Pachychoroid Associated With Acute Retinal Necrosis Secondary to Varicella Zoster Virus.

Purpose: To report a case of pachychoroid associated with acute retinal necrosis secondary to the varicella zoster virus (VZV). Methods: A retrospective review of a single case was performed. Results: The VZV-related acute retinal necrosis with pachychoroid resolved with quiescence of the acute infectious process. Conclusions: Acute retinal necrosis can result in choroidal thickening adjacent to retinitis. Previous reports have described choroidal sparing in these cases.

CHOROIDAL NEOVASCULAR MEMBRANES ASSOCIATED WITH PAPILLITIS IN A PATIENT ON CHECKPOINT INHIBITOR.

PURPOSE: The purpose of this study was to describe a case of bilateral peripapillary choroidal neovascular membranes in the setting of a patient with papillitis associated with pembrolizumab for Stage IIIA adenocarcinoma of the lung. METHODS: This was a retrospective case report with fundus photography, fluorescein angiography, optical coherence tomography, and optical coherence tomography angiography. RESULTS: A 59-year-old woman with Stage IIIA adenocarcinoma of the lung on pembrolizumab therapy presented with symptoms of blurry vision. She was found to have bilateral papillitis with right eye peripapillary subretinal hemorrhage and serous retinal detachment involving the fovea. Fluorescein angiography suggested peripapillary neovascularization with leakage in both eyes. Intravitreal bevacizumab injections were given in both eyes on a monthly basis with dramatic resolution of subretinal hemorrhage and fluid and control of peripapillary choroidal neovascular membranes. CONCLUSION: Pembrolizumab has been associated with many ocular adverse effects, and to the best of our knowledge, we report the first case of pembrolizumab associated with papillitis and peripapillary choroidal neovascular membranes. Control of the neovascularization was achieved with antivascular endothelial growth factor therapy.

Pneumatic Displacement of Hemorrhagic Bacillary Layer Detachment.

PURPOSE: To describe the management of a hemorrhagic bacillary layer detachment in a patient with neovascular age-related macular degeneration (nAMD). METHODS: The clinical records and imaging were reviewed. RESULTS: A 74-year-old female presented with acute onset hemorrhagic nAMD with a large hemorrhagic bacillary layer detachment (BALAD). The intra-BALAD hemorrhage was amenable to displacement with SF6 pneumatic displacement with subsequent visual acuity recovery. CONCLUSION: Sulfur hexafluoride (SF6) pneumatic displacement in combination with aflibercept injection is a viable means by which to manage a hemorrhagic bacillary layer detachment in the context of nAMD. Displacement of large intra-BALAD hemorrhages can result in good visual recovery.

Intravitreal sirolimus with adjunct aflibercept versus aflibercept monotherapy for persistent, exudative age-related macular degeneration: a pilot study.

BACKGROUND: To determine the safety and efficacy of intravitreal sirolimus and adjunct aflibercept in subjects with persistent, exudative age-related macular degeneration despite previous intravitreal anti-vascular endothelial growth factor (VEGF) treatment. METHODS: This institutional review board approved, registered (NCT02732899), prospective, subject-masked, single center, randomized controlled trial in subjects with persistent, exudative age-related macular degeneration compared alternating monthly intravitreal sirolimus and aflibercept (combination) versus aflibercept monotherapy (control) every 2 months over the course of 36 weeks. The primary measure of efficacy in the study was the mean change in central subfield thickness. RESULTS: 20 subjects were enrolled in the study, with 10 subjects assigned to each treatment group. Subjects had an average of 38 previous anti-VEGF injections. Mean central subfield thickness decreased in the combination group by 54.0 µm compared to 0.1 µm in the control group (p = 0.28). Mean visual acuity improved in the combination group by 2.5 ETDRS letters versus 0.8 ETDRS letters in the control group (p = 0.42). There were no serious ocular adverse events in either group; however, there were three serious systemic events in the combination group, including hospitalizations due to pancreatitis, pneumonia, and worsening hypertension. CONCLUSION: There was no statistically significant difference in the mean central subfield thickness change between the combination and control groups. However, intravitreal sirolimus with adjunct aflibercept did appear to have potential anatomical benefits as a treatment for persistent, exudative age-related macular degeneration and requires further investigation with a larger cohort to better understand the potential risks and benefits. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02732899. Registered 11 March 2016, https://clinicaltrials.gov/ct2/show/NCT02732899 . This trial was approved by the institutional review board at Advarra. Funding was provided by an investigator-initiated grant from Santen. Santen played no role in the design or implementation of this study.

