Topical tacrolimus for high-risk corneal transplantation: a randomized, clinical trial.

BACKGROUND: The prevalence of rejection is 10-30% in penetrating keratoplasty (PKP) case, and the rate is higher in cases of high-risk patients. Although using topical corticosteroids is a standard method for management the rejection of post-PKP patients, it may not be sufficiently potent in high-risk patients. Topical administration of tacrolimus (TAC) may be effective in suppression rejection after corneal transplantation. This study aimed to investigate the efficacy and safety of topical TAC in high-risk PKP patients in Japan. METHODS: This study was a single centre, single-blinded, randomized controlled trial. Patients with a history of PKP, graft rejection, atopic dermatitis, or deep corneal neovascularisation who underwent PKP were enrolled. They were randomly assigned to receive 0.1% TAC ophthalmic suspension or artificial tear (AT) up to week 52 after surgery. All participants received 0.1% betamethasone up to week 13 after surgery then they received 0.1% fluorometholone up to week 52. The incidence of immunological rejection during the observation period was the main outcome measure in this study. RESULTS: Thirty patients were enrolled in this study, and 12 eyes in the TAC group and 13 eyes in the AT group completed the study, respectively. Five out of 30 patients discontinued participation after providing informed consent. No serious adverse effects were developed in patients who received 0.1% TAC ophthalmic suspension. No rejection episodes occurred in the TAC group, while one eye in the AT group had rejection. Graft clarity, best spectacle-corrected visual acuity, intraocular pressure, and corneal endothelial cell density were not significantly different between the TAC and AT groups. CONCLUSION: Our results demonstrated that good tolerability of 0.1% TAC ophthalmic suspension. However, we failed to demonstrate its efficacy in preventing immunological rejection in high-risk patients undergoing PKP. TRIAL REGISTRATION: This study was first registered in the University Hospital Medical Information Network (UMIN000029669, Date of registration: November 1, 2017). With the enforcement of the Clinical Trial Act in Japan, the study re-registered in the Japan Registry of Clinical Trials (jRCTs031180342, Date of registration: March 18, 2019).

Three-Dimensional Assessment of Descemet Membrane Reflectivity by Optical Coherence Tomography in Fuchs Endothelial Corneal Dystrophy.

PURPOSE: This study aimed to evaluate Descemet membrane reflectivity using anterior segment optical coherence tomography (AS-OCT) in eyes with Fuchs endothelial corneal dystrophy (FECD). METHODS: We retrospectively assessed 144 eyes of 88 consecutive participants (41 FECD, 15 pseudophakic bullous keratopathies [BKs], and 32 healthy controls, 63.5 ± 16.5 years). FECD was graded 0 to 3 based on the guttae areas using specular microscopy. The sum of AS-OCT reflectivity of the 3-dimensional volume from 10 µm thickness from the endothelial surface of the cornea and residual stromal area was calculated as D sum (endo) and D sum (stroma) in the central area of 3- and 6-mm diameters, respectively. The D ES ratio was defined as the ratio of D sum (endo) to D sum (stroma). The percentage of the guttae area in the specular images was calculated using MATLAB. D sum (endo) and D ES ratio were compared among FECD, BK, and healthy controls. RESULTS: D sum (endo) in FECD grade 3 was significantly higher than that in healthy control eyes, FECD patients with mild and moderate guttae, and BK (all P ≤ 0.040). The D ES ratio in FECD patients with mild to severe guttae (grade 1-3) was significantly higher than that in healthy control eyes and BK (all P ≤ 0.035). The percentage of the guttae area was significantly correlated with D sum (endo) (R = 0.488, P < 0.001 for 3 mm, R = 0.512, P < 0.001 for 6 mm) and D ES ratio (R = 0.450, P < 0.001 for 3 mm, R = 0.588, P < 0.001 for 6 mm). CONCLUSIONS: Descemet membrane reflectivity in AS-OCT can be objective biomarkers for assessing guttae and FECD severity from early to end-stage FECD.

Incidence and Clinical Features of Immunologic Rejection After Deep Anterior Lamellar Keratoplasty.

