Comparative Analysis of Two Clinical Diagnostic Methods of the Corneoscleral Geometry.

PURPOSE: To compare the sagittal height (SH) measurements and best fit sphere (BFS) scleral curvature obtained with two different diagnostic technologies. METHODS: Prospective, nonrandomized, and comparative study analyzing 23 healthy eyes of 23 patients (age, 14-52 years) was conducted. A complete eye examination was performed including a corneoscleral topographic analysis with the Scheimpflug camera-based system Pentacam (Oculus GmbH, Wetzlar, Germany) and afterward with the Fourier domain profilometer Eye Surface Profiler (ESP) (Eaglet-Eye, Houten, the Netherlands). Differences between devices in temporal SH (TSH), nasal SH (NSH), and mean SH (MSH) measurements at 13- and 15-mm chord length and in scleral BFS were analyzed. RESULTS: Statistically significant differences were found in TSH, NSH, and MSH obtained with Pentacam and ESP (P≤0.017), with a range of agreement from 0.21 to 1.28 mm, and a clear trend of the Pentacam system to provide higher SH measurements. Significant differences were found between Pentacam scleral BFS and ESP outer BFS (P<0.001) (range agreement, 3.57 mm). Significant correlations were found between spherical equivalent and differences between devices in 15-mm TSH (r=0.485; P=0.048), as well as between the difference between devices for some SH measurements and the magnitude of such SH values (r≥0.504; P≤0.014). CONCLUSION: Sagittal height and scleral BFS measurements obtained with the two devices are not interchangeable, with an increased difference in SH measures between devices in eyes with less myopic refractive error and increased SH values.

Study and characterization of morphogeometric parameters to assist diagnosis of keratoconus.

BACKGROUND: In case of significant imperfections on the cornea, data acquisition is difficult and a significant level of missing data could require the interpolation of important areas of the cornea, resulting in a very ambiguous model. The development of methods to define in vivo customised geometric properties of the cornea based only on real raw data is extremely useful to diagnose and assess the progression of diseases directly related to the corneal architecture. The present work tries to improve the prognostic of corneal ectasia creating a 3D customised model of the cornea and analysing different geometric variables from this model to determine which variables or combination of them could be defined as an indicator of susceptibility to develop keratoconus. METHODS: A corneal geometric reconstruction was performed using zonal functions and retrospective Scheimpflug tomography data from 187 eyes of 187 patients. Morphology of healthy and keratoconic corneas was characterized by means of geometric variables. The performance of these variables as predictors of a new geometric marker was assessed and their correlations were analysed. RESULTS: The more representative variable to classify the corneal anomalies related to keratoconus was posterior apex deviation (area under receiver operating characteristic curve > 0.899; p < 0.0001). However, the strongest correlations in both healthy and pathological corneas were provided by the metrics directly related to the thickness, as deviations of the anterior/posterior minimum thickness points. CONCLUSIONS: The presented morphogeometric approach based on the analysis and custom geometric modelling of the cornea demonstrates to be useful for the characterization and diagnosis of keratoconus disease, stating that geometrical deformation is an effective marker of the ectatic disease's progression.

Optimizing Genipin Concentration for Corneal Collagen Cross-Linking: An ex vivo Study.

PURPOSE: Studying genipin variable concentrations, treatment durations, and delivery methods as a substance to increase corneal stiffness by inducing corneal collagen cross-linking (CXL). MATERIALS AND METHODS: 100 bovine corneas treated with different genipin concentrations (0.1, 0.5, and 1%) and treatment durations (15 min, 40 min, 2 h, and 3 days) through different delivery methods compared to 10 controls treated with riboflavin/UV. Histology examination, enzymatic digestion with collagenase and thermal differential scanning calorimetry were performed on the different samples. RESULTS: Bovine corneas soaked in 0.5% genipin morphologically showed 4.7% CXL in comparison to 5.6% in controls (p < 0.05). Corneas treated with topical 0.5% genipin, by a 140-µL drop applied hourly for 2 h, showed 7% corneal CXL. Corneas treated with topical genipin 0.5% for 30 min, 1 and 2 h showed 54 ± 6, 40 ± 7, and 39 ± 9% enzymatic degradation, respectively, in comparison to controls (74%). Corneas treated with 0.5% genipin for 1, 2, and 8 h showed higher thermal denaturation resistance (Td values of 64.9 ± 0.3, 64.7 ± 0.0 and 67.3 ± 0.9), respectively, in comparison to the control group (64.6 ± 0.5) (p < 0.05). CONCLUSIONS: Genipin 0.5%, in a 140-µL drop applied hourly for 2 h, showed better potential to enhance corneal stiffness and stability through inducing CXL.

