Keratoconus is a chronic ectatic disease of the cornea.1 Through changing the natural shape of the cornea into a more cone-like shape due to thinning of the corneal stroma, patients develop astigmatism, reducing their quality of vision and life.2–4 Ectasia is progressive and can only be stopped with interventions such as cross-linking, otherwise only symptomatic therapy options including spectacles and contact lenses are helpful.5,6 However, sometimes these interventions do not compensate for the deficit in vision effectively so more drastic treatment such as corneal transplantation might be needed.4–7
Although the advanced stage of the disease is indicated by vision impairment, the early stages of the disease can present few to no symptoms and it is therefore difficult to diagnose and screen.8 Screening for keratoconus plays an important role when a patient is considering refractive surgery (eg, LASIK) because the disease is a risk factor for postoperative ectasia.9–11 This complication is consequential, leading to worse visual acuity, and therefore any ectatic change in the eye has to be excluded by preoperative examination before a patient undergoes refractive surgery.12 Due to the difficulty in detecting early forms of keratoconus, we focused this study on patients who had only unilateral diagnosed keratoconus because we know that the fellow eye is also likely to develop an ectasia.13,14 Therefore, in this cohort we were able to study variables of the cornea in keratoconus progression at an early stage without ectatic changes, compare them to a control group, and find the best suitable parameters for early keratoconus detection.
Patients and Methods
A total of 27 patients diagnosed as having unilateral keratoconus were followed up at the Department of Ophthalmology at Goethe University in Frankfurt, Germany. The fellow non-ectatic eye (keratoconus suspect) was examined and screened for early signs of keratoconus. To be included in this study, patients had to have one eye diagnosed as having keratoconus (6 eyes = stage 1, 16 eyes = stage 2, 5 eyes = stage 3 according to the Amsler–Krumeich classification) and a fellow eye that did not clinically meet the criteria for a diagnosis of keratoconus and also looked tomographically normal (according to elevation maps, corneal thickness, maximum keratometry, and D-index). Measurements were compared to another 50 eyes of healthy patients without any ocular surgery or diseases in their history to determine any variables that offer early differentiation between keratoconus suspects and normal.
For each patient, a Scheimpflug (Pentacam; Oculus Optikgeräte GmbH, Wetzlar, Germany) measurement was performed. Only imaging with a quality check of “ok” or better was used. During the follow-up, examinations of the fellow eye of the 27 keratoconic patients took place until the first signs of keratoconus disease were visible. The second measurement was on average 360 ± 246 days (range: 147 to 1,020 days) later. Typical variables used for keratoconus diagnosis were calculated and compared to our normal population to see which variables were the first to indicate keratoconus disease.
We used Belin/Ambrósio Enhanced Ectasia Software integrated into the Pentacam Oculus System to generate the D-index, consisting of five subgroups: Df (deviation of front surface elevation difference), Db (deviation of back surface elevation difference), Dp (deviation of pachymetric progression), Dt (deviation of thinnest point), and Da (deviation of ARTMax/Ambrósio relational thickness maximum).
Furthermore, elevation of the back (ELEB) and the front (ELEF) surface, maximum pachymetric progression index (RPImax), Ambrósio relational thickness maximum (ARTmax), minimum pachymetry (Pachymin), maximum kertometry (Kmax), keratoconus index (KI), central keratoconus index (CKI), index of vertical asymmetry (IVA), index of height asymmetry (IHA), index of height decentration (IHD), and index of surface variance (ISV) were analyzed.
The study was approved by the local ethics committee and was conducted in accordance with the tenets of the Declaration of Helsinki.
Statistical analyses were performed with SPSS (version 24; IBM Corporation, Armonk, NY) and Stata13 (StataCorp, College Station, TX) software.
Mean values of the variables of the keratoconus suspect cohort were calculated for both measurements. Average values for our control cohort were also calculated and used for comparison.
A receiver operating characteristic (ROC) curve was plotted for the initial measurement and the second measurement, which was on average 1 year later, and the area under the curve (AUC) was determined.
Additionally, differences in the variables between the first and second measurements of the keratoconus suspects were calculated and checked for statistical significance.
