Search

Characterization of the degradation of scotopic electroretinography recordings from patients in various stages of ADNIV reveal photoreceptors may sustain early insult and reveals a unique time frame for potential therapeutic intervention. PURPOSE: To characterize the changes found in the electroretinography (ERG) recordings of Autosomal Dominant Neovascular Inflammatory Vitreoretinopathy (ADNIV) patients and correlate with clinical stages of the disease. METHODS: Retrospective chart review. Bright and dim flash full-field scotopic, photopic, and 30 Hz flicker ERGs were obtained according to international standards. The scotopic ERGs were further processed to analyze the oscillatory potential (OP). The patient described in the case report underwent full ERG testing; five patients composed the archival case series data and included scotopic ERG recordings. RESULTS: Stage I ADNIV is characterized by a decrease in the b-wave amplitude on scotopic flash ERG and the disappearance of late OPs; however, the a-wave amplitude is normal. In stage II, attenuation of early OPs and the c-wave are observed in scotopic ERG recordings, but both a- and b-wave amplitudes are unchanged. For patients in stage III, there is a continued decline of both a- and b-wave amplitudes in scotopic ERG recordings. There was a loss of recordable scotopic ERG response in patients with stage IV disease. CONCLUSIONS: ERG may be valuable in determining optimal timing for therapeutic intervention and response prior to loss of recordable retinal function in CAPN5 vitreoretinopathy.

Pentosan polysulfate (PPS) sodium (Elmiron) is the only Food and Drug Administration (FDA)-approved oral medication to treat interstitial cystitis, also known as bladder pain syndrome. A symptomatic pigmentary maculopathy associated with PPS was reported in 2018. Since then, recognition of this unique drug toxicity has increased rapidly. This potentially sight-threatening side effect prompted the FDA in June 2020 to update the label for PPS to warn about "retinal pigmentary changes." A challenging feature of pentosan maculopathy is its ability to mimic many other retinal conditions, including inherited retinal dystrophies such as pattern dystrophy, mitochondrially inherited diabetes and deafness, and Stargardt disease, and age-related macular degeneration. In this review, we discuss the history of PPS maculopathy and its implications for thousands of at-risk interstitial cystitis patients. We use published literature and an illustrative case from our institution to highlight the importance of diagnosing PPS maculopathy. We also compare PPS maculopathy to age-related macular degeneration, explain why differentiating between the 2 is clinically important, and highlight avenues for further research. Finally, we highlight the paucity of data on patients of color and why this lack of understanding may impact patient care.

Purpose To describe the retention of large, tubular, nondissolving foreign bodies because of a complication of the intravitreal dexamethasone implant (Ozurdex). Methods This is a single-center, retrospective chart review of patients who were found to have retained, nondissolvable tubular foreign bodies in the vitreous cavity for more than 6 months (the expected dissolution time of the implants) after Ozurdex injections. Ocular symptomatology and multimodal imaging were reviewed. Results Five patients had retained, nondissolvable tubular foreign bodies in the vitreous that persisted for months (mean 28.2 months, range 9-67 months) after intravitreal injection of Ozurdex. Two patients were symptomatic due to the foreign bodies and chose alternate local therapy, but none of the patients opted for surgical explantation. Conclusion Persistent, nondissolving, tubular foreign bodies can be seen in the vitreous cavity for years after injection of the Ozurdex implant. Clinicians should be aware of this complication that has the potential to cause visual symptoms and ocular morbidity.

PURPOSE: 1) To describe a case of autoimmune retinopathy mimicking heritable photoreceptor degeneration in a patient with common variable immune deficiency, and 2) to investigate the humoral and cell-mediated branches of the immune system in this patient to better understand the mechanism of immune-mediated photoreceptor damage in this disease. METHODS: Retrospective chart review with evaluation of multimodal imaging, genotype analysis, and investigation of circulating autoantibodies and T cell response to retinal antigens. RESULTS: A 40-year-old woman with bilateral, progressive vision loss was referred for evaluation of a possible inherited retinal degeneration. She was found to have asymmetric peripheral visual field constriction, cystoid macular edema, vitreous cells, and bone-spicule-like pigmentary changes in both eyes. An extensive workup for underlying infectious or inflammatory causes was unrevealing, and molecular analysis for heritable retinal degeneration failed to identify a plausible disease-causing genotype. Screening for anti-retinal antibodies showed the presence of multiple anti-retinal antibodies, consistent with a diagnosis of autoimmune retinopathy. Immunologic workup demonstrated markedly decreased levels of serum IgA and IgG, consistent with common variable immune deficiency. T-cells isolated from the patient showed increased proliferation when stimulated with human retinal proteins, supporting a role for both cell and humoral-mediated autoimmunity. Treatment with mycophenolate mofetil and intravenous immunoglobin therapy slowed the progression of disease and resulted in preservation of her central vision. CONCLUSIONS: Autoimmune retinopathy can be seen in common variable immune deficiency and have clinical findings similar to heritable photoreceptor degeneration. Both the humoral and cellular immune responses are involved in the pathophysiology. Immune modulatory therapy has stabilized the disease course in this patient and may play an important role in the management of autoimmune retinopathy.

PURPOSE: Autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV) is a rare disorder characterized by uveitis, retinal neovascularization, and retinal degeneration. We sought to describe the course of treated and untreated ADNIV and to identify risk factors for severe vision loss. DESIGN: Observational case series. METHODS: Clinical data from ADNIV patients from 4 families seen from 1967 through 2019 at a single academic, tertiary referral center were reviewed. The main outcome measures were visual acuity at baseline and follow-up, as well as risk factors for vision loss. RESULTS: A total of 130 eyes from 65 ADNIV patients (45 female, 20 male; mean age 40.8 years, range 6–77 years) were included. Mean best corrected visual acuity (BCVA) at presentation was LogMAR 0.59 (about Snellen 20/80). Longitudinal analysis included 84 eyes from 42 patients (31 female, 11 male), with mean follow-up of 17.3 years (range 2–43.6 years). Mean BCVA at last follow-up was LogMAR 1.48 (about Snellen 20/600). The disease accelerated in the fifth decade of life, during which the majority of eyes went from normal vision or mild vision loss to at least moderate vision loss (20/70 Snellen equivalent); 25 eyes from 16 patients (29.8%;) showed a steep trajectory of vision loss to no light perception. Tractional retinal detachment was the greatest risk factor for severe vision loss (BCVA

In this retrospective cohort study, we describe intrafamilial phenotypic variability of retinal hemangioblastoma (RH) in families with von Hippel-Lindau (VHL) disease. Patients with molecularly-confirmed VHL evaluated at our institution were identified and records reviewed. For individuals with sufficient follow up and imaging (n=27), number and location of RHs at the initial and most recent follow up visits were recorded along with treatment method and systemic manifestations. A strategy for zonal classification of RH location was used. Intrafamilial phenotypic variation was identified in 3 families. Intrafamilial phenotypic variability of RH exists between family members with VHL with the same genetic mutation.

