Maria Gkika

Corneal collagen cross-linking using riboflavin and ultraviolet-A irradiation: a review of clinical and experimental studies

Corneal collagen cross-linking (CXL) using riboflavin and ultraviolet-A irradiation is a common method of tissue stabilization and has been developed primarily to address the need of treating keratoconus. CXL’s promising results on keratoconus indicated that it might be effective in other corneal diseases as well. This new treatment promises a slowing effect on the progression of these diseases and its initial results show that it is safe and reasonably curative. The purpose of this review is to critically evaluate this treatment, to explore its benefits, to highlight its limitations in terms of efficacy and long-term safety and finally to identify areas for future research in this topic with a significant potential to change the way we treat our patients. In addition, in this unbiased review we try to bring together all the scientific information from both laboratory and clinical trials that have been conducted during recent years and to review the most recent publications regarding the therapeutic indications of CXL.

Corneal biomechanical properties and anterior segment parameters in forme fruste keratoconus

Purpose. To evaluate the sensitivity and specificity of corneal biomechanical metrics, anterior segment data, and a combination model in differentiating forme fruste keratoconus (FFK) from normal corneas. Methods. A total of 50 FFK eyes were identified by calculation of the KISA index and recruited FFK group. Results were compared with 50 normal eyes (NG group) randomly selected from 50 patients. The following parameters were evaluated for their diagnostic capacity by evaluation of their receiver operating characteristic curves (ROC): corneal hysteresis (CH), corneal resistance factor (CRF), corneal astigmatism (Cyl), anterior chamber depth (ACD), corneal volume (CV) at 3 mm (CV3) and at 5 mm (CV5), maximum posterior elevation value (PEL), central corneal thickness (CCT), thinnest corneal thickness (TCT) and its coordinates (TCTx, TCTy), the ratio TCT/CCT, pachymetric progression indexes (PPImin, PPIavg, and PPImax), and Ambrósios relational thickness (ARTmin, ARTavg, and ARTmax). Logistic regression was attempted for identification of a combined diagnostic model. Results. Significant differences were detected in all studied parameters except the Cyl, ACD, TCTx, and CV. Among individual parameters, the highest predictive accuracy was for ARTavg (area under the curve [AUC] 95.4%, sensitivity 90%, specificity 88.9%) and TCT (AUC 95.3%, sensitivity 90.9%, specificity 89%). Sufficient predictive accuracy (AUC 99.4%, sensitivity 98.8%, specificity 94.6%) was identified in a diagnostic model that combined the CRF, ARTavg, and PEL parameters. Conclusions. None of the individual parameters provide sufficient diagnostic capacity in FFK. However, diagnostic models that combine biomechanical and tomographic data seem to provide high accuracy in differentiating FFK from normal corneas.

Anterior chamber volume measurements with Visante optical coherence tomography and Pentacam: repeatability and level of agreement

Background:  The purpose of this study is to examine the repeatability of Pentacam‐derived anterior chamber volume measurements, and assess the level of agreement of anterior chamber volume measurements obtained with the Visante and the Pentacam imaging devices.

Tonometry in keratoconic eyes before and after riboflavin/UVA corneal collagen crosslinking using three different tonometers.

Purpose To evaluate the Goldmann applanation tonometer (GAT), the Pascal dynamic contour tonometer (PDCT), and the ocular response analyzer (ORA) tonometer in measuring intraocular pressure (IOP) in keratoconic eyes before and after riboflavin/ultraviolet A corneal collagen crosslinking (CXL), to assess agreement among devices and to analyze the impact of some ocular parameters on their measurements. Methods Fifty keratoconic eyes were included. Intraocular pressure was measured with GAT, PDCT, and ORA before and after CXL. Fifty nonkeratoconic eyes served as controls. Device agreements were calculated by Bland-Altman analysis. The effect of some ocular characteristics on IOP measurement differences between tonometers was determined. Results Between the 2 groups, there were statistically significant differences in all examined parameters. Preoperatively, in both groups a statistically significant difference was found in IOP measurements among devices (p<0.05). Bland-Altman analysis showed a bias among devices. On average, PDCT overread GAT and ORA. The IOP measurement differences were better predicted by corneal resistance factor. Postoperatively, in keratoconus eyes, there was no statistically significant difference in IOP measurements among the 3 tonometers (p>0.05). The IOP readings with all tonometers after treatment were higher than those obtained preoperatively; however, not to a statistically significant level, with the exception of PDCT and ORA readings at the first month postoperatively. Corneal resistance factor measurements have no significant change after CXL. Conclusions Pascal dynamic contour tonometer could provide more consistent and closer to the true IOP readings than GAT and ORA in healthy eyes with corneal thickness outside the 520-550 μm range, in keratoconus patients and after CXL. Corneal resistance factor was associated significantly with agreement among devices.

