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Keeffe JE, Casson RJ, Pesudovs K, Taylor HR, Cicinelli MV, Das A, Flaxman SR, Jonas JB, Kempen JH, Leasher J, Limburg H, Naidoo K, Silvester AJ, Stevens GA, Tahhan N, Wong TY, Resnikoff S, Bourne RRA, of the of Study VLEGGBD. Prevalence and causes of vision loss in South-east Asia and Oceania in 2015: magnitude, temporal trends and projections. Br J Ophthalmol 2019;103(7):878-884.Abstract
BACKGROUND: To assess prevalence and causes of vision impairment in South-east Asia and Oceania regions from 1990 to 2015 and to forecast the figures for 2020. METHODS: Based on a systematic review of medical literature, prevalence of blindness (presenting visual acuity (PVA) <3/60 in the better eye), moderate and severe vision impairment (MSVI; PVA <6/18 but ≥3/60), mild vision impairment (PVA <6/12 but ≥6/18) and near vision impairment (>N5 or N8 in the presence of normal vision) were estimated for 1990, 2010, 2015 and 2020. RESULTS: The age-standardised prevalence of blindness for all ages and both genders was higher in the Oceania region but lower for MSVI when comparing the subregions. The prevalence of near vision impairment in people≥50 years was 41% (uncertainty interval (UI) 18.8 to 65.9). Comparison of the data for 2015 with 2020 predicts a small increase in the numbers of people affected by blindness, MSVI and mild VI in both subregions. The numbers predicted for near VI in South-east Asia are from 90.68 million in 2015 to 102.88 million in 2020. The main causes of blindness and MSVI in both subregions in 2015 were cataract, uncorrected refractive error, glaucoma, corneal disease and age-related macular degeneration. There was no trachoma in Oceania from 1990 and decreasing prevalence in South-east Asia with elimination predicted by 2020. CONCLUSIONS: In both regions, the main challenges for eye care come from cataract which remains the main cause of blindness with uncorrected refractive error the main cause of MSVI. The trend between 1990 and 2015 is for a lower prevalence of blindness and MSVI in both regions.
Wu W, Yang Y, Lei H. Progress in the application of CRISPR: From gene to base editing. Med Res Rev 2019;39(2):665-683.Abstract
The system of clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated endonucleases (Cas) has been utilized for genome editing with great accuracy and high efficiency in generating gene knockout, knockin, and point mutations in eukaryotic genomes. However, traditional CRISPR/Cas9 technology introduces double-stranded DNA breaks (DSBs) at a target locus as the first step to make gene corrections, which easily results in undesired mutations. Thus, it is necessary to develop new methods for correcting the unwanted mutations. In this review, we summarize the recent developments and a new approach to genome and base editing by using CRISPR/Cas9. This methodology renders a conversion of one target base into another, for example, C to T (or G to A), and A to G (or T to C) without producing DSBs, requiring a donor DNA template, or generating excessive insertions and deletions. Furthermore, CRISPR/Cas9-derived base editing also improves efficiency in repairing point mutations in the genome.
