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作者 Ribeiro M., Barbosa C., Correia P., Torrao L., Neves Cardoso P., Moreira R., Falcao-Reis F., Falcao M., Pinheiro-Costa J.
Margarida Ribeiro,1,2,* Margarita Ribeiro, 1.2* Claudia Barbosa, 3 years* Claudia Barbosa, 3 years* 2 Bio Faculty of Medicine – Faculty of Medicine of the University of Porto, Porto, Portugal 3 Faculty of Medicine of the University of Porto, Porto, Portugal; 4Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal 4 Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal *These authors contributed equally to this work. Hernâni Monteiro Porto, 4200-319, Portugal, email [email protected] Purpose: We evaluated the corneal posterior surface adjusted for the same Best Fit Sphere Back (BFSB) between time scale measurements (AdjEleBmax) and BFSB radius ( BFSBR) The maximum height itself was used as a new tomographic parameter to record the progression of dilatation and compared with the latest reliable parameters of keratoconus progression (KK). Results. We evaluated Kmax, D index, posterior curvature radius, and ideal cutoff point from 3.0 mm thinnest point centered (PRC), EleBmax, BFSBR, and AdjEleBmax as independent parameters to record KC progression (defined as two or more variables ), we found sensitivities of 70%, 82%, 79%, 65%, 51%, and 63%, and 91%, 98%, 80%, 73%, 80%, and 84% specificities for detecting KC progression. . The area under the curve (AUC) for each variable was 0.822, 0.927, 0.844, 0.690, 0.695, 0.754, respectively. Conclusion: Compared to EleBmax without any adjustment, AdjEleBmax has higher specificity, higher AUC and better performance with similar sensitivity. AUC. Since the shape of the posterior surface is more aspherical and curved than the anterior surface, which may help detect changes, we suggest including AdjEleBmax in the assessment of KC progression along with other variables to improve the reliability of our clinical evaluation and early detection. progressions.Key words: keratoconus, cornea, progression, best spherical dorsal shape, maximum height of the posterior surface of the cornea.
Keratoconus (KK) is the most common primary corneal ectasia. It is now considered to be a bilateral (albeit asymmetric) chronically progressive disease leading to multiple structural changes followed by stromal thinning and scarring. 1,2 Clinically, patients present with irregular astigmatism and myopia, photophobia, and/or monocular diplopia with impaired vision, maximally corrected visual acuity (BCVA) and reduced quality of life. 3,4 The manifestations of RP usually begin in the second decade of life and progress to the fourth decade, followed by clinical stabilization. The risk and rate of progression is higher in people younger than 19 years of age. 5.6
Although there is still no definitive cure, the current treatment for ocular keratoconus has two important goals: improving visual function and stopping the progression of dilation. 7,8 The former may be seen in glasses, rigid or semi-rigid contact lenses, intracorneal rings, or in corneal transplants when the disease is too severe. 9 The latter goal is the holy grail of these patient therapies, currently only achievable through crosslinking. This operation leads to an increase in the biomechanical resistance and stiffness of the cornea and prevents further progression. 10-13 Although this can be done at any stage of the disease, the greatest benefit is obtained in the earlier stages. 14 Efforts should be made to detect progression early and prevent further deterioration, and to avoid unnecessary treatment of other patients, thereby reducing the risk of cross-complications such as infection, endothelial cell loss, and severe postoperative pain. 15.16
Despite several studies aimed at defining and detecting progression,17-19 there is still neither a consistent definition of dilatation progression nor a standardized way of documenting it. 9,20,21 In the Global Consensus on Keratoconus and Dilated Diseases (2015), progression of keratoconus is defined as a sequential change in at least two of the following topographic parameters: anterior corneal steepening, posterior corneal steepening, thinning and/or thickness of the cornea Rate of change increases from the perimeter to the thinnest point. 9 However, a more specific definition of progress is still needed. Efforts have been made to find the most robust variables to detect and explain progress. 19:22–24
Given that the shape of the posterior corneal surface, which is more aspherical and curved than the anterior surface, may be useful for detecting changes,25 the main aim of this study was to evaluate the characteristics of the maximum posterior corneal elevation angle. adapted to the same most suitable area. Time scale measurement (BFSB) (AdjEleBmax) and BFSB radius (BFSBR) alone served as new parameters to record dilation progression and compared them to the most commonly used parameters used for KC progression.
A total of 113 eyes of 76 consecutive patients diagnosed with keratoconus were examined in this retrospective cohort study at the Department of Ophthalmology at the Central Hospital of the University of São João, Portugal. The study was approved by the local ethics committee of the Centro Hospitalar Universitário de São João/Faculdade de Medicina da Universidade do Porto and was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants and, if the participant is under 16 years of age, from the parent and/or legal guardian.