Acellular human corneal matrix sheets seeded with human adipose-derived mesenchymal stem cells integrate functionally in an experimental animal model.

PURPOSE: To evaluate the in vivo biocompatibility of grafts composed of sheets of decellularized human corneal stroma with or without the recellularization of human adipose derived adult stem cells (h-ADASC) into the rabbit cornea. METHODS: Sheets of human corneal stroma of 90 µm thickness were decellularized, and their lack of cytotoxicity was assayed. The recellularization was achieved by the injection of 2 × 10(5) labeled h-ADASC in the graft followed by five days of cell culture. The grafts were implanted in vivo into a stromal pocket at 50% depth. After a triple-masked three-month follow-up, the animals were euthanized and the biointegration of the graft, the viability of the stem cells and the expression of keratocan (human keratocyte-specific protein) were assessed. RESULTS: The decellularized stromal sheets showed an intact extracellular matrix with a decellularization rate of 92.8% and an excellent recellularization capacity in vitro with h-ADASC. A complete and stable graft transparency was observed during the full follow-up, with absence of any clinical sign of rejection. The postmortem analysis demonstrated the survival of the transplanted human stem cells inside the graft and their differentiation into functional keratocytes, as assessed by the expression of human keratocan. CONCLUSIONS: We report a new model of lamellar keratoplasty that requires only a simple and safe procedure of liposuction and a donor allogeneic cornea to provide an optically transparent autologous stromal graft with excellent biocompatibility and integration into the host tissue in a rabbit model.

Professional perspective and practice patterns of vision therapy in Spain.

CLINICAL RELEVANCE: An analysis of the professional perspective of vision therapy (VT) by eye care professionals allows understanding the current controversies about this therapeutic option of which aspects can be improved for its correct application in clinical practice. BACKGROUND: The aim of the current study was to analyse the perception of VT and the clinical protocols in this context followed among optometrists and ophthalmologists in Spain. METHODS: A cross-sectional survey among Spanish optometrists and ophthalmologists. Google Forms tool was used to collect data via an online questionnaire divided into 4 sections (40 questions): consent to participate, demographic characteristics, opinion of the professional perspective of VT, and protocols. Only one submission from each email address was permitted by the survey tool. RESULTS: A total of 889 Spanish professionals answered (age, 25-62 years): 848 optometrists (95.4%) and 41 ophthalmologists (4.6%). VT was considered as a scientifically-based procedure by 95.1% of participants, but its recognition and prestige was considered as low. The main cause reported for this was bad reputation or perception of placebo therapy (27.3%). The main indication of VT according to the surveyed professionals was convergence and/or accommodation problems (72.4%). Significant differences were found in the perception of VT among optometrists and ophthalmologists (p ≤ 0.027). A total of 45.3% of professionals reported performing VT in their current clinical practice. A combination of training sessions in office and home was regularly prescribed by 94.5% of them, but with significant variability in the duration of such sessions. CONCLUSIONS: VT is perceived by Spanish optometrists and ophthalmologists as a therapeutic option with scientific basis, but with limited recognition and prestige, although with more negative perception among ophthalmologists. A great variability was found in the clinical protocols followed between specialists. Future efforts should be focused on creating internationally recognised evidence-based protocols for this therapeutic option.

Relationship between Axial Length and Corneo-Scleral Topography: A Preliminary Study.