Jamshidi F, Place EM, Mehrotra S, Navarro-Gomez D, Maher M, Branham KE, Valkanas E, Cherry TJ, Lek M, MacArthur D, Pierce EA, Bujakowska KM. Contribution of noncoding pathogenic variants to RPGRIP1-mediated inherited retinal degeneration. Genet Med 2019;21(3):694-704.Abstract
PURPOSE: With the advent of gene therapies for inherited retinal degenerations (IRDs), genetic diagnostics will have an increasing role in clinical decision-making. Yet the genetic cause of disease cannot be identified using exon-based sequencing for a significant portion of patients. We hypothesized that noncoding pathogenic variants contribute significantly to the genetic causality of IRDs and evaluated patients with single coding pathogenic variants in RPGRIP1 to test this hypothesis. METHODS: IRD families underwent targeted panel sequencing. Unsolved cases were explored by exome and genome sequencing looking for additional pathogenic variants. Candidate pathogenic variants were then validated by Sanger sequencing, quantitative polymerase chain reaction, and in vitro splicing assays in two cell lines analyzed through amplicon sequencing. RESULTS: Among 1722 families, 3 had biallelic loss-of-function pathogenic variants in RPGRIP1 while 7 had a single disruptive coding pathogenic variants. Exome and genome sequencing revealed potential noncoding pathogenic variants in these 7 families. In 6, the noncoding pathogenic variants were shown to lead to loss of function in vitro. CONCLUSION: Noncoding pathogenic variants were identified in 6 of 7 families with single coding pathogenic variants in RPGRIP1. The results suggest that noncoding pathogenic variants contribute significantly to the genetic causality of IRDs and RPGRIP1-mediated IRDs are more common than previously thought.
Higgs C, Crow YJ, Adams DM, Chang E, Hayes D, Herbig U, Huang JN, Himes R, Jajoo K, Johnson BF, Reynolds SD, Yonekawa Y, Armanios M, Boulad F, DiNardo CD, Dufour C, Goldman FD, Khan S, Kratz C, Myers KC, Raghu G, Alter BP, Aubert G, Bhala S, Cowen EW, Dror Y, El-Youssef M, Friedman B, Giri N, Helms Guba L, Khincha PP, Lin TF, Longhurst H, McReynolds LJ, Nelson A, Olson T, Pariser A, Perona R, Sasa G, Schratz K, Simonetto DA, Townsley D, Walsh M, Stevens K, Agarwal S, Bertuch AA, Savage SA, for (CCCTAA) CCCT-associated A. Understanding the evolving phenotype of vascular complications in telomere biology disorders. Angiogenesis 2019;22(1):95-102.Abstract
Vascular complications such as bleeding due to gastrointestinal telangiectatic anomalies, pulmonary arteriovenous malformations, hepatopulmonary syndrome, and retinal vessel abnormalities are being reported in patients with telomere biology disorders (TBDs) more frequently than previously described. The international clinical care consortium of telomere-associated ailments and family support group Dyskeratosis Congenita Outreach, Inc. held a workshop on vascular abnormalities in the TBDs at the National Cancer Institute in October 2017. Clinicians and basic scientists reviewed current data on vascular complications, hypotheses for the underlying biology and developed new collaborations to address the etiology and clinical management of vascular complications in TBDs.
Borboli-Gerogiannis S, Jeng-Miller KW, Koulisis N, Moustafa GA, Chang KK, Chen SH, Gardiner MF, Greenstein SH, Luo Z, Chen TC, Loewenstein JI, Miller JW, Haviland MJ, Kloek CE. A Comprehensive Surgical Curriculum Reduced Intra-operative Complication Rates of Resident-performed Cataract Surgeries. J Surg Educ 2019;76(1):150-157.Abstract
OBJECTIVES: To evaluate the impact of a comprehensive cataract surgery curriculum on the incidence of intraoperative complications. DESIGN: We retrospectively compared the total number of cataract surgeries that the residents performed in all of the teaching sites, and the incidences of intraoperative complications (anterior capsule tear, posterior capsule rent, vitreous loss, anterior vitrectomy, zonular dialysis, iris trauma, hemorrhage, dropped lens fragment, corneal wound burn, incorrect intraocular lens) for the surgeries performed at Massachusetts Eye & Ear by residents in the pre-intervention group (residents graduating in 2004 and 2005), before the implementation of a surgical curriculum, and the residents in the post-intervention group (residents graduating in 2014 and 2015). SETTING: Ophthalmology residency program at a major academic institution. PARTICIPANTS: Residents graduating in 2004, 2005, 2014, and 2015. RESULTS: We reviewed 4373 charts. 2086 of those surgeries were performed at Massachusetts Eye & Ear. The incidence of posterior capsule rent/vitreous loss/anterior vitrectomy was lower in the post-intervention group (1.4% versus 7.7%, p < 0.0001). Other complications were also lower in the post-intervention group. CONCLUSIONS: Implementation of a comprehensive cataract surgery curriculum focusing on pre-operative, intra-operative and post-operative interventions, with an emphasis on patient outcomes resulted in a decrease in the rate of intraoperative complications.
