Cornea

Rashad R, Shanbhag SS, Kwan J, Chodosh J, Saeed S, Saeed HN. Chronic ocular complications in lamotrigine vs. trimethoprim-sulfamethoxazole induced Stevens-Johnson syndrome/toxic epidermal necrolysis. Ocul Surf 2021;21:16-18.Abstract
PURPOSE: The purpose of this study is to compare the severity of chronic ocular complications of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) induced by lamotrigine (LT) vs. trimethoprim-sulfamethoxazole (TS). METHODS: This retrospective cross-sectional study evaluated all SJS/TEN patients treated within our hospital network from 2008 to 2018. Inclusion criteria included patients with reactions identified as caused by either LT or TS, and patients with at least one ophthalmology follow up in the chronic phase (≥3 months from disease onset). Primary outcome measures included LogMAR best-corrected VA at most recent visit and the presence or absence of severe ocular complications (SOC). Secondary outcome measures included chronic ocular complication severity scores using a modified Sotozono scoring system. RESULTS: Forty-eight eyes of 24 patients were included in the study. The mean duration of follow-up was 39.50 ± 35.62 vs. 48.17 ± 33.09 months, respectively (p = 0.482). The LT group had worse average VA at the most recent visit (LogMAR VA; 0.508 vs. 0.041, p < 0.0001) and had a higher prevalence of SOCs (66.7% vs. 8.3%, p = 0.0038). The LT group scored worse on Sotozono chronic complications scores for the cornea (1.875 vs. 0.5, p = 0.0018), eyelid margin (5.583 vs.3.083, p = 0.0010), and overall condition (8.500 vs. 4.833, p = 0.0015). Sub-analyses showed that a moderate or severe acute ocular severity score was a significant predictor of chronic outcomes. CONCLUSIONS: Compared to patients with TS-induced SJS/TEN, patients with LT-induced SJS/TEN developed worse chronic ocular complications on several parameters. Future prospective studies are warranted to provide additional insight into the drug type as a predictor of chronic ocular complications.
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.
Makuloluwa AK, Hamill KJ, Rauz S, Bosworth L, Haneef A, Romano V, Williams RL, Dartt DA, Kaye SB. The conjunctival extracellular matrix, related disorders and development of substrates for conjunctival restoration. Ocul Surf 2021;Abstract
The conjunctiva can be damaged by numerous diseases with scarring, loss of tissue and dysfunction. Depending on extent of damage, restoration of function may require a conjunctival graft. A wide variety of biological and synthetic substrates have been tested in the search for optimal conditions for ex vivo culture of conjunctival epithelial cells as a route toward tissue grafts. Each substrate has specific advantages but also disadvantages related to their unique physical and biological characteristics, and identification and development of an improved substrate remains a priority. To achieve the goal of mimicking and restoring a biological material, requires information from the material. Specifically, extracellular matrix (ECM) derived from conjunctival tissue. Knowledge of the composition and structure of native ECM and identifying contributions of individual components to its function would enable using or mimicking those components to develop improved biological substrates. ECM is comprised of two components: basement membrane secreted predominantly by epithelial cells containing laminins and type IV collagens, which directly support epithelial and goblet cell adhesion differentiation and growth and, interstitial matrix secreted by fibroblasts in lamina propria, which provides mechanical and structural support. This review presents current knowledge on anatomy, composition of conjunctival ECM and related conjunctival disorders. Requirements of potential substrates for conjunctival tissue engineering and transplantation are discussed. Biological and synthetic substrates and their components are described in an accompanying review.
Diel RJ, Mehra D, Kardon R, Buse DC, Moulton E, Galor A. Photophobia: shared pathophysiology underlying dry eye disease, migraine and traumatic brain injury leading to central neuroplasticity of the trigeminothalamic pathway. Br J Ophthalmol 2021;105(6):751-760.Abstract
BACKGROUND: Photophobia is a potentially debilitating symptom often found in dry eye disease (DE), migraine and traumatic brain injury (TBI). METHODS: We conducted a review of the literature via a PubMed search of English language articles with a focus on how photophobia may relate to a shared pathophysiology across DE, migraine and TBI. RESULTS: DE, migraine and TBI are common conditions in the general population, are often comorbid, and share photophobia as a symptom. Across the three conditions, neural dysregulation of peripheral and central nervous system components is implicated in photophobia in various animal models and in humans. Enhanced activity of the neuropeptide calcitonin gene-related peptide (CGRP) is closely linked to photophobia. Current therapies for photophobia include glasses which shield the eyes from specific wavelengths, botulinum toxin, and inhibition of CGRP and its receptor. Many individuals have persistent photophobia despite the use of these therapies, and thus, development of new therapies is needed. CONCLUSIONS: The presence of photophobia in DE, migraine and TBI suggests shared trigeminothalamic pathophysiologic mechanisms, as explained by central neuroplasticity and hypersensitivity mediated by neuropeptide CGRP. Treatment strategies which target neural pathways (ie, oral neuromodulators, transcutaneous nerve stimulation) should be considered in patients with persistent photophobia, specifically in individuals with DE whose symptoms are not controlled with traditional therapies.