Additional Applications of Corneal Cross Linking

Corneal collagen cross-linking (CxL) is a prevalent surgical method for the management of keratoconus. However, literature suggests that, further to keratoconus, CxL has a beneficial impact on a series of corneal related diseases and states. This article attempts to provide a contemporary review for all additional applications of CxL. Specifically, it outlines the most recent studies that demonstrate the beneficial impact of CxL for iatrogenic ectasias, pellucid marginal degeneration, infectious keratitis, bullous keratitopathy, and for ulcerative keratitis. The outcome of this review indicates that CxL could serve as a primary or adjuvant therapeutic modality for all aforementioned corneal-related pathologic states.

Psychometric properties of the Greek NEI-RQL-42

Purpose To evaluate the psychometric properties of the Greek National Eye Institute Refractive Error Quality of Life Questionnaire (NEI-RQL-42). Methods We developed the Greek version of the instrument using forward and backward translation. To examine reliability, Cronbach alpha for each subscale was used as an index of internal consistency. Test-retest reliability was evaluated with intraclass correlation coefficients (ICC). Regarding construct validity, both convergent and discriminant validities were calculated by means of multi-trait analysis. Furthermore, the instrument was evaluated by Rasch analysis, as well. Results Three patient groups were studied (emmetropes (n=20), myopes (n=41), and hyperopes (n=18)). Emmetropes scored significantly better in the majority of subscales, while myopes scored better than hyperopes in clarity of vision (p=0.012), near vision (p<0.001), and satisfaction with correction (p=0.001). Cronbach alpha ranged from 0.490 (glare) to 0.948 (expectations), with most subscales having high internal consistency. The ICCs ranged from 0.76 to 0.93 for all subscales. All items passed the convergent and discriminant validity tests. Strong correlations were detected between uncorrected visual acuity and near vision, expectations, activity limitations, dependence on correction, worry, and suboptimal correction subscales. Rasch analysis revealed potential weaknesses of the instrument that are associated with the assumptions of the model itself. Specifically, 3 items and 17.5% of the participants fell outside the tolerance box. Moreover, principal component analysis indicated average unidimensionality for the instrument. Conclusions Traditional validation methods indicate that the Greek NEI-RQL-42 scale has adequate psychometric properties for comparative studies in local populations. Rasch analysis indicates significant misfits to the model that should be taken into consideration and evaluated in future studies. These misfits might reflect inherent weaknesses of the original NEI-RQL-42 and not of its adaptation to Greek norms.

Reproducibility of OCT/SLO measurements in healthy eyes.

Purpose. To determine the reproducibility of optical coherence tomography/scanning laser ophthalmoscope (OCT/SLO) measurements within and between observers and within and between sessions in healthy eyes. Methods. Forty eyes of 40 healthy volunteers recruited from the outpatient service of the Department of Ophthalmology at the University Hospital of Alexandroupolis, Greece, were included. Retinal thickness scans were performed 3 times by two experienced operators within each of 3 sessions, which took place within a month, using the spectral OCT/SLO. The OCT/SLO provides retinal nerve fiber layer (RNFL) thickness and volume measurements and a 3D tomography analysis of optic nerve head. Statistical analysis was conducted using Bland-Altman plots, coefficient of variation (CoV), and intra-class correlation coefficient (ICC). Results. AS shown by the CoV values, RNFL parameters were generally found to have high reproducibility (CoV ranging from 4.3% to 10.9% for both operators), whereas optic disc parameters had scores reaching up to 22.5%. On the other hand, as shown by the ICC values, intraobserver and interobserver reproducibility for the OCT/SLO was high for optic disc parameters but low for RNFL thickness and volume measurements. Interobserver reproducibility was found to be highest for the maximum cup depth parameter and lowest for the superior volume. Bland-Altman plots indicate that bias is minimal for practically all parameters and scatterplot homoscedasticity is high. Conclusions. According to our data, SLO/OCT generally has a good reproducibility profile, as differences between the two operators were small. However, additional studies on the reproducibility of measurements with the OCT/SLO are needed.

Effect of Riboflavin/UVA Collagen Cross-linking on Central Cornea, Limbus and Intraocular Pressure. Experimental Study in Rabbit Eyes.

The Purpose of present study was to investigate the effect of riboflavin/ultraviolet-A-induced collagen cross-linking (CXL) on central cornea, limbus and intraocular pressure (IOP). This was an animal experimental study. The right corneas of 10 rabbits were ultraviolet-A irradiated (3 mW/cm2 for 30 minutes) after de-epithelialization and instillation of 0.1% riboflavin / 20% Dextran drops. Left corneas served as controls. Samples were examined histologically one month postoperatively. Before and after treatment, IOP measurements were recorded bilaterally. At central cornea of eyes underwent CXL keratocyte repopulation, normal arrangement of collagen fibres and a statistically significant change in fibres diameter were detected, compared to controls. At limbus area, there were not any significant histological differences after CXL. There was no statistically significant difference between pre- and postoperative IOP in all eyes.

