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Feature Review | Previous Articles
March 2002



NICOLE CARNT - B. Optom (UNSW) 1989

Research Optometrist
Cornea and Contact Lens Research Unit (CCLRU)
Cooperative Research Centre for Eye Research and Technology (CRCERT)


Manuscript Review

The Measurement of Corneal Epithelial Thickness in Response to Hypoxia Using Optical Coherence Tomography.

Jianhua Wang, Desmond Fonn, Trefford Simpson, and Lyndon Jones
American Journal of Ophthalmology 2002: Vol 133, No. 3


The corneal stroma has so far been reasonably predictable in terms of thickness changes in response to hypoxia. The epithelium's response however has not been consistent between studies (both short and long-term) and does not appear to be as predictable. Recent advances in equipment and the introduction of high Dk lens materials, which allow differentiation between hypoxia and lens effects, have led to a resurgence of interest in this area.


Short term studies have firmly established the 5-15% swelling response of the corneal stroma to hypoxia that is evidenced clinically by striae when greater than 5% and the additional presence of folds, when greater than 8% 1.

The classic Gothenburg study by Holden and colleagues showed thinning of the stroma with long term (62 29 months) wear of low Dk hydrogel lenses worn on an extended wear (EW) schedule 1. Recent studies have shown a decrease in posterior keratocyte density in long term EW of low Dk hydrogels that is most likely responsible for this reduced thickness 2, 3.


Associated with hypoxia, the epithelium exhibits:

  • a significant increase in microcysts 4,
  • abnormal metabolism that results in an acid shift in pH due to an accumulation in lactic acid and carbon dioxide 5,
  • a reduction in cell synthesis due to enzyme shifts 6,
  • reduced epithelial cell adhesion 7,
  • increased binding of bacteria to cells 8,
  • reduced apoptosis (or programmed cell death) 9
  • an increase in cell size 10.


The Gothenburg study showed not only a decrease in stromal thickness, but also a decrease in epithelial thickness (5.6% compared to the control eye) with long term (62 29 months) wear of low Dk hydrogel lenses on an EW schedule. However, this difference decreased after ceasing lens wear and after 2 days was not significant, exhibiting recovery of the epithelium 1.

A recent long-term clinical study (over 10 years of low Dk hydrogel daily lens wear) has not, however, found evidence of epithelial thinning 11. Possible reasons for this difference may be less hypoxia with DW compared to EW of low Dk soft lenses, longer term survival in low Dk hydrogel lens wear of the "fittest" corneas or possibly a longer term adaptive effect.


Most of the short-term studies have shown no change in epithelial thickness 12-15, although there have been several studies on excised rabbit corneas that have shown an increase in epithelial thickness with hypoxia 16-18.


The purpose of the study was to determine if there was an associated increase in epithelial thickness with corneal edema induced by a contact lens worn during eye closure. Twenty subjects wore thick (0.34-0.41mm) HEMA 38% water content lenses (average Dk/t of 2.1 x 10-9 on one eye which was patched for 3 hours. The contralateral eye of each subject, which did not wear a contact lens and was not patched, acted as the control.

Optical Coherence Tomography (OCT) setup (Humphrey Instruments, Zeiss-Humphrey, San Leandro, CA)

The method used to measure corneal tissue thickness was optical coherence tomography (OCT) which uses low coherence interferometry to produce high resolution cross-sectional maps of the anatomical structure. OCT is similar to ultrasound B-mode imaging, using light instead of acoustic waves. This is a new optical imaging technique that was originally designed for measuring different layers of the retina and has recently been used in several studies involving measurement of the cornea and the epithelium. Good reproducibility of OCT measurement of the thickness of the cornea and epithelium has been previously reported by this group 19.

Other methods to measure the thickness of the cornea include:
-in vivo confocal microscopy through focussing (CMTF) (the confocal microscope uses the one objective lens to illuminate and focus a bright spot of light and is thereby able to produce very sharp images; intensity curves of cell layers are generated and thickness calculated from the z-axis positions; invasive), and;
-modified optical pachymetry (an optical system that uses two parallel glass plates to bisect the image of the cornea; measurement is done by aligning the two images; non invasive but can be difficult to judge with increased light scatter as in stromal edema).