PURPOSE: The aim of this study was to investigate the incidence and clinical features of immunologic rejection after deep anterior lamellar keratoplasty (DALK). METHODS: This study included 411 patients (464 eyes, median age [interquartile range; IQR] 55.8 years [36.1-69.5]) who underwent DALK at Tokyo Dental College between June 1997 and 2021. Of 411 patients, 24 (24 eyes [5.2%], 51.9 years [IQR 31.6-65.4]) developed immunologic rejection. We characterized the clinical features, risk factors associated with immunologic rejection, and prognosis. RESULTS: The interval between DALK and immunologic rejection was 14.5 (range, 5-78) months. Immunologic rejection occurred after cessation/reduction of topical steroid in 9 (47.4%) and suture removal in 4 eyes (21.1%). The postoperative duration of topical steroid use in eyes with immunologic rejection was significantly shorter (10.0 months, [IQR 6.0-14.0]) than those without immunologic rejection (28.3 [IQR 15.8-42.7], P = 0.001). Immunologic rejection manifested as stromal edema in 19 (100.0%), ciliary hyperemia in 17 (89.5%), keratic precipitates in 13 (68.4%), epithelial edema in 13 (68.4%), infiltration in 9 (47.4%), corneal opacity in 4 (21.1%), and Descemet membrane detachment in 2 eyes (10.5%). After treatment, corneal clarity was restored in 17 eyes (89.5%); however, immunologic rejection led to corneal endothelial decompensation in 2 eyes (10.5%). Endothelial cell density decreased from 1795.7 ± 722.6 to 1651.6 ± 655.6 cells/mm2 after immunologic rejection (P = 0.074). CONCLUSIONS: Post-DALK immunologic rejection was associated with specific clinical triggers such as reduction/cessation of topical steroids or suture removal.

Corneal higher-order aberrations in corneal endothelial decompensation secondary to obstetric forceps injury.

Forceps corneal injuries during infant delivery cause Descemet membrane (DM) breaks, that cause corneal astigmatism and corneal endothelial decompensation. The aim of this study is to characterise corneal higher-order aberrations (HOAs) and corneal topographic patterns in corneal endothelial decompensation due to obstetric forceps injury. This retrospective study included 23 eyes of 21 patients (54.0 ± 9.0 years old) with forceps corneal injury, and 18 healthy controls. HOAs and coma aberrations were significantly larger in forceps injury (1.05 [0.76-1.98] µm, and 0.83 [0.58-1.69], respectively) than in healthy controls (0.10 [0.08-0.11], and 0.06 [0.05-0.07], respectively, both P < 0.0001). Patient visual acuity was positively correlated with coma aberration (rs = 0.482, P = 0.023). The most common topographic patterns were those of protrusion and regular astigmatism (both, six eyes, 26.1%), followed by asymmetric (five eyes, 21.7%), and flattening (four eyes, 17.4%). These results indicate that increased corneal HOAs are associated with decreased visual acuity in corneal endothelial decompensation with DM breaks and corneal topography exhibits various patterns in forceps injury.

Diagnostic Ability of a Smartphone App for Dry Eye Disease: Protocol for a Multicenter, Open-Label, Prospective, and Cross-sectional Study.

BACKGROUND: Dry eye disease (DED) is one of the most common ocular surface diseases. Numerous patients with DED remain undiagnosed and inadequately treated, experiencing various subjective symptoms and a decrease in quality of life and work productivity. A mobile health smartphone app, namely, the DEA01, has been developed as a noninvasive, noncontact, and remote screening device, in the context of an ongoing paradigm shift in the health care system, to facilitate a diagnosis of DED. OBJECTIVE: This study aimed to evaluate the capabilities of the DEA01 smartphone app to facilitate a DED diagnosis. METHODS: In this multicenter, open-label, prospective, and cross-sectional study, the test method will involve using the DEA01 smartphone app to collect and evaluate DED symptoms, based on the Japanese version of the Ocular Surface Disease Index (J-OSDI), and to measure the maximum blink interval (MBI). The standard method will then involve a paper-based J-OSDI evaluation of subjective symptoms of DED and tear film breakup time (TFBUT) measurement in an in-person encounter. We will allocate 220 patients to DED and non-DED groups, based on the standard method. The primary outcome will be the sensitivity and specificity of the DED diagnosis according to the test method. Secondary outcomes will be the validity and reliability of the test method. The concordance rate, positive and negative predictive values, and the likelihood ratio between the test and standard methods will be assessed. The area under the curve of the test method will be evaluated using a receiver operating characteristic curve. The internal consistency of the app-based J-OSDI and the correlation between the app-based J-OSDI and paper-based J-OSDI will be assessed. A DED diagnosis cutoff value for the app-based MBI will be determined using a receiver operating characteristic curve. The app-based MBI will be assessed to determine a correlation between a slit lamp-based MBI and TFBUT. Adverse events and DEA01 failure data will be collected. Operability and usability will be assessed using a 5-point Likert scale questionnaire. RESULTS: Patient enrollment will start in February 2023 and end in July 2023. The findings will be analyzed in August 2023, and the results will be reported from March 2024 onward. CONCLUSIONS: This study may have implications in identifying a noninvasive, noncontact route to facilitate a diagnosis of DED. The DEA01 may enable a comprehensive diagnostic evaluation within a telemedicine setting and facilitate early intervention for undiagnosed patients with DED confronting health care access barriers. TRIAL REGISTRATION: Japan Registry of Clinical Trials jRCTs032220524; https://jrct.niph.go.jp/latest-detail/jRCTs032220524. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/45218.

