July 2021

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Ruiz-Lozano RE, Garza-Garza LA, Davila-Cavazos O, Foster SC, Rodriguez-Garcia A. The clinical and pathogenic spectrum of surgically-induced scleral necrosis: A review. Surv Ophthalmol 2021;66(4):594-611.Abstract
The onset of scleral necrosis after ocular surgery may have catastrophic ocular and systemic consequences. The two most frequent surgeries causing surgically-induced scleral necrosis (SISN) are pterygium excision and cataract extraction. Several pathogenic mechanisms are involved in surgically induced scleral necrosis. All of them are poorly understood. Ocular trauma increasing lytic action of collagenases with subsequent collagen degradation, vascular disruption leading to local ischemia, and immune complex deposition activating the complement system represents some of the events that lead to scleral necrosis. The complex cascade of events involving different pathogenic mechanisms and the patient's abnormal immune response frequently leads to delayed wound healing that predisposes the development of scleral necrosis. The management of SISN ranges from short-term systemic anti-inflammatory drugs to aggressive immunosuppressive therapy and surgical repair. Therefore, before performing any ocular surgery involving the sclera, a thorough ophthalmic and systemic evaluation must be done to identify high-risk patients that may develop SISN.
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Saddala MS, Lennikov A, Mukwaya A, Yang X, Tang S, Huang H. Data mining and network analysis reveals C-X-C chemokine receptor type 5 is involved in the pathophysiology of age-related macular degeneration. J Biomol Struct Dyn 2021;:1-10.Abstract
Our previous studies found that the C-X-C motif chemokine receptor 5 (CXCR5) loss leads to retinal pigment epithelium (RPE) dysfunction and AMD pathogenesis. The current study aimed to characterize the G protein-coupled receptor (GPCR) structure of CXCR5 and analyze its interactions with AMD-related risk genes. The sequence alignments, homology model of CXCR5 and structural assessment analysis were performed. Data and text mining were then performed to identify AMD-related risk genes and their interaction with CXCR5 using statistical and mathematical algorithms. Sequence alignment and phylogenetic tree analysis revealed that human CXCR5 was highly similar (85.4839%) to the rabbit. The least similarity (33.871%) was found to be in zebrafish compared to the other species. The CXCR5 model structural assessment and secondary structure analysis exhibited an excellent model. Network analysis revealed that IL10, TNF, ICAM1, CXCL1, CXCL8, APP, TLR4, SELL, C3, IL17A and CCR2 were the most connected genes CXCR5. These findings suggest that CXCR5 signaling may regulate the biological function of RPE and modulate AMD pathophysiology via GPCR signaling and interacting with identified AMD risk genes. In summary, the data presented here provide novel and crucial insights into the molecular mechanisms of CXCR5 involvement in AMD.Communicated by Ramaswamy H. Sarma.
Silpa-Archa S, Ittharat W, Chotcomwongse P, Preble JM, Foster SC. Analysis of Three-Dimensional Choroidal Volume with Enhanced Depth Imaging Findings in Patients with Recurrent Vogt-Koyanagi-Harada Disease. Curr Eye Res 2021;46(7):1010-1017.Abstract
Purpose: To demonstrate changes in three-dimensional choroidal volume with enhanced depth imaging optical coherence tomography (EDI-OCT) in patients with recurrent stage of Vogt-Koyanagi-Harada disease (VKH).Materials and Methods: This prospective comparative case series included 9 patients with recurrent VKH, 10 patients with quiet VKH, and 15 healthy controls after sample size was calculated. All VKH cases with recurrences underwent raster scanning with EDI-OCT at active and inactive stages of the disease.Results: All choroidal parameters in the active stage significantly reduced when the inflammation subsided: total choroidal volume (P = .02), central choroidal volume (P = .01), central choroidal thickness (P = .03). The changes in central choroidal volume over the resolution phase were more pronounced than the changes in central choroidal thickness in 56% of cases. Two cases presenting with only subclinical posterior segment recurrence had their choroidal parameters recovered after prompt treatment.Conclusions: In the recurrent stage of VKH, alteration in choroidal volume was evident by EDI-OCT even in an absence of anterior segment inflammation. Central choroidal volume may serve as a biomarker for detecting choroidal morphological change.
