Epithelial thickness mapping in the care of refractive surgery patients

Knowledge of corneal epithelial thickness patterns in normal and abnormal refractive surgery cases may be beneficial in close-call clinical judgements. The epithelium is not of homogeneous depth over the Bowman layer and often compensates for stromal surface irregularities, becoming thicker over valleys and thinner over hills where the stroma protrudes, as it attempts to minimise abrupt changes in stromal thickness.

As a result, the anterior cornea may appear smoother on topography compared with the underlying anterior stroma. Therefore, assessment based on topography and total corneal pachymetry with no knowledge of epithelial depth may be misleading, and result in an incorrect assessment of preoperative keratoconus and postrefractive surgery ectasia progression.

As a result, I incorporate preoperative and postoperative corneal epithelial thickness mapping into my care of refractive surgery patients.

Preoperative mapping benefits

Epithelial thickness mapping can help us identify early keratoconus while screening patients for corneal refractive surgery. Although keratoconus can also be identified with topography, epithelial thickness mapping provides additional supporting evidence in the diagnosis, which allows us to offer alternative treatment options.

Kanellopoulos et al found that overall epithelial thickness appears increased in ectatic corneas. They suggested that overall average increased epithelial thickness may be a reliable early biological marker of loss of biomechanical corneal stability.

Their results indicated that, firstly, highly irregular epithelium is often an indicator for a thicker and ectatic cornea; secondly, the epithelium is thinner over the keratoconic protrusion, often by up to 30 μm; and thirdly, on average, there is a thicker epithelium in keratoconic corneas.¹

They further noted that nonprogressive and nonectatic conditions, such as contact lens warpage, can give similar topographic appearances, making clinical decision-making difficult.  They examined the relationship between epithelial thickness and corneal topography maps in patients with keratoconus or contact lens warpage and determined that there was focal epithelial thickening associated with the areas of corneal steepening in contact lens warpage, which was in contrast with the focal epithelial thinning associated with the areas of corneal steepening in keratoconus.

In conclusion, careful preoperative examination of epithelial thickness and its distribution may be a useful tool for detection of early keratoconus.²

Postoperative mapping benefits

Refractive regression
Post-operatively, corneal epithelial changes are known to play a role in refractive regression. This refractive effect should be considered when planning surgery, since it may help to increase the accuracy of the surgery results.

Corneal epithelium contributes to the refractive power of the cornea, and thus to total ocular refraction. The refractive power of the epithelium alone ranges from 0.55–1.85 D at the central 2.0-mm diameter zone and 0.29–1.60 D at the 3.6-mm diameter zone.³

Therefore, it is helpful to differentiate between regression due to epithelial hypertrophy and early corneal ectasia, where it thins over areas of relative increases in corneal curvature and thickens over areas of relative flattening in corneal curvature. Determining these findings could entirely change the management of a patient presenting with residual power for solution.

In the case of regression, enhancement is possible provided that adequate tissue is available. If the patient is an ectasia suspect, one would either only do crosslinking of the cornea or perform topography-guided PRK with a crosslinking procedure.

Central epithelial thickening
Because the natural shape of the cornea is altered by the laser during post-refractive surgery, the epithelium acts as a filler and tries to cover the areas where the curvature has been changed. Essentially, it tries to bring the cornea back into its original shape as a natural and compensatory mechanism.

Numerous reports have been published describing central epithelial thickening following central tissue removal by myopic excimer laser ablations, which has been related to myopic regression.^4,5 During myopic corrections, the tissue is removed from the central part of the cornea, which flattens postoperatively because of the treatment.

However, since the corneal epithelium can alter its thickness profile and either partially or totally mask the presence of an irregular underlying stromal surface, it shows a tendency toward proliferation in the central zone in its attempt to compensate for the central flattening.

My colleagues and I conducted a study of epithelial thickness changes following small incision lenticule extraction (SMILE) for myopia. We observed a statistically significant epithelial thickness increase in the central zone (6.83% for low, 9.26% for moderate and 12.7% for high myopia, P values <0.05 for all groups) and superior zone (3.98% for low, 7.82% for moderate and 9.87% for high myopia) across all the three groups, which correlated positively with the degree of myopia corrected (r²=0.723 for central zone, r²=0.585 for superior zone, P<0.001 for both zones) at 3 months’ follow-up.

Four eyes of two patients with high myopia (SE >-8D) had regression due to significant epithelial thickening. Therefore, we concluded that significant epithelial thickening may occur following SMILE, especially in high myopia, leading to regression and changes in refraction. The study of the epithelial thickness profile may differentiate between regression and under correction seen in the postoperative period.⁶

It may also be an indispensible tool to diagnose early ectasia prior to LASIK or SMILE and differentiate it from regression. In the former scenario, the epithelium would show thinning over the steepest portion of the cornea, while in the latter scenario it would show thickening in the central zone corresponding to the flattened area post-myopic laser refractive surgery.