The main objective of the current study was to investigate further the relationship of the overall length of the eye with a great variety of anterior segment parameters, including scleral geometry. A total of 64 eyes of 32 participants with ages from 12 to 52 years were included in this prospective non-randomized single-center study. All participants underwent a complete eye examination, including an analysis of corneo-scleral shape with a Fourier-domain profilometer. A strong negative correlation was found between axial length and temporal-nasal ocular sagittal height difference for different chord lengths. For the right eye, a consistent and stable linear model was obtained to predict the axial length from the spherical equivalent, the corneal diameter, the high-order aberrations root mean square, and the minimum sagittal height for 13- and 14-mm chord. For the left eye, a model was obtained to predict the axial length from the spherical equivalent and the mean corneal curvature, including other parameters such as corneal diameter or high-order aberrations, depending on the chord length, considered for estimating the sagittal height values. More studies with larger samples are needed to confirm these preliminary outcomes.

Intrasession repeatability of corneal, limbal and scleral measurements obtained with a fourier transform profilometer.

PURPOSE: To evaluate the intrasession repeatability of corneal, limbal and scleral measurements obtained by an experienced operator with a Fourier transform profilometer in healthy eyes. METHODS: Prospective, single-center study including 35 eyes of 35 participants with ages ranging from 13 to 52 years. All patients underwent three consecutive corneoscleral topographic evaluations with the Eye Surface Profiler (ESP) system (Eaglet Eye b.v.). Intrasession repeatability was analyzed for different geometric and sagittal height variables using the following parameters: the within-subject standard deviation (Sw) of the three consecutive measurements, intrasubject precision (1.96 × Sw), coefficient of variation (CV) and the intraclass correlation coefficient (ICC). RESULTS: Inner best fit sphere (BFS) showed good repeatability, with ICC of 0.844. Higher variability was observed for the repeated measurements of limbus and outer BFS, with ICCs of 0.636 and 0.739, respectively. For mean corneal and scleral radius, ICCs were 0.933 and 0.888, respectively. The repeatability of all sagittal height data was good for all chords evaluated (11-15 mm), with Sw values from 0.02 to 0.11 mm, and ICCs from 0.568 to 0.909. A significant positive correlation was found between the magnitude of temporal-nasal sagittal height difference for all measured chords and its Sw associated. CONCLUSION: The ESP system can provide consistent measurements of sagittal height data for different chord diameters as well as for mean corneal and scleral radius in healthy eyes. Best fit approaches for limbal and scleral areas were less repeatable, although within a clinically acceptable range.

Characterization of the geometric properties of the sclero-conjunctival structure: a review.

To revise the peer-reviewed literature on geometric properties of the scleral-conjunctival structure in order to define their clinical relevance and the potential relationship between their changes and myopia development or progression. A bibliographic search focused on the study of the geometry of conjunctiva and/or sclera as well as those studies evaluating the relationship between geometric changes in the scleral-conjunctival structure and myopia was carried out. Several studies have been performed with different diagnostic technologies, including optical coherence tomography, profilometry and Scheimpflug imaging, to detect geometric changes of the scleral-conjunctival tissue in different physiological conditions of the eye, after use of contact lenses and in different ocular pathologies. Likewise, these technologies have been shown to be a valuable clinical tool to optimize scleral contact lens fitting. Future studies should investigate new potential clinical applications of such technologies, including the evaluation of anterior scleral changes related to myopia, as well as to define standardized clinical standard operating procedures for obtaining accurate and reproducible clinical measurement of the scleral-conjunctival morphology.

Development of a Reference Model for Keratoconus Progression Prediction Based on Characterization of the Course of Nonsurgically Treated Cases.

PURPOSE: To evaluate and characterize long-term clinical changes in keratoconus cases not requiring surgical treatment because of the absence of clinically significant visual degradation and to design a predictive model for the progression rate. METHODS: This retrospective longitudinal study enrolled 68 nonsurgically treated keratoconic eyes of 46 patients (age range, 18-66 years), with a follow-up period of 6 years ± 12 months. Visual, refractive, topographic, and aberrometric changes were evaluated, detecting the abnormal levels of longitudinal changes in each clinical variable analyzed (percentiles 10% or 90%). Subsequently, the eyes were stratified into progression and no-progression groups based on the different variables evaluated, analyzing baseline differences between them. A progression index (PI%) was defined, and its relationship with baseline data was modeled using multiple linear regression analysis. RESULTS: Significant differences were detected in more quantity of baseline parameters between progression and no-progression groups for changes in sphere, spherical-like and coma-like root mean square, central mean keratometry (KM3mm), corneal asphericity (Q80mm), and central astigmatism (Ast3mm). The progression index (PI%) was defined using these variables, obtaining a mean value of 24.39 ± 51.09% and a median of 1.85%. This parameter was significantly related to the baseline sphere, K23 mm (steepest central keratometry), and Q80 mm (P < 0.001, R = 0.429). CONCLUSIONS: More pronounced progression seems to be present in myopic eyes with central localized steepening but normal mid-periphery flattening. A new index has been defined to characterize and predict the level of progression in nonsurgically treated keratoconus in a medium-long term.