UTILITY OF OCULAR ß- d -GLUCAN TESTING IN PATIENTS WITH FUNGAL ENDOPHTHALMITIS.

PURPOSE: To assess the diagnostic utility of (1→3)-ß- d -glucan (BDG) in ocular fluid of patients with fungal endophthalmitis. METHODS: This prospective pilot single-center study evaluated aqueous and vitreous humor BDG levels of suspected fungal endophthalmitis, bacterial endophthalmitis, and noninfectious controls with the standard Fungitell assay and the Fungitell STAT assay. ß- d -Glucan levels were compared using generalized linear models followed by post hoc pairwise comparisons. RESULTS: Seven fungal endophthalmitis, 6 bacterial endophthalmitis, and 17 noninfectious ocular samples were evaluated. Mean aqueous BDG concentrations were 204, 11.0, and 9.6 pg/mL for fungal endophthalmitis, bacterial endophthalmitis, and noninfectious controls, respectively ( P = 0.01, fungal vs. bacterial; P = 0.0005, fungal vs. noninfectious controls). Mean vitreous BDG concentrations were 165, 30.3, and 5.4 pg/mL, respectively ( P = 0.001 for fungal vs. bacterial; P < 0.0001 for fungal vs. noninfectious controls). Mean vitreous BDG index (Fungitell STAT) values were 1.7, 0.4, and 0.3, respectively ( P = 0.001, fungal vs. bacterial; P = 0.0004, fungal vs. noninfectious controls). The Pearson correlation between BDG levels and BDG index was high (correlation coefficient = 0.99, P < 0.001). CONCLUSION: Significantly elevated ocular BDG levels were found in fungal endophthalmitis compared with bacterial endophthalmitis and noninfectious controls. Our study suggests a potential utility for BDG testing in the diagnosis of fungal endophthalmitis, and a larger study is warranted.

ADULT-ONSET BEST1 -VITELLIFORM DYSTROPHY ASSOCIATED WITH ANGIOID STREAK-LIKE CHANGES IN TWO SIBLINGS.

BACKGROUND/PURPOSE: To describe the association between autosomal dominant Best disease and peripapillary angioid streak-like changes. METHODS: Case report of two siblings. RESULTS: A 76-year-old White man was referred for evaluation of bilateral macular changes and worsening visual distortion over the preceding 2 years. Best-corrected visual acuity measured 20/30 in the right eye and 20/80 in the left eye. Funduscopic examination revealed multifocal yellow lesions in the posterior pole that were hyperautofluorescent on short-wavelength excitation and corresponded with subretinal hyperreflective material on optical coherence tomography. The posterior pole examination was interesting because of the juxtapapillary involvement of the vitelliform lesions and the presence of bilateral peripapillary angioid streak-like changes despite no history of conditions associated with angioid streaks. On further workup, an electrooculogram revealed reduced Arden ratios and a known heterozygous missense mutation in BEST1 (c.903T>G; p .D301E) was found. The patient's 69-year-old younger brother was brought in and found to have a remarkably similar phenotype, including the presence of angioid streak-like changes associated with the same BEST1 mutation. CONCLUSION: These two cases demonstrate the possibility of late-onset multifocal vitelliform disease due to dominantly inherited BEST1 . A consistent phenotype in this family with macular lesions extending into the peripapillary region, associated with angioid streak-like changes, suggests susceptibility of this region to changes in dominant BEST1 -vitelliform macular dystrophy.

Hypercoagulability Testing and Hypercoagulable Disorders in Young Central Retinal Vein Occlusion Patients.