The changes after hyperopic LASIK, however, follow an opposite trend. Three-dimensional high-resolution ultrasound mapping of epithelial thickness profile after LASIK for hyperopia demonstrated thinner epithelium centrally and thicker epithelium paracentrally.⁷

Presumably, the paracentral epithelial thickening compensated in part for the stromal tissue removed by the hyperopic ablation, whereas the central epithelial thinning compensated for the localised increase in corneal curvature. A hyperopic ablation is designed to steepen the central cornea, which bears a similarity to the morphology of a keratoconic cornea, so the epithelial thickness profile after hyperopic ablation is expected to follow a similar pattern to that seen in keratoconus.

Reinstein et al found that the epithelial thickness profile across the central 8-mm diameter follows an epithelial doughnut pattern characterised by epithelial thinning over the cone surrounded by an annulus of epithelial thickening.⁸

This degree of epithelial thickening was significantly greater than the central epithelial thickening reported after myopic LASIK. Reinstein et al previously reported a maximum of 18 μm epithelial thickening after a −13.50 D myopic ablation.

This could be explained by the epithelial response according to the profile of tissue removed; hyperopic ablations induce a more abrupt change in curvature as the ablation must fit into half the cornea compared with myopic ablations where the change in curvature is more gradual across the diameter of the cornea. The epithelium appears to compensate more for a localised stromal irregularity.

Wound healing response
There are complex interactions between the corneal epithelium and the stroma that occur as part of the wound healing response after refractive surgery. Both the corneal epithelial thickness and the corneal response to injury can greatly influence the post-operative course.

Møller-Pedersen et al demonstrated that activated keratocyte-mediated rethickening of the photoablated stroma was a key biological factor responsible for post-PRK regression of myopia. They demonstrated that the corneal rethickening causes myopic regression mediated almost solely by stromal rethickening.

Only a minor contribution appeared to originate from restoration of the postoperative epithelial thickness.⁹ In their study, they found a significant thickening in the posterior stroma between 1 week and 1 month after surgery. Meanwhile, the spheroequivalent refraction changed considerably to the myopic side between these time points (−0.34 versus −0.57), but the difference was not statistically significant.

It is possible that the posterior stromal rethickening seen 1 month after LASIK may be related to the activated keratocytes, since the highest value for the thickness of the activated keratocyte zone was found at the 1-week postoperative examination point, and it is well known that activated keratocytes are associated with the healing process after excimer laser treatment.

Normally, it would be expected that a 10- to 15-μm rethickening of the posterior stroma produced a 1-D myopic shift, but the much greater rethickening observed in their study created only a small amount of refractive change.

This finding may suggest that the cornea simply swells after LASIK treatment and anterior curvature does not change despite a high degree of thickening. However, pachymetry data or corneal curvature measurement is required to support this hypothesis.

Conclusion

Corneal epithelial imaging is an important and must-have tool in the armamentarium of a refractive surgeon. Corneal epithelial thickness mapping may become an easy and objective tool in the diagnosis of biomechanically unstable corneas and perhaps a multitude of anterior segment disorders, such as dry eye, delayed epithelial healing and Meibomian gland dysfunction.

References

1.     Kanellopoulos AJ, Asimellis G. Anterior segment optical coherence tomography – assisted topographic corneal epithelial thickness distribution imaging of a keratoconus patient. Case Rep Ophthalmol. 2013;4:74-78.

2.     Schallhorn JM, et al. Distinguishing between contact lens warpage and ectasia: Usefulness of optical coherence tomography epithelial thickness mapping. J Cataract Refract Surg. 2017;43:60–66

3.     Simon G, et al. Optics of the corneal epithelium. Refract Corneal Surg. 1993;9(1):42-50.

4.     Reinstein DZ, et al. Epithelial Thickness Profile Changes Induced by Myopic LASIK as Measured by Artemis Very High-frequency Digital Ultrasound. J Refract Surg. 2009 May ;25(5):444–450.

5.     Lohmann CP, Guell JL. Regression after LASIK for the treatment of myopia: the role of the corneal epithelium. Semin Ophthalmol. 1998;13:79–82.

6.     Ganesh S , Brar S , Relekar KJ. Epithelial Thickness Profile Changes Following Small Incision Refractive Lenticule Extraction (SMILE) for Myopia and Myopic Astigmatism. J Refract Surg. 2016,32(7):473-482.

7.     Reinstein DZ1, et al. Epithelial thickness after hyperopic LASIK: three-dimensional display with Artemis very high-frequency digital ultrasound. J Refract Surg. 2010 Aug;26(8):555-64

8.     Reinstein DZ, Silverm, et al. 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

9.     Møller-Pedersen T, et al. Confocal microscopic characterization of wound repair after photorefractive keratectomy. Invest Ophthalmol Vis Sci. 1998;39:487-501.

Dr Sheetal Maharishi (Brar). M.B.B.S, MS, FPRS, FC

E: brar_sheetal@yahoo.co.in

Dr Maharishi (Brar) is a phacoemulsification and refractive and cornea surgeon at Nethradhama Super Specialty Eye Hospital in Bangalore, India. She has no financial disclosures to make.