Purpose Explore the spectrum of clinical manifestations of pentosan polysulfate sodium (PPS) maculopathy observed across a range of practice settings. Design Multi-institutional retrospective study. Participants Patients exhibiting findings suggestive of PPS maculopathy identified from April 30, 2019, to December 4, 2020. Methods Members of the Macula Society submitted cases of presumed PPS maculopathy for consideration in this series. Diagnosis was confirmed by masked review of fundus imaging. Clinical characteristics of confirmed cases were summarized with descriptive statistics. Main Outcome Measures Pentosan polysulfate exposure characteristics and fundus imaging features. Results There were 74 patients with PPS maculopathy included in the current study. Median (interquartile range) age at diagnosis was 62.0 years (56.0–65.8). The median duration of exposure to PPS was 14.0 years (10.2–18.9), with a median cumulative exposure of 1.5 kg (0.9–2.4). The most common presenting symptom was decreased or blurry vision (66.2%), followed by prolonged dark adaption or nyctalopia (32.4%). The most common referral diagnosis was age-related macular degeneration (54.1%); 16.2% of patients were referred for suspected PPS maculopathy. Novel imaging findings emerged, including highly asymmetric disease in 2 patients and a prominent vitelliform maculopathy in 2 patients. Conclusions Most patients with PPS maculopathy exhibit characteristic findings on multimodal fundus imaging in the setting of high cumulative exposure to the oral drug. Some patients in the current study manifested novel imaging findings, expanding our understanding of the phenotypic spectrum of this condition. We recommend considering standardized ophthalmic screening of patients treated with PPS.

Objective To elucidate molecular risk factors for posterior segment uveitis using a functional genomics approach. Design Genetic Association Cohort Study. Methods: Setting Single-center study at an academic referral center. Study Population 164 patients with clinically diagnosed uveitis of the posterior segment. Main Outcome Measures Exome sequencing was used to detect variants identified in 164 patients with posterior segment uveitis. A phenotype-driven analysis, protein structural modeling and in silico calculations were then used to rank and predict the functional consequences of key variants. Results A total of 203 single nucleotide variants, in 23 genes across 164 patients, were included in this study. Both known and novel variants were identified in genes previously implicated in specific types of syndromic uveitis — such as NOD2 (Blau Syndrome) and CAPN5 NIV (Neovascular Inflammatory Vitreoretinopathy) — as well as variants in genes not previously linked to posterior segment uveitis. Based on a ranked list and protein-protein-interaction network, missense variants in NOD-like receptor family genes (NOD2, NLRC4, NLRP3, and NLRP1), CAPN5, and TYK2 were characterized via structural modeling and in silico calculations to predict how specific variants might alter protein structure and function. The majority of analyzed variants were notably different from wild type. Conclusions This study implicates new pathways and immune signaling proteins that may be associated with posterior segment uveitis susceptibility. A larger cohort and functional studies will help validate the pathogenicity of the mutations identified. In specific cases, whole exome sequencing can help diagnose non-syndromic uveitis patients harboring known variants for syndromic inflammatory diseases.

Most patients needing diabetic tractional retinal detachment (TRD) surgery are working-age adults that drive and participate in other vision-dependent activities of daily living. We sought to determine the proportion of patients that achieve functional visual acuity (VA) based on the World Health Organization (WHO) definition of ‘low vision’ (≤ 20/80) and US driving standards (≥ 20/40) after vitrectomy for diabetic TRD. In this 10-year retrospective review, consecutive patients who underwent primary vitrectomy for TRD from proliferative diabetic retinopathy were studied. 240 eyes in 203 patients met criteria for analysis (38 eyes were lost to follow up at 3 months; 68 at 12 months; 146 at 60 months). While most patients (nearly 80%) having TRD surgery had low vision pre-op, almost half attained VA that was > 20/80 five years post-op. Those most likely to achieve significant visual improvement (p

Purpose To characterize the phenotype of patients with mild calpain-5 Neovascular Inflammatory Vitreoretinopathy (ADNIV). Observations The CAPN5 p.R243L mutation is typically associated with onset in the twenties and severe, progressive uveitis, retinal neovascularization, and intraocular fibrosis. Two subjects with this CAPN5 variant only showed mild peripheral retinal pigmentary degeneration and loss of the ERG b-wave at age 45 and 69, respectively, without signs of uveitis or neovascularization. Conclusions/Importance The phenotypic penetrance of a specific variant in CAPN5-vitreoretinopathy may vary significantly in severity. Patients with pigmentary retinal dystrophy may consider CAPN5 gene testing.

To evaluate ocular hypertension (OHT) after Ozurdex injection to determine the incidence of OHT, therapy for OHT, and any associative factors such as diagnosis, underlying glaucoma and therapy, or sequential Ozurdex injection(s). Retrospective consecutive case series with patients receiving one or more intravitreal Ozurdex implantations at a tertiary care academic center. Ocular hypertension was defined as a single measurement of ≥30 mmHg or an increase of ≥10 mmHg from baseline. Ninety-four injections in 52 patients (59 eyes) were reviewed. Forty eyes received a single injection, and 19 eyes received multiple injections. Ocular hypertension developed in 14 patients (26.9%). Thirteen patients (25%) had preexisting glaucoma or suspicion of glaucoma, and 6 of these developed OHT. Glaucoma eye drops were initiated after 13 injections (13.8%). Invasive surgery for glaucoma was required in 3 patients (3.2%): all had glaucoma or suspicion of glaucoma (one case was related to neovascular glaucoma and unlikely related to steroid response after Ozurdex). There was no difference in relative intraocular pressure increase (i.e., difference between final follow-up or subsequent intravitreal injection vs. baseline) between single versus multiple Ozurdex injections (P = 0.883). Patients (26.9%) who received Ozurdex developed OHT. Glaucoma or glaucoma-suspicion factors were present in all patients who required invasive surgery for glaucoma. A greater proportion of patients who received multiple injections had an intraocular pressure elevation, but the relative intraocular pressure increase was not significant.

