Cornea

B
Bakshi SK, Paschalis EI, Graney J, Chodosh J. Lucia and Beyond: Development of an Affordable Keratoprosthesis. Cornea 2019;38(4):492-497.Abstract
PURPOSE: Severe corneal disease contributes significantly to the global burden of blindness. Corneal allograft surgery remains the most commonly used treatment, but does not succeed long term in every patient, and the odds of success fall with each repeated graft. The Boston keratoprosthesis type I has emerged as an alternative to repeat corneal allograft. However, cost limits its use in resource-poor settings, where most corneal blind individuals reside. METHODS: All aspects of the Boston keratoprosthesis design process were examined to determine areas of potential modification and simplification, with dual goals to reduce cost and improve the cosmetic appearance of the device in situ. RESULTS: Minor modifications in component design simplified keratoprosthesis manufacturing. Proportional machinist time could be further reduced by adopting a single axial length for aphakic eyes, and a single back plate diameter. The cosmetic appearance was improved by changing the shape of the back plate holes from round to radial, with a petaloid appearance, and by anodization of back plate titanium to impute a more natural color. CONCLUSIONS: We have developed a modified Boston keratoprosthesis type I, which we call the "Lucia." The Lucia retains the 2 piece design and ease of assembly of the predicate device, but would allow for manufacturing at a reduced cost. Its appearance should prove more acceptable to implanted patients. Successful keratoprosthesis outcomes require daily medications for the life of the patient and rigorous, frequent, postoperative care. Effective implementation of the device in resource-poor settings will require further innovations in eye care delivery.
Bakshi SK, Graney J, Paschalis EI, Agarwal S, Basu S, Iyer G, Liu C, Srinivasan B, Chodosh J. Design and Outcomes of a Novel Keratoprosthesis: Addressing Unmet Needs in End-Stage Cicatricial Corneal Blindness. Cornea 2020;39(4):484-490.Abstract
PURPOSE: The most commonly applied prosthetic devices for corneal blindness in the setting of severe cicatricial keratoconjunctivitis are the Boston keratoprosthesis type II and the modified osteo-odonto-keratoprosthesis, with these requiring either normal eyelid skin or a healthy cuspid tooth, respectively. For patients with neither attribute, we developed a new keratoprosthesis device combining positive aspects of both Boston keratoprosthesis type II and modified osteo-odonto-keratoprosthesis, which we have named the "Lux." METHODS: Short-term postoperative outcomes for the Lux keratoprosthesis, best-corrected visual acuity (BCVA), device retention, and complications, were examined in a retrospective case series of 9 eyes of 9 patients implanted at 4 centers. RESULTS: Seven of 9 (77.8%) eyes had cicatricial corneal blindness due to autoimmune disease and 2 (22.2%) from severe burns. Preoperative BCVA was ≤hand motions in all patients. Three (33.3%) had previously received at least 1 keratoprosthesis in the affected eye, and 4 (44.4%) had previously undergone ≥1 therapeutic keratoplasty. One patient had 19 previous eye surgeries. The mean duration of postoperative follow-up was 18.7 months (range 7-28 months). BCVA of ≥20/200 was achieved in all 9 patients, with 2 (22.2%) reaching 20/20 at the last examination, and all 9 (100%) of the devices were retained. One recipient developed a retinal detachment 2 months after implantation. Two (22.2%) patients required placement of a glaucoma drainage device. CONCLUSIONS: The Lux keratoprosthesis was developed for patients with severe cicatricial keratoconjunctivitis who were otherwise not candidates for existing keratoprosthesis designs. Short-term outcomes after implantation of the Lux keratoprosthesis were encouraging.
Bal S, Tahvildari M, Jurkunas U. Scleral Perforation Secondary to Cyclophotocoagulation. Ophthalmology 2021;128(5):662.
Bauskar A, Mack WJ, Mauris J, Argüeso P, Heur M, Nagel BA, Kolar GR, Gleave ME, Nakamura T, Kinoshita S, Moradian-Oldak J, Panjwani N, Pflugfelder SC, Wilson MR, Fini EM, Jeong S. Clusterin Seals the Ocular Surface Barrier in Mouse Dry Eye. PLoS One 2015;10(9):e0138958.Abstract

Dry eye is a common disorder caused by inadequate hydration of the ocular surface that results in disruption of barrier function. The homeostatic protein clusterin (CLU) is prominent at fluid-tissue interfaces throughout the body. CLU levels are reduced at the ocular surface in human inflammatory disorders that manifest as severe dry eye, as well as in a preclinical mouse model for desiccating stress that mimics dry eye. Using this mouse model, we show here that CLU prevents and ameliorates ocular surface barrier disruption by a remarkable sealing mechanism dependent on attainment of a critical all-or-none concentration. When the CLU level drops below the critical all-or-none threshold, the barrier becomes vulnerable to desiccating stress. CLU binds selectively to the ocular surface subjected to desiccating stress in vivo, and in vitro to the galectin LGALS3, a key barrier component. Positioned in this way, CLU not only physically seals the ocular surface barrier, but it also protects the barrier cells and prevents further damage to barrier structure. These findings define a fundamentally new mechanism for ocular surface protection and suggest CLU as a biotherapeutic for dry eye.

