corneal epithelium is able to alter its thickness to mask subepithelial stromal irregularities and maintain a smooth anterior surface of the eye .
laser refractive surgery such as lasik alters the anterior corneal contour and leads to remodeling of corneal epithelium .
we estimated the extent of the epithelial remodeling after lasik with a mathematical model in a previous study .
however , in that study , we did not have the capability to measure the corneal epithelial thickness to validate the model directly .
instead , we constructed the model constants based on regression in manifest refraction after lasik .
direct measurement of epithelial thickness change may help to better understand corneal epithelial remodeling after lasik and improve lasik ablation patterns with less regression and surgery - induced aberrations .
previous studies used confocal microscopy to measure epithelial thickness , but the number of points measured was limited   and the measurement was time consuming . very high - frequency digital ultrasound was also used to map corneal epithelium and stromal thickness [ 4 , 5 ] . however , because ultrasound can not pass through air , this technique required immersing the cornea in a fluid bath .
though both confocal microscopy and very high - frequency digital ultrasound are feasible in measuring corneal epithelial thickness , they are not often used in routine lasik because they required touching the cornea .
optical coherence tomography ( oct ) is a noncontact imaging technique based on principles of low - coherence interferometry .
the current generation of oct is based on fourier - domain technique [ 6 , 7 ] . in a recent article
, we demonstrated that a commercial fourier - domain oct could automatically map the corneal epithelial thickness with good repeatability . in this study , we use this algorithm to map corneal epithelial thickness for eyes before and after myopic lasik surgeries .
the changes in epithelial thickness were used to validate the smoothing model we mentioned above .
this prospective observational study was conducted at doheny eye institute , los angeles , ca .
the lasik subjects enrolled in this study had no history of eye surgery and were comprehensively examined to exclude any eye diseases including dry eye .
soft contact lenses wearers were asked to stop wearing contact lenses at least two weeks prior to lasik .
the treatment of study subjects was in accordance with the tenets of the declaration of helsinki .
the laser settings were based on manifest and cycloplegic refractions calculated at the corneal plane .
the lasik flap was created with a 60  khz femtosecond laser ( intralase , abbott medical optics , santa ana , ca ) .
the femtosecond flap thickness was programmed to 110  m with a diameter of 9.0  mm and a 70-degree angled side cut .
the stromal ablations were performed with visx star s4 ir customvue excimer laser ( abbott medical optics , santa ana , ca ) .
the optical zone was set to 6.5  mm in diameter centered on the pupil center with blend / transition zones up to 8.0  mm . to measure epithelial thickness before and after lasik , a commercial fourier - domain oct system ( rtvue , optovue inc . ,
fremont , ca ) with a speed of 26,000 axial scans per second was used .
a  pachymetry + cpwr  scan pattern ( 6 mm scan diameter , 8 radials , 1024 axial - scans each , repeated 5 times ) centered at the pupil center was used to map the cornea .
the subjects were asked to look straight ahead and fixate on the internal fixation target of the oct system .
the oct scan pattern was repeated 2 times on each eye during the same visit .
the algorithm was described in a previous article   and was available in the commercial rtvue software .
the average epithelial thickness over the central 1  mm diameter , 1~2  mm , 2~3  mm , 3~4  mm , 4~5  mm , and 5~6  mm annular zones , was used in the analysis .
correlation of lasik - induced change in epithelial thickness with the amount of spherical equivalent of lasik correction was investigated . a smoothing constant  
based on our epithelial smoothing model , the change in epithelial thickness could be calculated by applying a first - order , 2-dimensional butterworth low - pass filter to the ablation profile .
the cutoff frequency of the butterworth filter was the reciprocal of the smoothing constant . if we simulated the ablation profile for 1  d special myopic lasik using munnerlyn algorithm   and assumed the optical zone diameter to be 6.5  mm , the smoothing contact could be estimated .
the smoothing constant has a unit of length and can be thought of as the radius over which epithelial smoothing occurs .