Makuloluwa AK, Hamill KJ, Rauz S, Bosworth L, Haneef A, Romano V, Williams RL, Dartt DA, Kaye SB. Biological tissues and components, and synthetic substrates for conjunctival cell transplantation. Ocul Surf 2021;Abstract
The conjunctiva is the largest component of the ocular surface. It can be damaged by various pathological processes leading to scarring, loss of tissue and dysfunction. Depending on the amount of damage, restoration of function may require a conjunctival graft. Numerous studies have investigated biological and synthetic substrates in the search for optimal conditions for the ex vivo culture of conjunctival epithelial cells that can be used as tissue grafts for transplantation. These substrates have advantages and disadvantages that are specific to the characteristics of each material; the development of an improved material remains a priority. This review is the second of a two-part review in The Ocular Surface. In the first review, the structure and function of the conjunctiva was evaluated with a focus on the extracellular matrix and the basement membrane, and biological and mechanical characteristics of the ideal substrate with recommendations for further studies. In this review the types of biological and synthetic substrates used for conjunctival transplantation are discussed including substrates based on the extracellular matrix. .
Yu K, Guo Y, Ge Q-M, Su T, Shi W-Q, Zhang L-J, Shu H-Y, Pan Y-C, Liang R-B, Li Q-Y, Shao Y. Altered spontaneous activity in the frontal gyrus in dry eye: a resting-state functional MRI study. Sci Rep 2021;11(1):12943.Abstract
This study investigated neurologic changes in patients with dry eye (DE) by functional magnetic resonance imaging (fMRI) and to used regional homogeneity (ReHo) analysis to clarify the relationship between these changes and clinical features of DE. A total of 28 patients with DE and 28 matched healthy control (HC) subjects (10 males and 18 females in each group) were enrolled. fMRI scans were performed in both groups. We carried out ReHo analysis to assess differences in neural activity between the 2 groups, and receiver operating characteristic curve (ROC) analysis was performed to evaluate the performance of ReHo values of specific brain areas in distinguishing DE patients from HCs. The relationship between average ReHo values and clinical characteristics was assessed by correlation analysis. ReHo values of the middle frontal gyrus, inferior frontal gyrus, and superior frontal gyrus were significantly lower in DE patients compared to HCs. The ROC analysis showed that ReHo value had high accuracy in distinguishing between DE patients and HCs (P < 0.0001). The ReHo values of the middle frontal gyrus and dorsolateral superior frontal gyrus were correlated to disease duration (P < 0.05). Symptoms of ocular surface injury in DE patients are associated with dysfunction in specific brain regions, which may underlie the cognitive impairment, psychiatric symptoms, and depressive mood observed in DE patients. The decreased ReHo values of some brain gyri in this study may provide a reference for clinical diagnosis and determination of treatment efficacy.
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.
Geoffrion D, Robert M-C, Chodosh J, Di Polo A, Harissi-Dagher M. Perspectives for preclinical mouse models of glaucoma after Boston keratoprosthesis type 1. Exp Eye Res 2021;208:108615.Abstract
Animal models of the Boston keratoprosthesis type 1 (KPro) are needed to study glaucoma damage after KPro implantation to control for confounding comorbidities common in human KPro recipients. The purpose of this study was to determine the feasibility of establishing a reproducible mouse model of glaucoma after KPro surgery, specifically that of a miniaturized mouse model of KPro (mKPro). In the present study, a total of 20 corneas of donor C57BL/6 mice (n = 10) were implanted in one eye of each recipient BALB/C mouse (n = 20), assembled as part of the mKPro, either with or without intraoperative lensectomy. Main feasibility outcomes consisted in incidence rates of loss of tone, capsule nicking, and lens extrusion, as well as acquisition of posterior segment optical coherence tomography (OCT) images. With lensectomy (n = 10), loss of ocular tone and retinal detachment occurred in 100% of mice. Without lensectomy (n = 10), capsule nicking and opening, as well as lens extrusion, occurred in 80% of mice. Causes of these complications included the large proportion of intraocular volume occupied by the lens, the shallow anterior chamber, and thus the lack of available intraocular volume to implant the KPro if the lens remains present. Successful mouse KPro surgery may require a great deal of practice to be useful as a reproducible model. Animal KPro models ought to be pursued further by research teams in future studies.
