keratoconus is described as a degenerative bilateral , progressive , noninflammatory corneal disorder characterized by ectasia , thinning , and increased curvature.1,2 it is associated with loss of visual acuity particularly in relation to progressive cornea irregularity,3,4 and usually is manifested asymmetrically between the two eyes of the same patient.5,6 occasionally , the patient may present with symptoms of photophobia , glare , and monocular diplopia .
the problem of specificity and sensitivity of keratoconus assessment , particularly the diagnosis of early signs of ectasia and/or subclinical keratoconus , and for monitoring the progression of the disease , has been extensively studied.7 the commonly used options for the clinician include optically - based anterior segment imaging modalities , eg , placido corneal topography8,9 and slit or scheimpflug imaging,10 that provide corneal surface qualitative and quantitative data .
rotating camera scheimpflug imagery ( pentacam , oculus optikgerte gmbh , wetzlar , germany ) , provides a multitude of corneal refractive ( keratometric ) , topometric , tomographic , and pachymetric data.11,12 in addition , specific anterior - surface irregularity indices have been developed for the grading and classification of keratoconus development , as well as the post - operative assessment.1319 the aim of this study was to investigate the values of these indices , the repeatability of their measurement , and their correlation with best spectacle - corrected distance visual acuity ( cdva ) , keratometry , and commonly used keratoconus classification in a large pool of clinically diagnosed keratoconic eyes .
rotating camera scheimpflug imagery ( pentacam , oculus optikgerte gmbh , wetzlar , germany ) , provides a multitude of corneal refractive ( keratometric ) , topometric , tomographic , and pachymetric data.11,12 in addition , specific anterior - surface irregularity indices have been developed for the grading and classification of keratoconus development , as well as the post - operative assessment.1319 the aim of this study was to investigate the values of these indices , the repeatability of their measurement , and their correlation with best spectacle - corrected distance visual acuity ( cdva ) , keratometry , and commonly used keratoconus classification in a large pool of clinically diagnosed keratoconic eyes .
this study received approval from the ethics committee of the authors institution , adherent to the tenets of the declaration of helsinki .
informed consent was obtained from each subject at the time of the first clinical visit .
subjects ages ranged from 1957 years ( average 31.9  7.5 years ) . each case
was subjected to a complete ocular examination , including subjective refraction , cdva measurement with this refraction , and slit - lamp biomicroscopy for clinical signs of keratoconus .
inclusion criteria included a minimum age of 18 years and definite findings consistent with keratoconus , such as those described by the cleck ( collaborative longitudinal evaluation of keratoconus ) group.20 exclusion criteria included systemic disease , previous corneal surgery , history of chemical injury or delayed epithelial healing , and pregnancy or lactation during the study ( for the female patients ) .
anterior segment evaluation , including anterior segment imaging measurements with the pentacam scheimpflug rotating camera , was performed on each case .
the pentacam measurements were obtained and processed via the examination software ( version 1.17r47 ) . for each eye , four consecutive measurements were obtained and processed to test for data acquisition repeatability .
descriptive and comparative statistics , analysis of variance between keratoconus amsler  krumeich stage subgroups , and linear regression were performed with statistics tools provided by minitab version 1.6 ( minitab inc , coventry , uk ) and origin version 9 ( originlab corporation , northampton , ma , usa ) .
subjects ages ranged from 1957 years ( average 31.9  7.5 years ) . each case
was subjected to a complete ocular examination , including subjective refraction , cdva measurement with this refraction , and slit - lamp biomicroscopy for clinical signs of keratoconus .
inclusion criteria included a minimum age of 18 years and definite findings consistent with keratoconus , such as those described by the cleck ( collaborative longitudinal evaluation of keratoconus ) group.20 exclusion criteria included systemic disease , previous corneal surgery , history of chemical injury or delayed epithelial healing , and pregnancy or lactation during the study ( for the female patients ) .
anterior segment evaluation , including anterior segment imaging measurements with the pentacam scheimpflug rotating camera , was performed on each case .
the pentacam measurements were obtained and processed via the examination software ( version 1.17r47 ) . for each eye , four consecutive measurements were obtained and processed to test for data acquisition repeatability .