Sun JK, Glassman AR, Beaulieu WT, Stockdale CR, Bressler NM, Flaxel C, Gross JG, Shami M, Jampol LM, Jampol LM. Rationale and Application of the Protocol S Anti-Vascular Endothelial Growth Factor Algorithm for Proliferative Diabetic Retinopathy. Ophthalmology 2019;126(1):87-95.Abstract
PURPOSE: To present the rationale, guidelines, and results of ranibizumab treatment for proliferative diabetic retinopathy (PDR) in Diabetic Retinopathy Clinical Research Network (DRCR.net) Protocol S. DESIGN: Post hoc analyses from a randomized clinical trial. PARTICIPANTS: Three hundred five participants (394 study eyes) having PDR without prior panretinal photocoagulation (PRP). METHODS: Intravitreous ranibizumab (0.5 mg) versus PRP for PDR. Ranbizumab-assigned eyes (n = 191) received monthly injections for 6 months unless resolution was achieved after 4 injections. After 6 months, injections could be deferred if neovascularization was stable over 3 consecutive visits (sustained stability). If neovascularization worsened, monthly treatment resumed. Panretinal photocoagulation could be initiated for failure or futility criteria. MAIN OUTCOME MEASURES: Neovascularization status through 2 years. RESULTS: At 1 month, 19% (35 of 188) of ranibizumab-assigned eyes showed complete neovascularization resolution and an additional 60% (113) showed improvement. At 6 months, 52% (80 of 153) showed neovascularization resolution, 3% (4) were improved, 37% (56) were stable, and 8% (13) had worsened since the last visit. Among eyes with versus without resolved neovascularization at 6 months, the median (interquartile range) number of injections between 6 months and 2 years was 4 (1-7; n = 73) versus 7 (4-11; n = 67; P < 0.001). Injections were deferred in 68 of 73 eyes (93%) meeting sustained stability at least once during the study; 62% (42 of 68) resumed injections within 16 weeks after deferral. At 2 years, 43% (66 of 154) showed neovascularization resolution, 5% (7) showed improvement, 23% (36) were stable, and 27% (42) had worsened since the last visit. Only 3 eyes met criteria for failure or futility through 2 years. CONCLUSIONS: The DRCR.net treatment algorithm for PDR can provide excellent clinical outcomes through 2 years for patients initiating anti-vascular endothelial growth factor (VEGF) therapy for PDR. When choosing between anti-VEGF and PRP as first-line therapy for PDR, treatment decisions should be guided by consideration of the relative advantages of each therapeutic method and anticipated patient compliance with follow-up and treatment recommendations.
Grob SR, Wolkow N, Jakobiec FA, Lefebvre DR. Osseous cavernous hemangioma of the superior orbital rim. Orbit 2019;38(3):259.Abstract
A 53-year-old male presented with a bony lesion over the superior orbital rim increasing in size over several months. CT imaging showed a circumscribed, osseous lesion involving the outer table of the right frontal bone and superior orbital rim with a honeycomb appearance. Anterior orbitotomy revealed an osseous lesion along the superior orbital rim with purple cavernous spaces. Histopathological examination demonstrated cavernous vascular channels with variably-sized lumens and variably-thickened vascular walls interspersed among bony trabeculae consistent with an osseous cavernous hemangioma.
