Keratoconus (KC) is a bilateral corneal condition characterized by progressive corneal thinning that results in corneal protrusion, irregular astigmatism, and decreased vision1 and has a typical onset during teenage years. Spectacles and contact lenses are the main treatment options for the mild and moderate stages of KC. In severe cases, the central cornea becomes extremely thin and irregular and corneal transplantation surgery is required to restore vision.2,3 Typically, KC is diagnosed through a combination of slit-lamp biomicroscopy, retinoscopy, keratometry, and/or the use of computerized topographic systems to assess corneal changes.
The detection of KC at the earliest preclinical stages is typically very difficult. The term forme fruste KC or subclinical KC typically refers to the early stage of KC where there are no noticeable signs on slit-lamp biomicroscopic examination but subtle changes can be detected via topographic and pachymetric features, similar to clinical KC.4–9 It is essential to differentiate between normal and ectatic corneas as it has been reported that patients with ectatic corneas have a poor outcome following refractive surgeries. There have been numerous attempts by various authors to differentiate subclinical KC from normal eyes including Arbelaez et al.10 defining a new classification algorithm based on the corneal measurements to discriminate among normal or subclinical KC eyes, Fontes et al.11,12 evaluating the accuracy of corneal biomechanical metrics to differentiate KC from healthy corneas, and Muftuoglu et al.13 indicating back surface elevation to be a better parameter in diagnosing early ectatic condition. Ucakhan et al.14 suggested that changes in several power, elevation, and pachymetry measurements and indices could be quantified using the Pentacam. However, the ability to discriminate between eyes with subclinical KC and normal eyes is limited, when the discrimination is based on an individual parameter.14 Thus, the assessment of anterior segment characteristics, particularly anterior corneal curvature and pachymetry, is of paramount importance in monitoring and determining the management of KC.
Previous studies have assessed the anterior segment parameters in healthy eyes15,16 using various instruments. Others have confirmed the correlation between the shape of the anterior corneal surface and the shape of the posterior corneal surface in the normal and keratoconic eye.17–20 Abolbashari et al. recently reported changes in anterior segment parameters of KC eyes in an Asian population4–9 and showed that central corneal thickness (CCT), corneal thickness at the thinnest point (CTT), and anterior chamber depth (ACD) altered significantly with the progression of KC.21 However, their results were based on 48 eyes, and they did not consider axial length (AL), which is an important parameter to be considered in KC patients, for those undergoing keratoplasty as it appears to relate to postkeratoplasty refractive outcomes.22
We wished to evaluate changes in a wide range of anterior segment parameters, including AL (which has not been examined in many studies) in a large cohort of individuals at different stages of KC disease presentation, particularly a large subset of subclinical KC subjects.
Patients with KC were recruited from public clinics at the Royal Victorian Eye and Ear Hospital (Melbourne, Australia), private consulting rooms, optometry clinics, and mailouts to the general public. The study protocol was approved by the Royal Victorian Eye and Ear Hospital Human Research and Ethics Committee (Project#10/954H). This protocol followed the tenets of the Declaration of Helsinki and all privacy requirements were met. Nonkeratoconic subjects were refractive error subjects obtained through the Genes in Myopia (GEM) study where a similar testing protocol was used with the administration of a general questionnaire, comprehensive eye examination, and blood collection. The methodology for the GEM study has been published elsewhere.23
Inclusion and Exclusion Criteria
Individuals with KC of European background, presenting to clinics/private practices, were invited to participate in the study. Clinical KC was diagnosed on the basis of the presence of one or more of the following21,24,25:
- An irregular cornea, as determined by distortion of keratometric mires/and or computerized videokeratography
- Scissoring of the retinoscopic reflex
- Demonstrated at least one biomicroscopic sign, including Vogt striae, Fleicher ring, or corneal thinning and scarring typical of KC, and one or more of the following changes in topographic map:
- a. Focal steepening of areas greater than 47 diopters (D), located in the cone protrusion zone surrounded by concentric decreasing power zones
- b. Angling of the hemi meridians, exceeding 20 or 30 degrees, in the bow tie pattern
- c. Inferior-superior asymmetry greater than 1.4 D within the midperipheral cornea
The criteria for subclinical KC were presence of normal appearance on slit-lamp biomicroscopy and retinoscopy examination26 with abnormal corneal topography including inferior-superior localized steepening or asymmetric bowtie pattern.
Potential subjects with non-KC ocular disease in both eyes, such as corneal degenerations and dystrophies, macular disease, and optic nerve disease (e.g., optic neuritis and optic atrophy), were excluded from the study.