Purpose There is no prevention or treatment for diabetic retinal neurodegeneration (DRN), which is a complication of diabetes that can occur independently of diabetic retinopathy (DR). We hypothesized that an intravitreal fluocinolone acetonide (FAc) implant may affect the rate of DRN when used in patients with diabetic macular edema (DME). Methods In this retrospective analysis, optical coherence tomography with neuroretinal analysis was obtained at 3-month intervals from 130 patients in the USER study both before (mean duration 903 days, range 35-4005 days) and after administration of FAc (mean 408 days, range 7 to 756 days). The rate of DRN was defined as the change over time on inner neuroretinal thickness using logistic regression. A DRN rate was calculated independently for two areas: region 1 located within 1.5 mm of the fovea, and region 2 from 1.5 mm to 3.0 mm from the fovea. Results In regions of the macula more than 1.5 mm from the central fovea, there was a statistically significant decrease in the rate of DRN in the post-FAc period. The pre-FAc neuroretinal loss in this area occurred at 4.0 μm/y, compared with a post-FAc loss rate of 1.1 μm/y (P = 0.001). Conclusions This retrospective study suggests that FAc may decelerate the rate of inner retinal thinning in patients with persistent DME. Further prospective studies are necessary to determine the effects of FAc on the rate of DRN in patients with DME.

Purpose To evaluate the first association specific to exudative age-related macular degeneration (AMD) located near the matrix metalloproteinase 9 (MMP9) gene. Design Genetic association study. Participants One thousand seven hundred twelve patients with AMD (672 nonexudative, 1040 exudative) of predominantly northern European descent seeking treatment at the University of Iowa Hospitals and Clinics. Methods We reanalyzed the International AMD Genetics Consortium (IAMDGC) data to validate the association of polymorphisms near MMP9 with exudative AMD and to identify additional associated single nucleotide polymorphisms (SNPs), especially MMP9 coding sequence SNPs. We genotyped a cohort of 1712 AMD patients from Iowa with 3 SNPs identified with our analysis of the IAMDGC cohort using commercially available real-time quantitative polymerase chain reaction (PCR) assays. Firth regression was used to measure the association between MMP9 SNP genotypes and exudative AMD in our cohort of patients from Iowa. In addition, we developed a PCR-based assay to genotype the Iowa cohort at a short tandem repeat polymorphism (STRP) at the MMP9 locus. Main Outcome Measures Odds ratios and P values for exudative compared with nonexudative AMD patients in the Iowa cohort for MMP9 SNPs (rs4810482, rs17576, and rs17577) and STRP. Results We identified 3 SNPs in the MMP9 locus (rs4810482, rs17576, and rs17577) that are highly associated with exudative AMD in patient cohorts of the IAMDGC. These MMP9 SNPs also are associated with exudative AMD in the cohort of 1712 AMD patients from Iowa (rs4810482: odds ratio [OR], 0.82; P = 0.010; rs17576: OR, 0.86; P = 0.046; and rs17577: OR, 0.80; P = 0.041). We also genotyped the cohort of AMD patients from Iowa at rs142450006, another MMP9 polymorphism that previously was associated with exudative AMD. We detected a 4bp STRP, (TTTC)n, at the rs142450006 locus that is highly polymorphic and associated significantly with exudative AMD (OR, 0.78; P = 0.016). Conclusions This study independently confirms and expands an association between the MMP9 locus and exudative AMD, further implicating a role for extracellular matrix abnormalities in choroidal neovascularization.

Objective The objective of this study was to review the treatment outcomes of patients with secondary glaucoma in cases of autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV), a hereditary autoimmune uveitis due to mutations in CAPN5. Patients and methods A retrospective, observational case series was assembled from ADNIV patients with secondary glaucoma. The main outcome measures were intraocular pressure (IOP), visual acuity, use of antiglaucoma medications, ocular surgeries, and adverse outcomes. Perimetry and optic disk optical coherence tomography (OCT) were also analyzed. Results Nine eyes of five ADNIV patients with secondary glaucoma were reviewed. Each received a fluocinolone acetonide (FA) implant for the management of posterior uveitis. Following implantation, no eyes developed neovascular glaucoma. Five eyes (in patients 1, 2, and 5) required Ahmed glaucoma valve surgery for the management of steroid-responsive glaucoma. Patient 2 also developed angle closure with iris bombe and underwent laser peripheral iridotomy. Patient 4 had both hypotony and elevated IOP that required periodic antiglaucoma medication in the FA-implanted eye. Patient 3 did not develop steroid-response glaucoma in either eye. Optic disk examinations were obscured by fibrosis and better assessed with OCT. Conclusion ADNIV patients show combined mechanism secondary glaucoma best assessed by OCT of the optic disk. The FA implants have reduced uveitic and neovascular glaucoma. Nevertheless, IOP management remains complex due to steroid-response glaucoma, angle closure glaucoma, and hypotony.

PurposeTo identify specific mutations causing North Carolina macular dystrophy (NCMD).DesignWhole-genome sequencing coupled with reverse transcription polymerase chain reaction (RT-PCR) analysis of gene expression in human retinal cells.ParticipantsA total of 141 members of 12 families with NCMD and 261 unrelated control individuals.MethodsGenome sequencing was performed on 8 affected individuals from 3 families affected with chromosome 6–linked NCMD (MCDR1) and 2 individuals affected with chromosome 5–linked NCMD (MCDR3). Variants observed in the MCDR1 locus with frequencies

Retinal Vein Occlusions Preferred Practice Pattern® Guidelines New evidence-based Retinal Vein Occlusions Preferred Practice Pattern® (PPP) guidelines, discussing the prognosis and risk factors of retinal vein occlusions and the treatment options.