descriptive and comparative statistics , analysis of variance between keratoconus amsler  krumeich stage subgroups , and linear regression were performed with statistics tools provided by minitab version 1.6 ( minitab inc , coventry , uk ) and origin version 9 ( originlab corporation , northampton , ma , usa ) .
the sample population consisted of 212 cases , which consisted of 65 female and 147 male patients .
the preponderance towards males in the population is consistent with the authors clinical experience in male / female incidence in keratoconic patients21 and keratoconus incidence studies.22 of the 212 eyes , 113 were the right eye and 99 were the left eye .
the average age of all patients was 31.77  7.23 ( range 1957 ) years .
the average  standard deviation cdva ( expressed decimally ) for all eyes was 0.626  0.244 ( range 0.101.00 ) .
average , standard deviation , maximum and minimum corneal surface keratometry , and topometric indices for all eyes in the study are reported in table 1 .
intraindividual repeatability was assessed via the standard deviation of the four consecutive measurements undertaken for each eye .
the average  standard deviation of repeatability for the seven topometric indices in all 212 eyes measured is reported in table 2 .
the sample was presented with an average keratometry on the anterior surface flat axis of 46.7  5.89 d and 51.05  6.59 d on the steep axis .
the statistical analysis showed that 95% of the sample population had a steep axis keratometry > 46.025 d , consistent with the clek group standards.20 paired statistics between cdva and the index of height decentration ( ihd ) , index of surface variance ( isv ) , index of vertical asymmetry ( iva ) , keratoconus index ( ki ) , central keratoconus index ( cki ) , index of height asymmetry ( iha ) , and minimum radius of curvature ( rmin ) ( in the 8 mm zone ) and specifically the coefficient of determination ( r ) and pearson linear regression data between cdva and the ihd , isv , iva , ki , cki , iha , and rmin indices within all eyes in the study group ( n = 212 ) are reported in table 3 .
the correlations between the seven keratoconic anterior surface topometric indices with cdva are illustrated in figure 1a  g .
specifically , the scatter and fitted line plots of isv ( figure 1a ) , iva ( figure 1b ) , ki ( figure 1c ) , cki ( figure 1d ) , iha ( figure 1e ) , ihd ( figure 1f ) , and rmin ( figure 1 g ) versus cdva are plotted , in addition to the 95% confidence ( ci ) and 95% prediction interval ( pi ) lines . the paired data present with coefficient of determination ( r ) of linear correlation with cdva of 0.557 for isv , 0.34 for iva , 0.424 for ki , 0.396 for cki , 0.107 for iha , 0.393 for ihd , and 0.516 for rmin
. the pearson correlation values versus cdva were 0.746 for isv , 0.584 for iva , 0.680 for ki , 0.642 for cki , 0.344 for iha , 0.627 for ihd , and 0.718 for rmin . in all cases ,
the 212 eyes were subjected to keratoconus amsler - krumeich stages grading23 by the pentacam software .
the resulting grading designated n1 = ten eyes as stage i , n12 = eleven eyes as stage i  ii , n2 = 32 eyes as stage ii , n23 = 22 eyes as stage ii  iii , n3 = 54 eyes as stage iii , n34 = 45 eyes as stage iii  iv and n4 = four eyes as stage iv the correlations between cdva and the seven scheimpflug anterior surface keratometric and topometric indices with the above keratoconus grading are illustrated in figure 2a  h .
descriptive statistics for the keratoconus grading subgroups for cdva and the seven topometric indices are presented in table 4 , and two - sample t - test results ( not assuming equal variances ) between the keratoconus grading subgroups for cdva and the seven topometric indices are presented in table 5 .
the sample population consisted of 212 cases , which consisted of 65 female and 147 male patients .
the preponderance towards males in the population is consistent with the authors clinical experience in male / female incidence in keratoconic patients21 and keratoconus incidence studies.22 of the 212 eyes , 113 were the right eye and 99 were the left eye .
the average age of all patients was 31.77  7.23 ( range 1957 ) years .
the average  standard deviation cdva ( expressed decimally ) for all eyes was 0.626  0.244 ( range 0.101.00 ) .
average , standard deviation , maximum and minimum corneal surface keratometry , and topometric indices for all eyes in the study are reported in table 1 .