Singh RB, Liu L, Yung A, Anchouche S, Mittal SK, Blanco T, Dohlman TH, Yin J, Dana R. Ocular redness - II: Progress in development of therapeutics for the management of conjunctival hyperemia. Ocul Surf 2021;21:66-77.Abstract
Conjunctival hyperemia is one of the most common causes for visits to primary care physicians, optometrists, ophthalmologists, and emergency rooms. Despite its high incidence, the treatment options for patients with conjunctival hyperemia are restricted to over-the-counter drugs that provide symptomatic relief due to short duration of action, tachyphylaxis and rebound redness. As our understanding of the immunopathological pathways causing conjunctival hyperemia expands, newer therapeutic targets are being discovered. These insights have also contributed to the development of animal models for mimicking the pathogenic changes in microvasculature causing hyperemia. Furthermore, this progress has catalyzed the development of novel therapeutics that provide efficacious, long-term relief from conjunctival hyperemia with minimal adverse effects.
Singh RB, Liu L, Anchouche S, Yung A, Mittal SK, Blanco T, Dohlman TH, Yin J, Dana R. Ocular redness - I: Etiology, pathogenesis, and assessment of conjunctival hyperemia. Ocul Surf 2021;21:134-144.Abstract
The translucent appearance of the conjunctiva allows for immediate visualization of changes in the circulation of the conjunctival microvasculature consisting of extensive branching of superficial and deep arterial systems and corresponding drainage pathways, and the translucent appearance of the conjunctiva allows for immediate visualization of changes in the circulation. Conjunctival hyperemia is caused by a pathological vasodilatory response of the microvasculature in response to inflammation due to a myriad of infectious and non-infectious etiologies. It is one of the most common contributors of ocular complaints that prompts visits to medical centers. Our understanding of these neurogenic and immune-mediated pathways has progressed over time and has played a critical role in developing targeted novel therapies. Due to a multitude of underlying etiologies, patients must be accurately diagnosed for efficacious management of conjunctival hyperemia. The diagnostic techniques used for the grading of conjunctival hyperemia have also evolved from descriptive and subjective grading scales to more reliable computer-based objective grading scales.
Sinha S, Singh RB, Dohlman TH, Taketani Y, Yin J, Dana R. Prevalence and Risk Factors Associated With Corneal Perforation in Chronic Ocular Graft-Versus-Host-Disease. Cornea 2021;40(7):877-882.Abstract
PURPOSE: To determine the prevalence and risk factors associated with corneal perforation in patients with chronic ocular graft-versus-host disease (oGVHD). METHODS: We reviewed the case records of 405 patients diagnosed with chronic oGVHD over 8 years at a single academic center and assessed the prevalence of corneal perforation in the cohort. We reviewed patient demographics, indication for and type of hematopoietic stem cell transplantation (HSCT), time elapsed between HSCT and perforation, and clinical characteristics including oGVHD severity scores, ocular comorbidities, and topical medications at the time of perforation. Data were analyzed to determine the characteristics of patients with corneal perforation and establish the risk factors. RESULTS: Of the 405 patients with chronic oGVHD, 15 (3.7%) developed a corneal perforation. The mean age of patients at the time of perforation was 64 ± 11 years and 10 (67%) were men. The median time to corneal perforation was 3.3 years post-HSCT. Although perforation occurred unilaterally in all cases, 44% had epithelial defects and 38% had stromal abnormalities in the contralateral eye. Of the patients with corneal perforation, 9 (60%) had a National Institute of Health oGVHD severity score of 2 and 6 (40%) had a score of 3. Patients with chronic oGVHD on antiglaucoma drops had a significantly higher risk of corneal perforation (P < 0.001). CONCLUSIONS: Corneal perforation is a rare but vision-threatening complication of chronic oGVHD. Our study emphasizes the need for frequent and long-term follow-up of patients with oGVHD regardless of the severity of disease. In particular, patients with chronic oGVHD on topical antiglaucoma medications should be monitored closely due to a higher risk for corneal perforation.