Correlations between tear fluid and aqueous humor cytokine levels in bullous keratopathy.

PURPOSE: To evaluate the correlation between tear fluid and aqueous humor (AqH) cytokine levels in eyes with bullous keratopathy (BK) and with normal endothelium. METHODS: This prospective consecutive case-series study included 71 eyes of 71 patients: 31 eyes with BK, 18 eyes with non-BK corneal diseases, and 22 eyes with uncomplicated cataract (healthy controls). Total protein and cytokine (interleukin [IL]-1α, IL-1ß, IL-4, IL-6, IL-8, IL-10, MIP-1α, MIP-1ß, monocyte chemotactic protein [MCP]-1, E-selectin, P-selectin, soluble intercellular adhesion molecule [sICAM]-1, and IP-10) levels in the tear fluid and AqH were measured using multiplex beads immunoassay. The correlations between tear and AqH cytokine levels were assessed. RESULTS: The AqH protein level was significantly higher in BK eyes (1.09 ± 0.08 mg/mL) than in non-BK (0.63 ± 0.11, P = 0.0004) and healthy control (0.62 ± 0.06, P = 0.0002) eyes. The tear total protein and IL-4 levels were significantly higher in the BK group compared to healthy controls (P = 0.0374 and 0.0032, respectively). The AqH IL-8 and sICAM-1 levels were significantly higher in the BK group compared to controls (P = 0.0001 and 0.0083, respectively). In BK eyes, the tear IL-4 level was significantly correlated with the MCP-1(r = 0.563, P = 0.001) and total protein (r = 0.589, P = 0.001) AqH levels. The tear IL-8 level was significantly correlated with the MCP-1(r = 0.598, p = 0.001) and IL-4 (r = 0.781, p < 0.0001) AqH levels in BK eyes. However, no significant correlations were found between tear and AqH cytokine levels in non-BK and healthy controls eyes. CONCLUSIONS: The tear cytokine levels are correlated with those of AqH only in BK, but not in non-BK and healthy controls.

Corneal higher-order aberrations in phlyctenular keratitis.

PURPOSE: To characterize tomographic patterns and quantify corneal higher-order aberrations (HOAs) in eyes with corneal scar due to phlyctenular keratitis. STUDY DESIGN: Retrospective consecutive case series. METHODS: This study included 51 eyes of 38 patients (24 women; 14 men) with corneal scar due to phlyctenular keratitis. HOAs of the total cornea, and of the anterior and posterior surfaces were measured using anterior segment optical coherence tomography (AS-OCT). Corneal tomographic patterns were classified into five types: increased regular astigmatism, ectasia, asymmetric, flattening and minimal change patterns. The correlation between corneal HOAs and visual acuity was evaluated. RESULTS: Mean months from onset was 50.7 ± 74.7 and mean number of recurrences 2.1 ± 1.1 (1-5). Mean logarithm of the minimal angle of resolution (logMAR) was 0.19 ± 0.31. AS-OCT showed ectasia pattern in 16 eyes (31.4%), asymmetric pattern in 12 eyes (23.5%), increased regular astigmatism pattern in 9 eyes (17.6%), flattening pattern in 3 eyes (5.9%) and minimal change pattern in 11 eyes (21.6%). HOAs of the total cornea were 0.57 ± 0.44 µm and 1.16 ± 0.77 µm within a 4-mm and 6-mm diameter, significantly larger than in normal controls (P < 0.0001). LogMAR visual acuity was significantly correlated with corneal HOAs (4-mm: r = 0.558, P < 0.0001, 6-mm: r = 0.566, P < 0.0001), central corneal thickness (r = - 0.349, P = 0.016), and corneal astigmatism (r = 0.414, P = 0.004), but not with average keratometric value (r = - 0.092, P = 0.537). CONCLUSIONS: The most common tomographic pattern was ectasia, followed by a asymmetric pattern in eyes with phlyctenular keratitis. Corneal HOAs were associated with decreased visual acuity in phlyctenular keratitis patients.