Control subjects from the GEM study who had some form of moderate refractive error (−6 D\sphere\+6 D and astigmatism <4.00 D) and were mainly myopic were recruited. Individuals with known or subsequently identified ocular disorders that may lead to “changes” in refractive error, such as amblyopia (greater than a 2 line Snellen difference between the eyes), strabismus, visually significant lens opacification, glaucoma, or any other corneal abnormality, were excluded from the statistical analysis. Individuals with connective tissue disease such as Marfan or Stickler syndrome were also excluded from the study. The latter conditions were identified by the individual’s medical history obtained via a general questionnaire. The subjects were required to remove their contact lenses, if worn, at least 24 hours before examination.
The anterior segment of the eye was assessed using slit-lamp biomicroscopy examination. Axial length was recorded for each participant using noncontact partial coherence interferometry with an IOL Master (Carl Zeiss, Oberkochen, Germany). Five readings were taken and the average was calculated as per the manufacturer’s instructions. Corneal elevation measurements were obtained on all subjects using Pentacam (Oculus, Wetzlar, Germany). The results used in the study were from the four-map selectable display of Pentacam results incorporating front and back elevation maps, along with front sagittal curve and pachymetry. These maps were chosen to highlight the inferior decentration of the corneal apex on both the front and back surface, which assisted in the detection of KC. Mean corneal curvature (Km) was calculated automatically by the device as the mean value of horizontal and vertical central radial curvatures in the 3-mm zone. Mean front corneal curvature (Front Km), mean back corneal curvature (Back Km), CCT, corneal thickness at the apex (CTA), CTT, ACD, and corneal volume (CV) data were also generated in the four-map selectable display. The quality of the examination was checked by referring to the quality-specification section on the output map with “OK” quality-specification reading considered as accepted; otherwise, the measurements were repeated.
Data were analyzed using Intercooled STATA version 12.1 for Windows (StataCorp, College Station, TX). All statistical tests were two-tailed and p < 0.05 was considered statistically significant. The baseline characteristics of age and anterior segment parameters were compared among the groups using one-way analysis of variance (ANOVA) (with least significance difference post hoc comparison to compare anterior segment parameters between the different groups) whereas sex differences among the groups were compared using the chi-square test. Based on previous studies,21,22,27 Clinical KC eyes were classified into three subgroups according to Front Km readings (mild, Front Km ≤ 47.0 D; moderate, 47.0 < Front Km < 52.0 D; and severe, Front Km ≥ 52.0 D). Eye-specific data (i.e., the anterior segment parameters, including AL, Front Km, Back Km, CCT, CTA, CTT, ACD, and CV) from both eyes of each subject and also person-specific data (age and sex) were used in the analyses. A power calculation using 33 control, 91 subclinical KC, and 232 clinical KC subjects suggested that the current study had 100% power to detect values of p < 0.05 for all the parameters that we used. Generalized estimating equation (GEE) models with independent correlation matrix were used to estimate the crude associations between the candidate variables (age, sex, and KC disease status) and the outcome variables (anterior segment parameters). Multivariable-adjusted models were then constructed to assess associations between age and sex. Covariables included in the models were either categorical (e.g., sex and KC disease status) or continuous (age). Eyes that were ungradable for either the study or the outcome factor were excluded from analyses. Pearson correlation coefficients (r) were used to assess the correlation of the Front Km with other anterior segment parameters. The correlations were considered weak, moderate, or strong according to the following criteria: strong for r between 0.7 and 1.0, moderate for r between 0.3 and 0.7, and weak for r below 0.3. We used receiver operating characteristic (ROC) curve analysis to test the clinical usefulness of the different anterior segment parameters in the diagnosis of KC and subclinical KC.
A total of 181 individuals comprising 44 (24.3%) subclinical KC, 118 (65.2%) clinical KC, and 19 (10.5%) control subjects were analyzed. Table 1 shows the patient demographics. There were no significant differences in sex (p = 0.29) or age (p = 0.48) among the three (subclinical, KC, and control) groups. In the one-way ANOVA, there was a significant difference only in ACD between the subclinical KC and the control groups (p = 0.023). However, in the GEE model (including age, sex, and KC status), CTT and ACD were significantly different between these two groups. Front Km, Back Km, CTA, CTT, and ACD (p < 0.05) were all significantly different between the clinical KC and control groups in the one-way ANOVA, and all other parameters, except for CV, were significantly different in the GEE model.
As expected, Front and Back Km in the clinical KC group were statistically higher than those in the control group (p < 0.001). However, subclinical KC eyes were not significantly associated with Front and Back Km compared with control subjects (Front Km, p = 0.78; Back Km, p = 0.75) (Table 2).