PURPOSE: To determine frequency of hypercoagulability testing and hypercoagulable states in patients with central retinal vein occlusion (CRVO) younger than 50 years. DESIGN: Retrospective cohort study. PARTICIPANTS: Deidentified patients younger than 50 years with newly diagnosed CRVO from a national insurance claims database. METHODS: The de-identified Clinformatics Data Mart Database (Optum) containing medical claims from a commercial and Medicare Advantage insurance database was used. All outpatient medical claims (office visits, associated diagnoses, and laboratory testing) and demographic data for each beneficiary during their enrollment were accessible. MAIN OUTCOME MEASURES: Prevalence of (1) laboratory hypercoagulable workup within 90 days of CRVO diagnosis, (2) new diagnosis of a hypercoagulable state within 1 year of CRVO diagnosis, and (3) diagnosis of hypertension, diabetes mellitus (DM), and hyperlipidemia. RESULTS: One thousand one hundred eighty-one patients met inclusion criteria. Six hundred seventy-one patients (56.8%) were men, 450 patients (38.1%) had undergone hypercoagulable testing within 90 days, and 136 patients (11.5%) were diagnosed with a hypercoagulable state within 1 year after CRVO diagnosis. This proportion was similar between those patients with DM, hypertension, or hyperlipidemia (10.5% [65/620]) and those without (12.7% [71/561]; P = 0.28). Of the 136 patients diagnosed with a hypercoagulability state, 68.4% (93/136) had undergone testing within 90 days of CRVO diagnosis and 31.6% (43/136) did not. Of those who had not undergone hypercoagulability testing, 5.9% (43/731) were diagnosed with a hypercoagulable state within 1 year compared with 20.7% (93/450) in those who were tested (P < 0.001). CONCLUSIONS: The prevalence of a hypercoagulable state within 1 year of CRVO diagnosis in patients younger than 50 years was 11.5%, and the prevalence was similar between patients with atherosclerotic risk factors and those without. Rate of testing was only 38.1%. Future research should examine the usefulness of uniform hypercoagulable testing in young CRVO patients.

Proliferative retinopathy and retinal detachment in pediatric atypical hemolytic uremic syndrome.

We report the case of a 14-year-old boy with history of microangiopathic hemolytic crises secondary to atypical hemolytic uremic syndrome presenting with new-onset decreased vision, flashes, and floaters in his left eye. The patient had a history of chronic retinal detachment in the right eye and retinal neovascularization in the left eye treated with panretinal photocoagulation at age 5. He was now found to have a new combined tractional-rhegmatogenous retinal detachment in the left eye. Despite surgical reattachment of the retina, he had progressive retinal and optic nerve ischemia, with resultant left eye visual acuity of light perception. To our knowledge, this is the first reported case of proliferative retinopathy and tractional and rhegmatogenous retinal detachments in a pediatric patient with atypical hemolytic uremic syndrome.

Fibroblast Growth Factor Receptor Inhibitor-Associated Multifocal Serous Retinal Detachments: A Case Report.

Purpose: This report aims to describe a case of bilateral, multifocal neurosensory retinal detachments that developed during erdafitinib therapy for metastatic urothelial carcinoma. Methods: A case report with color fundus imaging and spectral-domain optical coherence tomography imaging is presented. Results: A 50-year-old man with metastatic urothelial carcinoma had an unremarkable baseline ophthalmic examination prior to starting erdafitinib. At 3-month follow up, an examination revealed bilateral, multifocal retinal detachments. Because the patient was asymptomatic and erdafitinib was the only drug to which his tumor had responded, he was kept on the medication with close ophthalmic monitoring. Conclusions: Erdafitinib, a fibroblast growth factor receptor inhibitor, can cause bilateral, multifocal retinal detachments. Continuation of erdafitinib may be considered in patients without significant visual impairment when the overall benefit of the medication appears to outweigh the risks.

Intravitreal sirolimus for persistent, exudative age-related macular degeneration: a Pilot Study.

