Early findings in a randomised controlled trial on crosslinking protocols using isoosmolar and hypoosmolar riboflavin for the treatment of progressive keratoconus.

PURPOSE: To present baseline characteristics and to present the perioperative corneal thickness during corneal crosslinking (CXL) treatment for progressive keratoconus and to describe how the addition of sterile water (SW) efficaciously can maintain the corneal thickness. The treatment efficacy will be evaluated when the 1-year follow-up is complete. METHODS: A randomised clinical study using epithelium-off CXL with continuous UVA irradiation (9 mW/cm2) and two kinds of riboflavin solutions: (i) isoosmolar dextran-based riboflavin (n = 27) and (ii) hypoosmolar dextran-free riboflavin (n = 27). INCLUSION CRITERIA: progressive keratoconus with an increase in maximum keratometry value (Kmax) of 1.0 dioptre (12 months) or 0.5 dioptres (6 months). Corneae thinner than 400 µm were also included. OUTCOME PARAMETERS: Perioperative corneal thickness and the effect of adding SW. RESULTS: Seventy-four per cent of the patients in the isoosmolar group and 15% in the hypoosmolar group required the addition of SW, which effectively maintained a corneal thickness of 400 µm in all cases during CXL. The addition of SW was primarily needed during the irradiation procedure and not the preoperative soaking period. CONCLUSIONS: Especially during the CXL irradiation phase, isoosmolar riboflavin causes a significant dehydrating effect leading to corneal thinning during CXL. The customised addition of SW is efficacious in maintaining the corneal thickness during CXL and could increase the safety of the procedure.

Repeatability of Epithelium Thickness Measured by an AS-OCT in Different Grades of Keratoconus and Compared to AS-OCT/Placido Topography.

PURPOSE: To compare agreement of corneal epithelium thickness (ET) between AS-OCT system (RTVue, Optovue) and AS-OCT/Placido topographer (MS-39, CSO) in eyes with different stages of keratoconus (KC), and to assess the repeatability of RTVue AS-OCT. DESIGN: Prospective reliability analysis. METHODS: KC eyes were classified into forme fruste KC (FFKC), mild, moderate, and severe KC. Agreement was evaluated with Bland-Altman plots and 95% limits of agreement (LoA). The repeatability of RTVue was assessed via within-subject standard deviation (Sw), test-retest variability (TRT), coefficient of variation (CoV), and intraclass correlation coefficient (ICC). RESULTS: A total of 119 KC eyes were enrolled, with 21 being FFKC, 26 mild, 39 moderate, and 34 severe. The 95% LoA ranged between -5.9 and 4.8 µm for center epithelium thickness (CET), between -5.7 and 8.2 µm for thinnest epithelium thickness (TET). At 1-mm measuring points, the 95% LoA of superior, inferior, nasal, and temporal were -4.2 to 4.7 µm, -5.2 to 6.0 µm, -7.9 to 10.2 µm, and -11.2 to 6.0 µm. At 3-mm measuring points, the corresponding values were -2.8 to 9.3 µm, -2.0 to 13.0 µm, -4.6 to 9.6 µm, and -6.3 to 9.7 µm, indicating that the 2 instruments were not interchangeable without adjustment. Despite that the repeatability of RTVue measurements in KC patients were acceptable, repeatability decreased gradually with the peripheralization of the measurement points. CONCLUSIONS: The 2 OCT-based devices, RTVue and MS-39, do not provide interchangeable measurements of epithelium thickness in KC patients. Repeatability decreases in cases of more severe KC, emphasizing the importance of grading before clinical examination to avoid diagnostic errors.

Assessing progression limits in different grades of keratoconus from a novel perspective: precision of measurements of the corneal epithelium.

