Rate of Change of Curvature of the Corneal Stromal Surface Drives Epithelial Compensatory Changes and Remodeling

CorrespondenceRate of Change of Curvature of the Corneal Stromal Surface Drives Epithelial Compensatory Changes and Remodeling Dan Z. Reinstein, MD, MA(Cantab), FRCOphth, , , MD, MA(Cantab), FRCOphth Timothy J. Archer, MA(Oxon), DipCompSci(Cantab), , and , MA(Oxon), DipCompSci(Cantab) Marine Gobbe, MST(Optom), PhD, , MST(Optom), PhD Dan Z. Reinstein, MD, MA(Cantab), FRCOphth , Timothy J. Archer, MA(Oxon), DipCompSci(Cantab) , and Marine Gobbe, MST(Optom), PhD Published OnlineNovember 13, 2014https://doi.org/10.3928/1081597X-20141113-02Cited by:27PDFView Full Text ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinkedInRedditEmail SectionsMore1.Kanellopoulos AJ, Asimellis G. Longitudinal postoperative lasik epithelial thickness profile changes in correlation with degree of myopia correction. J Refract Surg. 2014; 30:166–171. MedlineGoogle Scholar2.Reinstein DZ, Archer TJ, Gobbe M. Change in epithelial thickness profile 24 hours and longitudinally for 1 year after myopic LASIK: three-dimensional display with Artemis very high-frequency digital ultrasound. J Refract Surg. 2012; 28:195–201.10.3928/1081597X-20120127-02 LinkGoogle Scholar3.Kanellopoulos AJ, Aslanides IM, Asimellis G. Correlation between epithelial thickness in normal corneas, untreated ectatic corneas, and ectatic corneas previously treated with CXL: is overall epithelial thickness a very early ectasia prognostic factor?Clin Ophthalmol. 2012; 6:789–800.10.2147/OPTH.S31524 Crossref MedlineGoogle Scholar4.Reinstein DZ, Silverman RH, Coleman DJ. High-frequency ultrasound measurement of the thickness of the corneal epithelium. Refract Corneal Surg. 1993; 9:385–387. LinkGoogle Scholar5.Reinstein DZ, Archer TJ, Gobbe M, Silverman RH, Coleman DJ. Epithelial thickness in the normal cornea: three-dimensional display with Artemis very high-frequency digital ultra-sound. J Refract Surg. 2008; 24:571–581. LinkGoogle Scholar6.Gauthier CA, Holden BA, Epstein D, Tengroth B, Fagerholm P, Hamberg-Nystrom H. Factors affecting epithelial hyperplasia after photorefractive keratectomy. J Cataract Refract Surg. 1997; 23:1042–1050.10.1016/S0886-3350(97)80078-8 Crossref MedlineGoogle Scholar7.Wang J, Thomas J, Cox I, Rollins A. Noncontact measurements of central corneal epithelial and flap thickness after laser in situ keratomileusis. Invest Ophthalmol Vis Sci. 2004; 45:1812–1816.10.1167/iovs.03-1088 Crossref MedlineGoogle Scholar8.O'Brart DP, Corbett MC, Lohmann CP, Kerr Muir MG, Marshall J. The effects of ablation diameter on the outcome of excimer laser photorefractive keratectomy: a prospective, randomized, double-blind study. Arch Ophthalmol. 1995; 113:438–443.10.1001/archopht.1995.01100040054026 Crossref MedlineGoogle Scholar9.O'Brart DP, Gartry DS, Lohmann CP, Muir MG, Marshall J. Excimer laser photorefractive keratectomy for myopia: comparison of 4.00- and 5.00-millimeter ablation zones. J Refract Corneal Surg. 1994; 10:87–94. LinkGoogle Scholar10.Gauthier CA, Holden BA, Epstein D, Tengroth B, Fagerholm P, Hamberg-Nystrom H. Role of epithelial hyperplasia in regression following photorefractive keratectomy. Br J Ophthalmol. 1996; 80:545–548.10.1136/bjo.80.6.545 Crossref MedlineGoogle Scholar11.Reinstein DZ, Srivannaboon S, Gobbe M, et al.Epithelial thickness profile changes induced by myopic LASIK as measured by Artemis very high-frequency digital ultrasound. J Refract Surg. 2009; 25:444–450.10.3928/1081597X-20090422-07 LinkGoogle Scholar12.Hamberg-Nystrom H, Gauthier CA, Holden BA, Epstein D, Fagerholm P, Tengroth B. A comparative study of epithelial hyperplasia after PRK: Summit versus VISX in the same patient. Acta Ophthalmol Scand. 1996; 74:228–231.10.1111/j.1600-0420.1996.tb00081.x Crossref MedlineGoogle Scholar13.Lohmann CP, Guell JL. Regression after LASIK for the treatment of myopia: the role of the corneal epithelium. Semin Ophthalmol. 