Pathological processes in aqueous humor due to iris atrophy predispose to early corneal graft failure in humans and mice.

Corneal endothelial cell (CEnC) loss after corneal transplantation is the major cause of graft failure and remains a clinically relevant challenge to overcome. Accumulated knowledge derived from long-term clinical outcomes suggested that elevated protein levels in the aqueous humor are associated with CEnC loss. However, the full spectrum of driver proteins and molecular processes remains to be determined. Here, we defined the somatic microenvironmental landscape and cellular response across human aqueous humor in samples with poor corneal transplantation clinical outcomes using multiomics analyses and clarified specific driver alterations, including complement activation and disturbed energy homeostasis. These driver alterations were also confirmed in aqueous humor from a novel murine model that spontaneously develops iris atrophy, leading to CEnC loss. The application of the integrative multiomics performed in human samples to the novel murine model will help the development of therapeutic modalities for patients with CEnC loss after corneal transplantation.

The Effects of 3% Diquafosol Sodium Eye Drops on Tear Function and the Ocular Surface of Cu, Zn-Superoxide Dismutase-1 (Sod1) Knockout Mice Treated with Antiglaucoma Eye Medications.

Anti-glaucoma eye drop treatment often induces dry eyes and can lead to poor medication adherence. This study aimed to investigate the effects of 3% diquafosol sodium eye drops on tear function and the ocular surface epithelium in Sod1-/- mice after treatment with anti-glaucoma eye drops. The mice were divided into four groups: group 1, control group; group 2, anti-glaucoma eye drop; group 3, anti-glaucoma eye drops followed by a secretagogue eye drop (3% diquafosol); and group 4, simultaneous anti-glaucoma and secretagogue eye drop. Mice underwent assessments of tear quantity, tear film breakup time, and vital staining score. Mice in groups 3 and 4 showed significantly better tear stability and lower corneal staining scores than mice in group 2 after eye drop instillations (p < 0.05). Mice in group 4 showed significantly better tear stability, lower corneal staining scores, and higher goblet cell densities than those in group 1 after eye drop instillations (p < 0.05). The conjunctival epithelium showed stratification and abundance of Muc5AC-positive goblet cells in group 4, whereas thinning with desquamation was observed with a few goblet cells in group 2. Thus, simultaneous administration of 3% diquafosol sodium eye drops with topical anti-glaucoma drops showed favorable effects on tear stability and the corneal epithelium against the ocular surface toxicity inflicted by the anti-glaucoma eye drops.

Corneal higher-order aberrations in Stevens-Johnson syndrome and toxic epidermal necrolysis.

PURPOSE: To characterize the topography patterns and quantify corneal higher-order aberrations (HOAs) in the chronic phase of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). METHODS: This retrospective, consecutive case series included 84 eyes of 49 patients in the chronic phase of SJS/TEN. HOAs of the total cornea, and of the anterior and posterior surfaces were measured using anterior segment optical coherence tomography (AS-OCT). Corneal topography patterns were classified into one of the 4 types: ectasia-, asymmetric-, flattening- and minimal change- patterns. RESULTS: Mean logarithm of the minimal angle of resolution (logMAR) was 0.93 ±â€¯0.95. AS-OCT showed ectasia pattern in 16 eyes (19.0%), asymmetric pattern in 28 eyes (33.3%), flattening pattern in 11 eyes (13.0%) and minimal change pattern in 29 eyes (34.5%). The HOAs of the total cornea were 1.23 ±â€¯1.04 µm within a 4-mm diameter, which were significantly larger than those in normal controls (P < 0.0001). LogMAR visual acuity was significantly correlated with corneal HOAs (4-mm: r = 0.793, P < 0.0001, 6-mm: r = 0.798, P < 0.0001) and corneal astigmatism (r = 0.508, P < 0.0001), but not with average keratometric value (r = 0.198, P = 0.065). When the participants were stratified based on corneal opacity, logMAR was significantly correlated with corneal HOAs within a 4-mm diameter in opacity grades 0 (35 eyes, r = 0.649, P < 0.0001), 1 (23 eyes, r = 0.678, P = 0.0004), and 2-3 (26 eyes, r = 0.570, P = 0.0024). Ectasia pattern was derived from either corneal thinning (68.7%) or epithelial hyperplasia (31.3%). CONCLUSIONS: The most common topographic patterns for SJS/TEN were minimal change pattern and asymmetric pattern. Corneal HOAs were associated with decreased visual acuity in SJS/TEN.