Bayraktutar BN, Ozmen CM, Muzaaya N, Dieckmann G, Koseoglu DN, Müller RT, Cruzat A, Cavalcanti BM, Hamrah P. Comparison of clinical characteristics of post-refractive surgery-related and post-herpetic neuropathic corneal pain. Ocul Surf 2020;Abstract
PURPOSE: To compare the clinical characteristics and in vivo confocal microscopy (IVCM) findings of patients with neuropathic corneal pain (NCP) due to refractive surgery (RS-NCP) and herpetic eye disease (H-NCP) to controls. METHODS: Sixteen patients with RS-NCP and 7 patients with H-NCP, and 37 healthy reference age- and sex-matched healthy controls were included to the study. The medical records were reviewed for demographic features, detailed disease history, ocular surface disease index (OSDI), ocular pain assessment survey (OPAS) scores. IVCM images of patients were analyzed and compared to reference controls by two masked observers. RESULTS: The mean pain intensity score for the last 24 h (5.1 ± 2.4 vs. 3.9 ± 1.2; p = 0.27), last 2 weeks (6.1 ± 2.5 vs. 4.8 ± 2.3; p = 0.13) for RS-NCP vs. H-NCP respectively, and quality of life scores (p = 0.23) were similar in both groups. Quality of life, especially mood (p = 0.06) and enjoying life/relations to others (p = 0.10) were affected in both groups, but were not statistically significant between groups. The mean total nerve density was lower in RS-NCP (5702.4 ± 4599.0 μm/mm) compared to their respective controls (26,422.8 ± 4491.0; p < 0.001) and in the H-NCP group (2149.5 ± 2985.9) compared to their respective controls (22,948.8 ± 3169.0; p < 0.001). Alterations in DC density were similar between all groups (38.3 ± 48.0 cells/mm in RS-NCP, 61.0 ± 76.9 in H-NCP, p = 0.95). CONCLUSION: Neuropathic corneal pain patients due to refractive surgery show similar clinical characteristics, pain levels, quality of life impact, and IVCM findings as patients with NCP due to herpetic eye disease.
Behlau I, Martin KV, Martin JN, Naumova EN, Cadorette JJ, Sforza TJ, Pineda R, Dohlman CH. Infectious endophthalmitis in Boston keratoprosthesis: incidence and prevention. Acta Ophthalmol 2014;92(7):e546-55.Abstract
PURPOSE: To determine the cumulative worldwide incidence of infectious endophthalmitis and associated vision loss after Boston keratoprosthesis (B-KPro) Type I/II implantation and to propose both safe and inexpensive prophylactic antibiotic regimens. METHODS: Two retrospective methods were used to determine the incidence, visual outcomes and aetiologies of infectious endophthalmitis associated with the B-KPro divided per decade: (i) systematic review of the literature from 1990 through January 2013 and (ii) a surveillance survey sent to all surgeons who implanted B-KPros through 2010 with 1-year minimum follow-up. In addition, a single-Boston surgeon 20-year experience was examined. RESULTS: From 1990 through 2010, there were 4729 B-KPros implanted worldwide by 209 U.S. surgeons and 159 international surgeons. The endophthalmitis cumulative mean incidence declined from 12% during its first decade of use to about 3% during its second decade in the Unites States and about 5% internationally during the second decade. There remains a large incidence range both in the United States (1-12.5%) and internationally (up to 17%). Poor compliance with daily topical antibiotics is an important risk factor. While Gram-positive organisms remained dominant, fungal infections emerged during the second decade. CONCLUSIONS: Daily prophylactic topical antibiotics have dramatically reduced the endophthalmitis incidence. Although Gram-positive organisms are the most common aetiology, antimicrobials must be inclusive of Gram-negative organisms. Selection of prophylactic regimens should be tailored to local antibiotic susceptibility patterns, be cost-effective, and should not promote the emergence of antimicrobial resistance. An example of a broad-spectrum, low-cost prophylactic option for non-autoimmune patients includes trimethoprim/polymyxinB once daily.
