AL group (AL 22.5 to 25 mm), a short AL group (AL < 22.5 mm) and a long AL group (AL > 25 mm). The mean CBL in the normal AL group was 3311 µm (SD ± 427), in the short AL group 2936 µm (SD ± 335) and in the long AL group 3715 µm (SD ± 365), and differed significantly (p < 0.0001) when compared. CONCLUSION: For interventions requiring pars plana access (as an intravitreal injection or vitreoretinal surgery), an incision distance of 3.5-4.0 mm posterior to the limbus is recommended. In our research, however, a difference of 0.77 mm in mean CBL between the group with short AL and the group with long AL is demonstrated, implying that the mean CBL in very short and very long eyes differs significantly. These findings suggest that the AL should be taken into account for pars plana access and that it would be advisable to prefer the shorter or longer recommended distance (3.5 and 4.0 mm, respectively) from the limbus, which correlates with the AL. If AL is > 25 mm, a distance of 4.0 mm from the limbus should be chosen; and if AL is < 22.5 mm, a distance of 3.5 mm seems adequate. TRIAL REGISTRATION NUMBER AND DATE: NCT00564291, 27 Nov 2007.

Oxygen Kinetics During Corneal Cross-linking With and Without Supplementary Oxygen.

PURPOSE: To measure and simulate oxygen kinetics during corneal cross-linking at different irradiances with and without supplementary oxygen. DESIGN: Experimental, laboratory study. METHODS: In de-epithelialized porcine eyes, a femtosecond-laser-generated tunnel was used to place a fiber probe in corneal depths of 100, 200, and 300 µm to measure the local oxygen concentration. After riboflavin imbibition, the corneas were irradiated at 3, 9, 18, and 30 mW/cm2 while the oxygen concentration was measured. All experiments were performed under normoxic (21%) and hyperoxic (>95%) conditions. The obtained data were used to identify parameters of a numerical model for oxygen consumption and diffusion. RESULTS: The equilibrium stromal oxygen concentration under atmospheric oxygen at 3 mW/cm2 was 2.3% in 100 µm decreasing to <1% in 300 µm. With 9, 18, and 30 mW/cm2, no oxygen was available in 200 µm, respectively, 100 µm or deeper. Using a hyperoxic environment, the concentration was 50% using 3 mW/cm2 in 100 µm, decreasing to 40% in 300 µm. At 9 mW/cm2, the concentrations were 5%, 3%, and 1% in 100, 200 and 300 µm, respectively. Using 18 and 30 mW/cm2, all oxygen was depleted at 100 µm; however, oxygen half-lives were longer at 18 mW/cm2 than at 30 mW/cm2. The oxygen model was able to reproduce the experiments and indicated an exponential decay with increasing distance to the anterior surface. CONCLUSION: Supplementary oxygen increases the oxygen availability during corneal cross-linking. At higher irradiances, supplementary oxygen is beneficial and eliminates the bottleneck of oxygen allowing a potentially more efficient cross-linking. The calibrated numerical model can quantify the spatial oxygen concentration related to different scenarios such as irradiance or environmental oxygen concentration.

Conjunctival Microangiopathy in Diabetes Mellitus Assessed with Optical Coherence Tomography Angiography.

Purpose: To detect and quantify conjunctival microangiopathy with optical coherence tomography angiography (OCTA). Methods: Imaging was performed in the temporal and nasal quadrant of the conjunctiva using a Heidelberg Spectralis spectral domain-OCT in OCTA mode adding a 25D lens to the standard 30° fundus lens. Images were acquired within a 10° × 5° cube at the limbus. Binary images were analyzed using ImageJ (Fiji software version 2.0) and an average relative conjunctival vessel density was assessed. Results: Thirty-two patients with diabetes mellitus type 1 and 2 and 42 healthy individuals were included. Vessel density in healthy individuals was 16.7 ± 5.2% in the nasal and 17.9 ± 6.4% in the temporal quadrant. In patients with diabetes without retinopathy, vessel density was 16.3 ± 6.7% in the nasal and 15.3 ± 7.3% in the temporal conjunctiva. In patients with diabetic retinopathy, vessel density was 13.7 ± 4.3% in the nasal and 15.2 ± 6.5% in the temporal conjunctiva. There were statistically significant higher values in both nasal and temporal measurements among healthy individuals than in patients with diabetic retinopathy (P = 0.03 and P = 0.01, respectively). Conclusions: Patients with diabetic retinopathy exhibit reduced vessel density, which may suggest diabetic microangiopathy in the conjunctiva. Anterior segment OCTA may detect conjunctival microangiopathy in patients with visual axis opacifications, where retinal OCTA is not possible. Translational Relevance: The findings of this study bridge the gap between experimental anterior segment OCTA imaging and clinical screening for diabetic complications.