Comparison of the Accuracy of Newer Intraocular Lens Power Calculation Methods in Eyes That Underwent Previous Phototherapeutic Keratectomy.

PURPOSE: To evaluate the accuracy of intraocular lens (IOL) power calculations using ray tracing software in patients who had undergone phototherapeutic keratectomy (PTK). METHODS: In this retrospective case series, 37 eyes of 22 patients (mean age: 69.4 years; range: 56 to 85 years) who underwent cataract surgery after PTK were reviewed. The prediction error, defined as the difference between the estimated postoperative spherical equivalent and the postoperative manifest refraction at the spectacle plane, was calculated using the following formulas: OKULIX (Tedics, Dortmund, Germany), PhacoOptics (IOL Innovations ApS, Aarhus, Denmark), Barrett True K No History (NH), and Camellin-Calossi. The PhacoOptics formula was used in three different ways: historical method (H), no history method (NH), and C-constant method (C). The median values of the arithmetic and absolute prediction errors among these six IOL calculation methods were compared. RESULTS: The median arithmetic errors (in diopters [D]) and percentages of eyes within ±0.50 D of the absolute errors were as follows: OKULIX (0.33, range: -2.20 to 2.50, 30.6%), PhacoOptics (H) (-0.12, range: -3.28 to 4.85, 22.2%), PhacoOptics (NH) (-0.25, range: -2.08 to 1.70, 48.4%), PhacoOptics (C) (0.04, range: -1.40 to 2.18, 48.5%), Barrett True K (NH) (-0.35, range: -1.90 to 1.89, 48.6%), and Camellin-Calossi (-0.19, range: -1.78 to 1.47, 59.5%). CONCLUSIONS: The PhacoOptics, especially the C-constant method (C), and Camellin-Calossi formulas were good options for calculating IOL powers in eyes that underwent PTK. [J Refract Surg. 2019;35(5):310-316.].

Association of Iris Damage With Reduction in Corneal Endothelial Cell Density After Penetrating Keratoplasty.

PURPOSE: To evaluate the effect of iris damage on endothelial cell loss in the early phase after penetrating keratoplasty (PKP). METHODS: This prospective consecutive study included 74 patients who underwent PKP without graft rejection during the follow-up period. Endothelial cell density (ECD) was measured using specular microscopy at 1, 3, 6, and 12 months after PKP. Iris damage scores (IDSs) were determined on the basis of slit-lamp microscopy or anterior segment optical coherence tomography imaging. Graft survival rates were compared among the different IDSs. Using multivariate analysis, the factors influencing postoperative ECD were assessed, taking into consideration the presence of glaucoma, history of graft failure, donor age, and graft ECD as independent variables. RESULTS: Graft ECD decreased from 2674 ± 329 cells/mm to 2114 ± 570 at 1 month, 1907 ± 629 at 3 months, 1669 ± 738 at 6 months, and 1404 ± 792 at 12 months (all, P < 0.0001). ECD at 12 months was associated with the IDS (ß = -0.444, P < 0.0001), graft ECD (ß = 0.309, P = 0.003), and history of graft failure (ß = -0.251, P = 0.016). The IDS was significantly correlated with %ECD loss at 1 month (r = 0.427, P = 0.003), at 3 months (r = 0.376, P = 0.002), at 6 months (r = 0.301, P = 0.013), and at 12 months (r = 0.517, P < 0.0001). The graft survival rates in eyes with severe iris damage were significantly lower than those in eyes with either no or mild iris damage (P < 0.0001). CONCLUSIONS: Severe iris damage is associated with rapid reduction in ECD and graft endothelial failure after PKP.

Preoperative Aqueous Cytokine Levels are Associated With Endothelial Cell Loss After Descemet's Stripping Automated Endothelial Keratoplasty.