BACKGROUND: To assess repeatability and reproducibility of corneal epithelium thickness (ET) measured by a spectral-domain optical coherence tomographer (SD-OCT)/Placido topographer (MS-39, CSO, Florence, Italy) in keratoconus (KC) population at different stages, as well as to determine the progression limits for evaluating KC progression. METHODS: A total of 149 eyes were enrolled in this study, with 29 eyes in the forme fruste keratoconus (FFKC) group, 34 eyes in the mild KC group, 40 eyes in the moderate KC group, and 46 eyes in the severe KC group. Employing the within-subject standard deviation (Sw), test-retest variability (TRT), coefficient of variation (CoV), and intraclass correlation coefficient (ICC) to evaluate intraoperator repeatability and interoperator reproducibility. RESULTS: The repeatability and reproducibility of MS-39 in patients with KC were acceptable, according to ICC values ranging from 0.732 to 0.954. However, patients with more severe KC and progressive peripheralization of the measurement points had higher TRTs but a thinning trend. The current study tended to set the cut-off values of mild KC, moderate KC, and severe KC to 4.9 µm, 5.2 µm, and 7.4 µm for thinnest epithelium thickness (TET). When differences between follow-ups are higher than those values, progression of the disease is possible. As for center epithelium thickness (CET), cut-off values for mild KC, moderate KC, and severe KC should be 2.8 µm, 4.4 µm, and 5.3 µm. This might be useful in the follow-up and diagnosis of keratoconus. CONCLUSIONS: This study demonstrated that the precision of MS-39 was reduced in measuring more severe KC patients and more peripheral corneal points. In determining disease progression, values should be differentiated between disease-related real changes and measurement inaccuracies. Due to the large difference in ET measured by MS-39 between various stages of disease progression, it is necessary to accurately grade KC patients to avoid errors in KC clinical decision-making.

Early findings in a prospective randomised study on three cross-linking treatment protocols: interruption of the iontophoresis treatment protocol.

PURPOSE: To present the outcome of the interrupted iontophoresis-assisted treatment arm in an ongoing randomised clinical trial (NCT04427956). METHODS: A randomised clinical study of corneal cross-linking (CXL) using continuous UV-A irradiation at a rate of 9 mW/cm2 and three different types of riboflavin and riboflavin delivery mode: (1) iso-osmolar dextran-based riboflavin (epithelium-off), (2) hypo-osmolar dextran-free riboflavin (epithelium-off) and (3) iontophoresis-assisted delivery of riboflavin (epithelium-on) for the treatment of progressive keratoconus. Inclusion criteria were an increase in the maximum keratometry value (Kmax) of 1.0 dioptre over 12 months or 0.5 dioptre over 6 months. The primary outcome in evaluating treatment efficacy was Kmax. Recently presented stratified detection limits were used post hoc to confirm the enrolment of patients with truly progressive keratoconus and in the assessment of the need for re-CXL. RESULTS: Thirteen patients had been randomised to iontophoresis-assisted CXL when the treatment arm was interrupted; two patients dropped out. Of the remaining 11 patients, 7 were deemed as having truly progressive disease according to the more recent stratified detection limits. The disease continued to progress in three patients according to the original definition (increase in Kmax≥1 D), necessitating re-CXL with epithelium-off CXL. This progression was confirmed by post hoc analysis using the stratified detection limits for progression. CONCLUSIONS: The iontophoresis-assisted CXL protocol failed to halt further disease progression in 27% of the patients. The failure rate increased to 38% when considering only the patients deemed to have truly progressive disease using the stratified detection limits.

Patient experience and repeatability of measurements made with the Pentacam HR in patients with keratoconus.

BACKGROUND: To investigate whether the repeatability of measurements with the Pentacam HR in patients with keratoconus is improved by patients gaining more experience of the measurement situation. Such an improvement could enhance the accuracy with which progressive keratoconus can be detected. METHODS: Four replicate measurements were performed on Day 0 and on Day 3. Parameters commonly used in the diagnosis of progressive keratoconus were included in the analysis, namely the flattest central keratometry value (K1), the steepest central keratometry value (K2), the maximum keratometry value (Kmax), and the parameters A, B and C from the Belin ABCD Progression Display. In addition, quality parameters used by the Pentacam HR to assess the quality of the measurements were included, namely the analysed area (front + back), 3D (front + back), XY, Z, and eye movements. RESULTS: Neither the diagnostic parameters nor the quality parameters showed any statistically significant improvement on Day 3 compared to Day 0. The quality parameter "eye movements" deteriorated significantly with increasing Kmax. CONCLUSION: Gaining experience of the measurement situation did not increase the accuracy of the measurements. Further investigations should be performed to determine whether the increasing number of eye movements with increasing disease severity has a negative effect on the repeatability of the measurements.