Lessons learned from quantitative fundus autofluorescence.

Quantitative fundus autofluorescence (qAF) is an approach that is built on a confocal scanning laser platform and used to measure the intensity of the inherent autofluorescence of retina elicited by short-wavelength (488 nm) excitation. Being non-invasive, qAF does not interrupt tissue architecture, thus allowing for structural correlations. The spectral features, cellular origin and topographic distribution of the natural autofluorescence of the fundus indicate that it is emitted from retinaldehyde-adducts that form in photoreceptor cells and accumulate, under most conditions, in retinal pigment epithelial cells. The distributions and intensities of fundus autofluorescence deviate from normal in many retinal disorders and it is widely recognized that these changing patterns can aid in the diagnosis and monitoring of retinal disease. The standardized protocol employed by qAF involves the normalization of fundus grey levels to a fluorescent reference installed in the imaging instrument. Together with corrections for magnification and anterior media absorption, this approach facilitates comparisons with serial images and images acquired within groups of patients. Here we provide a comprehensive summary of the principles and practice of qAF and we highlight recent efforts to elucidate retinal disease processes by combining qAF with multi-modal imaging.

Efficacy of Amniotic Membrane Transplantation for the Treatment of Corneal Ulcers.

PURPOSE: To evaluate the outcome of amniotic membrane transplantation (AMTX) as a treatment for corneal ulcers. METHODS: Patients treated with AMTX for refractory corneal ulcers between 2012 and 2017 were evaluated in a retrospective analysis. Primary outcome measure was complete reepithelialization. RESULTS: A total of 149 patients were included (mean age 68 ± 18 years). The mean duration between ulcer onset and AMTX was 42 ± 46 days. The longest time between ulcer diagnosis and AMTX was found in bacterial ulcers and the shortest time to AMTX in eyes with trauma/chemical burns (mean 65 ± 15 days and 14 ± 4 days, respectively). In 70% of the patients, a single AMTX procedure was sufficient to achieve epithelial closure (21% <1 month, 40% within 1 -3 months, and 9% within 3-6 months). Treatment failure was observed in 30% of all patients, and most of them underwent further interventions. Highest closure rates were found in bacterial ulcers, herpetic ulcers, and neurotrophic ulcers (80%, 85%, and 93%, respectively), whereas the lowest reepithelialization rates were found in ulcers after corneal surgery and ulcers associated with rheumatic disease (52% and 57%, respectively). CONCLUSIONS: AMTX is a valuable treatment option to achieve corneal epithelial wound healing in cases refractory to conventional treatment. Success rates differ depending on the etiology of ulcer.

Fundus Autofluorescence Lifetime Patterns in Retinitis Pigmentosa.

Purpose: We investigated whether fundus autofluorescence (FAF) lifetimes in patients with retinitis pigmentosa display a disease-specific lifetime pattern. Methods: Fundus autofluorescence lifetime imaging ophthalmoscopy (FLIO) was performed in two spectral channels (498-560 and 560-720 nm) after excitation with a 473 nm pulsed laser in patients with retinitis pigmentosa and compared to healthy controls of a similar age range. Corresponding FAF intensity and spectral domain optical coherence tomography (OCT) data, as well as best corrected visual acuity (BCVA) were acquired and compared to fluorescence lifetime data. Results: We investigated 43 eyes from 43 patients with retinitis pigmentosa (mean age 45 ± 15 years) and compared them to eyes of 13 age-matched healthy participants. Mean FAF lifetimes were prolonged in areas of photoreceptor atrophy with preserved retinal pigment epithelium (RPE) (P = 0.0036) and even longer in areas with total atrophy of photoreceptors and RPE (P = 0.0002). The prevalence of perifoveal ring structures characterized by prolonged fluorescence lifetimes in FLIO was higher (63% vs. 49%) and the rings were wider compared to the hyperautofluorescent rings in qualitative fundus autofluorescence intensity images. In the central fovea with intact retinal layer structure identified by OCT, fluorescence lifetimes were slightly prolonged compared to those of age-matched healthy controls (short spectral channel [SSC], P = 0.0044; long spectral channel [LSC], P = 0.0128). Short lifetimes within the macular center were negatively correlated with BCVA (R2 = 0.33, P < 0.0001) as well as the greatest diameter of the ellipsoid band in OCT. Conclusions: FLIO in retinitis pigmentosa reveals characteristic patterns that allow identification of areas of photoreceptor atrophy, RPE atrophy, and remaining photoreceptor segments in areas of RPE atrophy. Fluorescence lifetimes can be used to identify ellipsoid zone loss that correlates with functional parameters.