ablation simulations were performed using matlab software version 5.3 ( the mathworks , inc . ,
paired t - test was used to compare the difference of preoperative and postoperative epithelial thickness .
generalized estimating equation was used to account for the intereye correlation in the variance of t - test .
statistical analysis was performed using the microsoft excel and sas 9.1 ( sas institute inc . , cary , nc , usa ) .
nineteen eyes ( 10 right eyes , 9 left eyes ) from 11 myopic lasik patients ( 6 women , 5 men ) were analyzed in the study .
the spherical equivalent of lasik correction ranged from 1.69  d to 6.75  d ( mean : 4.39  1.63  d ) .
corneal epithelium was thicker on the inferior side compared to that on the superior side both before ( figure 1(a ) ) and after lasik ( figure 1(b ) ) .
the average central epithelial thickness was measured to be 52.6  4.1  m ( 40.9~60.6  m ) before lasik and 56.2  4.3  m ( 50.0~65.5  m ) 3 months after lasik ( p = 0.013 , figure 2 ) .
the average epithelial thickness at 5~6  mm annular zone was 51.6  6.6  m ( 39.6~67.4  m ) before lasik and 54.8  4.3  m ( 49.8~68.0  m ) 3 months after lasik ( p = 0.024 , figure 2 ) .
the epithelial thickening reached maximum at about 4  mm diameter and tapered off toward the peripheral ( figure 3 ) .
the change in average central epithelial thickness was significantly correlated with lasik spherical equivalent setting ( figure 4 ) .
the slope of 1.15 indicated that , for every diopter of myopic lasik correction , the central epithelial thickness increased by 1.15  m , which corresponded to a smoothing constant of about 0.46  mm . based on this smoothing constant
pattern ; that is , the maximum epithelial thickening occurred at an annular area around the center ( figure 5 ) .
previous studies have demonstrated that it is feasible to use oct to measure the thickness of different layers of the cornea , such as the epithelium , stroma , and lasik flap using time - domain oct . however , the axial resolution of the earlier oct systems was low and the manual computer - caliper measurement was time consuming . in this study , we used newer fourier - domain oct which has faster scan rate and higher axial resolution with automated measurement of epithelial thickness .
the finding agreed with previous oct studies [ 8 , 12 ] as well as results with very high - frequency digital ultrasound .
the asymmetry might be caused by the movement of upper eyelids during blinking [ 4 , 13 ] .
similar inferior / superior asymmetry in the thickness of corneal epithelium was also found after lasik ( figure 1(b ) ) .
the average central epithelial thickening was about 3.6  m at the 3-month followup for a mean spherical equivalent correction of 4.39  d. this finding is in agreement with previous studies that demonstrated the correlation between central epithelial thickening and the amount of myopia correction [ 5 , 1419 ] . using confocal microscopy , spadea et al .   demonstrated that epithelial thickness increased within the first week after lasik , with a maximum increase of approximately 6.5  m by the third month for a mean spherical equivalent correction of 10.48  d. using very high - frequency digital ultrasound , reinstein et al . found that there was a central approximately 5  mm zone of epithelial thickening of up to 7.5  m 1 year after lasik for a mean spherical equivalent correction of 3.34  d. in a recent study where a similar oct system was used , kanellopoulos and asimellis   found that increases in central ( 0~2  mm diameter ) , midperipheral ( 5  mm diameter ) , and overall mean epithelial thickness appeared to be in almost a linear correlation with the amount of targeted myopic correction ( 1.39  m / d for midperipheral region ) .
the authors hypothesized that epithelial hyperplasia might be caused by a thinned cornea which was biomechanically unstable .
this hypothesis was also supported by a study of epithelial thickness changes after collagen cross - linking ( cxl ) .
however , the epithelial thickness changes could actually be explained by the simultaneous topography - guided ablation to reduce the cone . in other words ,
the epithelial thickness changes could be a response to focal curvature changes   in addition to corneal biomechanical properties .
the average central epithelial thickening was significantly correlated with lasik spherical equivalent setting . for every diopter of
the 1.15  m per diopter epithelial thickening was matched to a smoothing constant of 0.46  mm .