Li M, Mittal SK, Foulsham W, Amouzegar A, Sahu SK, Chauhan SK. Mast cells contribute to the induction of ocular mucosal alloimmunity. Am J Transplant 2019;19(3):662-673.Abstract
Beyond their historical role as the effector cells in allergic disorders, mast cells have been implicated in regulating both innate and adaptive immune responses. Possessing considerable functional plasticity, mast cells are abundant at mucosal surfaces, where the host and external environments interface. The purpose of this study was to evaluate the contribution of mast cells to allograft rejection at the ocular surface. Using a well-characterized murine model of corneal transplantation, we report that mast cells promote allosensitization. Our data show mast cell frequencies and activation are increased following transplantation. We demonstrate that mast cell inhibition (a) limits the infiltration of inflammatory cells and APC maturation at the graft site; (b) reduces allosensitization and the generation of Th1 cells in draining lymphoid tissues; (c) decreases graft infiltration of alloimmune-inflammatory cells; and (d) prolongs allograft survival. Our data demonstrate a novel function of mast cells in promoting allosensitization at the ocular surface.
Roelofs KA, Starks V, Yoon MK. Orbital Emphysema: A Case Report and Comprehensive Review of the Literature. Ophthalmic Plast Reconstr Surg 2019;35(1):1-6.Abstract
PURPOSE: The objective of this study was to report a case of persistent and likely self-induced orbital emphysema (OE) following functional endoscopic sinus surgery with dislodgement of a previously placed orbital floor implant and to review the literature surrounding etiologies, pathophysiology, and management of OE. METHODS: Case report and review of the literature. RESULTS AND DISCUSSION: While blunt trauma resulting in disruption of the medial orbital wall is the most common cause of OE, there are an additional 25 underlying etiologies reported in the current literature. Pathophysiology of OE is somewhat dependent on underlying etiology but often involves a 1-way ball valve mechanism such that air may enter the orbit but not exit. When sufficient air enters the orbit, complications secondary to increased intraorbital pressure, including central retinal artery occlusion and compressive optic neuropathy, can occur. Mild cases of OE are typically observed, with most resolving within 7 to 10 days. Moderate cases are often managed by lateral canthotomy and cantholysis with possible needle decompression. Severe cases may require urgent surgical decompression. While the majority of cases of OE are benign and self-limited, there have been 4 reports in the literature documenting significant vision loss. CONCLUSIONS: Although there is often a history of trauma in patients presenting with OE, many other underlying etiologies have been reported with several cases occurring spontaneously. As such, OE should be included on the differential for a patient presenting with a sudden onset of orbital signs.
Totsuka K, Ueta T, Uchida T, Roggia MF, Nakagawa S, Vavvas DG, Honjo M, Aihara M. Oxidative stress induces ferroptotic cell death in retinal pigment epithelial cells. Exp Eye Res 2019;181:316-324.Abstract
The dysfunction and cell death of retinal pigment epithelial (RPE) cells are hallmarks of late-stage dry (atrophic) age-related macular degeneration (AMD), for which no effective therapy has yet been developed. Previous studies have indicated that iron accumulation is a source of excess free radical production in RPE, and age-dependent iron accumulation in RPE is accelerated in patients with dry AMD. Although the pathogenic role of oxidative stress in RPE in the development of dry AMD is widely accepted, the mechanisms of oxidative stress-induced RPE cell death remain elusive. Here, we show that ferroptotic cell death, a mode of regulated necrosis mediated by iron and lipid peroxidation, is implicated in oxidative stress-induced RPE cell death in vitro. In ARPE-19 cells we observed that the ferroptosis inhibitors ferrostatin-1 and deferoxamine (DFO) rescued tert-butyl hydroperoxide (tBH)-induced RPE cell death more effectively than inhibitors of apoptosis or necroptosis. tBH-induced RPE cell death was accompanied by the three characteristics of ferroptotic cell death: lipid peroxidation, glutathione depletion, and ferrous iron accumulation, which were all significantly attenuated by ferrostatin-1 and DFO. Exogenous iron overload enhanced tBH-induced RPE cell death, but this effect was also attenuated by ferrostatin-1 and DFO. Furthermore, mRNA levels of numerous genes known to regulate iron metabolism were observed to be influenced by oxidative stress. Taken together, our observations suggest that multiple modes of cell death are involved in oxidative stress-induced RPE cell death, with ferroptosis playing a particularly important role.