A Distinct Phenotype of Eyes Shut Homolog (EYS)-Retinitis Pigmentosa Is Associated With Variants Near the C-Terminus.

PURPOSE: Mutations in the eyes shut homolog (EYS) gene are a frequent cause of autosomal recessive retinitis pigmentosa (arRP). This study used multimodal retinal imaging to elucidate genotype-phenotype correlations in EYS-related RP (EYS-RP). DESIGN: Cross-sectional study. METHODS: Multimodal retinal imaging and electrophysiologic testing were assessed for 16 patients with genetic confirmation of EYS-RP. RESULTS: A total of 27 unique EYS variants were identified in 16 patients. Seven patients presented with an unusual crescent-shaped hyperautofluorescent (hyperAF) ring on fundus autofluorescence (FAF) imaging encompassing a large nasal-superior area of the posterior pole. Three patients had a typical circular or oval perifoveal hyperAF ring and 6 patients had no hyperAF ring. Spectral-domain (SD) and en face optical coherence tomography (OCT) showed preserved ellipsoid zone and retinal thickness spatially corresponding to areas within the hyperAF rings. Eleven patients presented with a rod-cone dystrophy on full-field electroretinogram (ffERG), 1 patient presented with cone-rod dystrophy, and 4 patients did not undergo ffERG testing. A significant spatial association was found between EYS variant position and FAF phenotype, with variants occurring at a nucleotide position greater than GRCh37 6:65300137 (c.5617C) being more associated with patients exhibiting hyperAF rings at presentation. CONCLUSIONS: EYS-RP is a heterogeneous manifestation. Variants occurring in positions closer to the C-terminus of EYS are more common in patients presenting with hyperAF rings on FAF imaging.

The Rapid-Onset Chorioretinopathy Phenotype of ABCA4 Disease.

PURPOSE: To characterize patients affected by a uniquely severe, rapid-onset chorioretinopathy (ROC) phenotype of ABCA4 disease. DESIGN: Comparative cohort study. PARTICIPANTS: Sixteen patients were selected from a large clinically diagnosed and genetically confirmed cohort (n = 300) of patients diagnosed with ABCA4 disease. MAIN OUTCOME MEASURES: Phenotypic characteristics were assessed on color fundus photographs, short-wavelength autofluorescence (488-nm), and near-infrared autofluorescence (NIR-AF, 787-nm) images. Subfoveal thickness measurements were obtained from enhanced-depth imaging OCT. Generalized retinal function was determined with full-field electroretinogram (ffERG) testing, and lipofuscin accumulation was assessed by quantitative autofluorescence (qAF). RESULTS: All patients exhibited advanced disease features, including pigment migration in the macula and retinal vessel attenuation at an early age, and reported a symptomatic onset, on average, at 7.4 years (average for ABCA4 disease is 21.9 years, P < 0.0001). Deterioration of the macula was observed to begin with an intense, homogeneous signal on short-wavelength autofluorescence, which corresponds to an attenuated NIR-AF signal and progresses to a patchy, coalescing pattern of chorioretinal atrophy within the subsequent decade. Measurement of choroidal thickness revealed a more rapid thinning of choriocapillaris with age of Sattler's layer compared with the rate in most other patients with ABCA4 disease (P < 0.001). Levels of qAF in the macula before atrophy were above both the 95% confidence intervals for healthy individuals and patients with Stargardt disease (STGD1) (>1000 qAF units). Severe attenuation of cone responses and notable decreases in rod responses were detected by ffERG. Sequencing of the ABCA4 gene revealed exclusively deleterious, null mutations, including stop codons; frameshift deletions; variants in canonical splice sites, which completely abolish splicing; and known deleterious missense alleles. CONCLUSIONS: The ROC phenotype is a unique classification of ABCA4 disease, which is caused by deleterious null biallelic ABCA4 mutations and is characterized by the rapid deterioration of retinal pigment epithelium and photoreceptor layers in the macula and significant choroidal thinning within the first 2 decades of life.