Sokol JT, Schechet SA, Komati R, Eliott D, Vavvas DG, Kaplan RI, Ittiara ST, Farooq AV, Sheth VS, MacCumber MW, Ke R, Gentile RC, Skondra D. Macular Hole Closure with Medical Treatment. Ophthalmol Retina 2021;5(7):711-713.
Song A, Deshmukh R, Lin H, Ang M, Mehta JS, Chodosh J, Said DG, Dua HS, Ting DSJ. Post-keratoplasty Infectious Keratitis: Epidemiology, Risk Factors, Management, and Outcomes. Front Med (Lausanne) 2021;8:707242.Abstract
Post-keratoplasty infectious keratitis (PKIK) represents a unique clinical entity that often poses significant diagnostic and therapeutic challenges. It carries a high risk of serious complications such as graft rejection and failure, and less commonly endophthalmitis. Topical corticosteroids are often required to reduce the risk of graft rejection but their use in PKIK may act as a double-edged sword, particularly in fungal infection. The increased uptake in lamellar keratoplasty in the recent years has also led to complications such as graft-host interface infectious keratitis (IIK), which is particularly difficult to manage. The reported incidence of PKIK differs considerably across different countries, with a higher incidence observed in developing countries (9.2-11.9%) than developed countries (0.02-7.9%). Common risk factors for PKIK include the use of topical corticosteroids, suture-related problems, ocular surface diseases and previous corneal infection. PKIK after penetrating keratoplasty or (deep) anterior lamellar keratoplasty is most commonly caused by ocular surface commensals, particularly Gramme-positive bacteria, whereas PKIK after endothelial keratoplasty is usually caused by Candida spp. Empirical broad-spectrum antimicrobial treatment is the mainstay of treatment for both PKIK, though surgical interventions are required in medically refractory cases (during the acute phase) and those affected by visually significant scarring (during the late phase). In this paper, we aim to provide a comprehensive overview on PKIK, encompassing the epidemiology, risk factors, causes, management and outcomes, and to propose a treatment algorithm for systematically managing this challenging condition.
Starr CE, Dana R, Pflugfelder SC, Holland EJ, Zhang S, Owen D, Brazzell K. Dry eye disease flares: A rapid evidence assessment. Ocul Surf 2021;22:51-59.Abstract
PURPOSE: Characteristics of periodic flares of dry eye disease (DED) are not well understood. We conducted a rapid evidence assessment to identify evidence for and characteristics of DED flares. METHODS: Literature searches were performed in Embase® via Ovid®, MEDLINE®, and PubMed®. Clinical trials and observational studies published 2009-2019 were included if they investigated patients aged ≥18 years with clinically diagnosed DED who experienced a flare, defined as a temporary or transient episode of increased ocular discomfort, typically lasting days to a few weeks. Triggers of flares, patient-reported outcomes (symptoms), clinician-measured outcomes (signs), and changes in tear molecules were captured. RESULTS: Twenty-one publications that included 22 studies met inclusion criteria. Five observational studies described evidence of DED flares in daily life, 5 studies reported changes following cataract/refractive surgery in patients with preoperative DED, and 12 studies employed controlled environment (CE) models. Real-world triggers of DED flares included air conditioning, wind, reading, low humidity, watching television, and pollution. CE chambers (dry, moving air) and surgery also triggered DED flares. Exacerbations of symptoms and signs of DED, assessed through varied measures, were reported during flares. Across studies, matrix metalloproteinase-9 and interleukin-6 increased and epidermal growth factor decreased during DED flares. CONCLUSIONS: Evidence from 22 studies identified triggers and characteristics of DED flares. Further research is needed to assist clinicians in early diagnosis and treatment of patients experiencing flares.