intraindividual repeatability was assessed via the standard deviation of the four consecutive measurements undertaken for each eye .
the average  standard deviation of repeatability for the seven topometric indices in all 212 eyes measured is reported in table 2 .
the sample was presented with an average keratometry on the anterior surface flat axis of 46.7  5.89 d and 51.05  6.59 d on the steep axis .
the statistical analysis showed that 95% of the sample population had a steep axis keratometry > 46.025 d , consistent with the clek group standards.20 paired statistics between cdva and the index of height decentration ( ihd ) , index of surface variance ( isv ) , index of vertical asymmetry ( iva ) , keratoconus index ( ki ) , central keratoconus index ( cki ) , index of height asymmetry ( iha ) , and minimum radius of curvature ( rmin ) ( in the 8 mm zone ) and specifically the coefficient of determination ( r ) and pearson linear regression data between cdva and the ihd , isv , iva , ki , cki , iha , and rmin indices within all eyes in the study group ( n = 212 ) are reported in table 3 .
the correlations between the seven keratoconic anterior surface topometric indices with cdva are illustrated in figure 1a  g .
specifically , the scatter and fitted line plots of isv ( figure 1a ) , iva ( figure 1b ) , ki ( figure 1c ) , cki ( figure 1d ) , iha ( figure 1e ) , ihd ( figure 1f ) , and rmin ( figure 1 g ) versus cdva are plotted , in addition to the 95% confidence ( ci ) and 95% prediction interval ( pi ) lines . the paired data present with coefficient of determination ( r ) of linear correlation with cdva of 0.557 for isv , 0.34 for iva , 0.424 for ki , 0.396 for cki , 0.107 for iha , 0.393 for ihd , and 0.516 for rmin
. the pearson correlation values versus cdva were 0.746 for isv , 0.584 for iva , 0.680 for ki , 0.642 for cki , 0.344 for iha , 0.627 for ihd , and 0.718 for rmin . in all cases ,
paired statistics between cdva and the index of height decentration ( ihd ) , index of surface variance ( isv ) , index of vertical asymmetry ( iva ) , keratoconus index ( ki ) , central keratoconus index ( cki ) , index of height asymmetry ( iha ) , and minimum radius of curvature ( rmin ) ( in the 8 mm zone ) and specifically the coefficient of determination ( r ) and pearson linear regression data between cdva and the ihd , isv , iva , ki , cki , iha , and rmin indices within all eyes in the study group ( n = 212 ) are reported in table 3 .
the correlations between the seven keratoconic anterior surface topometric indices with cdva are illustrated in figure 1a  g .
specifically , the scatter and fitted line plots of isv ( figure 1a ) , iva ( figure 1b ) , ki ( figure 1c ) , cki ( figure 1d ) , iha ( figure 1e ) , ihd ( figure 1f ) , and rmin ( figure 1 g ) versus cdva are plotted , in addition to the 95% confidence ( ci ) and 95% prediction interval ( pi ) lines . the paired data present with coefficient of determination ( r ) of linear correlation with cdva of 0.557 for isv , 0.34 for iva , 0.424 for ki , 0.396 for cki , 0.107 for iha , 0.393 for ihd , and 0.516 for rmin .
the pearson correlation values versus cdva were 0.746 for isv , 0.584 for iva , 0.680 for ki , 0.642 for cki , 0.344 for iha , 0.627 for ihd , and 0.718 for rmin . in all cases ,
the 212 eyes were subjected to keratoconus amsler - krumeich stages grading23 by the pentacam software .
the resulting grading designated n1 = ten eyes as stage i , n12 = eleven eyes as stage i  ii , n2 = 32 eyes as stage ii , n23 = 22 eyes as stage ii  iii , n3 = 54 eyes as stage iii , n34 = 45 eyes as stage iii  iv and n4 = four eyes as stage iv the correlations between cdva and the seven scheimpflug anterior surface keratometric and topometric indices with the above keratoconus grading are illustrated in figure 2a  h .
descriptive statistics for the keratoconus grading subgroups for cdva and the seven topometric indices are presented in table 4 , and two - sample t - test results ( not assuming equal variances ) between the keratoconus grading subgroups for cdva and the seven topometric indices are presented in table 5 .