HYPERREFLECTIVE DEPOSITION IN THE BACKGROUND OF ADVANCED STARGARDT DISEASE.

PURPOSE: To describe an unusual manifestation of hyperreflective deposits in the subretinal space in a group of patients with clinically and genetically confirmed Stargardt disease. METHODS: Retrospective review of color fundus, autofluorescence, infrared reflectance, red-free images, and spectral domain optical coherence tomography in 296 clinically diagnosed and genetically confirmed (2 expected disease-causing mutations in ABCA4) patients with Stargardt disease. Full-field electroretinogram (ffERG), medical history, and genotype data (in silico predictions) were further analyzed from the selected cohort. RESULTS: Eight of 296 patients (2.7%) were found to exhibit small crystalline deposits that were detectable on certain imaging modalities, such as color, infrared reflectance and red-free images, but not autofluorescence. The deposits were most prevalent in the superior region of the macula, and spectral domain optical coherence tomography revealed their presence in the subretinal space. All patients presented with these findings at a notably advanced disease stage with abnormal ffERG and a high proportion of highly deleterious ABCA4 alleles. CONCLUSION: Hyperreflective subretinal deposits may be a manifestation of advanced ABCA4 disease, particularly in regions susceptible to disease-related changes, such as lipofuscin accumulation.

Quantitative Autofluorescence Intensities in Acute Zonal Occult Outer Retinopathy vs Healthy Eyes.

Importance: Acute zonal occult outer retinopathy (AZOOR) remains a challenging diagnosis. Early recognition of the disease depends on advances in imaging modalities that can improve phenotyping and contribute to the understanding of the underlying pathogenesis. Objectives: To expand the range of approaches available to assist in the identification of AZOOR by multimodal imaging and to analyze the fundus lesions by quantifying short-wavelength fundus autofluorescence (quantitative fundus autofluorescence [qAF]) and spectral-domain optical coherence tomography. Design, Setting, and Participants: In this observational study, patients underwent imaging at Columbia University Medical Center between November 2010 and March 2016 and were analyzed between September 2015 and August 2016. Six patients diagnosed as having AZOOR were studied by qAF and spectral-domain optical coherence tomography and were compared with 30 age and race/ethnicity­matched controls from a database of 277 healthy control eyes. Main Outcomes and Measures: In unaffected regions of the macula, qAF was calculated within predetermined circularly arranged segments (qAF8). In addition, qAF was measured within specified regions of interest positioned at the autofluorescent lesion border (AZOOR line). Electroretinograms and electro-oculograms were recorded in 5 of 6 patients. Results: Among 6 patients (age range, 26-61 years; 4 female; 4 of white race/ethnicity, 1 Asian, and 1 Hispanic), 5 exhibited an autofluorescent AZOOR line in short-wavelength fundus autofluorescence images, delineating the peripapillary lesion. The mean (SD) region-of-interest qAF measured on the AZOOR line was 60 (26) times higher than in healthy control eyes (P = .03) at equivalent fundus locations. The qAF8 within nondiseased macular regions were within the normal range. At the lesion border, spectral-domain optical coherence tomography revealed a loss of outer retinal integrity in all patients. Single-flash cone b-wave latency and 30-Hz flicker latency responses were significantly delayed bilaterally. Lesions with smooth, homogeneous borders exhibited only minimal expansion in size over time, while the lesion in a patient with a heterogeneous border progressed more rapidly. Conclusions and Relevance: The finding that qAF is elevated at the border between diseased and nondiseased retina in patients with AZOOR contributes to the understanding of the natural history of the disease.

A Comparison of En Face Optical Coherence Tomography and Fundus Autofluorescence in Stargardt Disease.