Beining MW, Magno M, Moschowits E, Olafsson J, Vehof J, Dartt DA, Utheim TP. In-office thermal systems for the treatment of dry eye disease. Surv Ophthalmol 2022;Abstract
Dry eye disease affects millions of people worldwide, causing pain, vision disturbance, and reduced productivity. Meibomian gland dysfunction (MGD), a major cause of dry eye, is characterized by chronic glandular inflammation, thickening of the meibum, obstruction of terminal ducts, and glandular atrophy. Treatment of MGD can utilize heat and pressure applied to the meibomian glands, increasing meibum expression. With self-treatments, however, not all patients achieve lasting improvement, and compliance is often low. In-office thermal systems offer a second line of treatment and could be a much-needed addition for patients who do not respond to conventional treatment. We critically evaluated the efficacy and safety of LipiFlow, iLux and TearCare based on existing literature. While the studies found a single in-office thermal treatment to be safe and effective in improving short-term signs and symptoms in patients with dry eye, long-term efficacy needs to be further studied. Thus, well-controlled, long-term efficacy studies are warranted to draw clear conclusions. The treatment seemed to provide rapid relief of symptoms that may last up to one year, but at a considerably higher cost than the at-home treatments. The choice of treatment depends on cost, compliance with at-home treatment, and personal preference.
Belmonte C, Nichols JJ, Cox SM, Brock JA, Begley CG, Bereiter DA, Dartt DA, Galor A, Hamrah P, Ivanusic JJ, Jacobs DS, McNamara NA, Rosenblatt MI, Stapleton F, Wolffsohn JS. TFOS DEWS II pain and sensation report. Ocul Surf 2017;15(3):404-437.Abstract
Pain associated with mechanical, chemical, and thermal heat stimulation of the ocular surface is mediated by trigeminal ganglion neurons, while cold thermoreceptors detect wetness and reflexly maintain basal tear production and blinking rate. These neurons project into two regions of the trigeminal brain stem nuclear complex: ViVc, activated by changes in the moisture of the ocular surface and VcC1, mediating sensory-discriminative aspects of ocular pain and reflex blinking. ViVc ocular neurons project to brain regions that control lacrimation and spontaneous blinking and to the sensory thalamus. Secretion of the main lacrimal gland is regulated dominantly by autonomic parasympathetic nerves, reflexly activated by eye surface sensory nerves. These also evoke goblet cell secretion through unidentified efferent fibers. Neural pathways involved in the regulation of meibomian gland secretion or mucin release have not been identified. In dry eye disease, reduced tear secretion leads to inflammation and peripheral nerve damage. Inflammation causes sensitization of polymodal and mechano-nociceptor nerve endings and an abnormal increase in cold thermoreceptor activity, altogether evoking dryness sensations and pain. Long-term inflammation and nerve injury alter gene expression of ion channels and receptors at terminals and cell bodies of trigeminal ganglion and brainstem neurons, changing their excitability, connectivity and impulse firing. Perpetuation of molecular, structural and functional disturbances in ocular sensory pathways ultimately leads to dysestesias and neuropathic pain referred to the eye surface. Pain can be assessed with a variety of questionaires while the status of corneal nerves is evaluated with esthesiometry and with in vivo confocal microscopy.
Bengani LC, Kobashi H, Ross AE, Zhai H, Salvador-Culla B, Tulsan R, Kolovou PE, Mittal SK, Chauhan SK, Kohane DS, Ciolino JB. Steroid-eluting contact lenses for corneal and intraocular inflammation. Acta Biomater 2020;116:149-161.Abstract
Ocular inflammation is one of the leading causes of blindness worldwide, and steroids in topical ophthalmic solutions (e.g. dexamethasone eye drops) are the mainstay of therapy for ocular inflammation. For many non-infectious ocular inflammatory diseases, such as uveitis, eye drops are administered as often as once every hour. The high frequency of administration coupled with the side effects of eye drops leads to poor adherence for patients. Drug-eluting contact lenses have long been sought as a potentially superior alternative for sustained ocular drug delivery; but loading sufficient drug into contact lenses and control the release of the drug is still a challenge. A dexamethasone releasing contact lens (Dex-Lens) was previously developed by encapsulating a dexamethasone-polymer film within the periphery of a hydrogel-based contact lens. Here, we demonstrate safety and efficacy of the Dex-Lens in rabbit models in the treatment of anterior ocular inflammation. The Dex-Lens delivered drug for 7 days in vivo (rabbit model). In an ocular irritation study (Draize test) with Dex-Lens extracts, no adverse events were observed in normal rabbit eyes. Dex-Lenses effectively inhibited suture-induced corneal neovascularization and inflammation for 7 days and lipopolysaccharide-induced anterior uveitis for 5 days. The efficacy of Dex-Lenses was similar to that of hourly-administered dexamethasone eye drops. In the corneal neovascularization study, substantial corneal edema was observed in rabbit eyes that received no treatment and those that wore a vehicle lens as compared to rabbit eyes that wore the Dex-Lens. Throughout these studies, Dex-Lenses were well tolerated and did not exhibit signs of toxicity. Dexamethasone-eluting contact lenses may be an option for the treatment of ocular inflammation and a platform for ocular drug delivery. STATEMENT OF SIGNIFICANCE: Inflammation of the eye can happen either on the ocular surface (i.e. the cornea) or inside the eye, both of which can result in loss of vision or even blindness. Ocular inflammation is normally treated by steroid eye drops. Depending on the type and severity of inflammation, patients may have to take drops every hour for days at a time. Such severe dosing regimen can lead to patients missing doses. Also, more than 95% drug in an eye drop never goes inside the eye. Here we present a contact lens that release a steroid (dexamethasone) for seven days at a time. It is much more efficient than eye drops and a significant improvement since once worn, the patient will avoid missing doses.