the pentacam software compares the measured values with the means and standard deviations of a normal population , and helps provide color - coded  flags .  for example , measured values which exceed the standard deviation by a factor of more than 2.5 are classified as abnormal and highlighted in yellow , and pathological values , ie , values that exceed the standard deviation by a factor of more than three , are highlighted in red .
namely , these indices are the following : isv the unitless standard deviation of individual corneal sagittal radii from the mean curvature .
it is elevated in all types of corneal surface irregularity ( eg , scars , astigmatism , deformities caused by contact lenses , pachymetry ) . according to the manufacturer s user manual,24 an isv larger than 37 is considered abnormal ( marked with yellow ) and larger than 41 is pathological ( marked with red ) .
iva : measure ( expressed in mm ) of the mean difference between superior and inferior corneal curvature ( similar to the commonly used inferior / superior ratio).25 iva is thus the value of curvature symmetry , with respect to the horizontal meridian as the axis of reflection . an iva larger than 0.28 is considered abnormal , and larger than 0.32 is pathological .
ki : a unitless index is expressing the ratio between mean radius values in the upper and lower segment ( r sagittal superior to r sagittal inferior ) . a ki value larger than 1.07 is considered abnormal and/or pathological .
cki : the ratio between mean radius values in a peripheral ring divided by a central ring : r sag ( mean peripheral ) to r sag mean center ( no units ) .
cki is elevated especially in central pachymetric , and increases with the severity of central keratoconus .
iha : the mean difference between height values superior minus height values inferior with horizontal meridian as mirror axis ( expressed in m). iha is calculated by the height data symmetry comparison of the superior and inferior area , and provides the degree of symmetry of height data with respect to the horizontal meridian as the axis of reflection .
iha is similar to the iva but based on corneal elevation , and is thus more sensitive .
an iha value larger than 19 is considered abnormal , and larger than 21 is pathological .
ihd : the value of the decentration of elevation data in the vertical direction ( expressed in m ) , and is calculated from a fourier analysis . this index provides the degree of decentration in the vertical direction , calculated on a ring with radius 3 mm .
an ihd value larger than 0.014 is considered abnormal , and larger than 0.016 is pathological .
it is a measurement of the smallest radius of sagittal corneal curvature ( ie , the maximum steepness of the cone ) .
values of rmin less than 6.71 mm are considered abnormal and/or pathological , considering that the average radius of the anterior corneal surface is 7.87  0.27 mm.26 association with these indices with clinical keratoconus observations is provided by the manufacturer and is listed in table 6 .
the clinical suspicion of early - stage keratoconus may be based on refraction criteria such as a change in refractive power and the axis of astigmatism , fluctuating refraction , and several clinical findings ( eg , conspicuous retinoscopy signs ) .
optical imaging , such as topometry and topography , provides valuable supplementary information , and it has long been supported that the contribution of proper evaluation and analysis of anterior surface irregularity derived from topography27 or more recently from pentacam topometry ( eg , the seven topographic indices studied in this manuscript ) , may provide an invaluable aid in the diagnosis and progression evaluation of the disease.28 only two reports have been identified that address this matter of correlation of the above pentacam - derived indices with cdva29 and the severity of keratoconus classification.30 the correlation between the seven anterior surface topographic indices and cdva appears not very strong in our study . the rmin ( r = 0.516 , p < 0.001 ) and isv ( r = 0.557 , p <
0.001 ) were found to be the strongest correlated indices with cdva , in comparison to the other indices .
the least correlated index was iha ( r = 0.107 , p < 0.001 ) .
this could be a result of significantly worse intraindividual repeatability of this index , possibly as a result of the complicated nature of its algorithm .
as indicated in table 2 , repeatability , measured by the standard deviation of the measured index over four consecutive acquisitions , was as good as 1.50% on average for rmin and up to 4.6% for ihd and iva ; however , the iha index had a distinctive 43.78% average standard deviation among any four consecutive measurements , indicating very poor repeatability .
in addition , the iha index had the worst correlation with keratoconus severity ( figure 2f ) with two stages not statistically significant and the remaining also borderline .