A vector analysis was performed to standardize the astigmatism of our fellow eye cohort and to evaluate the differences between the two measurements afterward. Total corneal refractive power (TCRP), and corneal astigmatism of the front (CA) and back (CP) surface were considered for this evaluation.
The control group (anterior astigmatism = 1.1 ± 0.7 diopters [D], posterior astigmatism = 0.3 ± 0.1 D, Kmax = 44.4 ± 2.1 D, corneal thickness at thinnest point = 548 ± 36.9 μm) was matched by age (32 ± 11 years). Average values of the first and second measurements from our keratoconus suspect cohort can be seen in Table A (available in the online version of this article). Dp, Da, and total D-index, together with ELEB, ARTmax, and IHD showed the most significant (P < .001) difference between both measurements. For example, the mean difference between the measurements was 0.57 ± 0.38 for D-index and 3.7 ± 3.65 μm for ELEB.
Mean Values, Differences, and Pair Significance
Elevation, pachymetry, and keratometry are most effected by keratoconus disease, so for these three variables we visualized our results (Figure A, available in the online version of this article). For example, the inferior point of each graph is the elevation in the beginning and the superior point is the endpoint from our second measurement; therefore, a long vertical graph indicates a large difference between the first and second measurements. Although in the keratometry and pachymetry graphs only a few curves show a progression, almost every curve in the elevation graph shows a progression. Figure 1 and Figure B (available in the online version of this article) illustrate one sample case of progression into manifest keratoconus.
Changes in (A) elevation at the thinnest point of the posterior corneal surface, (B) corneal thickness at the thinnest point, and (C) the maximum keratometry (Kmax) value of the anterior corneal surface. Each colored line stands for changes of one eye.
(A) A tomographically healthy right eye in the Belin/Ambrósio Display. There is only a minimal shift of the thinnest point into an inferotemporal direction, yet within a range that would not raise concerns about potential progression into keratoconus. However, looking at the sagittal curvature map, there is already a slight asymmetry between keratometry values of the superior and inferior anterior corneal surface. This is also reflected by an index of height decentration of 0.012, which is above the cut-off value of 0.0115 found in the receiver operating characteristic analysis. (B) The same eye 1 year later shows an increase in asymmetry and the D-index. Also, the thinnest point has shifted further inferotemporally, corneal thickness has decreased, and an elevation at the posterior corneal surface has become visible. Knowing that the left eye has manifest keratoconus, at this stage the right eye can be labelled as having subclinical keratoconus, despite minimal tomographic changes and no visible clinical signs. (C) Manifest keratoconus, now also with clinical signs, can be seen in the right eye 3 years later.
Left eye of patient in Figure 1. Manifest keratoconus is tomographically visible.
The first ROC revealed IHD with an AUC of 0.788 ± 0.054 as the most suitable to identify differentiation between healthy and keratoconic eyes, followed by IVA (0.772 ± 0.057) and KI (0.743 ± 0.062). AUC, P values, and 95% confidence intervals can be found in Table 1 (first ROC).
First Receiver Operating Characteristic Analyses
However, the second ROC showed the highest AUC for D-index (0.876 ± 0.039), followed by IHD (0.855 ± 0.046) and IVA (0.842 ± 0.046) (P < .001 for all three). AUC, 95% confidence intervals, and P values for the second analysis can be found in Table 2 (second ROC). During the interval from the first to the second measurement, D-index and IHD increased significantly (P < .01 for both).
Second Receiver Operating Characteristic Analysis
Vector analysis was performed with TCRP, CA, and CB. The calculated mean difference between both measurements in the cylinder was 0.07 ± 0.32 D for TCRP, 0.12 ± 0.28 D for CA, and 0.02 ± 0.10 D for CB.
Differing from previous studies where eyes with subclinical keratoconus were only compared to healthy eyes, in our analysis we additionally showed early changes in progression of the disease by comparing multiple examinations of eyes with subclinical keratoconus over time. This allows us to better understand early changes in the disease and consequently allows us to better detect patients who might have a predisposition to ectasia before inclusion of refractive surgical procedures.