Wolkow N, Weinberg DA, Bersani TA, Yoon MK, Lefebvre DR, Lee NG, Sutula FC, Mandeville JT, Hatton MP, Freitag SK. Ophthalmic Plastic Surgery in Patients 100 Years and Older. Ophthalmic Plast Reconstr Surg 2019;35(1):71-76.Abstract
PURPOSE: The centenarian population is growing and ophthalmic plastic surgeons are providing care to an increasing number of elderly patients. Outcomes of centenarians have not been previously studied in the ophthalmic plastic surgery literature. The goal of the current review was to examine the baseline characteristics, surgical problems, and outcomes of this select group of patients. METHODS: A retrospective chart review was performed. Patients who underwent ophthalmic plastic surgery at age 100 or older between January 2000 and June 2016 by a member of the New England Oculoplastics Society were included in the study. RESULTS: Fifteen patients met inclusion criteria. The majority (66%) were female. More than half (60%) presented with a surgical problem of an urgent nature. Most disorders involved the lacrimal system or eyelids, and many were the result of trauma or infection. There were no cases of orbital tumor or thyroid eye disease. There were no surgical or anesthesia-related complications. Most patients (80%) had no documented history of dementia, and only 1 was diabetic. Notably, 33% of patients presented with no light perception vision in at least 1 eye. CONCLUSIONS: Ophthalmic plastic surgery can be performed safely in select patients 100 years of age and older. Formal prospective studies are needed to improve surgical care in this group.
Tang SM, Lau T, Rong SS, Yazar S, Chen LJ, Mackey DA, Lucas RM, Pang CP, Yam JC. Vitamin D and its pathway genes in myopia: systematic review and meta-analysis. Br J Ophthalmol 2019;103(1):8-17.Abstract
OBJECTIVE: To conduct a systematic review and meta-analysis of the association of blood vitamin D (25-hydroxyvitamin D, 25(OH)D) concentration and vitamin D pathway genes with myopia. METHODS: We searched the MEDLINE and EMBASE databases for studies published up to 29 January 2018. Cross-sectional or cohort studies which evaluated the blood 25(OH)D concentration, blood 25(OH)D3 concentration or vitamin D pathway genes, in relation to risk of myopia or refractive errors were included. Standard mean difference (SMD) of blood 25(OH)D concentrations between the myopia and non-myopia groups was calculated. The associations of blood 25(OH)D concentrations and polymorphisms in vitamin D pathway genes with myopia using summary ORs were evaluated. RESULTS: We summarised seven studies involving 25 008 individuals in the meta-analysis. The myopia group had lower 25(OH)D concentration than the non-myopia group (SMD=-0.27 nmol/L, p=0.001). In the full analysis, the risk of myopia was inversely associated with blood 25(OH)D concentration after adjusting for sunlight exposure or time spent outdoors (adjusted odds ratio (AOR)=0.92 per 10 nmol/L, p<0.0001). However, the association was not statistically significant for the <18 years subgroup (AOR=0.91 per 10 nmol/L, p=0.13) and was significant only for 25(OH)D3 (likely to be mainly sunlight derived), but not total 25(OH)D (AOR=0.93 per 10 nmol/L, p=0.00007; AOR=0.91 per 10 nmol/L, p=0.15). We analysed four single nucleotide polymorphisms in the VDR gene from two studies; there was no significant association with myopia. CONCLUSIONS: Lower 25(OH)D is associated with increased risk of myopia; the lack of a genetic association suggests that 25(OH)D level may be acting as a proxy for time outdoors.