Artificial Intelligence (AI) has long promised to increase healthcare affordability, quality and accessibility but FDA, until recently, had never authorized an autonomous AI diagnostic system. This pivotal trial of an AI system to detect diabetic retinopathy (DR) in people with diabetes enrolled 900 subjects, with no history of DR at primary care clinics, by comparing to Wisconsin Fundus Photograph Reading Center (FPRC) widefield stereoscopic photography and macular Optical Coherence Tomography (OCT), by FPRC certified photographers, and FPRC grading of Early Treatment Diabetic Retinopathy Study Severity Scale (ETDRS) and Diabetic Macular Edema (DME). More than mild DR (mtmDR) was defined as ETDRS level 35 or higher, and/or DME, in at least one eye. AI system operators underwent a standardized training protocol before study start. Median age was 59 years (range, 22–84 years); among participants, 47.5% of participants were male; 16.1% were Hispanic, 83.3% not Hispanic; 28.6% African American and 63.4% were not; 198 (23.8%) had mtmDR. The AI system exceeded all pre-specified superiority endpoints at sensitivity of 87.2% (95% CI, 81.8–91.2%) (>85%), specificity of 90.7% (95% CI, 88.3–92.7%) (>82.5%), and imageability rate of 96.1% (95% CI, 94.6–97.3%), demonstrating AI’s ability to bring specialty-level diagnostics to primary care settings. Based on these results, FDA authorized the system for use by health care providers to detect more than mild DR and diabetic macular edema, making it, the first FDA authorized autonomous AI diagnostic system in any field of medicine, with the potential to help prevent vision loss in thousands of people with diabetes annually. ClinicalTrials.gov NCT02963441

Deep learning algorithms, typically implemented as Convolutional Neural Networks (CNNs), in recent years have gained traction in medical image analysis. The majority of CNNs employed in retinal image diagnosis applications are image-based; wherein input is the retinal image and output is the classification/diagnosis, resulting in a blackbox like algorithm. In contrast, hybrid lesion-based algorithms employ multiple CNN-based detectors to categorically detect various lesions in the image, and final diagnosis is computed from combination of detector outputs. Such algorithms are more physiologically plausible and provides explainability of the final prediction through intermediate detector outputs. Both classes of algorithms have reported equal diagnostic performance and outperform clinical experts in detecting referable diabetic retinopathy (rDR). However, CNNs are sensitive to adversarial images where a limited number of pixels are modified by a fraction of intensity while preserving global image context; leading to CNN misclassification. We compared diagnostic accuracy of the two classes of algorithms on adversarial images generated from rDR retinal images and results show that image-based CNNs are significantly more susceptible to adversarial images than hybrid lesion-based algorithms.

Importance Acute macular neuroretinopathy (AMN) is a rare, idiopathic condition resembling other acute maculopathies such as paracentral acute middle maculopathy. The pathophysiology of AMN is not well understood, and the role of the choroid in the pathogenesis of AMN remains controversial. Objective To describe initial and serial multimodal imaging findings in AMN, with attention to choroidal vascular changes. Design, Setting, and Participants Retrospective case series at a single institution, tertiary referral center. The case series included 7 patients with clinical diagnosis of AMN. Main Outcomes and Measures Multimodal imaging findings, including fundus photography, fluorescein angiography, spectral-domain optical coherence tomography (OCT), en face near-infrared imaging, fundus autofluorescence, optical coherence tomography angiography (OCTA), and automated quantification of the regional structural context of choroidal flow interest between different imaging modalities, using an automatic algorithm. Results Nine eyes from 7 patients (5 women and 2 men; mean age, 40.1 years) with a diagnosis of AMN were included. Mean duration of follow-up was 11 weeks (range, 1-25 weeks). All eyes had inner choroidal flow void on OCTA that topographically corresponded to regions of abnormal hyperreflectance of the outer retinal layers on spectral-domain OCT and hyporeflectance on en face near-infrared imaging (dice similarity coefficient, 0.76). For each patient, these areas of choroidal flow void on OCTA persisted during the follow-up period, while the abnormal hyperreflectance of outer plexiform layer and inner nuclear layer on spectral-domain OCT was observed to improve. Conclusions and Relevance These findings suggest that areas of inner choroidal vascular flow void on OCTA are seen in patients with AMN. These areas may persist weeks after the onset of symptoms and suggest that vascular compromise of the inner choroid may be involved in the pathogenesis of AMN.

Purpose Fundus fluorescein angiography (FFA) is the standard modality to diagnose and manage choroidal neovascularization (CNV). However, FFA is costly and has considerable morbidity from allergic reactions and a mortality of 1 per 220 000. Since the advent of anti-vascular endothelial growth factor (VEGF) therapy for CNV, OCT has been used extensively to manage CNV, but FFA is still widely used. One recent study found the sensitivity and specificity of OCT compared with FFA in diagnosis of CNV were 100% and 80.8%, respectively. We hypothesize that FFA does not affect the management of patients initially suspected of having CNV to a clinically significant degree. Design Evaluation of diagnostic test using vignettes. Participants A total of 99 patients (99 eyes) who had an initial presentation of later confirmed CNV. Methods We retrospectively extracted in de-identified form the FFA, OCT, and clinical histories of the subjects. Vignettes were created with a standard narrative clinical history, posterior-pole color fundus image, central B-scan OCT of the initial visit, and early, mid, and late FFA of the affected eye. Four masked retinal specialists reviewed, in randomized order, these vignettes without FFA images (FFA- arm) and answered a forced choice management question: observation, 3 consecutive anti-VEGF injections, or other. After re-randomization, experts again reviewed the vignettes with the addition of the FFA images (FFA+ arm). Main Outcome Measures Intraobserver and interobserver concordance and reliability statistics within and between specialists. Results Among our retina specialists, intraobserver concordances were 89.7%, 88.7%, 88.7%, and 95.9% (average 90.7%, 95% confidence interval [CI], 83.7–97.6). The average interobserver concordance for the FFA− arm was 84.0% (95% CI, 72.6–95.4), and for the FFA+ arm, 81.8% (95% CI, 68.5–95.2); paired t testing demonstrated no significant difference between the FFA− and FFA+ arms: t = 0.6, P = 0.55. Conclusions Our data suggest a high degree of agreement in clinical decision making whether FFA was used or not. There was a similar level of agreement among specialists in the FFA− and FFA+ groups, albeit at higher, not statistically significant, variability. We believe these findings further support deferring the use of FFA in the initial management of CNV in AMD, except in treatment failures and nonstandard cases.