Patients with KC aged 14 to 30 years were identified and sequentially included in our ophthalmic and corneal follow-up during October-December 2021.
All selected patients were followed for one year by a corneal specialist and underwent at least three Scheimpflug tomographic measurements (Pentacam®; Oculus, Wetzlar, Germany). Patients stopped wearing contact lenses at least 48 hours before measurements. All measurements were performed by a trained orthopedist and only scans with a quality check of “OK” were included. If automatic image quality assessment is not marked as “OK”, the test will be repeated. Only two scans for each eye were analyzed to detect progression, with each pair separated by 12 ± 3 months. Eyes with subclinical KC were also included (in these cases, the other eye must have shown clear signs of clinical KC).
We excluded from analysis KC eyes that had previously undergone ophthalmic surgery (corneal crosslinking, corneal rings, or corneal transplant) and eyes with very advanced disease (corneal thickness at thinnest <350 µm, hydrokeratosis, or deep corneal scarring) as the group consistently fails “OK” after internal scan quality checks.
Demographic, clinical and tomographic data were collected for analysis. To detect progression of KC, we collected several tomographic variables including maximum corneal curvature (Kmax), mean corneal curvature (Km), flat meridional corneal curvature (K1), steepest meridional corneal curvature (K2), corneal astigmatism (Astig = K2 – K1 ). ), minimum thickness measurement (PachyMin), maximum posterior corneal height (EleBmax), posterior radius of curvature (PRC) 3.0 mm centered on thinnest point, Belin/Ambrosio D-index (D-index), BFSBR and EleBmax were adjusted to BFSB (AdjEleBmax). As shown in fig. 1, AdjEleBmax is obtained after we manually determine the same BFSB radius in both machine tests using the BFSR value from the second estimate.
Rice. 1. Comparison of Pentacam® images in an upright posterior position with true clinical progression with a 13-month interval between examinations. In panel 1, EleBmax was 68 µm at the first examination and 66 µm at the second, so there was no progression in this parameter. The best sphere radii automatically given by the machine for each evaluation are 5.99 mm and 5.90 mm, respectively. If we click on the BFS button, a window will appear where a new BFS radius can be defined manually. We determined the same radius in both tests using the second measured BFS radius value (5.90mm). In panel 2, the new value of EleBmax (EleBmaxAdj) corrected for the same BFS in the first assessment is 59 µm, indicating a 7 µm increase in the second assessment, indicating progression according to our 7 µm threshold.
To analyze progression and evaluate the effectiveness of new study variables, we used parameters commonly used as progression markers (Kmax, Km, K2, Astig, PachyMin, PRC, and D-Index) as well as thresholds described in the literature. although not empirically). Table 1 lists the values ​​representing the progress of each analysis parameter. Progression of KC was defined when at least two of the studied variables confirmed progression.
Table 1 Tomographic parameters generally accepted as markers of the progression of RP progression and corresponding thresholds described in the literature (although not confirmed)
In this study, the performance of three variables was tested for progression (EleBmax, BFSB, and AdjEleBmax) based on the presence of progression of at least two other variables. Ideal cut-off points for these variables were calculated and compared with other variables.
Statistical analysis was performed using SPSS statistical software (version 27.0 for Mac OS; SPSS Inc., Chicago, IL, USA). Sample characteristics are summarized and data presented as numbers and proportions of categorical variables. Continuous variables are described as mean and standard deviation (or median and interquartile range when the distribution is skewed). The change in keratometric index was obtained by subtracting the original value from the second measurement (i.e., a positive delta value indicates an increase in the value of a particular parameter). Parametric and non-parametric tests were performed to evaluate the distribution of corneal curvature variables classified as progressive or non-progressive, including independent-sample t-test, Mann-Whitney U-test, chi-square test, and Fisher’s exact test (if needed). The level of statistical significance was set at 0.05. To assess the effectiveness of Kmax, D-index, PRC, BFSBR, EleBmax, and AdjEleBmax as individual progression predictors, we built receiver performance curves (ROC) and calculated ideal cutoff points, sensitivity, specificity, positive (PPV), and Negative Predictive Value (NPV). ) and area under the curve (AUC) when at least two variables exceed certain thresholds (as described earlier) to classify the progression as control.
A total of 113 eyes of 76 patients with RP were included in the study. The majority of patients were male (n=87, 77%) and the mean age at first assessment was 24.09 ± 3.93 years. With respect to KC stratification based on increased total Belin/Ambrosio dilatation deviation (BAD-D index), the majority (n=68, 60.2%) of the eyes were moderate. The researchers unanimously chose a cut-off value of 7.0 and differentiated between mild and moderate keratoconus according to the literature26. However, the rest of the analysis includes the entire sample. Demographic, clinical and tomographic characteristics of the sample, including mean, minimum, maximum, standard deviation (SD) and measurements with 95% confidence intervals (IC95%), as well as the first and second measurements. The difference between the values ​​after 12 ± 3 months can be found in table 2.