Benischke A-S, Vasanth S, Miyai T, Katikireddy KR, White T, Chen Y, Halilovic A, Price M, Price F, Liton PB, Jurkunas UV. Activation of mitophagy leads to decline in Mfn2 and loss of mitochondrial mass in Fuchs endothelial corneal dystrophy. Sci Rep 2017;7(1):6656.Abstract
Human corneal endothelial cells (HCEnCs) are terminally differentiated cells that have limited regenerative potential. The large numbers of mitochondria in HCEnCs are critical for pump and barrier function required for corneal hydration and transparency. Fuchs Endothelial Corneal Dystrophy (FECD) is a highly prevalent late-onset oxidative stress disorder characterized by progressive loss of HCEnCs. We previously reported increased mitochondrial fragmentation and reduced ATP and mtDNA copy number in FECD. Herein, carbonyl cyanide m-chlorophenyl hydrazone (CCCP)-induced mitochondrial depolarization decreased mitochondrial mass and Mfn2 levels, which were rescued with mitophagy blocker, bafilomycin, in FECD. Moreover, electron transport chain complex (I, V) decrease in FECD indicated deficient mitochondrial bioenergetics. Transmission electron microscopy of FECD tissues displayed an increased number of autophagic vacuoles containing degenerated and swollen mitochondria with cristolysis. An elevation of LC3-II and LAMP1 and downregulation of Mfn2 in mitochondrial fractions suggested that loss of fusion capacity targets fragmented mitochondria to the pre-autophagic pool and upregulates mitophagy. CCCP-induced mitochondrial fragmentation leads to Mfn2 and LC3 co-localization without activation of proteosome, suggesting a novel Mfn2 degradation pathway via mitophagy. These data indicate constitutive activation of mitophagy results in reduction of mitochondrial mass and abrogates cellular bioenergetics during degeneration of post-mitotic cells of ocular tissue.
Besner S, Scarcelli G, Pineda R, Yun S-H. In Vivo Brillouin Analysis of the Aging Crystalline Lens. Invest Ophthalmol Vis Sci 2016;57(13):5093-5100.Abstract

Purpose: To analyze the age dependence of the longitudinal modulus of the crystalline lens in vivo using Brillouin scattering data in healthy subjects. Methods: Brillouin scans were performed along the crystalline lens in 56 eyes from 30 healthy subjects aged from 19 to 63 years. Longitudinal elastic modulus was acquired along the sagittal axis of the lens with a transverse and axial resolution of 4 and 60 μm, respectively. The relative lens stiffness was computed, and correlations with age were analyzed. Results: Brillouin axial profiles revealed nonuniform longitudinal modulus within the lens, increasing from a softer periphery toward a stiffer central plateau at all ages. The longitudinal modulus at the central plateau showed no age dependence in a range of 19 to 45 years and a slight decrease with age from 45 to 63 years. A significant intersubject variability was observed in an age-matched analysis. Importantly, the extent of the central stiff plateau region increased steadily over age from 19 to 63 years. The slope of change in Brillouin modulus in the peripheral regions were nearly age-invariant. Conclusions: The adult human lens showed no measurable age-related increase in the peak longitudinal modulus. The expansion of the stiff central region of the lens is likely to be the major contributing factor to age-related lens stiffening. Brillouin microscopy may be useful in characterizing the crystalline lens for the optimization of surgical or pharmacological treatments aimed at restoring accommodative power.