Purpose: To compare morphologic changes on en face images derived from wide-field swept-source optical coherence tomography (ssOCT) to hypo- and hyperautofluorescent (hypoAF, hyperAF) areas on short-wavelength autofluorescence (SW-AF), and near-infrared (NIR)-AF in recessive Stargardt disease (STGD1). Methods: Wide-field ssOCT cube scans were obtained from 16 patients (16 eyes). Averaged B-scans and SW-AF images were obtained using Spectralis HRA+OCT. NIR-AF images were obtained from 6 eyes. The inner/outer segment (IS/OS), OS/RPE, and RPE/Bruch's membrane boundaries were segmented, and en face slab images generated. A subRPE slab image was used to measure the abnormal RPE area, and an IS/OS slab image, the IS/OS junction loss area. These were compared to hypo- and abnormal SW-AF areas, and hypoNIR-AF areas. A preRPE(OS) slab image was used to evaluate the spatial and intraretinal locations of flecks. Results: For all eyes, RPE atrophy was visualized as a central hyperreflective area on the subRPE slab, and IS/OS junction loss as an abnormal reflective area on the IS/OS slab; the latter was significantly larger (P = 0.04). There was good agreement between the hyperreflective area on the subRPE slab image and hypoSW-AF area, and between the abnormal reflective area on the IS/OS slab and hypo-hyperSW-AF area; the hypoNIR-AF area indicated that the hyperreflective area on the subRPE slab underestimated RPE atrophy. The spatial locations of hyperreflective flecks on the en face preRPE(OS) slab image corresponded to those on the SW-AF images. Conclusions: Wide-field en face OCT imaging has the potential to be a clinically useful tool for the management of STGD1.

Electroretinography Reveals Difference in Cone Function between Syndromic and Nonsyndromic USH2A Patients.

Usher syndrome is an inherited and irreversible disease that manifests as retinitis pigmentosa (RP) and bilateral neurosensory hearing loss. Mutations in Usherin 2A (USH2A) are not only a frequent cause of Usher syndrome, but also nonsyndromic RP. Although gene- and cell-based therapies are on the horizon for RP and Usher syndrome, studies characterizing natural disease are lacking. In this retrospective analysis, retinal function of USH2A patients was quantified with electroretinography. Both groups had markedly reduced rod and cone responses, but nonsyndromic USH2A patients had 30 Hz-flicker electroretinogram amplitudes that were significantly higher than syndromic patients, suggesting superior residual cone function. There was a tendency for Usher syndrome patients to have a higher distribution of severe mutations, and alleles in this group had a higher odds of containing nonsense or frame-shift mutations. These data suggest that the previously reported severe visual phenotype seen in syndromic USH2A patients could relate to a greater extent of cone dysfunction. Additionally, a genetic threshold may exist where mutation burden relates to visual phenotype and the presence of hearing deficits. The auditory phenotype and allelic hierarchy observed among patients should be considered in prospective studies of disease progression and during enrollment for future clinical trials.

Retrospective Analysis of Structural Disease Progression in Retinitis Pigmentosa Utilizing Multimodal Imaging.

In this report, we assess the natural progression rate of retinitis pigmentosa (RP) over an average of three years using spectral-domain optical coherence tomography (SD-OCT) and short wavelength fundus autofluorescence (SW-AF). Measurement of the ellipsoid zone (EZ) line width and hyperautofluorescent ring diameters was performed in 81 patients with RP in a retrospective, longitudinal fashion. Rate of structural disease progression, symmetry between eyes, and test-retest variability were quantified. We observed on average, EZ-line widths decreased by 140 µm (5.2%, p < 0.001) per year, and average horizontal and vertical hyperautofluorescent ring diameters decreased by 149 µm (3.6%, p < 0.001) and 120 µm (3.9%, p < 0.001) per year, respectively. The 95th percentile of this cohort had differences in progression slopes between eyes that were less than 154 µm, 118 µm, and 132 µm for EZ-line width and horizontal and vertical ring diameters, respectively. For all measures except horizontal ring diameter, progression rates were significantly slower at end-stage disease. From our data, we observed a statistically significant progression rate in EZ line width and SW-AF ring diameters over time, verifying the utility of these measurements for disease monitoring purposes. Additionally, calculated differences in progression slopes between eyes may prove useful for investigators evaluating the efficacy of unilateral treatments for RP in clinical trials.

Efficacy of rituximab in non-paraneoplastic autoimmune retinopathy.