Purpose: To evaluate the association between endothelial cell density (ECD) after Descemet's stripping automated endothelial keratoplasty (DSAEK) and preoperative cytokine levels in the aqueous humor (AqH). Methods: This prospective consecutive case series included 97 consecutive patients who underwent DSAEK (64 eyes) or cataract surgery (33 eyes). AqH samples were collected at the beginning of each surgery. The levels of cytokines (IL-1α, IL-1ß, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, IL-17A, IFN-α, IFN-γ, monocyte chemotactic protein [MCP]-1, E-selectin, P-selectin, and soluble intercellular adhesion molecule [sICAM]-1) in the AqH were measured by multiplex beads immunoassay. The correlations between preoperative aqueous cytokine levels and the ECD at 12 months after DSAEK were analyzed. Results: The ECD decreased from 2747 ± 259 cells/mm2 in the donor graft to 1235 ± 607 cells/mm2 at 12 months after DSAEK. In all subjects undergoing DSAEK, the postoperative ECD at 12 months was significantly correlated with the preoperative levels of MCP-1 (r = -0.467, 95% confidence interval [CI]: -0.650 to -0.222, P = 0.0003). In an analysis excluding Fuchs endothelial corneal dystrophy (11 eyes), the ECD at 12 months after DSAEK was significantly correlated with preoperative levels of IL-17A (r = -0.635, 95% CI: -0.819 to -0.319, P = 0.0004), MCP-1 (r = -0.605, 95% CI: -0.779 to -0.345, P < 0.0001), IFN-γ (r = -0.633, 95% CI: -0.796 to -0.385, P < 0.0001), E-selectin (r = -0.516, 95% CI: -0.756 to -0.276, P = 0.0004), and sICAM-1 (r = -0.537, 95% CI: -0.735 to -0.253, P = 0.0005). Conclusions: Higher preoperative levels of IL-17A, MCP-1, IFN-γ, E-selectin, and sICAM-1 in the AqH were associated with lower ECD after DSAEK for bullous keratopathy.

Elevated Aqueous Cytokine Levels in Eyes With Ocular Surface Diseases.

PURPOSE: To evaluate cytokine and protein levels in the aqueous humor (AqH) of eyes with ocular surface diseases. DESIGN: Prospective consecutive case series. METHODS: This study includes 14 patients (aged 62.4 ± 13.7 years) with chronic-phase ocular surface diseases (4 with ocular cicatricial pemphigoid, 5 with chemical burns, 2 with a thermal burn, 2 with Stevens-Johnson syndrome, and 1 with exposure keratitis), 14 matched patients without ocular surface disease (controls with corneal scar), and 30 patients who underwent cataract surgery (healthy controls). AqH samples were collected at the beginning of surgery. AqH levels of cytokines (interleukin [IL]-1α, IL-1ß, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, IL-17A, monocyte chemotactic protein [MCP]-1, interferon [IFN]-α, IFN-γ, macrophage inflammatory protein [MIP]-1α, MIP-1ß, P-selectin, E-selectin, soluble-intercellular adhesion molecule [s-ICAM]-1, tumor necrosis factor [TNF]-α, granulocyte-macrophage colony-stimulating factor [GM-CSF], IFN-γ-induced protein [IP]-10) were measured using multiplex beads immunoassays. RESULTS: The levels of IL-6, IL-10, IL-17A, GM-CSF, E-selectin, P-selectin, and s-ICAM in AqH were significantly elevated in eyes with ocular surface diseases (in pg/mL: 1696 ± 804, 4.0 ± 1.0, 24.3 ± 9.8, 26.0 ± 18.3, 5150 ± 1232, 13122 ± 7219, and 7914 ± 2813, respectively), compared to healthy controls (IL-6: 6.36 ± 0.94, P = .001; IL-10: 1.68 ± 0.04, P = .0006; IL-17A: 3.7 ± 0.2, P = .008; GM-CSF: 2.7 ± 0.3, P = .007; E-selectin: 2093 ± 37, P = .0001; P-selectin: 3658 ± 137, P = .0001; sICAM-1: 1397 ± 119, P = .008). The levels of IL-6, IL-17A, E-selectin, and P-selectin in AqH were significantly higher in eyes with ocular surface diseases compared to those with corneal scar (IL-6: 44.1 ± 15.0, P = .0077; IL-17A: 4.1 ± 0.7, P = .034; E-selectin: 2439 ± 302, P = .039; and P-selectin: 5673 ± 1553, P = .017). CONCLUSIONS: Multiple AqH cytokine levels were elevated in chronic ocular surface diseases.

Association between corneal endothelial cell densities and elevated cytokine levels in the aqueous humor.

Annual reduction rate of corneal endothelial cell density (ECD) varies among etiologies, however, the cause of chronic endothelial cell loss is still unknown. We recently reported the elevation of inflammatory cytokines in the aqueous humor (AqH) in eyes with bullous keratopathy and low ECD. To evaluate the association between ECD and aqueous cytokine levels, we collected a total of 157 AqH samples prospectively. The AqH levels of cytokines were measured and multivariate analyses were conducted to find the correlation between ECD, aqueous cytokine levels and clinical factors, such as number of previous intraocular surgeries and protein concentration in AqH. As a result, ECD was negatively correlated with specific cytokine levels, including IL-1α, IL-4, IL-13, MIP-1ß, TNF-α and E-selectin (all P < 0.05). The aqueous cytokine levels showed different correlations with these clinical factors; the number of previous intraocular surgeries was associated with all cytokines except MIP-1α. The AqH protein concentration and the status of intraocular lens showed similar patterns of elevation of IL-1α, IL-4, IL-6, IL-8, IL-10, IL-13, IL-17A, MIP-1ß, MCP-1, E-selectin, P-selectin and sICAM-1. In conclusion, elevation of AqH cytokine levels was associated with reduced ECDs. AqH cytokine levels showed significant correlations with clinical factors associated with low ECDs.