Bhattacharya S, García-Posadas L, Hodges RR, Makarenkova HP, Masli S, Dartt DA. Alteration in nerves and neurotransmitter stimulation of lacrimal gland secretion in the TSP-1 mouse model of aqueous deficiency dry eye. Mucosal Immunol 2018;11(4):1138-1148.Abstract
The purpose of this study is to determine neural, vascular, protein secretion, and cellular signaling changes with disease progression in lacrimal glands of the thrombospondin-1 (TSP-1) mouse model of dry eye compared to C57BL/6 wild-type (WT) mice. Neural innervation was reduced in TSP-1 lacrimal glands compared to WT controls, whereas the number of blood vessels was increased. Intracellular Ca stores and the amount of lysosomes, mitochondria, and secretory granules, but not the endoplasmic reticulum, were reduced in TSP-1 compared to WT acini at 12 weeks of age. Ex vivo high KCl-evoked secretion was decreased in TSP-1 compared to WT lacrimal gland tissue pieces. The α-adrenergic agonist-stimulated response was increased in TSP-1 at 4 and 24 weeks but decreased at 12 weeks, and the ATP and MeSATP-stimulated peak [Ca] responses were decreased at 24 weeks. These changes were observed prior to the appearance of mononuclear infiltrates. We conclude that in the lacrimal gland the absence of TSP-1: injures peripheral nerves; blocks efferent nerve activation; decreases protein secretion; and alters intracellular Ca stores. Through these effects the absence of TSP-1 leads to disruption of ocular surface homeostasis and development of dry eye.
Bian Y, Ma KK, Hall NE, Alice Lorch TE, Miller JW, Dana R, Yin J. Neurotrophic Keratopathy in the United States: an IRIS® Registry (Intelligent Research in Sight) Analysis. Ophthalmology 2022;Abstract
PURPOSE: To describe the characteristics of neurotrophic keratopathy (NK) in the US. DESIGN: Retrospective database study. SUBJECTS: 31,915 eyes from 27,483 patients with a diagnosis of NK. METHODS: Retrospective analysis of visits associated with a diagnosis of NK between 2013 and 2018 using the American Academy of Ophthalmology IRIS® Registry (Intelligent Research in Sight). MAIN OUTCOME MEASURES: Demographic information, prevalence, visual acuity (VA), concomitant diagnosis and procedure codes, risk factors impacting visual acuity closest after NK onset date. RESULTS: Mean age at initial diagnosis of NK was 68.0 (SD=16.0) years. 58.91% of patients were female (p<0.0001). Presentation was unilateral in 58.14%, bilateral in 16.13%, and unspecified in 25.73%. Average 6-year prevalence of NK in the IRIS Registry was 21.34 cases per 100,000 patients. Mean logMAR VA was 0.60 (SD=0.79) prior to diagnosis, and 0.88 (SD=0.94) after diagnosis (p<0.0001). Most common concomitant diagnoses included herpetic keratitis (33.70%), diabetes (31.59%), and corneal dystrophy (14.28%). Common procedures for NK management included the use of amniotic membrane (29.90%), punctal plugs (29.65%), and bandage contact lenses (22.67%). Age, male sex, Black race, Hispanic or Latino ethnicity, unilateral involvement, concomitant diagnoses of diabetes, corneal transplant, or herpetic keratitis were significantly associated with worse VA. CONCLUSION: Based on the IRIS Registry, the prevalence of NK is 21.34 cases per 100,000 patients. VA was significantly worse after NK diagnosis compared to other time points. NK was most commonly associated with herpetic keratitis and diabetes. Worse VA in NK patients was associated with several demographic characteristics, history of diabetes, corneal transplant, and herpetic keratitis.
Birnbaum FA, Hamrah P, Jacobs DS, Song BJ. Acquired Corneal Neuropathy and Photoallodynia Associated With Malposition of an Ex-PRESS Shunt. J Glaucoma 2017;26(1):e19-e21.Abstract

PURPOSE: Corneal neuropathy is a recently described disease process that is not well understood and is likely underdiagnosed as a result. This is the first reported case of an acquired corneal neuropathy associated with malposition of an Ex-PRESS shunt. METHODS: A single case report. RESULTS: We report the case of a 50-year-old man with a history of multiple procedures for glaucoma who subsequently developed photoallodynia and corneal neuropathy in association with malposition of an Ex-PRESS shunt in the peripheral cornea. Laser confocal microscopy (HRT3/RCM) of the cornea showed the presence of neuromas, decreased nerve density, and a significant increase of dendritiform immune cells consistent with our diagnosis. Initial treatment with steroid pulse therapy did not result in decreased inflammation or symptomatic improvement leading to surgical explantation of the shunt. One month after surgery, there was noticeable improvement in the patient's pain and photoallodynia (approximately 40%) as well as the abnormalities seen on confocal microscopy. CONCLUSIONS: We hypothesize that poor Ex-PRESS shunt positioning can act as a nidus for corneal inflammation, resulting in corneal neuropathy and lowering of the nociception threshold.