Table 2. Demographic, clinical and tomographic characteristics of patients. Results are expressed as mean ± standard deviation for continuous variables (*results are expressed as median ± IQR), 95% confidence interval (95% CI), male gender and right eye are expressed as number and percent
Table 3 shows the number of eyes classified as progressors considering each tomographic parameter (Kmax, Km, K2, Astig, PachyMin, PRC and D-Index) separately. Taking into account the progression of KC, defined by observed changes in at least two tomographic variables, 57 eyes (50.4%) showed progression.
Table 3 Number and frequency of eyes classified as progressors, taking into account each tomographic parameter separately
Kmax, D-index, PRC, EleBmax, BFSB, and AdjEleBmax scores as independent predictors of KC progression are shown in Table 4. For example, if we define a threshold value for increasing Kmax by 1 diopter (D) to mark progression, although this parameter exhibits a sensitivity of 49 %, it has a specificity of 100% (all cases identified as progressive on this parameter were in fact true). progressors above) with a positive predictive value (PPV) of 100%, a negative predictive value (NPV) of 66%, and an area under the curve (AUC) of 0.822. However, the calculated ideal cutoff for kmax was 0.4, giving a sensitivity of 70%, a specificity of 91%, a PPV of 89%, and an NPV of 75%.
Table 4 Kmax, D-Index, PRC, BFSB, EleBmax, and AdjEleBmax scores as isolated predictors of KC progression (defined as a significant change in two or more variables)
In terms of the D index, the ideal cut-off point is 0.435, sensitivity is 82%, specificity is 98%, PPV is 94%, NPV is 84%, and AUC is 0.927. We confirmed that of the 50 eyes that progressed, only 3 patients did not progress on 2 or more other parameters. Of the 63 eyes in which the D index did not improve, 10 (15.9%) showed progression in at least two other parameters.
For PRC, the ideal cutoff point to define progression was a decrease of 0.065 with a sensitivity of 79%, specificity of 80%, PPV of 80%, NPV of 79%, and AUC of 0.844.
With regard to posterior surface elevation (EleBmax), the ideal threshold for determining progression was an increase of 2.5 µm with a sensitivity of 65% and a specificity of 73%. When adjusted to the second measured BSFB, the sensitivity of the new parameter AdjEleBmax was 63% and the specificity improved by 84% with an ideal cutoff point of 6.5 µm. The BFSB itself showed a perfect cutoff of 0.05 mm with a sensitivity of 51% and a specificity of 80%.
On fig. 2 shows the ROC curves for each of the estimated tomographic parameters (Kmax, D-Index, PRC, EleBmax, BFSB and AdjEleBmax). We see that the D-index is a more effective test with a higher AUC (0.927) followed by PRC and Kmax. AUC EleBmax is 0.690. When tuned for BFSB, this setting (AdjEleBmax) improved its performance by expanding the AUC to 0.754. BFSB itself has an AUC of 0.690.
Figure 2. Receiver performance curves (ROC) showing that the use of the D index to determine the progression of keratoconus achieved high levels of sensitivity and specificity, followed by PRC and Kmax. AdjEleBmax is still considered reasonable and generally better than Elebmax without BFSB tuning.
Abbreviations: Kmax, maximum corneal curvature; D-index, Belin/Ambrosio D-index; PRC, back radius of curvature from 3.0 mm centered on the thinnest point; BFSB, best suited for a spherical back; Height; AdjELEBmax, maximum elevation angle. the posterior surface of the cornea is adjusted to the most suitable spherical dorsum.
Considering EleBmax, BFSB, and AdjEleBmax, respectively, we confirmed that 53 (46.9%), 40 (35.3%), and 45 (39.8%) eyes showed progression for each isolated parameter, respectively. Of these eyes, 16 (30.2%), 11 (27.5%), and 9 (45%), respectively, had no true progression as defined by at least two other parameters. Of the 60 eyes not considered progressive by EleBmax, 20 (33%) eyes were progressive on 2 or more other parameters. Twenty-eight (38.4%) and 21 (30.9%) eyes were considered non-progressive according to BFSB and AdjEleBmax alone, respectively, showing true progression.
We intend to investigate the efficacy of BFSB and, more importantly, BFSB-adjusted maximum posterior corneal height (AdjEleBmax) as a novel parameter to predict and detect KC progression and compare them with other tomographic parameters commonly used as markers of progression. Comparisons were made with thresholds reported in the literature (though not validated), namely Kmax and D-Index.20
When setting EleBmax to the BFSB radius (AdjEleBmax), we observed a significant increase in specificity – 73% for the unadjusted parameter and 84% for the adjusted parameter – without affecting the sensitivity value (65% and 63%). We also evaluated the BFSB radius itself as another potential predictor of dilatation progression. However, the sensitivity (51% vs 63%), specificity (80% vs 84%) and AUC (0.69 vs 0.75) of this parameter were lower than those of AdjEleBmax.