The clinical significance of glaucoma-related quality of life studies

In order to understand the clinical significance of glaucoma-related quality of life (QoL) studies, the term visual ability (VA) must be conceptualized. In fact, VA is a rather subjective term that is supposed to encompass the overall perception of the environment from the visual system. However, it is well-known that the way we perceive and interact with our environment is still not fully understood; furthermore, our visual system interacts with the rest of the systems in a highly individualized manner, making difficult to extrapolate research data in larger populations. In simple words, the impact of a visionthreatening disease like glaucoma on VA is highly variable in a multifactorial way. Because of these facts, in clinical settings, VA is rarely used as an index of the severity of the glaucoma or of the efficacy of the therapy. On the other hand, easily measurable indexes like the mean deviation (MD), the visual function index (VFI) or the retinal nerve fibre layer (RNFL) are considered the ‘gold standards’ for the evaluation both of the current and potentially of the future state of the glaucoma patient. Unfortunately, despite the fact that these prevalent indexes quantify certain aspects of the functional status of the patient, they provide only indirect and often misleading information regarding the overall VA for two primary reasons: (i) the majority of them (i.e. MD, VFI) derive from clinical tests that simulate poorly the actual environment; and (ii) the correlation of objective indexes like the RNFL with VA is yet to be fully explored. Quality of life questionnaires attempt to construct the variable VA by introducing four major, a priori, assumptions that determine the overall interaction of the patient with the environment. These assumptions are: (i) each glaucoma patient has a certain capacity of VA; (ii) certain activities require certain capacities of VA; (iii) two different glaucoma patients with the same capacity of VA should, ideally, be able to perform the same range of activities; and (iv) two different glaucoma patients with different capacities of visual abilities should, ideally, differ in the range of activities that are able to perform. Thus, if a glaucoma patient is able to perform the whole range of interactions with the environment, then he/she should have a perfect VA score. On the other hand, when the glaucoma patient cannot interact with the environment then the VA score should be zero. Between these extreme values and closer to zero, is the visual disability or impairment (VI) score. Further to the assessment of the VA, QoL instruments provide valuable information by evaluating limitations of specific activities of daily living (ADL) of the glaucoma patient. These limitations are quantified by the subscale scores and demonstrate those areas of human activities that glaucoma primarily exerts its negative impact. For example, QoL studies suggest that the outdoor mobility and the driving ability is among the most affected activities in glaucoma patients. In accordance to the above, the clinical value of the QoL studies in glaucoma is the quantification of the variable VA and of the ADLs in the daily clinical praxis, for a series of reasons: (i) VA reflects the overall functional visual capability of the patient and not certain aspects of it; (ii) ADL scores are directly associated with specific activities of the patient; (iii) ADLs directly quantify specific limitations of the patient; and (iv) they allow the identification of those ADLs that are more important to the patient according to his/her needs/wants. Thus, further to the traditional management of the glaucoma patient, which is primarily based on the performance of the prevalent clinical indexes like the MD, the VFI and the RNFL, VA and ADLs indexes attempt to introduce a contemporary, individualized patient management methodology that is supposed to be more compatible with the patient’s specific needs. In simple words, the ‘peripheral vision’ subscale score might provide more information regarding the overall efficacy of the therapy in a young glaucoma patient than the MD index in a specific time-frame within the disease continuum. In fact, QoL studies outcomes are considered so important that in certain countries they actually determine the reimbursement policies of the insurance funds. It becomes obvious that the performance of the QoL instruments depends heavily on three fundamental properties that they should have: (i) the capability to explore the whole spectrum of interactions of the glaucoma patient with the environment, efficiently; (ii) the capability to correlate, even, minor difficulties in the interaction with the environment with VA; and (iii) the capability to identify non-glaucoma-related reasons that interfere with the glaucoma patient’s activities. Aforementioned capabilities of the QoL instruments are evaluated during their psychometric validation. Summarizing, QoL studies introduce a contemporary framework for the assessment of the impact of glaucoma with high clinical significance.

Corneal Collagen Cross-Linking Using Riboflavin and Ultraviolet-A Irradiation in Keratitis Treatment

Cross-linking is a common method of tissue stabilization. For example, cross-linking is used for formaldehyde-induced tissue stiffening and fixation in pathologic specimens. Corneal collagen Crosslinking (CXL) is performed with ultraviolet-A (UVA) irradiation at 370 nm and the photosensitizer riboflavin (vitamin B2). According to Wollensak (Wollensak, 2006), the photosensitizer is excited into its triplet state generating reactive oxygen species (ROS), which are mainly singlet oxygen and to a much lesser degree superoxide anion radicals. ROS can react further with various molecules inducing chemical covalent bonds that form bridges between amino groups of collagen fibrils (type II photochemical reaction). The biomechanical effect occurs immediately after irradiation leading to an increase of the biomechanical rigidity of the cornea of about 300%. The optimal wavelength of the ultraviolet (UV) radiation is 370 nm, at which riboflavin presents maximal absorption. Interestingly, a similar mechanism has been detected in the human crystalline lens (Krishna et al., 1991).