Yuan A, Ma K, Sharifi S, Pineda R. Biomechanical testing of flanged polypropylene sutures in scleral fixation. Am J Ophthalmol 2021;Abstract
OBJECTIVE: To optimize the flanged belt-loop technique of scleral fixation through biomechanical testing and report clinical outcomes of resultant modifications. DESIGN: Experimental study. METHODS: The force to disinsert flanged polypropylene suture from human cadaveric sclera was assessed using a tensile testing machine and compared to the breaking strengths of 9-0 and 10-0 polypropylene. The effects of modifying suture gauge (5-0, 6-0, 7-0 or 8-0), amount of suture cauterized (0.5 or 1.0mm), and sclerotomy size (27-, 30-, 32-, 33-gauge) were investigated. Belt-loop intrascleral fixation using 6-0 and 7-0 polypropylene with 30- and 32-gauge needles respectively was performed in 5 patients. MAIN OUTCOME MEASURES: Flanged suture disinsertion force in cadaveric sclera. RESULTS: The average force to disinsert a flange created by melting 1.0mm of 5-0, 6-0, 7-0 and 8-0 polypropylene suture from human cadaveric sclera via 27-, 30-, 32- and 33-gauge needle sclerotomies was 3.0 ± 0.5N, 2.1 ± 0.3N, 0.9 ± 0.2N and 0.4 ± 0.1N respectively. The disinsertion forces for flanges formed by melting 0.5mm of the same gauges were 72-79% lower (p < 0.001). In comparison, the breaking strengths of 9-0 and 10-0 polypropylene were 1.0 ± 0.2N and 0.5 ± 0.0N. Belt-loop fixation using 6-0 and 7-0 polypropylene with 30- and 32-gauge sclerotomies demonstrated good outcomes at 6 months. CONCLUSIONS: The flanged belt-loop technique is a biomechanically sound method of scleral fixation using 1.0mm flanges of 5-0 to 7-0 polypropylene paired with 27-, 30- and 32- gauge sclerotomies. In contrast, 8-0 polypropylene and 0.5 mm flanges of any suture gauge will likely be unstable with this technique.
Luo ZK, Domenech-Estarellas EA, Han A, Lee D, Khatri R, Wahl JL, Cutler C, Armand P, Antin JH, Koreth J, Gooptu M, Alyea EP, Soiffer RJ, Ho VT. Efficacy and Safety of 1% Progesterone Gel to the Forehead for Ocular Chronic Graft-versus-Host Disease. Transplant Cell Ther 2021;27(5):433.e1-433.e8.Abstract
There is no Food and Drug Administration-approved treatments for ocular chronic graft-versus-host disease (oGVHD) to date, and current therapeutic options are limited. Forehead application of 1% progesterone gel provides corneal antinociception in preclinical models, suggesting it may be useful in alleviating ocular irritations. This study was conducted to evaluate the efficacy and safety of 1% progesterone gel in treating moderate to severe symptomatic oGVHD. Thirty-three patients with oGVHD following allogeneic stem cell transplantation were enrolled in this single-center, sponsor-initiated, prospective exploratory randomized double-masked placebo-controlled phase II clinical trial. The inclusion criteria included a National Institutes of Health consensus score of ≥2, moderate to severe ocular discomfort level, and receipt of a stable immunosuppression regimen. Twenty-one of the 22 patients in the progesterone arm and all 11 patients in the placebo arm completed the course of twice-daily forehead drug application for 10 weeks. The changes from baseline of self-reported ocular symptom scores and physician-recorded cornea fluorescein staining scores were analyzed using mixed-model repeated-measures regression model in an intention-to-treat population. The 33 patients included 12 women and 21 men, with a median age of 66 years (range, 24 to 75 years). At 10 weeks, there was a significant reduction in ocular symptoms from baseline in the progesterone group compared with the placebo group in symptom frequency (-30.7 versus -2.2; P < .001) and severity (-19.8 versus +1.6; P = .005). At 10 weeks, there was also greater reduction of cornea fluorescein staining centrally (-1.2 versus +.1; P = .001) and inferiorly (-1.4 versus -0.2; P = .005). No difference was noted in superior cornea staining. There were no severe adverse events in the progesterone group. Forehead application of 1% progesterone gel significantly improved ocular signs and symptoms within 10 weeks. It appears to be a safe and effective new therapy for oGVHD, and a novel mechanism for neuroaxis drug delivery. A multicenter phase III clinical trial is planned for further validation.