In the case of mild, moderate, and severe KC groups, Back Km, CCT, CTA, and CTT were significantly associated (p < 0.001) with increasing disease severity in both one-way ANOVA and GEE models (Table 3).
Axial length, ACD, and CV were not significantly associated with increasing severity (Table 3). Back Km steepened with increasing KC severity, whereas CCT, CTA, and CTT decreased with increasing severity of KC.
Correlation of Front Km and Back Km with Anterior Segment Parameters
We assessed the correlation between anterior and posterior corneal curvature features with anterior segment parameters in the three KC severity groups. There was a very strong correlation between Front Km and Back Km (r = −0.94; p < 0.01) and so we used the Front Km to represent other correlations (Table 4). Front Km showed a significantly moderate to strong negative correlation with CCT, CTA, and CTT (−0.6, −0.7, and −0.8, respectively; p < 0.01). There were no significant correlations between Front Km and AL and ACD (p > 0.01).
In discriminating the KC group from the control group, a high area under the ROC curve (AUC) value was observed for pachymetric parameters, mainly in the clinical KC group (Table 5). The AUC values were highest for CTT in both KC groups (0.68 for subclinical KC and 0.82 for clinical KC), and in the clinical KC group, the next highest AUC values were observed for CTA (0.78) and CCT (0.75).
The current study has allowed us to identify anterior chamber parameters that differ between subclinical and clinical KC as well as the severity of KC. It is interesting to note that there is a significant reduction in corneal pachymetric values, including CTT between control and subclinical eyes, although there is no significant alteration in Front and Back Km or AL between the two groups. Further, we analyzed the steepest and flattest anterior and posterior curvature in the control, subclinical, and clinical KC groups (data not included) to identify any further corneal changes; however, there was no significant difference between the control and subclinical KC group, but there was a significant difference between the control and clinical KC group between the steepest and flattest front curvature and flattest posterior corneal curvature. These findings suggest that changes in subclinical KC may begin with corneal pachymetric changes wherein there is a significant thinning noticed not only in the center but also in the periphery of the cornea. Also, this study showed that clinical KC eyes had lower values of CCT, CTA, and CTT than control and subclinical KC eyes. These results are in agreement with the Piñero et al.17 study, which showed that the mean CCT and CTT in a subclinical group were significantly lower than that in normal eyes and higher than that in their KC group. Also, a progressive reduction in the pachymetric readings at the pupil center, apex, and thinnest corneal point was identified when comparing mild to severe KC groups. These findings agree with those of previous reports17,24 where progressive corneal thinning is a well-known pathophysiological feature of KC29. Our study confirms the fact that along with Front Km, CCT, CTA, and CTT are other important markers of KC progression. Hence, a decrease of these measures is an important sign of KC progression and would be beneficial in monitoring KC. Previous studies have indicated that eyes with early or subclinical disease might lead to ectatic progression after refractive surgery.28,29
We further did ROC analysis to confirm the importance of pachymetric parameters in differentiating between control and KC eyes. The AUC value of CTT for the diagnosis of subclinical and clinical KC was 0.68 and 0.82, respectively, which showed that it may be a potential marker for the early detection and prevention of KC. Our results emphasize the importance of corneal pachymetry in patients undergoing refractive surgery, which will assist in identifying those likely presenting with subclinical KC. This early detection may aid in early management decisions of the disease (by methods such as collagen cross-linking) and thus improve quality of life by virtue of delaying (if not eliminating) the need for subsequent corneal transplantation.
It is interesting to note that the values of CCT and CTA are similar in mild KC, with both beginning to decrease as disease severity increases. These findings are similar to those previously reported by Ahmadi Hossein et al.30 and Ambrosio et al.,31 who reported significantly lower values of CTA in subclinical and clinical KC eyes compared with control subjects, suggesting tissue loss at the cornea. In addition, peripheral corneal thinning has also been reported to be accompanied by a minor alteration in keratocyte orientation but with no tissue loss.32 This decrease in corneal thinning does not appear to result in a significant change in CV in the current study. It is noteworthy that CV has been proposed as a new index in diagnosing KC in the screening of refractive surgery patients.33 However, we found no significant difference in CV between control, subclinical, and clinical KC eyes or at varying stages of KC. These results are in line with Piñero et al.17 who suggested that, in the early stages of the disease, redistribution of CV occurred but without associated tissue loss. However, Ahmadi Hossein et al.30 and Ambrosio et al.31 reported significantly lower values of CTA in subclinical and clinical KC eyes than in control eyes, suggesting tissue loss at the cornea. Thus, it is likely that corneal thinning leads to a redistribution of CV, reflecting changes in keratocyte redistribution and orientation in keratoconic cornea34 rather than a reduction in CV. The trend we observed toward an increase in ACD with progression of KC is in agreement with the results of the study by Emre et al.24 Using Pentacam imaging, the aforementioned study found a progressively increasing and significant change in ACD values in mild, moderate, and severe KC subjects, with the highest values in the latter group.