Our ROC revealed that only a few variables are able to discriminate keratoconic eyes from healthy ones in the early stages of the disease, (ie, IVA and IHD), whereas other indices such as keratometry were not as suitable. This contradicts findings from previous groups, including Muftuoglu et al.,15 who found the D-index to be better at diagnosing early keratoconus. This is probably because the subclinical keratoconus examined by Muftuoglu et al. was already at a more advanced stage than in our cohort, as evident by a higher D-value. ISV is another variable other groups have shown to be suitable for early diagnosis but this is not in line with our findings for ISV (it performed worse in the ROC analysis than IVA and IHD).16 Again, we think this is due to the early stage of subclinical keratoconus in our cohort. Although there are different findings for these variables, our outcome for IVA is in line with recent results from other groups such as Hashemi et al.17 finding IVA to be the most precise variable for early detection of subclinical keratoconus.
Our results suggest examining IVA and IHD and carefully evaluating these before a patient undergoes refractive surgery. Our finding that D-index seems to be unsuitable for early keratoconus disease detection is in accordance with other groups who also found no differentiation of the D-index in the subclinical fellow eyes of keratoconic patients.18,19
When the disease progresses, we found other variables to be more exact in differentiating between keratoconic and normal eyes. Our results showed that the D-index, IHD, and IVA performed best in differentiation. At our first measurement, mean D-index was 0.91 ± 0.39, which was compared to a cut-off value of 1.45, classified by Ambrósio et al.20 as a normal eye. Meanwhile, at our second measurement, mean D-index was 1.48 ± 0.45; this corresponds to early changes seen in potentially ectatic eyes. ROC analysis revealed the highest AUC for the D-index with 0.876 ± 0.039 (P < .001).
Nevertheless, Silverman et al.21 showed that Pentacam Scheimpflug imaging is effective in diagnosing keratoconus, but is even more effective when combined with Artemis-1 (Arscan, Morrison, CO) data. Further studies should be performed to see whether combined data might help improve differentiation between early keratoconic and normal eyes with our suggested variables.
Increases in keratometry and elevation and decreases in pachymetry are the typical changes in an ectatic cornea. However, our results show that elevation had the most impact on the corneal surface when it comes to ectasia caused by keratoconus; in nearly all of our 27 patients, a progression in elevation took place, whereas keratometry and pachymetry did not necessarily change between the measurement points. Therefore, parameters associated with elevation might be better suited to screening for keratoconus than other values, particularly in the early stages of the disease. This is in accordance with other groups who found the posterior surface elevation a suitable screening parameter.22–24
Our vector analysis revealed another noteworthy fact: although developing irregular astigmatism was one of the most frequently encountered problems that accompanied the diagnosis of keratoconus in our cohort, only marginal progression of astigmatism in the early stages was found. A reason for this could be that the biochemical alteration of the cornea occurs significantly earlier than visible changes to its shape, which might only be secondary.25 This may explain why at our first measurement only small topographical changes were detected and astigmatism, one of the main side effects of the disease, had not yet shown significant changes.
Therefore, we recommend using IVA and IHD when screening to prevent ectasia after refractive surgery. In addition, differences in elevation parameters might be suitable. Astigmatism, keratometry, and pachymetry did not perform well in our cohort. When the disease is progressing and slowly becoming clinical, the D-index seems to be better suited to early stage keratoconus diagnosis.