Bitar MS, Liu C, Ziaei A, Chen Y, Schmedt T, Jurkunas UV. Decline in DJ-1 and decreased nuclear translocation of Nrf2 in Fuchs endothelial corneal dystrophy. Invest Ophthalmol Vis Sci 2012;53(9):5806-13.Abstract
PURPOSE: This study sought to determine factors involved in nuclear factor erythroid 2-related factor 2 (Nrf2) regulation and their response to oxidative stress in Fuchs endothelial corneal dystrophy (FECD) and normal corneal endothelial cells (CECs). METHODS: FECD corneal buttons were obtained from transplantations and normal human corneas from tissue banks. Oxidative stress was induced by tert-butyl hydroperoxide (tBHP). Protein and mRNA levels of Nrf2, DJ-1, p53, and Kelch-like ECH-associated protein1 (Keap1) were investigated using Western blotting and real-time PCR. Immunoprecipitation was used to detect levels of oxidized DJ-1 protein and Cullin 3- (Cul3)-regulated degradation of DJ-1 in immortalized FECD (FECDi) and normal CEC (HCECi) cell lines. Nrf2 subcellular localization was assessed by immunocytochemistry. RESULTS: Nrf2 protein stabilizer, DJ-1, decreased significantly in FECD CECs compared with normal, whereas Nrf2 protein repressor, Keap1, was unchanged at baseline but increased under oxidative stress. Under oxidative stress, normal CECs upregulated DJ-1 protein synthesis, whereas FECD CECs did not. DJ-1 decline correlated with increased DJ-1 oxidative modification and carbonylation in FECDi as compared with HCECi. Increased labeling of immunoprecipitated DJ-1 protein with anti-Cul3 antibody indicated enhanced DJ-1 degradation in FECDi as compared with HCECi. Following tBHP treatment, Nrf2 translocated from cytoplasm to nuclei in normal CECs, whereas Nrf2 nuclear localization was not observed in FECD. CONCLUSIONS: Decreased levels of DJ-1 in FECD at baseline and under oxidative stress correlate with impaired Nrf2 nuclear translocation and heightened cell susceptibility to apoptosis. Targeting the DJ-1/Nrf2 axis could yield a mechanism to slow CEC degeneration in FECD.
Blanco-Mezquita JT, Hutcheon AEK, Zieske JD. Role of thrombospondin-1 in repair of penetrating corneal wounds. Invest Ophthalmol Vis Sci 2013;54(9):6262-8.Abstract
PURPOSE: Thrombospondin-1 (THBS1) has been suggested as a corneal wound-healing modulator. Therefore, we compromised the integrity of the cornea to elucidate the role of THBS1. METHODS: Full-thickness penetrating corneal incisions (1.5 mm) were created in wild type (WT, 129S2/SvPas) and THBS1-deficient mice (Thbs1⁻/⁻), 129S2/SvPas-Thbs1(tm1Hyn)/Thbs1(tm1Hyn)), and allowed to heal up to 1 month, while being monitored by slit-lamp and intravital corneal examinations. Corneas also were examined by transmission electron microscopy and indirect immunofluorescence. To determine how THBS1 was involved in the healing process, we examined THBS1 and α-smooth muscle actin (SMA), a marker of myofibroblasts and myoepithelial cells. RESULTS: In WT mice by 1 month, corneas appeared transparent with a thin scar, and endothelium and Descemet's membrane (DM) were restored. In contrast, Thbs1⁻/⁻ corneas exhibited chronic edema and persistent opacity after wounding. The DM and endothelium were not restored, and wound contraction was impaired. The THBS1 was localized in epithelial cells at early stages of the healing process, and in the stroma and endothelial cells during later stages. The SMA-positive epithelial cells and myofibroblasts were observed within the healing area at day 4, peaked at day 14, and disappeared at day 30. The SMA-positive cells were reduced greatly in Thbs1⁻/⁻ mice. CONCLUSIONS: In the current study, we demonstrated that corneal restoration is strikingly compromised by a penetrating incision in Thbs1⁻/⁻ mice. The wound results in persistent edema and wound gaping. This appears to be the result of the lack of endothelial migration and DM restoration. In addition, myofibroblast formation is compromised, resulting in the lack of wound contraction.