Purpose Birdshot chorioretinopathy (BCR) is a bilateral, chronic uveitis primarily involving the posterior segment that often results in progressive vision loss. Histopathology on eyes with BCR has been limited, but we had the rare opportunity to study the eyes of a donor with BCR. We sought to compare immunolabeling in the eyes of this donor who was treated with immunosuppression for over 30 years to age-matched controls. Methods From each eye, a macular punch and superotemporal regions were used for cryostat sectioning, and immunohistochemistry was performed on the sections using antibodies directed against CD45, intercellular adhesion molecule-1, IBA1, and GFAP. The vasculature-binding lectin, Ulex europaeus agglutinin-I (UEA-I), was also used to perform lectin histochemistry. Results At death, her visual acuity was 20/25 right eye, 20/250 left eye with extensive chorioretinal atrophy, vascular attenuation, and disk pallor. Compared with controls, the BCR donor had extensive degeneration of the outer nuclear layer and retinal pigment epithelium as well as choroidal thinning with inner retinal preservation. Loss of UEA-I+ choroidal endothelial cells was extensive, and atypical intercellular adhesion molecule-1 labeling and IBA+ microglia/macrophages were present along with widespread GFAP labeling throughout the retina. Conclusion The BCR may cause progressive chorioretinal and optic atrophy with long-standing increased leukocyte abundance throughout the retina and microglial activation especially at the retina-choroid interface.

Paul S Tlucek,1 James C Folk,1 Warren M Sobol,2 Vinit B Mahajan1,3 1Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, USA; 2Retina Physicians and Surgeons, Dayton, OH, USA; 3Omics Laboratory, University of Iowa, Iowa City, IA, USA Objective: To review fibrosis of fluocinolone acetonide (FA) implants in subjects with CAPN5 autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV). Methods: A retrospective case series was assembled from ADNIV patients in which there was fibrotic encapsulation of a fluocinolone acetonide implant. CAPN5 genotypes and surgical repair techniques were reviewed. Results: Two eyes of two ADNIV patients developed a fibrotic capsule over the fluocinolone acetonide implant. Both patients had Stage IV disease. Patient A had a c.731T > C mutation in the CAPN5 gene and patient B had a c.728G > T mutation. The fibrotic membrane was surgically excised and the implant function was restored. Conclusion: The exuberant fibrotic response in later stages of ADNIV may be resistant to local immunosuppression with steroids. Surgical excision of fibrotic membranes over FA implants can reestablish local steroid delivery in cases of severe proliferative vitreoretinopathy. Keywords: autosomal dominant neovascular inflammatory vitreoretinopathy, ADNIV, CAPN5, calpain-5, Retisert, fluocinolone acetonide, fibrotic encapsulation

PURPOSE To report the long-term findings of acquired retinoschisis whose posterior border was

To report the unique response of a patient with exudative age-related macular degeneration who developed sequential episodes of acute noninfectious uveitis following separate intravitreal injections of bevacizumab and ranibizumab.Retrospective interventional case report. Chart review.A 73-year-old white woman, who received monthly intravitreal bevacizumab injections for exudative age-related macular degeneration in the right eye, developed decreased vision 4 days after her last injection. She had trace anterior chamber cells and 1+ vitritis, consistent with a bevacizumab-associated uveitis. The patient improved on topical steroids and cycloplegics. Subsequently, her exudative age-related macular degeneration was treated with monthly ranibizumab injections. Optical coherence tomography demonstrated persistent subretinal fluid despite treatment. Seven days after her 11th ranibizumab injection, she developed sudden decreased vision, 2+ anterior chamber cell, and 4+ vitritis. Presumptive treatment for an exogenous bacterial endophthalmitis was given after a vitreous biopsy was performed, which demonstrated severe sterile infiltrates that were culture negative. All injections were stopped. Three months later, the subretinal fluid had disappeared, the vitritis has nearly resolved, but some intraretinal fluid persisted.Acute noninfectious uveitis, a known risk following injection with either bevacizumab or ranibizumab, may develop sequentially in the same patient, suggesting the possibility of cross-sensitivity. Additionally, spontaneous anatomical improvement after uveitis from antibody-based vascular endothelial growth factor inhibition implies a suppressive immunomodulatory effect on vascular permeability or choroidal neovascularization. The availability of agents with alternative molecular structures, such as aflibercept, may permit additional insights into the complex relationship between choroidal neovascularization, vitritis, and innate and other immunologic processes.

PURPOSE To study the incidence and characteristics of intraoperative sclerotomy-related retinal breaks encountered during 23-gauge pars plana vitrectomy. METHODS A retrospective consecutive case series was assembled from the surgical logs and charts of patients who underwent 23-gauge pars plana vitrectomy. Demographic data and preoperative, intraoperative, and postoperative records were examined. RESULTS A total 548 eyes met the inclusion criteria. Of them, 145 eyes underwent pars plana vitrectomy for repair of a rhegmatogenous retinal detachment (RRD) and 403 eyes for other indications. Sclerotomy-related retinal breaks were found in 8 of 548 (1.45%) eyes. No breaks were found in the 145 RRD eyes. In non-RRD cases, 8 of 403 (1.98%) eyes had sclerotomy-related breaks. All breaks were adjacent to the superior sclerotomies. The incidence of postoperative retinal detachment was 0% (0 of 403) in the non-RRD group. In eyes with breaks, the primary surgical indication was vitreomacular traction in six of eight eyes and epiretinal membrane in two of eight eyes. Posterior vitreous detachment was absent in six of eight eyes, and six of eight eyes were phakic. Eyes with vitreomacular traction had a significantly higher incidence of breaks (P < 0.0001). Eyes with a surgical indication other than RRD had a higher incidence of breaks, but this was not statistically significant when compared with eyes with RRD (P = 0.087). CONCLUSION Pars plana vitrectomy (23-gauge) is associated with a low incidence of sclerotomy-related retinal breaks and postoperative retinal detachments. Eyes with breaks are more likely to be phakic and without a preoperative posterior vitreous detachment. The presence of vitreomacular traction may be a risk factor for the development of intraoperative sclerotomy-related breaks.