The intra- and inter-day repeatability of corneal densitometry measurements in subjects with keratoconus and in healthy controls.

The healthy cornea is transparent, however, disease can affect its structure, rendering it more or less opaque. The ability to assess the clarity of the cornea objectively could thus be of considerable interest for keratoconus patients. It has previously been suggested that densitometry can be used to diagnose early keratoconus, and that the values of densitometry variables increase with increasing disease severity, indicating that densitometry could also be used to assess progressive keratoconus. Previous studies have only assessed the repeatability of corneal densitometry measurements on the same day, which does not reflect the clinical setting in which changes are evaluated over time. We have therefore evaluated the inter-day repeatability of densitometry measurements in both patients with keratoconus and healthy controls. Measurements in the middle layer of the 2-6 mm zone of the cornea showed the best repeatability. Although an objective measure of the corneal transparency could be interesting, the generally poor repeatability of densitometry measurements limits their use. The repeatability of corneal clarity measurements could be improved by using other approaches such as optical coherence tomography, but this remains to be investigated. Such improvements would allow the more widespread use of corneal densitometry in clinical practice.

Current clinical practice in corneal crosslinking for treatment of progressive keratoconus in four Nordic countries.

PURPOSE: To evaluate clinical practice in the diagnosis and treatment of progressive keratoconus with corneal crosslinking (CXL) in four Nordic countries. METHODS: A questionnaire was sent to all centres at which keratoconus patients are evaluated and CXL is performed in Sweden, Denmark, Norway and Iceland. Nineteen of 20 centres participated. RESULTS: CXL is performed approximately 1300 times per year in these four Nordic countries with a population of around 21.7 million (2019). In most cases, progression is evaluated using the Pentacam HR, and the maximum keratometry reading (Kmax ) is considered the most important parameter. The most frequently used treatment protocol in Scandinavia is the 9 mW/cm2 epi-off protocol, using hydroxylpropyl methylcellulose riboflavin (HPMC-riboflavin). The participants deemed the following areas to be in most need of improvement: adaptation of the CXL protocol to individual patients (5/19), the development of effective epi-on treatment protocols (4/19), optimal performance of CXL in thin corneas (4/19), improvement of the definition of progression (2/19), and diagnosis of the need for re-treatment (2/19). CONCLUSIONS: We concluded that the diagnosis of progressive keratoconus and the diagnostic equipment used are similar. Treatment strategies are also similar but are suitably different to provide an interesting basis for the comparison of treatment outcomes. The high degree of participation in this survey indicates the possibility of future scientific collaboration on CXL focusing on the areas deemed to need improvement. It would also be of interest to evaluate the possibility of creating a Nordic CXL Registry. The high number of CXL treatments performed ensures sufficient statistical power to solve many questions. Such a registry could be an important contribution to evidence-based care and would allow for longitudinal evaluation.

An inter-day assessment of the ABC parameters in the evaluation of progressive keratoconus.

The progression of keratoconus is commonly determined by comparing the results of corneal tomographic measurements on different occasions. However, investigations on the repeatability of measurements are commonly performed within the same day, thus not taking the inter-day variation into account. The effect of keratoconus disease severity on the measurement error is also seldom considered. In this post hoc investigation, the parameters A, B and C in the Belin ABCD Progression Display were evaluated in relation to disease severity in intra-day and inter-day measurements. Four consecutive measurements were performed on 61 patients with keratoconus on the same day (intra-day). In another cohort, four consecutive measurements were obtained and then repeated 3 days later in 25 patients with keratoconus and 25 healthy controls (inter-day). The results suggest that the diagnosis of disease progression would benefit from inter-day measurements, and the stratification of the parameters A and C according to disease severity. It is also recommended that tomographic systems such as the Pentacam HR be modified to allow the comparison of both single measurements and the mean of replicate measurements of the parameters used in the assessment of progression of keratoconus.