BACKGROUND AND OBJECTIVE: To evaluate the safety and efficacy of intravitreal sirolimus for persistent, exudative age-related macular degeneration (AMD). METHODS: This institutional review board approved, registered (NCT02357342), prospective, subject-masked, single center, randomized controlled trial in subjects with persistent, exudative Age-related macular degeneration compared intravitreal sirolimus monotherapy (every 2 months) versus monthly anti-vascular endothelial growth factor (VEGF) over six months. RESULTS: 20 subjects were randomized to each arm of the trial. Upon completion of the trial 20 patients were analyzed in the control (anti-vascular endothelial growth factor) group and 17 patients were analyzed in the treatment (sirolimus) group. On average, subjects had 33 previous anti-VEGF injections prior to entry. The primary end-point, mean central subfield thickness (CST), increased by 20 µm in the anti-vascular endothelial growth factor group and decreased by 40 µm in the sirolimus group (p = 0.03). Visual acuity outcomes were similar between groups. Serious ocular adverse events in the sirolimus group included one subject each with anterior uveitis, central retinal artery occlusion and subretinal hemorrhage. CONCLUSION: Monotherapy with intravitreal sirolimus for subjects with persistent, exudative age-related macular degeneration appears to have a limited positive anatomic benefit. The presence of adverse events in the experimental group merits further evaluation, potentially as an adjuvant therapy. Trial registration This trial was registered with the clinicaltrials.gov, NCT02357342, and was approved by the institutional review board at Advarra. Funding was provided by an investigator-initiated grant from Santen. Santen played no role in the design or implementation of this study.

Microbial Spectrum and Antibacterial Susceptibility of Endophthalmitis Cultures in a Tertiary Referral Center in the Midwestern United States: An Analysis From 295 Patients.

Purpose: This work evaluates the microbial spectrum and antibiotic susceptibility pattern of endophthalmitis cases in a large tertiary referral center in the Midwestern United States. Methods: This retrospective case series included patients with clinically diagnosed endophthalmitis between April 14, 2006 and April 14, 2016, in whom ocular samples were submitted to the Microbiology Department at Indiana University. The patients were assessed by 11 vitreoretinal surgeons from 6 different sites in Indianapolis, including Indiana University and private practices, who receive patients from urban, suburban, and rural agricultural areas. Submitted specimens were cultured with the following media: blood agar, chocolate agar, MacConkey agar, and thioglycolate broth. Results: A total of 327 specimens from 295 patients were analyzed, with 96 (32.5%) samples from 90 (30.5%) patients meeting the criteria of confirmed growth. Of these 96 positive specimens, 83 (86.5%) organisms were identified as bacterial, and 13 (13.5%) were identified as fungal. Coagulase-negative Staphylococcus was the most common isolate (37.5%). Fifty gram-positive isolates and 10 gram-negative isolates underwent susceptibility testing. All 40 of the gram-positive isolates tested for vancomycin sensitivity were susceptible, whereas all 7 of the gram-negative isolates tested for ceftazidime sensitivity were susceptible. Conclusions: Empiric treatment with vancomycin and ceftazidime remains appropriate in most cases of endophthalmitis in the Midwestern United States, with 100% susceptibility of bacterial organisms tested with these antibiotics in this series. The high fungal culture rates in this study highlight the utility of obtaining vitreous cultures and potential need for antifungal agents in suspicious cases.

Vital Dyes in Vitreomacular Surgery.

Vital dyes contain complex molecules with chromophores that stain living tissues and have greatly enhanced identification and removal of transparent vitreoretinal tissues during surgery. Several "chromovitrectomy" dyes are frequently used by vitreoretinal specialists, including indocyanine green, trypan blue, brilliant blue G, and triamcinolone acetonide; other dyes are also under investigation. Trypan Blue was approved by the U.S. Food and Drug Administration (FDA) for epiretinal membrane removal, and preservative-free triamcinolone acetonide was approved by the FDA for intraocular use. However, currently available chromovitrectomy dyes have their limitations, and of particular concern for some of them is the possibility for acute and chronic toxicity to the neurosensory retina and retinal pigmented epithelium. The potentially irreversible acute toxicity and other limitations, such as lack of long-term safety profiles, highlight the need for further advancements. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:788-798.].

Real-world Outcomes of Anti-Vascular Endothelial Growth Factor Therapy in Diabetic Macular Edema in the United States.