Purpose To compare performance of a deep-learning enhanced algorithm for automated detection of diabetic retinopathy (DR), to the previously published performance of that algorithm, the Iowa Detection Program (IDP)-without deep learning components-on the same publicly available set of fundus images and previously reported consensus reference standard set, by three US Board certified retinal specialists. Methods We used the previously reported consensus reference standard of referable DR (rDR), defined as International Clinical Classification of Diabetic Retinopathy moderate, severe nonproliferative (NPDR), proliferative DR, and/or macular edema (ME). Neither Messidor-2 images, nor the three retinal specialists setting the Messidor-2 reference standard were used for training IDx-DR version X2.1. Sensitivity, specificity, negative predictive value, area under the curve (AUC), and their confidence intervals (CIs) were calculated. Results Sensitivity was 96.8% (95% CI: 93.3%-98.8%), specificity was 87.0% (95% CI: 84.2%-89.4%), with 6/874 false negatives, resulting in a negative predictive value of 99.0% (95% CI: 97.8%-99.6%). No cases of severe NPDR, PDR, or ME were missed. The AUC was 0.980 (95% CI: 0.968-0.992). Sensitivity was not statistically different from published IDP sensitivity, which had a CI of 94.4% to 99.3%, but specificity was significantly better than the published IDP specificity CI of 55.7% to 63.0%. Conclusions A deep-learning enhanced algorithm for the automated detection of DR, achieves significantly better performance than a previously reported, otherwise essentially identical, algorithm that does not employ deep learning. Deep learning enhanced algorithms have the potential to improve the efficiency of DR screening, and thereby to prevent visual loss and blindness from this devastating disease.

Elevated intraocular pressure is relatively common following pars plana vitrectomy and intraocular gas tamponade. We discuss a series of patients who experienced elevated intraocular pressure from pupillary block and angle closure secondary to trapped gas in the posterior chamber.Case series.Case 1 is a patient who underwent pars plana vitrectomy for retinal detachment repair. The intraocular pressure was elevated on postoperative Day 3 because of trapped gas in the posterior chamber, and it did not lower with prone positioning, maximal medical therapy, and laser peripheral iridotomies. Aspiration of the trapped gas was done with the patient sitting upright using a 27-gauge needle at the limbus, which was curative. Case 2 provides anterior-segment optical coherence tomography images that confirmed the location of the trapped gas resulting in angle closure. Case 3 demonstrates the unfortunate sequelae of a central retinal artery occlusion following delayed recognition of this entity. Case 4 highlights the challenges encountered when migratory gas is also seen elsewhere in the eye.Clinicians should be aware of elevated intraocular pressure secondary to trapped gas in the posterior chamber, which may be recalcitrant to medical therapy. Aspiration of the trapped gas can alleviate both pupillary block and angle closure without compromising the gas tamponade.

To report the clinical course of four women treated with intravitreal bevacizumab during pregnancy.Observational case series.Four pregnant women were treated with intravitreal bevacizumab for choroidal neovascularization (CNV) because of presumed ocular histoplasmosis syndrome punctate inner choroidopathy, or sarcoid uveitis. Patients received a mean of 2.6 ± 2.3 injections (range, 1-6 injections) while pregnant. One patient was treated with five additional injections while breastfeeding. The mean follow-up duration after the most recent injection was 14 ± 2.9 months (range, 11-18 months). Snellen visual acuity improved in all 4 patients with a mean of 5.75 ± 2.2 lines (range, 3-8 lines). At the most recent follow-up, all patients had involuted CNV that did not require additional treatment. All patients had an uneventful prenatal course and delivered healthy full-term infants. All children have remained healthy, exhibiting normal development and growth during infancy.Offering pregnant patients intravitreal bevacizumab therapy during pregnancy for off-label ocular indications can result in significant visual improvement. No adverse events related to treatment occurred in any patient included in this study. Additional studies with more patients and longer follow-up duration are required to identify any risks associated with treatment.

Purpose To compare the performance of automated diabetic retinopathy (DR) detection, using the algorithm that won the 2009 Retinopathy Online Challenge Competition in 2009, the Challenge2009, against that of the one currently used in EyeCheck, a large computer-aided early DR detection project. Design Evaluation of diagnostic test or technology. Participants Fundus photographic sets, consisting of 2 fundus images from each eye, were evaluated from 16 670 patient visits of 16 670 people with diabetes who had not previously been diagnosed with DR. Methods The fundus photographic set from each visit was analyzed by a single retinal expert; 793 of the 16 670 sets were classified as containing more than minimal DR (threshold for referral). The outcomes of the 2 algorithmic detectors were applied separately to the dataset and were compared by standard statistical measures. Main Outcome Measures The area under the receiver operating characteristic curve (AUC), a measure of the sensitivity and specificity of DR detection. Results Agreement was high, and examination results indicating more than minimal DR were detected with an AUC of 0.839 by the EyeCheck algorithm and an AUC of 0.821 for the Challenge2009 algorithm, a statistically nonsignificant difference (z-score, 1.91). If either of the algorithms detected DR in combination, the AUC for detection was 0.86, the same as the theoretically expected maximum. At 90% sensitivity, the specificity of the EyeCheck algorithm was 47.7% and that of the Challenge2009 algorithm was 43.6%. Conclusions Diabetic retinopathy detection algorithms seem to be maturing, and further improvements in detection performance cannot be differentiated from best clinical practices, because the performance of competitive algorithm development now has reached the human intrareader variability limit. Additional validation studies on larger, well-defined, but more diverse populations of patients with diabetes are needed urgently, anticipating cost-effective early detection of DR in millions of people with diabetes to triage those patients who need further care at a time when they have early rather than advanced DR. Financial Disclosure(s) Proprietary or commercial disclosure may be found after the references.

Background and Objective:The Accreditation Council for Graduate Medical Education has mandated that residency programs teach and assess six specific competencies (ie, medical knowledge, patient care, communication and interpersonal skills, professionalism, practice-based learning, and systems-based learning). To the authors’ knowledge, there is no standardized and widely used curriculum for teaching and assessing resident competencies in retinal lasers.Methods:The pertinent literature on resident education in retinal lasers is reviewed and specific “good practices” for teaching and assessing laser competency are presented.Results:Development and deployment of educational tools that teach and assess laser competency simultaneously; are reliable, reproducible, and valid; have low faculty time burden; and are affordable, generalizable, and fair are recommended.Conclusion:Retinal laser competency can be taught and assessed in ophthalmology residency training programs. Future research will be needed to provide evidence that these teaching and assessment tools produce improved educational and patient outcomes and provide verifiable, reliable, and valid evidence of resident competence in retinal lasers.