The current study is the first to have investigated changes in AL in differing degrees of KC. Interestingly, although AL in clinical KC was significantly different from the control group, there was no significant increase in AL as KC severity increased despite the increase in Front Km. In addition, although ACD was significantly different between the subclinical group and the control group and between the KC group and the control group, ACD was not significantly associated with KC severity. This suggests that there may be a compensatory mechanism to optimize axial elongation in eyes with steeper corneas while maintaining the ACD. The caveat to this is that it should be noted that AL measures are typically taken on a central (vertical) axis but the thinning of the cornea typically does not align with this meridian; thus, this measure may not provide the maximal measure of AL in the eye. Ernst et al. reported an increase in AL in KC subjects compared with control subjects and no significant association between AL and corneal curvature.35 However, in the current study, AL of the control group is longer than that of the KC group, and this difference is likely to be attributed to the control groups used in the two studies—our control subjects were mild to moderate myopic, whereas the former study group used emmetropic control subjects. There were no significant correlations between Front Km and AL and ACD. Similarly, Bao et al.36 reported no significant correlation between corneal curvature and AL. However, Abolbashari et al.21 reported a correlation between ACD with mean K reading and Back Km. These differences in correlation between corneal curvature and ocular biometry suggest a multifactorial relationship rather than a simple bivariate relationship.
Further, we assessed the correlation between corneal curvatures and other anterior segment parameters. The strong correlation between anterior and posterior corneal curvature adds weight to existing evidence18,20 that suggests that posterior corneal curvature can be predicted from the anterior corneal curvature. CCT, CTA, CTT, and CV correlated significantly with both Front and Back Km in approximately the same magnitude but in opposite directions. These findings suggest that there are similar correlations between anterior/posterior corneal curvatures and other parameters and that corneal thinning is a common indicator of KC progression.30,37,38
These findings also support our recent replication of genome-wide association studies39–41 that showed an association of KC with CCT genes wherein we confirmed the association of two CCT genes with KC.42 Within the general population, CCT is a normally distributed quantitative trait, with evidence from twin and familial studies indicating that it is highly heritable.43–45 Thus, identifying genes involved in corneal thickness may provide a better understanding of the genetic basis of this trait. The main strengths of the study include a large number of subclinical and clinical KC eyes that allows a more accurate interpretation of findings. Further studies comparing the anterior segment parameters in KC patients from different ethnic backgrounds will help us understand the difference in the distribution of these parameters.
In conclusion, corneal thickness at the center and at the apex is an important marker for detecting subclinical KC and different levels of disease severity. These changes result in significant alterations in these parameters as severity of the disease increases. In addition to this, corneal pachymetric readings correlate well with corneal curvature. This suggests that the effect of KC is limited to corneal thickness rather than to other potential anterior segment parameters including AL, CV, and ACD as they appear to undergo a compensatory mechanism to optimize the corneal changes. The results presented here will provide clinicians with guidance in terms of which parameters to assess when detecting subclinical KC in preoperative examination for refractive surgery. This has the advantage of potentially limiting the occurrence of postoperative ectasia and also enables them to better understand changes in varying degrees of KC, which may lead to further advancement in future management of KC.
Centre for Eye Research Australia
Level 1, Royal Victorian Eye and Ear Hospital
32 Gisborne Street
East Melbourne, Victoria, 3002
The authors thank participants from the keratoconus study and the GEM study who made this work possible. The authors also thank the Eye Surgery Associates, Lindsay and Associates, Keratoconus Australia, and Mr. Tony Ngo for assistance with recruitment. A preliminary report on some of these data was presented at the Eucornea Conference, Amsterdam, Netherlands, in October 2013.
This project was funded by the National Health and Medical Research Council (NHMRC) Clinical Research Excellence grant 529923—Translational Clinical Research in Major Eye Diseases, NHMRC Senior Research Fellowship 1028444 (PNB), The Royal Victorian Eye and Ear Hospital Small Research Grants, and the Angior Family Foundation. The Centre for Eye Research Australia receives Operational Infrastructure Support from the Victorian Government. The sponsors or funding organizations had no role in the design or conduct of this research. No conflicting relationship exists for any author.
Received September 14, 2013; accepted April 14, 2014.
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