PURPOSE: This study assessed real-world visual acuity (VA) outcomes of anti-vascular endothelial growth factor (anti-VEGF) therapy for diabetic macular edema (DME). DESIGN: This retrospective analysis was performed on a large database of aggregated, longitudinal electronic medical records from a geographically and demographically diverse sample of patients of United States retina specialists (Vestrum Health Retina Database). PARTICIPANTS: DME patient eyes that underwent ≥3 monthly anti-VEGF injections within 4 months of the first injection and between January 2011 and March 2017 were eligible if follow-up data were available prior to March 2018. METHODS: The eyes were divided into 3 groups based on choice of initial intravitreal anti-VEGF agent (aflibercept, bevacizumab, or ranibizumab). These eyes were then subdivided into 3 cohorts, depending on length of follow-up (6, 12, or 24 months), with each cohort being mutually exclusive. MAIN OUTCOME MEASURES: VA outcomes and number of treatments were assessed on each cohort and stratified by baseline VA. RESULTS: A total of 15,608 DME patient eyes were included in this analysis. In the 12-month cohort, of 1379 eyes initially treated with aflibercept, the mean 12-month improvement was +5.5 letters (95% confidence interval [CI] +4.5 to +6.6 letters, P < 0.001) after 7.5 injections on average, with similar outcomes for bevacizumab (3109 eyes, +5.5 letters, 95% CI +4.7 to +6.3 letters, P < 0.001, average 7.9 injections), and for ranibizumab (1352 eyes, +4.0 letters, 95% CI +2.9 to +5.2 letters, P < 0.001, average 7.7 injections). The mean numbers of corticosteroid, macular, and panretinal laser treatment sessions were similar in each group. In the 12-month cohort, when stratified by baseline VA of 20/201 or worse, 20/71 to 20/200, 20/41 to 20/70, and 20/40 or better, the final mean letters gained or lost were +28.0, +10.2, +2.8, and -2.5 in the aflibercept group, +36.0, +7.8, +2.9, and -2.0 letters in the bevacizumab group, and +30.5, +7.9, +1.6, and -2.7 letters in the ranibizumab group, respectively. CONCLUSIONS: Real-world VA outcomes following anti-VEGF therapy for DME were meaningfully inferior to those noted in randomized, controlled trials. Eyes with better baseline VA experienced fewer letters gained compared with those with worse baseline VA. The initial choice of anti-VEGF agent did not correlate with visual outcomes.

The acute and chronic effects of intravitreal anti-vascular endothelial growth factor injections on intraocular pressure: A review.

The acute and chronic effects of repeated intravitreal antivascular endothelial growth factor (VEGF) injections on intraocular pressure have not been fully characterized, and the development of sustained ocular hypertension could adversely affect patients who are at risk of glaucomatous optic neuropathy. As expected, volume-driven, acute ocular hypertension immediately follows intravitreal injection, but this pressure elevation is generally transient and well tolerated. Several medications have been investigated to limit acute ocular hypertension following anti-VEGF therapy, but the benefits of pretreatment are not conclusive. Chronic, sustained ocular hypertension, distinct from the short-term acute ocular hypertension after each injection, has also been associated with repeated intravitreal anti-VEGF injections. Risk factors for chronic ocular hypertension include the total number of injections, a greater frequency of injection, and preexisting glaucoma. Proposed mechanisms for chronic ocular hypertension include microparticle obstruction, toxic or inflammatory effects on trabecular meshwork, as well as alterations in outflow facility by anti-VEGF agents. Although limiting anti-VEGF therapy could minimize the risk of both acute and chronic ocular hypertension, foregoing anti-VEGF therapy risks progression of various macular diseases with resulting permanent central vision loss. While definitive evidence of damage to the retinal nerve fiber layer is lacking, patients receiving repeated injections should be monitored for ocular hypertension and patients in whom sustained ocular hypertension subsequently developed should be periodically monitored for glaucomatous changes with optic nerve optical coherence tomography and static visual fields.

Gene therapy for inherited retinal and optic nerve degenerations.

INTRODUCTION: The eye is a target for investigational gene therapy due to the monogenic nature of many inherited retinal and optic nerve degenerations (IRD), its accessibility, tight blood-ocular barrier, the ability to non-invasively monitor for functional and anatomic outcomes, as well as its relative immune privileged state.Vectors currently used in IRD clinical trials include adeno-associated virus (AAV), small single-stranded DNA viruses, and lentivirus, RNA viruses of the retrovirus family. Both can transduce non-dividing cells, but AAV are non-integrating, while lentivirus integrate into the host cell genome, and have a larger transgene capacity. AREAS COVERED: This review covers Leber's congenital amaurosis, choroideremia, retinitis pigmentosa, Usher syndrome, Stargardt disease, Leber's hereditary optic neuropathy, Achromatopsia, and X-linked retinoschisis. EXPERT OPINION: Despite great potential, gene therapy for IRD raises many questions, including the potential for less invasive intravitreal versus subretinal delivery, efficacy, safety, and longevity of response, as well as acceptance of novel study endpoints by regulatory bodies, patients, clinicians, and payers. Also, ultimate adoption of gene therapy for IRD will require widespread genetic screening to identify and diagnose patients based on genotype instead of phenotype.