Keratoconus Detection Based on a New Corneal Volumetric Analysis.

There are numerous tomographic indices for the detection of keratoconus risk. When the indexes based on corneal volume are analyzed, two problems are presented: on the one hand, they are not very sensitive to the detection of incipient cases of keratoconus because they are not locally defined in the primary developmental region of the structural abnormalities; and on the other hand, they do not register the geometric decompensation driven by the asymmetry present during the disease progression. This work performed a morphogeometric modeling of the cornea by the aid of CAD tools and using raw topographic data (Sirius system, CSO, Firenze). For this method, four singular points present on the corneal surfaces were located and the following parameters based on corneal volume were calculated: VOLmct, defined by the points of minimal thickness; VOLaap, defined by the anterior corneal apex, and VOLpap, defined by the posterior corneal apex. The results demonstrate that a further reduction of corneal volume in keratoconus happens and significantly progresses along the disease severity level. The combination of optical and volumetric data, that collect the sensitivity of the asymmetry generated by the disease, allows an accurate detection of incipient cases and follow up of the disease progression.

A new approach to keratoconus detection based on corneal morphogeometric analysis.

PURPOSE: To characterize corneal structural changes in keratoconus using a new morphogeometric approach and to evaluate its potential diagnostic ability. METHODS: Comparative study including 464 eyes of 464 patients (age, 16 and 72 years) divided into two groups: control group (143 healthy eyes) and keratoconus group (321 keratoconus eyes). Topographic information (Sirius, CSO, Italy) was processed with SolidWorks v2012 and a solid model representing the geometry of each cornea was generated. The following parameters were defined: anterior (Aant) and posterior (Apost) corneal surface areas, area of the cornea within the sagittal plane passing through the Z axis and the apex (Aapexant, Aapexpost) and minimum thickness points (Amctant, Amctpost) of the anterior and posterior corneal surfaces, and average distance from the Z axis to the apex (Dapexant, Dapexpost) and minimum thickness points (Dmctant, Dmctpost) of both corneal surfaces. RESULTS: Significant differences among control and keratoconus group were found in Aapexant, Aapexpost, Amctant, Amctpost, Dapexant, Dapexpost (all p<0.001), Apost (p = 0.014), and Dmctpost (p = 0.035). Significant correlations in keratoconus group were found between Aant and Apost (r = 0.836), Amctant and Amctpost (r = 0.983), and Dmctant and Dmctpost (r = 0.954, all p<0.001). A logistic regression analysis revealed that the detection of keratoconus grade I (Amsler Krumeich) was related to Apost, Atot, Aapexant, Amctant, Amctpost, Dapexpost, Dmctant and Dmctpost (Hosmer-Lemeshow: p>0.05, R2 Nagelkerke: 0.926). The overall percentage of cases correctly classified by the model was 97.30%. CONCLUSIONS: Our morphogeometric approach based on the analysis of the cornea as a solid is useful for the characterization and detection of keratoconus.

Biocompatibility and Biomechanical Effect of Single Wall Carbon Nanotubes Implanted in the Corneal Stroma: A Proof of Concept Investigation.