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Venkateswaran N, Sripawadkul W, Karp CL. The role of imaging technologies for ocular surface tumors. Curr Opin Ophthalmol 2021;32(4):369-378.Abstract
PURPOSE OF REVIEW: This review will discuss the utility of high-resolution anterior segment optical coherence tomography (HR-OCT), in-vivo confocal microscopy (IVCM) and ultrasound biomicroscopy (UBM) in characterizing and diagnosing various ocular surface tumors, namely ocular surface squamous neoplasia (OSSN), conjunctival lymphoma and conjunctival melanoma. The strengths and limitations of each imaging modality will be discussed along with the characteristics findings of each lesion on each imaging platform. RECENT FINDINGS: HR-OCT can consistently be utilized in the clinic setting to distinguish between epithelial ocular surface tumors such as OSSN as compared with subepithelial tumors such as conjunctival lymphoma and conjunctival melanoma given their distinctive findings. IVCM can be used as an adjunct to HR-OCT to obtain cellular and surface characteristics, whereas UBM can be used to assess tumor depth and thickness for larger and highly pigmented lesions as well as to detect intraocular invasion. SUMMARY: HR-OCT, IVCM and UBM are all helpful imaging modalities to diagnose and characterize various ocular surface tumors and can serve as valuable adjuncts to monitor treatment response and assess for recurrence ocular surface tumors.
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Yang S-A, Mitchell WG, Hall N, Elze T, Miller JW, Lorch AC, Zebardast N. Usage Patterns of Minimally Invasive Glaucoma Surgery (MIGS) Differ by Glaucoma Type: IRIS Registry Analysis 2013-2018. Ophthalmic Epidemiol 2021;:1-9.Abstract
Purpose: To examine patterns of standard (trabeculectomy or glaucoma drainage devices, GDDs) vs novel (minimally invasive glaucoma surgery, MIGS) surgical techniques in the US.Methods: We used the American Academy of Ophthalmology (AAO) IRIS® Registry (Intelligent Research in Sight) queried between 2013 and 2018 (inclusive) to calculate the cumulative proportion of stand-alone, concurrent (same day) or sequential (subsequent day) glaucoma surgical techniques performed in each glaucoma diagnosis type. Secondary analyses of adjusted proportions of concurrent and sequential surgeries stratified by glaucoma diagnosis were also performed.Results: Of 203,146 eyes receiving glaucoma surgeries, open angle glaucoma (OAG) was most likely to undergo all types of intervention. The iStent was the most commonly performed MIGS, primarily for those with normal tension glaucoma (NTG) or OAG (p < .001). Conversely, GDD was the most commonly performed procedure in secondary glaucoma or other (specified) glaucoma (p < .001). ECP and iStent were the most common concurrent procedures performed; most often for OAG and NTG (p < .001). After an initial standard surgery, most eyes underwent recurrent standard interventions (90.3%). ECP was the most common MIGS performed after an initial standard surgery; particularly in primary angle-closure (PACG) and secondary glaucoma eyes (p < .001).Conclusion: Glaucoma type may influence the choice of glaucoma procedures and the decision to perform concurrent as well sequential surgical procedures. Given the poorly understood long term safety and effectiveness of MIGS, and with substantially increasing use of MIGS procedures in recent years, future studies comparing their safety and effectiveness vs standard interventions, for a variety of glaucoma types, is needed.