A Novel Entity of Corneal Diseases with Irregular Posterior Corneal Surfaces: Concept and Clinical Relevance.

Various corneal diseases, such as hereditary corneal dystrophies, corneal infection, and bullous keratopathy, cause corneal opacity, scarring, and edema, leading to severely decreased visual acuity and loss of vision. These diseases were regarded as corneal opacity diseases, and the decreased visual acuity was considered to be predominantly caused by corneal opacity. The influence of corneal irregular astigmatism on vision has been poorly understood to date, mainly because accurate quantification of irregular astigmatism has been technically challenging. We have performed detailed analyses of the corneal higher-order aberrations (HOAs) of the anterior and posterior surfaces and total cornea in corneal diseases, using an anterior segment imaging system combined with a ray-tracing method. Subsequently, we conducted correlation analyses between corneal HOAs and visual acuities and characterized the typical HOA patterns in the corneal diseases. Our recent studies demonstrated that corneal HOAs directly degrade visual acuity in eyes with mild-to-moderate corneal opacities, such as corneal dystrophies, corneal scarring, and bullous keratopathy. The findings also suggested that correction of corneal HOAs using rigid gas-permeable contact lenses is effective in eyes with a smooth posterior surface and useful in certain patients with corneal scarring to some extent. Our data will be useful for decision making regarding surgical interventions, based on the amount of corneal HOAs. Our results further indicate the clinical relevance of irregular astigmatism in the posterior surfaces in assessing the visual function of eyes with various corneal diseases.

Corneal Higher-order Aberrations and Visual Improvement Following Corneal Transplantation in Treating Herpes Simplex Keratitis.

PURPOSE: To examine corneal higher-order aberrations (HOAs) and visual improvement following corneal transplantation in treating corneal scar caused by herpes simplex keratitis (HSK). DESIGN: Retrospective consecutive case series. METHODS: This study included a total of 52 eyes: 18 eyes of normal subjects, and 34 eyes of consecutive patients with corneal scar owing to HSK who underwent penetrating keratoplasty (PKP, 17 eyes) or deep anterior lamellar keratoplasty (DALK, 17 eyes). HOAs of the anterior, posterior surfaces and the total cornea were analyzed by anterior segment optical coherence tomography. The correlations between corneal HOAs and visual improvement were also analyzed. RESULTS: Mean logarithm of the minimal angle of resolution (logMAR) visual acuity significantly improved from 1.40 ± 0.70 to 0.46 ± 0.45 after corneal transplantation (P < .0001). Mean corneal HOAs of the anterior surface significantly decreased after corneal transplantation (PKP: from 1.16 ± 0.59 µm to 0.58 ± 0.35 µm, P = .035, DALK: from 0.94 ± 0.57 µm to 0.37 ± 0.18 µm, P = .004). Visual acuity following corneal transplantation was correlated with the corneal HOAs at 12 months (r = 0.53, P = .01). Visual improvement at 3, 6, and 12 months was positively correlated with preoperative HOAs of the total cornea and posterior surface (all P < .01). CONCLUSIONS: Preoperative corneal HOAs were associated with the visual improvement in treating corneal scar caused by HSK. Thus, the preoperative assessment of corneal HOAs, especially of the posterior surface, is important in the decision to perform corneal transplantation in eyes with HSK.

Preoperative Aqueous Cytokine Levels Are Associated With a Rapid Reduction in Endothelial Cells After Penetrating Keratoplasty.