Corneal ectatic disorders are characterized by a progressive weakening of the tissue due to biomechanical alterations of the corneal collagen fibers. Carbon nanostructures, mainly carbon nanotubes (CNTs) and graphene, are nanomaterials that offer extraordinary mechanical properties and are used to increase the rigidity of different materials and biomolecules such as collagen fibers. We conducted an experimental investigation where New Zealand rabbits were treated with a composition of CNTs suspended in balanced saline solution which was applied in the corneal tissue. Biocompatibility of the composition was assessed by means of histopathology analysis and mechanical properties by stress-strain measurements. Histopathology samples stained with blue Alcian showed that there were no fibrous scaring and no alterations in the mucopolysaccharides of the stroma. It also showed that there were no signs of active inflammation. These were confirmed when Masson trichrome staining was performed. Biomechanical evaluation assessed by means of tensile test showed that there is a trend to obtain higher levels of rigidity in those corneas implanted with CNTs, although these changes are not statistically significant (p > 0.05). Implanting CNTs is biocompatible and safe procedure for the corneal stroma which can lead to an increase in the rigidity of the collagen fibers.

The economic and quality of life impact of seasonal allergic conjunctivitis in a Spanish setting.

INTRODUCTION: Seasonal allergic conjunctivitis (SAC) is a highly prevalent condition that exacts a range of costs from its sufferers. The aim of this study was to examine quality of life (QoL) and economic consequences of SAC amongst private health care patients in Spain. METHODS: 201 sufferers of SAC and 200 controls were recruited from four private eye clinics and one public hospital in five Spanish cities: Alicante, Madrid, Albacete, Las Palmas de Gran Canarias and Valladolid. Participants were between 10 and 80 years of age and Spanish speaking. All potential participants were asked selected questions and sorted into one of the two groups or excluded. Sufferers were administered a set of four questionnaires by researchers consisting of the EQ-5D Health Questionnaire, the National Eye Institute (US) Visual Functioning Questionnaire 25 (VFQ-25), the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) and a Health Economic and Demographic Questionnaire (HEDQ). Control participants self-administered the full EQ-5D and VFQ-25 and abbreviated versions of the RQLQ and HEDQ. RESULTS: The groups were comparable in terms of age and sex, but sufferers had a significantly higher hourly income than controls (p = 0.02). Sufferers exhibited a significantly higher incidence of asthma, nasal symptoms, perennial allergic conjunctivitis, food allergies and other allergies (p < 0.01 for all comorbidities). Sufferers returned significantly lower quality of life scores than controls in all EQ-5D domains other than mobility (p = 0.14). SAC VFQ-25 scores were significantly less than in controls in the overall vision (p < 0.01), distance vision (p < 0.01), ocular pain (p < 0.01), mental health (p = 0.01), role limitations (p < 0.01), and dependency (p = 0.01) domains. Mean scores for the activity domain of the RQLQ were greater in the sufferer group than the control group (P < 0.01) . The total mean per-sufferer cost of SAC amongst our sample of private patients was 348.50 Euros. DISCUSSION: Sufferers experienced QoL reductions in general health and specific aspects of vision as a result of their SAC. In relative terms, the per-capita economic cost of the condition was higher than in a previous public health care study. This was ascribed to sufferers' willingness-to-pay for symptom alleviation. The unexpectedly high expenditure of the proportion of SAC sufferers who receive private health care serves to highlight the importance of SAC as a costly condition. It also illustrates the need to account for both private and public heath care modalities when attempting to ascribe a total cost to a medical condition.

Biointegration of corneal macroporous membranes based on poly(ethyl acrylate) copolymers in an experimental animal model.

Currently available keratoprosthesis models (nonbiological corneal substitutes) have a less than 75% graft survival rate at 2 years. We aimed at developing a model for keratoprosthesis based on the use of poly(ethyl acrylate) (PEA)-based copolymers, extracellular matrix-protein coating and colonization with adipose-derived mesenchymal stem cells. Human adipose tissue derived mesenchymal stem cells (h-ADASC) colonization efficiency of seven PEA-based copolymers in combination with four extracellular matrix coatings were evaluated in vitro. Then, macroporous membranes composed of the optimal PEA subtypes and coating proteins were implanted inside rabbit cornea. After a 3-month follow-up, the animals were euthanized, and the clinical and histological biointegration of the implanted material were assessed. h-ADASC adhered and survived when cultured in all PEA-based macroporous membranes. The addition of high hydrophilicity to PEA membranes decreased h-ADASC colonization in vitro. PEA-based copolymer containing 10% hydroxyethyl acrylate (PEA-HEA10) or 10% acrylic acid (PEA-AAc10) monomeric units showed the best cellular colonization rates. Collagen plus keratan sulfate-coated polymers demonstrated enhanced cellular colonization respect to fibronectin, collagen, or uncoated PEAs. In vivo implantation of membranes resulted in an extrusion rate of 72% for PEA, 50% for PEA-AAc10, but remarkably of 0% for PEA-HEA10. h-ADASC survival was demonstrated in all the membranes after 3 months follow-up. A slight reduction in the extrusion rate of h-ADASC colonized materials was observed. No significant differences between the groups with and without h-ADASC were detected respect to transparency or neovascularization. We propose PEA with low hydroxylation as a scaffold for the anchoring ring of future keratoprosthesis.