this value was larger than our previous estimate ( 0.32  mm )   probably because of the mix of spherical astigmatism subjects in this dataset .
our results showed more epithelial thickening centrally ( 1  mm diameter zone ) than that paracentrally ( 5 - 6  mm annular zone ) .
this does not agree with a previous study with very high - frequency digital ultrasound   where epithelial thinning was observed between the 5.6  mm and 8  mm diameters except superiorly .
we speculated that the discrepancy may be caused by larger optical zone ( 6.5  mm ) and use of transition zone ( up to 8.0  mm diameter ) in our study compared to the 6  mm optical zone used in the previous study . in figure 2 , if we could measure epithelial thickness beyond 6  mm diameter and the plot could be extrapolated , epithelial thinning would have been observed at the periphery .
however , because we did not have access to the proprietary ablation profiles of the laser companies nor had our current oct system the ability to measure a larger area , we could not provide a more concrete explanation for the disagreement . on the other hand , both clinical data ( figure 3 ) and simulation ( figure 5 ) showed that the maximum epithelial thickening occurred at an annular area about 3~4  mm in diameter , not at the center .
the difference was more obvious on the average epithelial change map from the clinical data than the simulation .
we speculated the reason being that the actual lasik ablation pattern might precompensate for the laser - induced spherical aberration , which meant that the actual ablation at the paracentral area would be deeper than munnerlyn 's algorithm used in the simulation which did not account for spherical aberrations .
in addition , after the compensatory remodeling of corneal epithelium to surface curvature changes , the area with increased epithelial thickening was most likely to be annular because of the ring shape of spherical aberration .
one limitation of this study was that it only included epithelial thickness measurements 3 months after lasik .
however , central epithelial thickening has been reported 1 year   up to 7 years   after excimer laser ablation , all of which found no statistically significant change in central epithelial thickness after 3 months .
therefore , it may be reasonable to assume that the epithelial thickness is stable 3 months after lasik .
it also should be pointed out that , besides focal corneal curvature , changes in corneal biomechanical properties , such as dry eye   and cross - linking [ 23 , 24 ] , may result in corneal remodeling as well .
therefore , it is important to take multiple factors into consideration if they are mixed . in summary ,
fourier - domain oct was demonstrated to be a valuable tool for noncontact measurements of corneal epithelial thicknesses change caused by lasik .
the maximum epithelial thickening occurred at an annular area about 3~4  mm in diameter .
however , wider scans are needed to measure epithelial thickness change toward the edge of the ablation zone .
 
 purpose . to quantify corneal epithelial thickness changes after myopic lasik by oct 
 . methods . 
 epithelial thickness before and after myopic lasik were measured by a fourier - domain oct system . 
 average central ( within 1  mm diameter ) and paracentral epithelial thickness ( 5~6  mm diameter ) before and after lasik were compared . 
 correlation between central epithelial thickness change and laser spherical equivalent setting was evaluated . 
 an epithelial smoothing constant was estimated based on a mathematical model published previously . 
 results . 
 nineteen eyes from 11 subjects were included in the study . 
 eyes had myopic lasik ranging from 1.69  d to 6.75  d spherical equivalent . 
 the average central epithelial thickness was 52.6  4.1  m before lasik and 56.2  4.3  m 3 months after lasik ( p = 0.002 ) . 
 the average paracentral epithelial thickness was 51.6  6.6  m before lasik and 54.8  4.3  m 3 months after lasik ( p = 0.007 ) . 
 the change in average central epithelial thickness was correlated with laser spherical equivalent ( r2 = 0.40 , p = 0.028 ) . 
 the epithelial smoothing constant was estimated to be 0.46  mm . 
 conclusions . corneal epithelial thickens 
 centrally and paracentrally after myopic lasik . the extent of epithelial remodeling correlated with the amount of lasik correction and could be predicted by a mathematical model . 
1. Introduction
2. Materials and Methods
3. Results
4. Discussion