Böhm M, Leon P, Wylęgała A, Ong Tone S, Condron T, Jurkunas U. Cost-effectiveness analysis of preloaded versus non-preloaded Descemet membrane endothelial keratoplasty for the treatment of Fuchs endothelial corneal dystrophy in an academic centre. Br J Ophthalmol 2022;106(7):914-922.Abstract
AIMS: To determine the cost-effectiveness of preloaded Descemet membrane endothelial keratoplasty (pDMEK) versus non-preloaded DMEK (n-pDMEK) for the treatment of Fuchs endothelial corneal dystrophy (FECD). METHODS: From a societal and healthcare perspective, this retrospective cost-effectiveness analysis analysed a cohort of 58 patients with FECD receiving pDMEK (n=38) or n-pDMEK (n=30) from 2016 to 2018 in the Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, USA. Exclusion criteria were previous ocular surgeries (other than uncomplicated cataract surgery), including other keratoplasty procedures, ocular pathological conditions as glaucoma, amblyopia, laser treatments, or any retinal or corneal disease. The main outcome parameters were the incremental cost-utility ratio (ICUR) and net monetary benefit (NMB). RESULTS: pDMEK was less costly compared with n-pDMEK (healthcare: $13 886 vs $15 329; societal: $20 805 vs $22 262), with a slighter greater utility (QALY 0.6682 vs QALY 0.6640) over a time horizon of 15 years. pDMEK offered a slightly higher clinical effectiveness (+0.0042 QALY/patient) at a lower cost (healthcare: -$1444 per patient; societal: -$1457 per patient) in improving visual acuity in this cohort of patients with FECD. pDMEK achieved a favourable ICUR and NMB compared with n-pDMEK. Based on sensitivity analyses performed, the economic model was robust. CONCLUSIONS: From the societal and healthcare perspective, pDMEK was less costly and generated comparable utility values relative to n-pDMEK. Therefore, pDMEK appears to be cost-effective and cost saving with respect to n-pDMEK. Further long-term follow-up data are needed to confirm these findings.
Böhm MS, Wylegala A, Leon P, Ong Tone S, Ciolino JB, Jurkunas UV. One-Year Clinical Outcomes of Preloaded Descemet Membrane Endothelial Keratoplasty Versus Non-Preloaded Descemet Membrane Endothelial Keratoplasty. Cornea 2021;40(3):311-319.Abstract
PURPOSE: To compare the one-year outcomes of preloaded Descemet membrane endothelial keratoplasty (pDMEK) and non-preloaded DMEK (n-pDMEK) in patients with Fuchs endothelial corneal dystrophy (FECD). METHODS: This retrospective comparative cohort study consecutively included 68 eyes with Fuchs endothelial corneal dystrophy who underwent either pDMEK (n = 38) or n-pDMEK (n = 30) performed by cornea fellows with an experienced surgeon between 2016 and 2018 at the Massachusetts Eye and Ear Infirmary. Exclusion criteria were previous surgery (other than uncomplicated cataract surgery) and any documented evidence of macular or other corneal diseases. Corrected distance visual acuity (CDVA), central corneal thickness, intraocular pressure, patient characteristics, postprocessing endothelial cell count, donor graft data, and complications were compared. RESULTS: CDVA showed similar results for pDMEK (0.12 ± 0.11 logarithm of the minimal angle of resolution [LogMAR]) and n-pDMEK (0.13 ± 0.13 LogMAR) (P = 0.827). Sixty-six percent of the pDMEK eyes and 57% of the n-pDMEK eyes achieved a VA of ≥0.1 LogMAR, and 95% and 97%, respectively, achieved a CDVA ≥0.3 LogMAR. The preoperative central corneal thickness of pDMEK and n-pDMEK (644 ± 62.2 μm, 660.5 ± 56.2 μm) decreased significantly after surgery (525.1 ± 43.6 μm, 526.5 ± 45.2 μm, P < 0.001), with no difference between groups (P = 0.840). The postprocessing endothelial cell count did not differ between pDMEK (2959.2 ± 182.9 cells/mm2) and n-pDMEK (2939.3 ± 278.7 cells/mm2) (P = 0.484). Complication rates were comparable with just the rebubbling performed in a minor procedure room showing a lower rate for pDMEK (13.16%) compared with n-pDMEK (33.33%) (P < 0.045). CONCLUSIONS: One-year clinical outcomes were similar between pDMEK and n-pDMEK procedures, rendering eye bank-prepared pDMEK tissues a useful tool in the treatment of endothelial dysfunction.