PURPOSE: To evaluate the influence of preoperative inflammatory cytokine levels in the aqueous humor (AqH) on the endothelial cell density (ECD) after penetrating keratoplasty (PKP). DESIGN: Prospective, interventional, consecutive case series. METHODS: This study includes 70 consecutive patients (mean age 73.7 ± 10.6 years) who underwent PKP (37 eyes) or cataract surgery (controls, 33 eyes). A total of 70 AqH samples were collected at the beginning of each surgery. The levels of cytokines (interleukin [IL]-1α, IL-1ß, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, IL-17A, interferon [IFN]-α, IFN-γ, monocyte chemotactic protein [MCP]-1, E-selectin and P-selectin) in AqH were measured by multiplex bead immunoassay. The subjects who underwent PKP were classified into 2 groups: ECD ≥ 1200 cells/mm2 at 6 months (24 eyes), and ECD < 1200 cells/mm2 at 6 months (13 eyes). RESULTS: The ECD at 3 months significantly correlated with the preoperative levels of IL-10 (r = -0.428, P = .02) and IFN-γ (r = -0.412, P = .029). The ECD at 6 months significantly correlated with the preoperative levels of IL-10 (r = -0.399, P = .024), MCP-1 (r = -0.444, P = .011), and IFN-γ (r = -0.474, P = .006). The preoperative levels of IL-6, IL-10, MCP-1, IFN-γ, and P-selectin in AqH were significantly higher in eyes with ECD < 1200 cells/mm2 compared with those with ECD ≥ 1200 cells/mm2 at 6 months (P < .05). CONCLUSIONS: Higher preoperative levels of IL-10, MCP-1, and IFN-γ in the AqH were associated with low ECD after PKP.

Iris Damage Is Associated With Elevated Cytokine Levels in Aqueous Humor.

Purpose: To evaluate the association between iris damage and cytokine levels in the aqueous humor (AqH). Methods: A total of 201 AqH samples from 201 consecutive patients (mean age 73.7 ± 10.6) were collected at the beginning of corneal transplantation or cataract surgery. Iris damage of each case was assessed from preoperative slit-lamp findings based on its severity. The subjects were classified into three groups: eyes without iris damage (126 eyes), eyes with mild iris damage (51 eyes), and eyes with severe iris damage (24 eyes). The levels of cytokines (IL-1α, IL-1ß, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, IL-17a, interferon gamma-induced protein [IP]-10, monocyte chemotactic protein [MCP]-1, IFN-α, IFN-γ, macrophage inflammatory protein [MIP]-1α, MIP-1ß, P-selectin, E-selectin, soluble intercellular adhesion molecule [sICAM]-1, TNF-α, and granulocyte-macrophage colony-stimulating factor [GM-CSF]) in AqH were measured by multiplex beads immunoassay. Results: The levels of aqueous protein, IL-1α, IL-1ß, IL-4, IL-6, IL-8, IL-10, IL-17A, MCP-1, TNF-α, E-selectin, P-selectin, and sICAM-1 in eyes with mild and severe iris damage were higher than in those without iris damage (P < 0.033). Multivariate analyses of clinical factors revealed that iris damage was associated with the history of complicated glaucoma, and the number of previous intraocular surgeries. The levels of AqH IL-6, IL-8, IL-13, MIP-1α, TNF-α, and sICAM-1 were significantly elevated in eyes with mild and severe iris damage in phakic eyes, and the levels of AqH IL-8 and sICAM-1 were significantly elevated in eyes with severe iris damage in pseudophakic eyes, compared with the eyes without iris damage (P < 0.045). Conclusions: Iris damage was associated with the elevation in the levels of aqueous protein and cytokines.

Objective classification of zonular weakness based on lens movement at the start of capsulorhexis.

PURPOSE: To quantify zonular weakness based on lens movement at the start of continuous curvilinear capsulorhexis (CCC) and establish a classification system for it. SETTING: Kozawa Eye Hospital and Diabetes Center, Mito, Japan. DESIGN: Retrospective interventional case series. METHODS: We examined 402 consecutive eyes of 316 patients who underwent CCC, phacoemulsification and aspiration (PEA), and intraocular lens (IOL) implantation. The movement of the lens capsule was measured using images from video recordings of the CCC procedure. Zonular weakness was classified based on the shifted distance: Grade I, less than 0.20 mm; Grade II, 0.20-0.39 mm; and Grade III, greater than 0.40 mm. For each of these grades, we examined the use of the capsule stabilization device during PEA, the surgical procedure for lens removal, and IOL fixation. RESULTS: We classified 276 eyes (68.6%) as Grade I, 102 eyes (25.4%) as Grade II, and 24 eyes (6.0%) as Grade III. As the grade increased, the use of the capsule stabilization device in PEA and scleral suture fixation of IOL increased. CONCLUSIONS: Zonular weakness was quantified by measuring the movement of the lens capsule. An objective classification of zonular weakness based on lens movement may be useful for selecting the appropriate device and procedure during cataract surgery.