1998; 13:79–82.10.3109/08820539809059822 Crossref MedlineGoogle Scholar14.Spadea L, Fasciani R, Necozione S, Balestrazzi E. Role of the corneal epithelium in refractive changes following laser in situ keratomileusis for high myopia. J Refract Surg. 2000; 16:133–139. LinkGoogle Scholar15.Reinstein DZ, Archer TJ, Gobbe M, Silverman RH, Coleman DJ. Epithelial thickness after hyperopic LASIK: three-dimensional display with Artemis very high-frequency digital ultrasound. J Refract Surg. 2010; 26:555–564.10.3928/1081597X-20091105-02 LinkGoogle Scholar16.Reinstein DZ, Archer TJ, Gobbe M. Epithelial thickness up to 26 years after radial keratotomy: three-dimensional display with Artemis very high-frequency digital ultrasound. J Refract Surg. 2011; 27:618–624.10.3928/1081597X-20110125-01 LinkGoogle Scholar17.Reinstein DZ, Gobbe M, Archer TJ, Couch D, Bloom B. Epithelial, stromal, and corneal pachymetry changes during orthokeratology. Optom Vis Sci. 2009; 86:E1006–E1014.10.1097/OPX.0b013e3181b18219 Crossref MedlineGoogle Scholar18.Reinstein DZ, Archer TJ, Gobbe M, Silverman RH, Coleman DJ. Epithelial, stromal and corneal thickness in the keratoconic cornea: three-dimensional display with Artemis very high-frequency digital ultrasound. J Refract Surg. 2010; 26:259–271.10.3928/1081597X-20100218-01 LinkGoogle Scholar19.Reinstein DZ, Gobbe M, Archer TJ, Couch D. Epithelial thickness profile as a method to evaluate the effectiveness of collagen cross-linking treatment after corneal ectasia. J Refract Surg. 2011; 27:356–363.10.3928/1081597X-20100930-01 LinkGoogle Scholar20.Reinstein DZ, Silverman RH, Sutton HF, Coleman DJ. Very high-frequency ultrasound corneal analysis identifies anatomic correlates of optical complications of lamellar refractive surgery: anatomic diagnosis in lamellar surgery. Ophthalmology. 1999; 106:474–482.10.1016/S0161-6420(99)90105-7 Crossref MedlineGoogle Scholar21.Reinstein DZ, Archer T. Combined Artemis very high-frequency digital ultrasound-assisted transepithelial phototherapeutic keratectomy and wavefront-guided treatment following multiple corneal refractive procedures. J Cataract Refract Surg. 2006; 32:1870–1876.10.1016/j.jcrs.2006.07.016 Crossref MedlineGoogle Scholar22.Reinstein DZ, Archer TJ, Gobbe M. Refractive and topographic errors in topography-guided ablation produced by epithelial compensation predicted by three-dimensional Artemis very high-frequency digital ultrasound stromal and epithelial thickness mapping. J Refract Surg. 2012; 28:657–663.10.3928/1081597X-20120815-02 LinkGoogle Scholar23.Reinstein DZ, Archer TJ, Gobbe M. Improved effectiveness of trans-epithelial phototherapeutic keratectomy versus topography-guided ablation degraded by epithelial compensation on irregular stromal surfaces. J Refract Surg. 2013; 29:526–533.10.3928/1081597X-20130719-02 LinkGoogle Scholar24.Reinstein DZ, Archer TJ, Dickeson ZI, Gobbe M. Trans-epithelial phototherapeutic keratectomy protocol for treating irregular astigmatism based population on epithelial thickness measurements by Artemis very high-frequency digital ultrasound. J Refract Surg. 2014; 30:380–387.10.3928/1081597X-20140508-01 LinkGoogle Scholar25.Reinstein DZ, Archer TJ, Gobbe M, Rothman RC. Epithelial thickness changes following the realignment of a malpositioned free cap. J Cataract Refract Surg. 2014; 40:1237–1239.10.1016/j.jcrs.2014.05.006 Crossref MedlineGoogle Scholar26.Kanellopoulos AJ, Asimellis G. Introduction of quantitative and qualitative cornea optical coherence tomography findings induced by collagen cross-linking for keratoconus: a novel effect measurement benchmark. Clin Ophthalmol. 2013; 7:329–335.10.2147/OPTH.S40455 Crossref MedlineGoogle ScholarJRSJournal of Refractive SurgeryJ Refract Surg1081-597X1938-2391SLACK IncorporatedThorofare, NJ10.3928/1081597X-20141113-0210.3928_1081597X-20141113-02Correspondence Reply:Kanellopoulos Anastasios John, , MD, and Asimellis George, , PhDAthens, GreeceDr. Kanellopoulos is a consultant to Alcon Surgical, Inc., Wavelight Laser Technologie AG, Avedro, Inc., Optovue, and i-Optics. Dr. Asimellis has no financial or proprietary interest in any material or method mentioned.01122014 3012802805Copyright 2014, SLACK Incorporated2014SLACK IncorporatedWe would like to thank Reinstein et