BACKGROUND: Autoimmune retinopathy (AIR) is a rare but potentially blinding condition that is often underdiagnosed. Common features in AIR presentation include rapidly progressive vision loss with abnormal electrophysiological responses of the retina associated with positive anti-retinal antibodies. AIR is also challenging to treat, and thus, the introduction of new potential therapeutic agents is welcomed. The goal of this communication is to assess the effects of rituximab infusions on electroretinogram (ERG) responses and visual function outcomes in patients with non-paraneoplastic autoimmune retinopathy (npAIR). RESULTS: Following infusion(s), three out of five patients showed no evidence of disease progression or improved, while two patients continued to progress on ERG. One patient demonstrated improvement in visual acuity (2 lines) in both eyes. ERG responses provided objective monitoring of patients' visual function and response to immunosuppression over time. CONCLUSIONS: These findings suggest that patients with npAIR unresponsive to other immunosuppression therapies may benefit from rituximab infusion, although stabilization rather than improvement was more frequently the outcome in our case series. Furthermore, regularly scheduled ERG follow-up examinations are recommended for monitoring patients' progression during treatment.

Evaluating Structural Progression of Retinitis Pigmentosa After Cataract Surgery.

PURPOSE: To determine whether cataract surgery accelerates disease progression in retinitis pigmentosa (RP). DESIGN: Retrospective cohort study. METHODS: Seventy eyes of 40 patients with RP were categorized as having had phacoemulsification with intraocular lens implantation vs no cataract surgery at a single tertiary-level institution. Spectral-domain optical coherence tomography (SDOCT) was used to measure the ellipsoid zone (EZ) width, which has been demonstrated to be a reliable marker of RP severity, at baseline and throughout follow-up (median 768 days). RP progression was calculated as the loss of EZ width over time for all patients. Additional postoperative data were collected for the cataract surgery group, including preoperative and postoperative best-corrected visual acuity, incidence of macular edema, posterior capsular opacification, epiretinal membrane, and intraocular lens subluxation. RESULTS: Multivariable analysis including age, baseline EZ width, mode of inheritance, and cataract surgery status showed that there was no significant difference in RP progression between the cataract surgery and control groups (P = .23). Mode of inheritance was associated with RP progression, with autosomal recessive RP progressing at 148 µm/year and autosomal dominant RP progressing at 91 µm/year (P = .003). Visual acuity improved in almost all eyes that underwent surgery (17/19, 89%) and remained stable in remaining eyes (2/19, 11%). There was a high incidence of postsurgical posterior capsular opacification (18/19, 95%). There were no serious complications, such as lens subluxation or endophthalmitis. CONCLUSIONS: Our findings suggest that cataract surgery is a safe and effective means of improving visual acuity in RP patients and that it does not seem to be associated with faster disease progression as measured using SDOCT.

Frequent hypomorphic alleles account for a significant fraction of ABCA4 disease and distinguish it from age-related macular degeneration.

BACKGROUND: Variation in the ABCA4 gene is causal for, or associated with, a wide range of phenotypes from early onset Mendelian retinal dystrophies to late-onset complex disorders such as age-related macular degeneration (AMD). Despite substantial progress in determining the causal genetic variation, even complete sequencing of the entire open reading frame and splice sites of ABCA4 identifies biallelic mutations in only 60%-70% of cases; 20%-25% remain with one mutation and no mutations are found in 10%-15% of cases with clinically confirmed ABCA4 disease. This study was designed to identify missing causal variants specifically in monoallelic cases of ABCA4 disease. METHODS: Direct sequencing and analysis were performed in a large familial ABCA4 disease cohort of predominately European descent (n=643). Patient phenotypes were assessed from clinical and retinal imaging data. RESULTS: We determined that a hypomorphic ABCA4 variant c.5603A>T (p.Asn1868Ile), previously considered benign due to high minor allele frequency (MAF) (~7%) in the general population, accounts for 10% of the disease, >50% of the missing causal alleles in monoallelic cases, ~80% of late-onset cases and distinguishes ABCA4 disease from AMD. It results in a distinct clinical phenotype characterised by late-onset of symptoms (4th decade) and foveal sparing (85%). Intragenic modifying effects involving this variant and another, c.2588G>C (p.Gly863Ala) allele, were also identified. CONCLUSIONS: These findings substantiate the causality of frequent missense variants and their phenotypic outcomes as a significant contribution to ABCA4 disease, particularly the late-onset phenotype, and its clinical variation. They also suggest a significant revision of diagnostic screening and assessment of ABCA4 variation in aetiology of retinal diseases.

Genotypic spectrum and phenotype correlations of ABCA4-associated disease in patients of south Asian descent.