Kmax is a well-known parameter for predicting the progression of KC. 27 There is no consensus on which cut-off limit is more appropriate. 12,28 In our study, we considered an increase of 1D or more as a definition of progression. At this threshold, we observed that all patients identified as progressing were confirmed by at least two other parameters, suggesting a specificity of 100%. However, its sensitivity was relatively low (49%), and progression could not be detected in 29 eyes. However, in our study, the ideal Kmax threshold was 0.4 D, sensitivity was 70%, and specificity was 91%, which means that with a relative decrease in specificity (from 100% to 91%), we improved. Sensitivity ranged from 49% to 70%. However, the clinical relevance of this new threshold is questionable. According to the Kreps study on the repeatability of Pentacam® measurements, the repeatability of Kmax was 0.61 in mild catarrhal cancer and 1.66 in moderate caesarean colpitis,19 which means that the statistical cut-off value in this sample is not clinically significant as it defines a stable situation. when the maximum possible progress is applied to other samples. Kmax, on the other hand, characterizes the steepest anterior corneal curvature of the small region 29 and cannot reproduce the changes that occur in the anterior cornea, posterior cornea, and other areas of pachymetry. 30-32 Compared to the new posterior parameters, AdjEleBmax showed higher sensitivity (63% vs. 49%). 20 progressive eyes were correctly identified using this parameter and missed using Kmax (compared to 12 progressive eyes detected using Kmax instead of AdjEleBmax). This finding supports the fact that the posterior surface of the cornea is steeper and more expanded in the center compared to the anterior surface, which may help detect changes. 25,32,33
According to other studies, the D-index is an isolated parameter with the highest sensitivity (82%), specificity (95%) and AUC (0.927). 34 Actually, this is not surprising, since this is a multi-parameter index. PRC was the second most sensitive variable (79%) followed by AdjEleBmax (63%). As mentioned earlier, the higher the sensitivity, the fewer false negatives and the better the screening parameters develop. 35 Therefore, we recommend using AdjEleBmax (with a cutoff of 7 µm for progression rather than 6.5 µm since the digital scale built into the Pentacam® does not include decimal places for this parameter) instead of the uncorrected EleBmax, which will be included along with other variables in assessment. progression of keratoconus to improve the reliability of our clinical evaluation and early detection of progression.
However, our study faces some limitations. First, we only used tomographic shapeflug imaging parameters to define and evaluate progression, but other methods are currently available for the same purpose, such as biomechanical analysis, which may precede any topographic or tomographic changes. 36 Second, we use a single measurement of all tested parameters and, according to Ivo Guber et al., averaging over multiple images results in lower measurement noise levels. 28 While measurements with Pentacam® were well reproducible in normal eyes, they were lower in eyes with corneal irregularities and corneal ectasia. 37 In this study, we only included eyes with built-in Pentacam® high-quality scan validation, which meant that advanced disease was ruled out. 17 Third, we define true progressors as having at least two parameters based on the literature but not yet confirmed. Finally, and perhaps more importantly, the variability in Pentacam® measurements is of clinical importance in assessing the progression of keratoconus. 18,26 In our sample of 113 eyes, when stratified according to the BAD-D score, most (n=68, 60.2%) eyes were moderate, with the remainder subclinical or mild. However, given the small sample size, we retained the overall analysis regardless of the severity of KTC. We have used a threshold value that is best for our entire sample, but we acknowledge that this may add noise (variability) to the measurement and raise concerns about measurement reproducibility. The reproducibility of measurements depends on the severity of KTC, as shown by Kreps, Gustafsson et al. 18,26. Therefore, we strongly recommend that future studies take into account the different stages of the disease and evaluate the ideal cut-off points for appropriate progress.
In conclusion, early detection of progression is of paramount importance in order to provide timely treatment to halt progression (via cross-linking)38 and help preserve vision and quality of life in our patients. 34 The main goal of our work is to demonstrate that EleBmax, tuned to the same BFS radius between time measurements, has better performance than EleBmax itself. This parameter shows higher specificity and efficacy compared to EleBmax, it is one of the most sensitive parameters (and therefore the best screening efficiency) and thus a potential early progression biomarker. It is highly recommended to create multi-parameter indexes. Future studies involving multivariate progression analysis should include AdjEleBmax.
The authors do not receive any financial support for the research, authorship and/or publication of this article.
Margarida Ribeiro and Claudia Barbosa are study co-authors. The authors report no conflict of interest in this work.
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