Liu Y, Rajamanickam VP, Parikh RS, Loomis SJ, Kloek CE, Kim LA, Hitchmoth DL, Song BJ, Xerras DC, Pasquale LR. Diabetic Retinopathy Assessment Variability Among Eye Care Providers in an Urban Teleophthalmology Program. Telemed J E Health 2019;25(4):301-308.Abstract
BACKGROUND: Teleophthalmology is an evidence-based method for diabetic eye screening. It is unclear whether the type of eye care provider performing teleophthalmology interpretation produces significant variability. INTRODUCTION: We assessed grading variability between an optometrist, general ophthalmologist, and retinal specialist using images from an urban, diabetic retinopathy teleophthalmology program. METHODS: Three readers evaluated digital retinal images in 100 cases (178 eyes from 90 patients with type 2 diabetes). Fisher's exact test, percent agreement, and the observed proportion of positive (P) or negative agreement (P) were used to assess variability. RESULTS: Among cases deemed gradable by all three readers (n = 65), there was substantial agreement on absence of any retinopathy (88% ± 4.6%, P = 0.91-0.95), presence of moderate nonproliferative or worse retinopathy (87% ± 3.9%, P = 0.67-1.00), and presence of macular edema (99% ± 0.9%, P = 0.67-1.00). There was limited agreement regarding presence of referable nondiabetic eye pathology (61% ± 11%, P = 0.21-0.59) and early, nonroutine referral for a follow-up clinical eye exam (66% ± 8.1%, P = 0.19-0.54). Among all cases (n = 100), there was acceptable agreement regarding which had gradable images (77% ± 5.0%, P = 0.50-0.90). DISCUSSION: Inclusion of multiple types of eye care providers as teleophthalmology readers is unlikely to produce significant variability in the assessment of diabetic retinopathy among high-quality images. Greater variability was found regarding image gradability, nondiabetic eye pathology, and recommended clinical referral times. CONCLUSIONS: Our results suggest that more extensive training and uniform referral standards are needed to improve consensus on image gradability, referable nondiabetic eye pathology, and recommended clinical referral times.
Hutchinson AK, Kraker RT, Pineles SL, VanderVeen DK, Wilson LB, Galvin JA, Lambert SR. The Use of β-Blockers for the Treatment of Periocular Hemangiomas in Infants: A Report by the American Academy of Ophthalmology. Ophthalmology 2019;126(1):146-155.Abstract
PURPOSE: To review the published literature assessing the efficacy of β-blockers for the treatment of periocular hemangioma in infants. METHODS: Literature searches were conducted in May 2018 in PubMed with no date restrictions and limited to studies published in English and in the Cochrane Library database without any restrictions. The combined searches yielded 437 citations. Of these,16 articles were deemed appropriate for inclusion in this assessment and assigned a level of evidence rating by the panel methodologist. RESULTS: None of the 16 studies included in this assessment were rated level I, 3 were rated level II, and 13 were rated level III. The most common treatment regimen was 2 mg/kg daily oral propranolol, but intralesional and topical β-blockers were also used. Treatment effect was most often measured in terms of reduction in the size of the lesions, which occurred in the majority of patients. β-Blockers were consistently shown to reduce astigmatism, but this reduction was shown to be statistically significant in only 2 series. The effect of β-blockers on amblyopia was not adequately documented. β-Blockers were generally well tolerated and had mild side effects (fatigue, gastrointestinal upset/diarrhea, restlessness/sleep disturbances, minor wheezing, and cold extremities). Complications severe enough to require cessation of treatment occurred in only 2 patients out of a total of 229 who received β-blockers. CONCLUSIONS: There is limited evidence to support the safety and efficacy of both topical and systemic β-blockers to promote regression of periocular hemangiomas. Additional research may confirm the best dosage and route of administration to maximize efficacy in reducing induced astigmatism and amblyopia associated with periocular hemangiomas while minimizing side effects.

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