Purpose To present a case report on a patient with retinal complications from a carotid-cavernous fistula. Methods Observational case report. Results A 26-year-old patient sustained head trauma following a motorcycle accident. Examination and retinal imaging demonstrated a venous stasis retinopathy with cystoid macular edema. The edema resolved with aflibercept, but not with bevacizumab. Conclusion The patient was diagnosed with venous stasis retinopathy secondary to carotid-cavernous fistula. Pathologic findings completely resolved with appropriate management.

Idiopathic Epiretinal Membrane and Vitreomacular Traction Preferred Practice Pattern® Guidelines New evidence-based Idiopathic Epiretinal Membrane and Vitreomacular Traction Preferred Practice Pattern® (PPP) guidelines, describing recommendations for the diagnosis, treatment, and management of patients.

OBJECTIVE: Digital retinal imaging is an established method of screening for diabetic retinopathy (DR). It has been established that currently about 1% of the world's blind or visually impaired is due to DR. However, the increasing prevalence of diabetes mellitus and DR is creating an increased workload on those with expertise in grading retinal images. Safe and reliable automated analysis of retinal images may support screening services worldwide. This study aimed to compare the Iowa Detection Program (IDP) ability to detect diabetic eye diseases (DED) to human grading carried out at Moorfields Reading Centre on the population of Nakuru Study from Kenya.PARTICIPANTS: Retinal images were taken from participants of the Nakuru Eye Disease Study in Kenya in 2007/08 (n = 4,381 participants [NW6 Topcon Digital Retinal Camera]).METHODS: First, human grading was performed for the presence or absence of DR, and for those with DR this was sub-divided in to referable or non-referable DR. The automated IDP software was deployed to identify those with DR and also to categorize the severity of DR.MAIN OUTCOME MEASURES: The primary outcomes were sensitivity, specificity, and positive and negative predictive value of IDP versus the human grader as reference standard.RESULTS: Altogether 3,460 participants were included. 113 had DED, giving a prevalence of 3.3% (95% CI, 2.7-3.9%). Sensitivity of the IDP to detect DED as by the human grading was 91.0% (95% CI, 88.0-93.4%). The IDP ability to detect DED gave an AUC of 0.878 (95% CI 0.850-0.905). It showed a negative predictive value of 98%. The IDP missed no vision threatening retinopathy in any patients and none of the false negative cases met criteria for treatment.CONCLUSIONS: In this epidemiological sample, the IDP's grading was comparable to that of human graders'. It therefore might be feasible to consider inclusion into usual epidemiological grading.

Eric K Chin, David RP Almeida, C Nathaniel Roybal, Philip I Niles, Karen M Gehrs, Elliott H Sohn, H Culver Boldt, Stephen R Russell, James C FolkDepartment of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, USAPurpose: To evaluate the effect and tolerance of oral mineralocorticoid antagonists, eplerenone and/or spironolactone, in recalcitrant central serous chorioretinopathy.Methods: Retrospective consecutive observational case series. Primary outcome measures included central macular thickness (CMT, µm), macular volume (MV, mm3), Snellen visual acuity, and prior treatment failures. Secondary outcomes included duration of treatment, treatment dosage, and systemic side effects.Results: A total of 120 patients with central serous chorioretinopathy were reviewed, of which 29 patients were treated with one or more mineralocorticoid antagonists. The average age of patients was 58.4 years. Sixteen patients (69.6%) were recalcitrant to other interventions prior to treatment with oral mineralocorticoid antagonists, with an average washout period of 15.3months. The average duration of mineralocorticoid antagonist treatment was 3.9±2.3months. Twelve patients (52.2%) showed decreased CMT and MV, six patients (26.1%) had increase in both, and five patients (21.7%) had negligible changes. The mean decrease in CMT of all patients was 42.4 µm (range, -136 to 255 µm): 100.7 µm among treatment-naïve patients, and 16.9 µm among recalcitrant patients. The mean decrease in MV of all patients was 0.20 mm3 (range, -2.33 to 2.90 mm3): 0.6 mm3 among treatment-naïve patients, and 0.0 mm3 among recalcitrant patients. Median visual acuity at the start of therapy was 20/30 (range, 20/20–20/250), and at final follow-up it was 20/40 (range, 20/20–20/125). Nine patients (39.1%) experienced systemic side effects, of which three patients (13.0%) were unable to continue therapy.Conclusion: Mineralocorticoid antagonist treatment had a positive treatment effect in half of our patients. The decrease in CMT and MV was much less in the recalcitrant group compared to the treatment-naïve group. An improvement in vision was seen only in the treatment-naïve group. Systemic side effects, even at low doses, may limit its usage in some patients.Keywords: central serous chorioretinopathy, mineralocorticoid antagonist, eplerenone, spironolactone, corticosteroids, central macular thickness, macular volume

David RP Almeida,1 Eric K Chin,1 Ryan M Tarantola,1 Elizabeth O Tegins,1 Christopher A Lopez,1 Herbert Culver Boldt,1 Karen M Gehrs,1 Elliott H Sohn,1 Stephen R Russell,1 James C Folk,1 Vinit B Mahajan1,2 1Department of Ophthalmology and Visual Sciences, 2Omics Laboratory, University of Iowa Hospitals and Clinics, Iowa City, IA, USA Purpose: To determine the outcomes in patients with rhegmatogenous retinal detachment (RRD) secondary to viral retinitis. Patients and methods: This was a retrospective, consecutive, noncomparative, interventional case series of 12 eyes in ten patients with RRD secondary to viral retinitis. Results of vitreous or aqueous biopsy, effect of antiviral therapeutics, time to retinal detachment, course of visual acuity, and anatomic and surgical outcomes were investigated. Results: There were 1,259 cases of RRD during the study period, with 12 cases of RRD secondary to viral retinitis (prevalence of 0.95%). Follow-up was available for a mean period of 4.4 years. Varicella zoster virus was detected in six eyes, herpes simplex virus in two eyes, and cytomegalovirus in two eyes. Eight patients were treated with oral valacyclovir and two patients with intravenous acyclovir. Lack of optic nerve involvement correlated with improved final visual acuity of 20/100 or greater. Pars plana vitrectomy (n=12), silicone-oil tamponade (n=11), and scleral buckling (n=10) provided successful anatomic retinal reattachment in all cases, with no recurrent retinal detachment and no cases of hypotony during the follow-up period. Conclusion: Varicella zoster virus was the most frequent cause of viral retinitis, and lack of optic nerve involvement was predictive of a favorable visual acuity prognosis. Vitrectomy with silicone-oil tamponade and scleral buckle placement provided stable anatomical outcomes. Keywords: viral retinitis, acute retinal necrosis, herpetic retinitis, vitrectomy, retinal detachment&nbsp