- Krachmer JH, Feder RS, Belin MW. Keratoconus and related noninflammatory corneal thinning disorders. Surv Ophthalmol. 1984;28:293–322. doi:10.1016/0039-6257(84)90094-8 [CrossRef]
- Critchfield JW, Calandra AJ, Nesburn AB, Kenney MC. Keratoconus: I. Biochemical studies. Exp Eye Res. 1988;46:953–963. doi:10.1016/S0014-4835(88)80047-2 [CrossRef]
- Jones-Jordan LA, Walline JJ, Sinnott LT, Kymes SM, Zadnik K. Asymmetry in keratoconus and vision-related quality of life. Cornea. 2013;32:267–272. doi:10.1097/ICO.0b013e31825697c4 [CrossRef]
- Bykhovskaya Y, Margines B, Rabinowitz YS. Genetics in keratoconus: where are we?Eye Vis (Lond). 2016;3:16. doi:10.1186/s40662-016-0047-5 [CrossRef]
- Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol. 2003;135:620–627. doi:10.1016/S0002-9394(02)02220-1 [CrossRef]
- Aldave AJ, Yellore VS, Salem AK, et al. No VSX1 gene mutations associated with keratoconus. Invest Ophthalmol Vis Sci. 2006;47:2820–2822. doi:10.1167/iovs.05-1530 [CrossRef]
- Gain P, Jullienne R, He Z, et al. Global survey of corneal transplantation and eye banking. JAMA Ophthalmol. 2016;134:167–173. doi:10.1001/jamaophthalmol.2015.4776 [CrossRef]
- Rabinowitz YS. Keratoconus. Surv Ophthalmol. 1998;42:297–319. doi:10.1016/S0039-6257(97)00119-7 [CrossRef]
- Randleman JB, Russell B, Ward MA, Thompson KP, Stulting RD. Risk factors and prognosis for corneal ectasia after LASIK. Ophthalmology. 2003;110:267–275. doi:10.1016/S0161-6420(02)01727-X [CrossRef]
- Randleman JB, Woodward M, Lynn MJ, Stulting RD. Risk assessment for ectasia after corneal refractive surgery. Ophthalmology. 2008;115:37–50. doi:10.1016/j.ophtha.2007.03.073 [CrossRef]
- Qin V, Saad A, Gatinel D. Unilateral post-LASIK ectasia and contralateral spontaneous ectasia. J Refract Surg. 2016;32:127–130. doi:10.3928/1081597X-20151119-03 [CrossRef]
- Binder PS, Lindstrom RL, Stulting RD, et al. Keratoconus and corneal ectasia after LASIK. J Cataract Refract Surg. 2005;31:2035–2038. doi:10.1016/j.jcrs.2005.12.002 [CrossRef]
- Rabinowitz YS, Nesburn AB, McDonnell PJ. Videokeratography of the fellow eye in unilateral keratoconus. Ophthalmology. 1993;100:181–186. doi:10.1016/S0161-6420(93)31673-8 [CrossRef]
- Lee LR, Hirst LW, Readshaw G. Clinical detection of unilateral keratoconus. Aust N Z J Ophthalmol. 1995;23:129–133. doi:10.1111/j.1442-9071.1995.tb00141.x [CrossRef]
- Muftuoglu O, Ayar O, Hurmeric V, Orucoglu F, Kilic I. Comparison of multimetric D index with keratometric, pachymetric, and posterior elevation parameters in diagnosing subclinical keratoconus in fellow eyes of asymmetric keratoconus patients. J Cataract Refract Surg. 2015;41:557–565. doi:10.1016/j.jcrs.2014.05.052 [CrossRef]
- Kanellopoulos AJ, Asimellis G. Revisiting keratoconus diagnosis and progression classification based on evaluation of corneal asymmetry indices, derived from Scheimpflug imaging in keratoconic and suspect cases. Clin Ophthalmol. 2013;7:1539–1548. doi:10.2147/OPTH.S44741 [CrossRef]
- Hashemi H, Beiranvand A, Yekta A, Maleki A, Yazdani N, Khabazkhoob M. Pentacam top indices for diagnosing subclinical and definite keratoconus. J Curr Ophthalmol. 2016;28:21–26. doi:10.1016/j.joco.2016.01.009 [CrossRef]
- Reinstein DZ, Archer TJ, Urs R, Gobbe M, RoyChoudhury A, Silverman RH. Detection of keratoconus in clinically and algorithmically topographically normal fellow eyes using epithelial thickness analysis. J Refract Surg. 2015;31:736–744. doi:10.3928/1081597X-20151021-02 [CrossRef]