al. for their letter in regard to our investigative work on epithelial remodeling following myopic LASIK by femtosecond laser,1 particularly the findings pertaining to a possible correlation between epithelial thickness increase versus attempted myopic correction. Their comments help us clarify further and summarize the recent findings in epithelial thickness imaging.To properly answer the well-presented and extensively documented points, one has to also consider the specifics of the optical coherence tomography (OCT) imaging modality employed in our work versus the ultrasound imaging modality employed in the past and used for comparison.Epithelial Thickness Mapping: Imaging Technologies ComparedThree-dimensional epithelial thickness maps were introduced using high-frequency ultrasound (HFU) by the system known as Artemis (ArcScan, Inc., Morrison, CO and/or Artemis Medical Technologies Inc., Vancouver, British Columbia, Canada). We also have had the opportunity to work with this exciting technology and report some compelling findings.2–4The recent ability of in vivo epithelial thickness mapping by Fourier-domain anterior segment OCT (AS-OCT) offered by the RtVue-100 (Optovue Inc., Fremont, CA) has further expanded the applicability and clinical importance of epithelial thickness mapping. Among the advantages of the newly emerging modality are the high repeatability,5,6 ease of use, and acquisition speed. Although the overall acquisition and data visualization still rely on interpolation from raw data derived from several meridional scans, there are specific advantages when one compares the OCT option for epithelial imaging to the HFU option. The first advantage derives from fact that the OCT does not need fluid coupling between the eye and the device. This feature not only facilitates clinical implementation even on the first postoperative day—something that is avoided for reasons of possible wound contamination when the Artemis system is involved—but also makes the acquisition reliable and repeatable. The second is that the OCT imaging of eight meridians is completed in less than a second, which compares to several minutes of successive manual changes (by means of rotating a steering wheel located at the back of the HFU system). The typical number of successive meridional scans required for the HFU imaging is four. Among the possible shortcomings associated with the current state of the OCT-based epithelial imaging is the fact that up to now, imaging is restricted to the central 6-mm corneal diameter, compared, for example, to the 9-mm diameter offered by the HFU system. Another is the fact that the current state of OCT-based epithelial imaging cannot differentiate the tear film, which is "collectively" reported within the epithelial thickness; in comparison, the HFU system may alter the epithelial in vivo state by intense hydration, associated with the capture process that requires the cornea within a "water bath."Therefore, a comparison of findings may not always be applicable. Differences in technology may account for the possibility that aspects of the epithelial layer distribution may be manifested in a different fashion.Epithelial Thickness Distribution CharacteristicsOver the past 5 years, we have extensively investigated AS-OCT imaging inspired from the work previously reported and have employed such routine imaging in all patient visits in our referral type specialized clinical center. Because of this, we have performed more than half a million individual eye scans, employing AS-OCT, and have reported corneal epithelial distribution in large groups of normal patients,7 patients with dry eye,8 and patients with keratoconus9 using epithelial remodeling following cataract surgery,10 Descemet stripping automated endothelial keratoplasty,11 cornea collagen cross-linking,12 and high-myopic LASIK intervention with concurrent prophylactic cross-linking.13 We have also investigated via the HFU system epithelial thickness mapping in corneas that were normal, ectatic, and ectatic previously treated with CXL.2 A novel finding of this work was that, in addition