Yin J. Advances in corneal graft rejection. Curr Opin Ophthalmol 2021;32(4):331-337.Abstract
PURPOSE OF REVIEW: Immune rejection after corneal transplantation is a major risk for graft failure. We aim to summarize recent advances in the understanding and management of graft rejection. RECENT FINDINGS: Immune rejection remains the leading cause of graft failure in penetrating keratoplasty (PKP). While ABO blood type and sex match between donor and recipient may reduce rejection, human leucocyte antigens class II matching in a randomized study did not reduce the risk of rejection in high-risk PKP. Compared with PKP, deep anterior lamellar keratoplasty, descemet stripping automated endothelial keratoplasty, and descemet membrane endothelial keratoplasty have lower immune rejection rates of 1.7-13%, 5-11.4%, and 1.7-2.8%, respectively, based on long-term (5 years and more) studies. Whether immune rejection is a major risk factor for graft failure in these lamellar keratoplasties is unclear. While there have not been major advances in the systemic management of graft rejection, topical nonsteroid agents such as tacrolimus and anti-vascular endothelial growth factor have shown promise in high-risk cases. SUMMARY: Immune rejection remains the leading cause of graft failure in PKP. Lamellar keratoplasties have significantly lower rejection rates compared with PKP. The significance of rejection in the failure of lamellar grafts warrants further investigation.
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Zhu R-L, Fang Y, Yu H-H, Chen DF, Yang L, Cho K-S. Absence of ephrin-A2/A3 increases retinal regenerative potential for Müller cells in Rhodopsin knockout mice. Neural Regen Res 2021;16(7):1317-1322.Abstract
Müller cells (MC) are considered dormant retinal progenitor cells in mammals. Previous studies demonstrated ephrin-As act as negative regulators of neural progenitor cells in the retina and brain. It remains unclear whether the lack of ephrin-A2/A3 is sufficient to promote the neurogenic potential of MC. Here we investigated whether the MC is the primary retinal cell type expressing ephrin-A2/A3 and their role on the neurogenic potential of Müller cells. In this study, we showed that ephrin-A2/A3 and their receptor EphA4 were expressed in retina and especially enriched in MC. The level of ephrinAs/EphA4 expression increased as the retina matured that is correlated with the reduced proliferative and progenitor cell potential of MC. Next, we investigated the proliferation in primary MC cultures isolated from wild-type and A2-/- A3-/- mice by 5-ethynyl-2'-deoxyuridine (EdU) incorporation. We detected a significant increase of EdU+ cells in MC derived from A2-/- A3-/- mice. Next, we investigated the role of ephrin-A2/A3 in mice undergoing photoreceptor degeneration such as Rhodopsin knockout (Rho-/-) mice. To further evaluate the role of ephrin-A2/A3 in MC proliferation in vivo, EdU was injected intraperitoneally to adult wild-type, A2-/- A3-/- , Rho-/- and Rho-/- A2-/- A3-/- mice and the numbers of EdU+ cells distributed among different layers of the retina. EphrinAs/EphA4 expression was upregulated in the retina of Rho-/- mice compared to the wild-type mice. In addition, cultured MC derived from ephrin-A2-/- A3-/- mice also expressed higher levels of progenitor cell markers and exhibited higher proliferation potential than those from wild-type mice. Interestingly, we detected a significant increase of EdU+ cells in the retinas of adult ephrin-A2-/- A3-/- mice mainly in the inner nuclear layer; and these EdU+ cells were co-localized with MC marker, cellular retinaldehyde-binding protein, suggesting some proliferating cells are from MC. In Rhodopsin knockout mice (Rho-/- A2-/- A3-/- mice), a significantly greater amount of EdU+ cells were located in the ciliary body, retina and RPE than that of Rho-/- mice. Comparing between 6 and 12 weeks old Rho-/- A2-/- A3-/- mice, we recorded more EdU+ cells in the outer nuclear layer in the 12-week-old mice undergoing severe retinal degeneration. Taken together, Ephrin-A2/A3 are negative regulators of the proliferative and neurogenic potentials of MC. Absence of ephrin-A2/A3 promotes the migration of proliferating cells into the outer nuclear layer and may lead to retinal cell regeneration. All experimental procedures were approved by the Animal Care and Use Committee at Schepens Eye Research Institute, USA (approval No. S-353-0715) on October 24, 2012.

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