Induced pluripotent stem cell-based therapy for age-related macular degeneration.

INTRODUCTION: In age-related macular degeneration (AMD), stem cells could possibly replace or regenerate disrupted pathologic retinal pigment epithelium (RPE), and produce supportive growth factors and cytokines such as brain-derived neurotrophic factor.  Induced pluripotent stem cells (iPSCs)-derived RPE was first subretinally transplanted in a neovascular AMD patient in 2014. Areas covered: Induced PSCs are derived from the introduction of transcription factors to adult cells under specific cell culture conditions, followed by differentiation into RPE cells. Induced PSC-derived RPE cells exhibit ion transport, membrane potential, polarized VEGF secretion and gene expression that is similar to native RPE. Despite having similar in vitro function, morphology, immunostaining and microscopic analysis, it remains to be seen if iPSC-derived RPE can replicate the myriad of in vivo functions, including immunomodulatory effects, of native RPE cells.  Historically, adjuvant RPE transplantation during CNV resections were technically difficult and complicated by immune rejection. Autologous iPSCs are hypothesized to reduce the risk of immune rejection, but their production is time-consuming and expensive.  Alternatively, allogenic transplantation using human leukocyte antigen (HLA)-matched iPSCs, similar to HLA-matched organ transplantation, is currently being investigated. Expert opinion: Challenges to successful transplantation with iPSCs include surgical technique, a pathologic subretinal microenvironment, possible immune rejection, and complications of immunosuppression.

Gene therapy for age-related macular degeneration.

INTRODUCTION: In neovascular age related macular degeneration (nAMD), gene therapy to chronically express anti-vascular endothelial growth factor (VEGF) proteins could ameliorate the treatment burden of chronic intravitreal therapy and improve limited visual outcomes associated with 'real world' undertreatment. Areas covered: In this review, the authors assess the evolution of gene therapy for AMD. Adeno-associated virus (AAV) vectors can transduce retinal pigment epithelium; one such early application was a phase I trial of AAV2-delivered pigment epithelium derived factor gene in advanced nAMD. Subsequently, gene therapy for AMD shifted to the investigation of soluble fms-like tyrosine kinase-1 (sFLT-1), an endogenously expressed VEGF inhibitor, binding and neutralizing VEGF-A. After some disappointing results, research has centered on novel vectors, including optimized AAV2, AAV8 and lentivirus, as well as genes encoding other anti-angiogenic proteins, including ranibizumab, aflibercept, angiostatin and endostatin. Also, gene therapy targeting the complement system is being investigated for geographic atrophy due to non-neovascular AMD. Expert opinion: The success of gene therapy for AMD will depend on the selection of the most appropriate therapeutic protein and its level of chronic expression. Future investigations will center on optimizing vector, promoter and delivery methods, and evaluating the risks of the chronic expression of anti-angiogenic or anti-complement proteins.

Survivorship of a Charnley total hip arthroplasty. A concise follow-up, at a minimum of thirty-five years, of previous reports.

The purpose of this study was to update the results, at a minimum of thirty-five years, in a single-surgeon series of primary Charnley total hip arthroplasties performed with cement. Twelve patients (fifteen hips) were alive, 249 patients (314 hips) had died, and one patient (one hip) had been lost to follow-up. Seven of the hips in the living patients had required at least one revision; 290 (88%) of the original group of total hip prostheses either continued to function or were in patients who had died. Since the time of a thirty-year study of this cohort, one hip that had previously been revised because of acetabular loosening required an additional revision because of acetabular loosening and two additional hips had evidence of radiographic loosening (of one acetabular and one femoral component). The survival rate with revision for any reason as the end point was 78%. This end result study should provide a benchmark for subsequent procedures and designs with the caveat that patient life expectancy will likely continue to increase and modern-design implants are being used in younger patients.