The Interday Repeatability of Parameters for the Assessment of Progressive Disease in Subjects With Less Advanced Keratoconus.

PURPOSE: To evaluate the interday repeatability in the measurement of parameters used for the detection of progression of keratoconus by prediction limits (PL) for single measurements, and the repeatability coefficient (RC) for the mean of replicate measurements. DESIGN: Prospective reliability analysis for cases and control eyes. METHODS: Twenty-five eyes in 25 subjects with KC and 25 eyes in 25 healthy controls were included. Four consecutive measurements were made, 3 days apart, with a Pentacam HR tomographic instrument (denoted the Pentacam) and a Nidek ARK 560-A auto-keratometer (denoted the keratometer). Main outcome measures were the intra- and interday RC of parameters used in the detection of progression of keratoconus. RESULTS: The most repeatable parameter obtained with the Pentacam was the curvature power of the central flat meridian (K1, 0.44 D [RC], -0.55 to 0.60 diopter [D] [PL]), followed by the central steep meridian (K2, 0.72 D [RC], -0.90 to 0.94 D [PL]). The interday repeatability of K1 and K2 was similar when using the keratometer (K1, 0.32 D [RC], -0.66 to 0.57 D [PL], K2, 0.93 D [RC], -1.36 to 1.08 D [PL]). The interday repeatability of the curvature power of the steepest point (Kmax, 0.84 D [RC], -0.90 to 1.11 D [PL]) would benefit from being stratified: RC = 0.44 D and PL = -0.49 to 0.67 D for Kmax < 49.0 D, and RC = 1.08 D and PL = -1.19 to 1.42 D for Kmax ≥ 49.0 D. CONCLUSIONS: The interday repeatability of measurements, single or replicate, in subjects with keratoconus should be considered when diagnosing progressive disease. K1 exhibited the best intraday repeatability. Kmax benefits from being stratified according to disease severity.

Association between keratoconus disease severity and repeatability in measurements of parameters for the assessment of progressive disease.

BACKGROUND: Progressive keratoconus can lead to severely impaired vision, but there is currently no consensus on the definition of progressive disease. Errors in the measurement of the parameters commonly used to establish progressive disease were evaluated in an attempt to determine the limits at which a true change in the values can be detected. The possible association between measurement error and disease severity was also investigated to evaluate the need for limits based on disease severity. METHODS: Sixty-one eyes were studied in 61 patients with keratoconus. Four replicate measurements were made in each patient using a Scheimpflug-based tomographic system (denoted the PC) and an auto-keratometer (denoted the AK). The repeatability coefficient, i.e., the level below which differences between two measurements are found in 95% of paired observations, was calculated. Patients were further divided into three groups based on disease severity (parameter magnitude). RESULTS: Increasing magnitude of all the keratometric parameters investigated was significantly associated with increasing measurement errors, and thus worse repeatability. The maximum keratometry value (Kmax) was the least repeatable parameter (1.23 D, 95% CI 1.11-1.35 D) and showed the strongest association between parameter magnitude and measurement error. The repeatability coefficient ranged between 0.32 and 1.62 D, depending on disease severity. The most repeatable parameter was the flattest central keratometry value (K1), measured with the PC (0.51 D, 95% CI 0.46-0.56 D) and the AK (0.54 D, 95% CI 0.48-0.59 D). K1 showed the weakest association between parameter magnitude and measurement error. The repeatability coefficient for K1 ranged between 0.40 and 0.54 D when using the PC, and between 0.34 and 0.70 D when using the AK in the three groups. CONCLUSIONS: The association between the magnitude of the keratometric parameters and their measurement errors suggests that limits should be based on disease severity to ensure reliable detection of progressive keratoconus. Further studies are, however, required.