to the specific/local epithelial distribution, overall epithelial thickness may be a possible indicator for corneal instability. In our opinion, this hypothesis seems to be a groundbreaking interpretation of the epithelial response to increased oscillation of a biomechanically "weakened" stroma encountered in progressive keratoconus and ectasia. Such a hypothesis will only survive the test of time and multiple corroborative elements of evidence such as a reliable device that may assess corneal biomechanical behavior.We have encountered several such elements over the course of our extensive investigation, which we would like to summarize: 1.In normal eyes, the epithelial thickness has a near-uniform distribution of approximately 53 μm, ranging between 45 and 60 μm. Epithelial thickness is slightly increased inferiorly. Average topographic variability, expressed by the standard deviation of several points, is 2 μm. The epithelial thickness range (difference minimum – maximum) is −8 μm, ranging from an average minimum of 48 μm to an average maximum of 56 μm.72.There is a noted overall increase of epithelial thickness in dry eyes (average 58 μm); however, the topographic variability is comparable to that of normal eyes (average 3 μm).83.In corneas characterized by ectasia, there is a noted increase in the spread of thickness values. We have noted an average epithelial thickness range of −23 μm and an average topographic variability of 10 μm.2,9 Investigation with OCT has verified the compensatory nature of epithelial distribution in response to anterior stromal surface irregularities: indeed, the epithelium is thinner over the steeper 'conic' section in a keratoconic eye and thicker over the flatter areas. In addition to this, however, we have noted an overall increase in epithelial thickness, particularly in younger patients with keratoconus.24.Epithelial thickness remodeling investigated after keratoplasty11 and cataract surgery10 has indicated a return to baseline levels after a 3-month interval.5.Epithelial thickness remodeling following partial anterior cornea normalization and cross-linking (Athens Protocol)2,12 has indicated that the epithelium is on average thinner compared to untreated eyes with keratoconus, and even compared to 'normal' corneas, despite the residual anterior corneal surface abnormality. The only justification for such a manifestation is perhaps the increased stromal rigidity.6.Epithelial thickness remodeling following LASIK has indicated a slight (average +3 μm) increase in epithelial thickness.1 A novel finding has been that the increase was rather non-lenticular (a finding reported by Reinstein et al.14), but more emphasized in the mid-periphery of 5 mm. Of course, the extent of epithelial remodeling over the entire affected area of perhaps up to 8 mm is still not clinically possible with the current state of OCT imaging. A second novel finding has been that the noted increase showed a positive correlation to the amount of attempted myopic correction: the larger the myopic correction, and thus the stromal flattening, the larger the noted epithelial thickness increase.7.The interpretation of the above finding is, in our opinion, the core of the argument posted by this correspondence. We respectfully disagree to attributing this finding exclusively to the rate of change of curvature and the resultant compensatory response of the epithelium remodeling. The reasons for our different opinion are based on two key findings. First, our investigation of matched groups of myopic ablation, between a 'standard' LASIK treatment and a LASIK treatment with concurrent prophylactic in situ cross-linking has indicated that there is no noted increase in epithelial remodeling when the cross-linking is applied.13 Second, our ongoing investigation of myopic correction applied with photorefractive keratectomy has routinely indicted a drastically different epithelial remodeling. The example in Figure 1 illustrates corneal and epithelial thickness mapping following 1 year of myopic correction with photorefractive keratectomy. In Figure 1A a 28-year-old