To evaluate the association of subretinal hyperreflective material (SHRM) with visual acuity (VA), geographic atrophy (GA), and scar in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT).Prospective cohort study within a randomized clinical trial.The 1185 CATT participants.Masked readers graded scar and GA on fundus photography and fluorescein angiography and graded SHRM on time-domain and spectral-domain (SD) optical coherence tomography (OCT) throughout 104 weeks. Measurements of SHRM height and width in the fovea, within the center 1 mm(2), or outside the center 1mm(2) were obtained on SD OCT images at 56 (n = 76) and 104 (n = 66) weeks.Presence of SHRM, as well as location and size, and associations with VA, scar, and GA.Among CATT participants, the percentage with SHRM at enrollment was 77%, decreasing to 68% at 4 weeks after treatment and to 54% at 104 weeks. At 104 weeks, scar was present more often in eyes with persistent SHRM than in eyes with SHRM that resolved (64% vs. 31%; P0.0001). Among eyes with detailed evaluation of SHRM at weeks 56 (n = 76) and 104 (n = 66), mean VA letter score was 73.5 (standard error [SE], 2.8), 73.1 (SE, 3.4), 65.3 (SE, 3.5), and 63.9 (SE, 3.7) when SHRM was absent, present outside the central 1 mm(2), present within the central 1 mm(2) but not the foveal center, or present at the foveal center (P = 0.02), respectively. When SHRM was present, the median maximum height under the fovea, within the central 1 mm(2) including the fovea and anywhere within the scan, was 86 μm, 120 μm, and 122 μm, respectively. Visual acuity was decreased with greater SHRM height and width (P0.05).In eyes with neovascular age-related macular degeneration (AMD), SHRM is common and often persists after anti-vascular endothelial growth factor treatment. At 2 years, eyes with scar were more likely to have SHRM than other eyes. Greater SHRM dimensions were associated with worse VA. In eyes with neovascular AMD, SHRM is an important morphologic biomarker.

To determine the long-term natural history of idiopathic juxtafoveal telangiectasia (IJRT).Record review in 2 university-based and 2 private vitreoretinal practices sought patients with IJRT documented by color photographs and fluorescein angiograms (FAs) during the period January 1, 1980, to December 31, 1993. Patients then had repeated examinations and FAs.Twenty patients with IJRT in 32 eyes had follow-up examinations. Fifteen patients had color photographs and FAs, and one had color photographs alone. Follow-up varied from 10 years to 21 years (average, 15 years). Six eyes were treated by laser photocoagulation at onset. Twenty-four of the 26 untreated eyes lost vision as measured by Snellen testing. Visual loss and morphologic progression depended on IJRT type. Six of 8 untreated eyes with type IA IJRT lost vision by/ or = 3 lines (Snellen), 4 to 20/70 or worse. Vision loss was caused by progressive telangiectatic changes and intraretinal edema. Fifteen of 20 initially untreated eyes with type IIA IJRT developed either central retinal pigment epithelium membranes or subretinal neovascularization with loss of vision to 20/80 or less.IJRT prognosis depends on type and clinical features. Long-term prognosis for central vision is poor.

Purpose Recent structural and histochemical data from our laboratory indicate that human drusen often possess distinct, structural core domains. A similar, corelike structure is frequently noted clinically in some drusen-related conditions. To assess the nature of the corelike structures observed clinically, we evaluated color photographs and fluorescein angiograms from patients with early-adult onset grouped drusen (EAOGD). Design Retrospective case series. Methods The areas of the six largest drusen and hyperfluorescent lesions for eight patients confirmed to have EAOGD were estimated by two masked examiners (RRG, JCF). Data were normalized using a logarithmic transformation and evaluated using a mixed model analysis to account for intragrader, interobserver and intrasubject effects. Results The average color to hyperfluorescence drusen area ratio was 2.29 (SE, 0.06). The area of drusen viewed in color photographs significantly exceeds that of the corresponding area of hyperfluorescence ( P 2 (SE, 0.001 mm 2 ) and the average hyperfluorescent lesion area was 0.006 mm 2 (SE, 0.0005 mm 2 ). The areas of the hyperfluorescent lesions do not vary among the capillary, venous, and washout angiographic phases. The lesions exceed choroidal intensity and demonstrate prominent, uniformly hyperintense fluorescence throughout all but the choroidal phases of the angiogram. Conclusions These data show that large visible drusen in EAOGD are concentric to regions of hyperfluorescence, suggesting that drusen may possess clinically detectable, substructural domains. Ongoing studies seek to determine whether clinical evidence of drusen substructure may exist in other drusen-associated disorders, such as in age-related macular degeneration.

PURPOSE: To evaluate the long-term clinical course of serpiginous choroiditis-a recurrent inflammatory disease that causes progressive visual loss-and to determine the efficacy of immunosuppressive therapy. METHODS: A retrospective study of patients who met inclusion criteria for serpiginous choroiditis at The University of Iowa Hospitals and Clinics was performed. Information collected included duration of follow-up, number of recurrences of inflammation, visual acuities, and development of choroidal neovascularization. The number of recurrences of inflammation in patients treated with immunosuppressive agents was compared with that in patients treated only with corticosteroids or observation. RESULTS: Seventeen patients were identified who had a mean age at presentation of 39.6 years. The mean duration of follow-up was 149.2 months, with 13 patients who were followed up for >60 months. Twelve eyes either presented with or developed macular choroidal neovascularization during follow-up. Thirteen of the patients were followed up for >12 months. Of these 13 patients, 6 received treatment with immunosuppressive agents along with corticosteroids. Four of the six patients developed no further inflammatory recurrence. Seven of the 13 patients were treated with corticosteroids or observation. All of these patients developed recurrences (P = 0.021, Fisher exact test). CONCLUSIONS: Immunosuppressive agents appear to reduce the rate of recurrent disease in serpiginous choroiditis compared with corticosteroids.