Williams IM, Pineda R, Neerukonda VK, Stagner AM. Mucopolysaccharidosis Type I-Associated Corneal Disease: A Clinicopathologic Study. Am J Ophthalmol 2021;231:39-47.Abstract
PURPOSE: To report the anterior segment clinical features and histopathologic and histochemical characteristics of explanted corneas from the largest reported cohort of patients with Hurler syndrome and other variants of mucopolysaccharidosis (MPS) I undergoing corneal transplantation. DESIGN: Retrospective observational case series. METHODS: This institutional study reviewed 15 corneas from 9 patients with MPS I spectrum disease who underwent corneal transplant to treat corneal clouding between May 2011 and October 2020. We reviewed the clinical data, hematoxylin-eosin-stained sections, and histochemical stains, including those for mucopolysaccharides (Alcian blue and/or colloidal iron). The main outcome measures were pathology observed under light microscopy and postsurgical clinical outcomes. RESULTS: Nine patients underwent 15 corneal transplants for corneal clouding (14/15 procedures were deep anterior lamellar keratoplasty). All corneas had mucopolysaccharide deposition visible on hematoxylin-eosin-stained sections, which was highlighted in blue with histochemical stains. All corneas also showed alterations in Bowman's layer and the majority also showed epithelial abnormalities. CONCLUSION: MPS I shows significant corneal clouding that is successfully treated with deep anterior lamellar keratoplasty. The excised corneas show characteristic epithelial changes, disruption or breaks in Bowman's membrane, and amphophilic collections of stromal granular mucopolysaccharides which are visible on hematoxylin-eosin-stained sections and highlighted by special histochemical stains (Alcian blue and collodial iron). These changes, although subtle, should alert the pathologist to the possibility of an underlying lysosomal storage disorder.
Simpson FC, McTiernan CD, Islam MM, Buznyk O, Lewis PN, Meek KM, Haagdorens M, Audiger C, Lesage S, Gueriot F-X, Brunette I, Robert M-C, Olsen D, Koivusalo L, Liszka A, Fagerholm P, Gonzalez-Andrades M, Griffith M. Collagen analogs with phosphorylcholine are inflammation-suppressing scaffolds for corneal regeneration from alkali burns in mini-pigs. Commun Biol 2021;4(1):608.Abstract
The long-term survival of biomaterial implants is often hampered by surgery-induced inflammation that can lead to graft failure. Considering that most corneas receiving grafts are either pathological or inflamed before implantation, the risk of rejection is heightened. Here, we show that bioengineered, fully synthetic, and robust corneal implants can be manufactured from a collagen analog (collagen-like peptide-polyethylene glycol hybrid, CLP-PEG) and inflammation-suppressing polymeric 2-methacryloyloxyethyl phosphorylcholine (MPC) when stabilized with the triazine-based crosslinker 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride. The resulting CLP-PEG-MPC implants led to reduced corneal swelling, haze, and neovascularization in comparison to CLP-PEG only implants when grafted into a mini-pig cornea alkali burn model of inflammation over 12 months. Implants incorporating MPC allowed for faster nerve regeneration and recovery of corneal sensation. CLP-PEG-MPC implants appear to be at a more advanced stage of regeneration than the CLP-PEG only implants, as evidenced by the presence of higher amounts of cornea-specific type V collagen, and a corresponding decrease in the presence of extracellular vesicles and exosomes in the corneal stroma, in keeping with the amounts present in healthy, unoperated corneas.
Ma KK, Ong Tone S, Chodosh J, Saeed HN. Ochrobactrum anthropi Keratitis in a Boston Type 1 Keratoprosthesis Recipient. Cornea 2021;40(5):662-663.Abstract
PURPOSE: To report a case of Ochrobactrum anthropi keratitis in an eye with a Boston type 1 keratoprosthesis. METHODS: This is a case report and review of the literature. RESULTS: A 78-year-old man with a history of implantation of a Boston type 1 keratoprosthesis in the left eye presented for a routine follow-up with no acute complaints. In the left eye, visual acuity was 20/60 and slit-lamp examination revealed a 1.5-mm inferotemporal corneal infiltrate adjacent to the optic stem. Corneal cultures grew abundant O. anthropi. After 7 weeks of topical antimicrobial therapy and placement of a temporary tarsorrhaphy, the keratitis resolved. CONCLUSIONS: Ochrobactrum anthropi is an organism associated with indwelling medical devices and can be pathogenic in eyes with implanted keratoprostheses.

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