Variants in the ABCA4 gene are the most common cause of juvenile-onset blindness affecting close to 1 in 10 000 people worldwide. Disease severity varies largely according to genotype, which can be specific to ethnic and racial groups. Here we investigate the spectrum of ABCA4 variation and its phenotypic expression in 38 patients of South Asian descent, notably from India, Pakistan, Bangladesh and Sri Lanka. Sequencing of all exons and flanking intronic sequences of ABCA4 revealed disease-causing variants in all patients: 3 in 2.6%, 2 in 81.6% and 1 in 15.8%. Altogether, 36 distinct variants were identified, including 9 previously not described. The most frequent variant c.5882G>A, p.(G1961E) was found in half the patients, the highest ever reported in a single study cohort. The South Asian founder variant c.859-9T>C was identified along with other founder variants ascribed to Danish, Chinese, Mexican and African patients. Patients carrying c.5882G>A, p.(G1961E) exhibited a consistently confined disease phenotype, normal quantitative autofluorescence (qAF) levels and preserved full-field ERG (ffERG) while c.859-9T>C resulted in widespread disease, significantly elevated qAF and reduced to non-detectable ffERG. South Asian patients present with a relatively unique ABCA4 profile comprised of various ethnic founder variants resulting in two or three major retinal phenotypes.

Quantifying Fundus Autofluorescence in Patients With Retinitis Pigmentosa.

Purpose: Using quantitative fundus autofluorescence (qAF), we analyzed short-wavelength autofluorescent (SW-AF) rings in RP. Methods: Short-wavelength autofluorescent images (486 nm excitation) of 40 patients with RP (69 eyes) were acquired with a confocal scanning laser ophthalmoscope equipped with an internal fluorescent reference. Mean qAF was measured in eight preset segments (qAF8) and in region of interest (ROI)-qAF (200-700 µm) within and external to the borders of the rings at superior, temporal, and inferior sites relative to the ring. For both groups, qAF in patients with RP was compared to age-similar and race/ethnicity-matched healthy eyes at equivalent retinal locations. Results: In 71% of eyes of RP patients, qAF8 acquired internal to the inner border of the ring, was within the 95% confidence interval (CI) for healthy eyes, while in the remaining RP eyes qAF8 was either higher or lower than the CI. Measured external to the ring, qAF8 values were within the CI in 47% of RP eyes with the other eyes being higher or lower. In 28% of sites measured by ROI-qAF within the SW-AF ring, values were above the 95% CI of healthy controls. Region of interest-qAF measured just external to the ring was within the CI of healthy eyes in 74% of locations. The average local elevation in qAF within the ring was approximately 15%. In SD-OCT scans, photoreceptor-attributable reflectivity bands were thinned within and external to the ring. Conclusions: Increased fluorophore production may be a factor in the formation of the SW-AF rings in RP.

MULTIMODAL IMAGING OF DISEASE-ASSOCIATED PIGMENTARY CHANGES IN RETINITIS PIGMENTOSA.

PURPOSE: Using multiple imaging modalities, we evaluated the changes in photoreceptor cells and retinal pigment epithelium (RPE) that are associated with bone spicule-shaped melanin pigmentation in retinitis pigmentosa. METHODS: In a cohort of 60 patients with retinitis pigmentosa, short-wavelength autofluorescence, near-infrared autofluorescence (NIR-AF), NIR reflectance, spectral domain optical coherence tomography, and color fundus images were studied. RESULTS: Central AF rings were visible in both short-wavelength autofluorescence and NIR-AF images. Bone spicule pigmentation was nonreflective in NIR reflectance, hypoautofluorescent with short-wavelength autofluorescence and NIR-AF imaging, and presented as intraretinal hyperreflective foci in spectral domain optical coherence tomography images. In areas beyond the AF ring outer border, the photoreceptor ellipsoid zone band was absent in spectral domain optical coherence tomography and the visibility of choroidal vessels in short-wavelength autofluorescence, NIR-AF, and NIR reflectance images was indicative of reduced RPE pigmentation. Choroidal visibility was most pronounced in the zone approaching peripheral areas of bone spicule pigmentation; here RPE/Bruch membrane thinning became apparent in spectral domain optical coherence tomography. CONCLUSION: These findings are consistent with a process by which RPE cells vacate their monolayer and migrate into inner retina in response to photoreceptor cell degeneration. The remaining RPE spread undergo thinning and consequently become less pigmented. An explanation for the absence of NIR-AF melanin signal in relation to bone spicule pigmentation is not forthcoming.