- Bae GH, Kim JR, Kim CH, Lim DH, Chung ES, Chung T-Y. Corneal topographic and tomographic analysis of fellow eyes in unilateral keratoconus patients using Pentacam. Am J Ophthalmol. 2014;157:103–109. doi:10.1016/j.ajo.2013.08.014 [CrossRef]
- Ambrósio R Jr, Faria-Correia F, Ramos I, et al. Enhanced screening for ectasia susceptibility among refractive candidates: the role of corneal tomography and biomechanics. Curr Ophthalmol Rep. 2013;1:28–38. doi:10.1007/s40135-012-0003-z [CrossRef]
- Silverman RH, Urs R, RoyChoudhury A, Archer TJ, Gobbe M, Reinstein DZ. Combined tomography and epithelial thickness mapping for diagnosis of keratoconus. Eur J Ophthalmol. 2017;27:129–134. doi:10.5301/ejo.5000850 [CrossRef]
- Kamiya K, Ishii R, Shimizu K, Igarashi A. Evaluation of corneal elevation, pachymetry and keratometry in keratoconic eyes with respect to the stage of Amsler-Krumeich classification. Br J Ophthalmol. 2014;98:459–463. doi:10.1136/bjophthalmol-2013-304132 [CrossRef]
- Uçakhan ÖÖ, Cetinkor V, Özkan M, Kanpolat A. Evaluation of Scheimpflug imaging parameters in subclinical keratoconus, keratoconus, and normal eyes. J Cataract Refract Surg. 2011;37:1116–1124. doi:10.1016/j.jcrs.2010.12.049 [CrossRef]
- Arbelaez MC, Versaci F, Vestri G, Barboni P, Savini G. Use of a support vector machine for keratoconus and subclinical keratoconus detection by topographic and tomographic data. Ophthalmology. 2012;119:2231–2238. doi:10.1016/j.ophtha.2012.06.005 [CrossRef]
- Piñero DP, Alió JL, Barraquer RI, Michael R, Jiménez R. Corneal biomechanics, refraction, and corneal aberrometry in keratoconus: an integrated study. Invest Ophthalmol Vis Sci. 2010;51:1948–1955. doi:10.1167/iovs.09-4177 [CrossRef]
First Receiver Operating Characteristic Analyses
|Parameter||Area Under the Curve||Standard Error||P||95% CI|
|Df||0.573||0.07||.283||0.435 to 0.71|
|Db||0.574||0.067||.272||0.295 to 0.556|
|Dp||0.542||0.066||.535||0.412 to 0.672|
|Dt||0.643||0.065||.035||0.516 to 0.769|
|Da||0.588||0.065||.196||0.459 to 0.716|
|D-index||0.622||0.065||.071||0.495 to 0.75|
|ELEF||0.564||0.074||.344||0.42 to 0.708|
|ELEB||0.545||0.071||.509||0.317 to 0.593|
|RPIaverage||0.538||0.067||.576||0.408 to 0.668|
|ARTmax||0.613||0.064||.094||0.26 to 0.513|
|Pachymin||0.643||0.065||.035||0.231 to 0.484|
|Kmax||0.52||0.066||.772||0.39 to 0.649|
|IVA||0.772||0.057||< .001||0.66 to 0.884|
|KI||0.743||0.062||< .001||0.621 to 0.86|
|CKI||0.568||0.067||.316||0.436 to 0.70|
|IHA||0.72||0.06||.001||0.603 to 0.838|
|IHD||0.788||0.054||< .001||0.681 to 0.894|
|ISV||0.713||0.063||.002||0.59 to 0.835|
Second Receiver Operating Characteristic Analysis
|Parameter||Area Under the Curve||Standard Error||P||95% CI|
|Df||0.706||0.066||.002||0.575 to 0.836|
|Db||0.529||0.068||.673||0.396 to 0.661|
|Dp||0.73||0.056||.001||0.621 to 0.839|
|Dt||0.665||0.062||.015||0.542 to 0.787|
|Da||0.75||0.055||< .001||0.642 to 0.857|
|D-index||0.876||0.039||< .001||0.799 to 0.952|
|ELEF||0.741||0.068||< .001||0.607 to 0.875|
|ELEB||0.725||0.062||.001||0.604 to 0.846|
|RPImax||0.796||0.049||< .001||0.699 to 0.893|
|ARTmax||0.814||0.048||< .001||0.093 to 0.279|
|Pachymin||0.666||0.062||.015||0.212 to 0.457|
|Kmax||0.504||0.066||.947||0.374 to 0.635|
|ISV||0.793||0.055||< .001||0.685 to 0.901|
|IVA||0.842||0.046||< .001||0.753 to 0.932|
|KI||0.664||0.073||.015||0.52 to 0.808|
|CK||0.585||0.067||.211||0.454 to 0.715|
|IHA||0.694||0.065||.004||0.566 to 0.822|
|IHD||0.855||0.046||< .001||0.764 to 0.945|
Mean Values, Differences, and Pair Significance