Borkar DS, Veldman P, Colby KA. Treatment of Fuchs Endothelial Dystrophy by Descemet Stripping Without Endothelial Keratoplasty. Cornea 2016;35(10):1267-73.Abstract

PURPOSE: To evaluate the effect of deliberate removal of the central Descemet membrane on endothelial function and morphology in patients with Fuchs endothelial dystrophy (FED) and cataract undergoing phacoemulsification. METHODS: In this retrospective case series, patients with FED and visually significant cataract underwent phacoemulsification in an academic cornea practice in Boston, MA. Four millimeters of the central Descemet membrane was stripped and removed after intraocular lens insertion. Vision, corneal pachymetry, and confocal imaging of the endothelial anatomy were performed before surgery and at 1, 3, 6, and 12 months after surgery. Patients were classified as fast responders, responders, slow responders, and nonresponders on the basis of postoperative time to resolution of corneal edema with visible central endothelial mosaic. RESULTS: Eleven patients (13 eyes) aged 51 to 91 years were included in the study. No eyes had countable central endothelial cells by confocal imaging before surgery. Preoperative visual acuity ranged from 20/25 to 20/400. All corneas showed stromal and microcystic edema in the area of Descemet stripping at days 1 and 7 after surgery. Four eyes demonstrated resolution of corneal edema with visible central endothelial cell mosaic (range: 410-864 cells/mm) by postoperative month 1 with visual acuity ranging between 20/25 and 20/40. Four additional eyes demonstrated a similar response by postoperative month 3 and an additional 2 eyes had resolution of corneal edema with an intact central endothelial mosaic at postoperative month 6 or later. Cell counts (range: 428-864 cells/mm) were maintained in all 10 responders at the last follow-up visit (range: postoperative months 6-24). Final vision ranged from 20/15 to 20/20 in these 10 eyes with the exception of 2 eyes with retinal pathology. Three eyes required endothelial keratoplasty. CONCLUSIONS: Repopulation of the central corneal endothelium with corneal deturgescence can occur after deliberate central Descemet stripping in patients with FED who underwent cataract removal. This may offer a novel treatment for patients with FED that could reduce the need for endothelial transplantation. Further studies are needed to delineate the optimal patient population for Descemet stripping because not all patients will respond to this intervention.

Botten N, Hodges RR, Li D, Bair JA, Shatos MA, Utheim TP, Serhan CN, Dartt DA. Resolvin D2 elevates cAMP to increase intracellular [Ca] and stimulate secretion from conjunctival goblet cells. FASEB J 2019;33(7):8468-8478.Abstract
Under physiologic conditions, conjunctival goblet cells (CGCs) secrete mucins into the tear film to preserve ocular surface homeostasis. Specialized proresolving mediators (SPMs), like resolvins (Rvs), regulate secretion from CGCs and actively terminate inflammation. The purpose of this study was to determine if RvD2 stimulated mucin secretion and to investigate the cellular signaling components. Goblet cells were cultured from rat conjunctiva. Secretion was measured by an enzyme-linked lectin assay, change in intracellular [Ca] ([Ca]) using Fura-2, and cellular cAMP levels by ELISA. RvD2 (10-10 M) stimulated secretion, increased cellular cAMP levels and the [Ca]. RvD2-stimulated increase in [Ca] and secretion was blocked by Ca chelator 1,2-bis(2-aminophenoxy)ethane-,,','-tetraacetic acid tetrakis and the PKA inhibitor -[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride but not by the cAMP exchange protein inhibitor α-[2-(3-chlorophenyl)hydrazinylidene]-5-(1,1-dimethylethyl)-b-oxo-3-isoxazolepropanenitrile. Forskolin, 3-isobutyl-1-methylxanthine, and 8-bromo-cAMP (8-Br-cAMP) increased [Ca]. Increasing cAMP with 8-Br-cAMP inhibited the increase in [Ca] stimulated by the cAMP-independent agonist cholinergic agonist carbachol. In conclusion, RvD2 uses both cellular cAMP and [Ca] to stimulate glycoconjugate secretion from CGCs, but the interaction of cAMP and [Ca] is context dependent. Thus RvD2 likely assists in the maintenance of the mucous layer of the tear film to sustain ocular surface homeostasis and has potential as a novel treatment for dry eye disease.-Botten, N., Hodges, R. R., Li, D., Bair, J. A., Shatos, M. A., Utheim, T. P., Serhan, C. N., Dartt, D. A. Resolvin D2 elevates cAMP to increase intracellular [Ca] and stimulate secretion from conjunctival goblet cells.

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