Cornea and ocular surface treatment.

In addition to being a protective shield, the cornea represents two thirds of the eye's refractive power. Corneal pathology can affect one or all of the corneal layers, producing corneal opacity. Although full corneal thickness keratoplasty has been the standard procedure, the ideal strategy would be to replace only the damaged layer. Current difficulties in corneal transplantation, mainly immune rejection and shortage of organ supply, place more emphasis on the development of artificial corneas. Bioengineered corneas range from prosthetic devices that solely address the replacement of the corneal function, to tissue-engineered hydrogels that allow regeneration of the tissue. Recently, major advances in the biology of corneal stem cells have been achieved. However, the therapeutic use of these stem cell types has the disadvantage of needing an intact stem cell compartment, which is usually damaged. In addition, long ex vivo culture is needed to generate enough cell numbers for transplantation. In the near future, combination of advanced biomaterials with cells from abundant outer sources will allow advances in the field. For the former, magnetically aligned collagen is one of the most promising ones. For the latter, different cell types will be optimal: 1) for epithelial replacement: oral mucosal epithelium, ear epidermis, or bone marrow- mesenchymal stem cells, 2) for stromal regeneration: adipose-derived stem cells and 3) for endothelial replacement, the possibility of in vitro directed differentiation of adipose-derived stem cells towards endothelial cells provides an exciting new approach.

Future design of a new keratoprosthesis. Physical and biological analysis of polymeric substrates for epithelial cell growth.

One of the main issues in the development of new biocolonizable materials is to understand the influence of the synthetic material on the biological response in terms of cellular adhesion, proliferation, and differentiation. In this study, we characterized different polymeric materials (with different hydrophobicity/hydrophilicity ratios and electrical charges) using dynamic-mechanical analysis, equilibrium water content, and surface energy. Cell adhesion, viability, morphology, and proliferation studies were conducted with these materials using a conjunctival epithelial cell line (IOBA-NHC). The biological data regarding physicochemical parameters of the materials were also correlated. When conjunctival epithelial cells were grown on poly(ethyl acrylate-co-hydroxyethyl acrylate) copolymers, P(EA-co-HEA), samples with up to 20% hydrophilic groups on their polymeric chain showed adhesion, viability, and proliferation, although these three factors decreased as the hydrophilic group content increased. The poly(ethyl acrylate-co-methacrylic acid) 90/10 copolymer, P(EA-co-MAAc) 90/10, showed better results than poly(ethyl acrylate-co-hydroxyethyl acrylate) copolymers and were even better than tissue control polystyrene (TCPS). This feature is explained by the presence of electrical charges on the surface of the poly(ethyl acrylate-co-methacrylic acid) 90/10 copolymer. The fact that the ionic groups are configured in domains structured in nanophases as happens in this copolymer improves cell adhesion even further.

Delayed and prolonged cholestatic hepatitis with ductopenia after long-term ciprofloxacin therapy for Crohn's disease.

Ciprofloxacin, a fluorinated quinolone, is a powerful antibiotic widely used for its broad spectrum of activity in ambulatory and long-term care setting. Until now, ciprofloxacin administration has been associated with a few cases of acute, sometimes cholestatic jaundice or fulminant hepatic failure believed mainly related to idiosyncratic hypersensitivity. We report a case of delayed and prolonged cholestatic hepatitis with ductopenia occurring after 6 months of treatment in a patient with Crohn's disease. This observation suggests the potential for the drug to induce long-term likely dose-related severe hepatotoxicity.