this study indicates that the correlation between keratoconus severity , and possibly very early progression indicators , and the anterior surface topographic indices can be better described with the isv ( with the exception of the highest stage [ stage iv ] , all other p - values were < 0.001 ) , followed by the ihd ( with the exception of the lowest stage [ stage i ] , all other p - values were < 0.001 ) .
in addition , our results indicate that the visual performance in keratoconus was not clearly predicable for keratoconus severity , and thus cdva can not be a dependable indicator of keratoconus severity and/or progression and therefore can not be employed in postoperative assessment aiming to arrest keratoconus progression by , for example , crosslinking with riboflavin.31 it is customary to assess severity based on visual function and , as noted above , appears to be deceiving .
for example , the data presented in this work ( figure 2a ) suggest that cdva is not very well correlated with the keratoconus severity , as the spread of cdva measurements within the same  severity stage 
the average coefficient of determination ( r ) was in the order of 0.5 , in agreement with previous studies.32 the above results are in agreement with the authors past clinical experience with a significant number of keratoconic patients followed for over 15 years .
the observation has been that visual acuity can present with large variations , and can sometimes be unexpectedly good for the corresponding keratometry and overall corneal asymmetry .
( ie , adaptable ) cornea in addition to possible advanced neural processing development in the individual . however , these  advantages  are , to a large degree , compromised by the procedure of crosslinking with riboflavin applied in young ( 1825 years old ) keratoconus patients in long - term clinical observations .
although not specifically studied herein , clinical assessment of this group is that cdva is poorly correlated to keratoconus severity mainly in younger patients .
as older keratoconus patients were encountered ( ie , those over 30 years old and in most of those over 40 years old ) , their cdva started to correlate with the isv and ihd .
this observation poses an even greater reason for clinicians to employ the strongest clinical suspicion in younger patients that may be at risk for developing keratoconus and may be labeled  normal  if a very good cdva performance is maintained .
this may be explained by the higher elasticity of the pathologic cornea in younger keratoconus patients .
this age - related difference may allow them to achieve high cdva values with monocular testing by squinting and/or head tilting .
isv and ihd assessment in younger patients with relative low keratometric values may be the crucial factor in early diagnosis of keratoconus .
we have encountered this clinical finding exaggerated in very young ( 1822 years ) keratoconic patients that had in the past undergone just cross - linking stabilization .
we theorize that by increasing the biomechanical stability with cxl , these patients start to more appreciate the existing corneal irregularity.31,33,34
the isv and iha , both derived from scheimpflug corneal imaging , may be more sensitive and specific tools than cdva in evaluating early diagnosis and possible progression in keratoconus patients and corneal ectasia . they may become a novel benchmark for future studies , and may aid in the development of new keratoconus diagnostic and follow - up criteria .
 purposeto survey the standard keratoconus grading scale ( pentacam-derived amsler  krumeich stages ) compared to corneal irregularity indices and best spectacle - corrected distance visual acuity ( cdva).patients and methodstwo - hundred and twelve keratoconus cases were evaluated for keratoconus grading , anterior surface irregularity indices ( measured by pentacam imaging ) , and subjective refraction ( measured by cdva ) . the correlations between cdva , keratometry , and the scheimpflug keratoconus grading and the seven anterior surface pentacam - derived topometric indices  index of surface variance , index of vertical asymmetry , keratoconus index , central keratoconus index , index of height asymmetry , index of height decentration , and index of minimum radius of curvature  were analyzed using paired two - tailed t - tests , coefficient of determination ( r2 ) , and trendline linearity.resultsthe average  standard deviation cdva ( expressed decimally ) was 0.626  0.244 for all eyes 
 ( range 0.101.00 ) . 
 the average flat meridian keratometry was ( k1 ) 46.7  5.89 d ; the average steep keratometry ( k2 ) was 51.05  6.59 d. the index of surface variance and the index of height decentration had the strongest correlation with topographic keratoconus grading ( p < 0.001 ) . 
 cdva and keratometry correlated poorly with keratoconus severity.conclusionit is reported here for the first time that the index of surface variance and the index of height decentration may be the most sensitive and specific criteria in the diagnosis , progression , and surgical follow - up of keratoconus . 
 the classification proposed herein may present a novel benchmark in clinical work and future studies . 