man received −5.00 diopters of correction and in Figure 1B a 27-year-old man received −8.00 D of correction. The remodeled epithelial pattern presented in these cases may not be justified with the compensatory theory for several reasons. First, the epithelial thickness increase is similar in both cases, despite the larger myopic correction, and thus stromal flattening. Second, the noted thickness increase (average +20 μm, compared to preoperative levels) is drastically larger when compared to similar myopic ablations performed with LASIK.1 Had the compensatory theory been valid in all cases, this is a finding impossible to explain. Therefore, other aspects (in this case the removal of Bowman's layer) or even a "steeper" transition zone between the ablation and the peripheral cornea that may be "smoother" in LASIK due to some overlying flap masking may also be some important contributing factors.Figure 1. One year postoperative corneal and epithelial thickness mapping of cases that received myopic correction by photorefractive keratectomy. (A) A case of a 28-year-old man who received −5.00 diopters of correction. (B) A case of a 27-year-old man who received −8.00 diopters of correction.We believe that the clinical differences observed, despite the possible attribution to the epithelial compensatory response, may not be fully justified with this theory. Our proposed hypothesis of epithelial response being related to corneal rigidity may offer an additional clinical finding, which has a follow-up potential. The anticipated clinical ramifications of this hypothesis is prospectively positive. Nevertheless, we have learned much from the preceding HFU experience and most of the credit of this body of work goes to the discussants.What we suggest as a clinical pearl to clinicians is that, in our current clinical setting, epithelial and total corneal three-dimensional mapping has become a critical diagnostic tool in the preoperative assessment of patients undergoing cataract refractive surgery and evaluation of dry eye and multiple other external disease modalities. Epithelial and total corneal mapping has also become an integral tool in monitoring visual recovery and quality of vision in both cataract and refractive surgery cases alongside traditional means of corneal imaging such as Placido-based topography and Scheimpflug tomography.15Anastasios John Kanellopoulos, MDGeorge Asimellis, PhD Athens, Greece Previous article Next article FiguresReferencesRelatedDetailsCited byZhou W, Reinstein D, Archer T, Nitter T, Feng Y, Mule G and Stojanovic A (2022) The Impact of Epithelial Remodeling on Surgical Techniques Used in Topography-guided Surface Ablation in Irregular Corneas, Journal of Refractive Surgery, 38:8, (529-537), Online publication date: 1-Aug-2022.Yu N, Ye Y, Chen P, Yang Y, Zhuang J and Yu K (2021) Corneal Epithelial Thickness Changes Following SMILE for Myopia With High Astigmatism, Journal of Refractive Surgery, 37:4, (224-230), Online publication date: 1-Apr-2021. 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Seven I, Lloyd J and Dupps W (2019) Differences in Simulated Refractive Outcomes of Photorefractive Keratectomy (PRK) and Laser In-Situ Keratomileusis (LASIK) for Myopia in Same-Eye Virtual Trials, International Journal of Environmental Research and Public Health, 10.3390/ijerph17010287, 17:1, (287) Mohr N, Shajari M, Krause D, Kassumeh S, Siedlecki J, Priglinger S, Mayer W and Luft N (2020) Pellucid marginal degeneration versus keratoconus: distinction with wide-field SD-OCT corneal sublayer pachymetry, British Journal of Ophthalmology, 10.1136/bjophthalmol-2020-316496, (bjophthalmol-2020-316496) Request Permissions InformationCopyright 2014, SLACK IncorporatedPDF downloadDr. Reinstein is a consultant for Carl Zeiss Meditec (Jena, Germany), has a proprietary interest in the Artemis technology (ArcScan, Inc., Morrison, CO), and is an author of patents related to VHF digital ultrasound administered by the Cornell Research Foundation, Ithaca, NY. The remaining authors have no financial or proprietary interest in the materials presented herein.