For the test eyes, there was a 13.8+/-2.3% increase in overall corneal thickness and a small (1.7+/-4.8%) but not statistically significant increase in epithelium thickness. However, there was slight thinning of the epithelium in the test eye on removal of the lens (up to 3.0+/-4.5%) over a 100 minute time period. In addition, the control eye showed a decrease in total corneal thickness after removal of the contact lens from the test eye, compared to baseline readings of the control eye.

There was good agreement between the measurements of the test and control eye and a low standard deviation compared to other methods of measurement of the corneal epithelium, indicating good reliability of the OCT for this type of measurement.


The increase in total thickness of the cornea falls within the 5-15% expected range and the small but not statistically significant increase in epithelium thickness is in line with the majority of previous short-term studies. It has been previously suggested that the absence of epithelial swelling may be due to a compensatory regulatory mechanism contained within the living epithelium or that radial rather than axial swelling of the epithelium occurs 12.

Epithelial thinning during the deswelling period has been previously reported 15 but confirmation of this phenomenon in this study leads the authors to hypothesize that this may be due to an auto-regulation effect where the cornea continues to expel fluid or thins beyond its baseline thickness.

The authors speculate that the corneal thinning of the control eye may be a sympathetic response. Sympathetic corneal swelling of the control eye has been previously reported, first by Harris and Mandell with PMMA 20 and more recently by Fonn et al 21, comparing the response with both low and high Dk lens wear (the control eye swelled more when the low Dk, compared to the high Dk lens was worn on the contralateral eye). Harris and Mandell proposed that the sympathetic response was due to an osmolarity effect as a result of lacrimation.


Clinically, striae and folds are rarely seen in high Dk EW and CW 22.

Recent long term studies have shown a decrease in stromal thickness and posterior stromal cell density with both long term wear of low and high Dk material lenses 2, 3. This suggests other factors other than hypoxia, such as the presence of a contact lens and lens wear schedules, may be exerting an influence on stromal thickness.


Microcyst levels are comparable to no lens wear and remain consistently low over at least 18 months of high Dk CW for new lens wearers 23. Patients transferring from low Dk EW to high Dk CW, show a transitory increase in the first three months of high Dk lens wear and then a decrease to levels similar to new high Dk lens wearers and non lens wearers 23.

Decreased bacterial binding of epithelial cells in high Dk soft lens EW and CW is arguably the most positive finding relating to the corneal epithelium 24, Article Review-Is it Time to Give Extended Wear Another Chance.

Dwight Cavanagh's group have also reported a decrease in epithelial thickness over the first 3 months of EW and CW of high Dk soft lenses, with adaptive recovery of epithelial thickness in subjects followed up to 12 months of lens wear . However, these changes were not as marked as those seen with high Dk RGP CW or low Dk EW 24.

The same study found an increase in the size of the corneal epithelial cells, however Stapleton et al have found no increase in epithelial cell size after 3months of CW of high Dk soft lenses 25.

The effect of long-term contact lens wear on epithelial thickness appears to be driven by not only hypoxia but also lens effects, as occurs with the corneal stroma.


Results with high Dk lenses are certainly positive. Research continues into the effects of hypoxia and contact lens wear, particularly high Dk EW and CW, on the corneal epithelium and the implications of these changes. New instrumentation such as the OCT has contributed to the surge in interest in this area and it will be interesting to see the results of long-term clinical studies with these new methods of measurement.

1. Holden BA, Sweeney DF, Vannas A, Nilsson K, Efron N. Effects of long-term extended contact lens wear on the human cornea. Invest Ophthalmol Vis Sci 1985;26:1489-1501.
2. Jalbert I, Stapleton F. Effect of lens wear on corneal stroma: preliminary findings. Australian & New Zealand Journal of Ophthalmology 1999;27(3-4):211-3.
3. Perez-Gomez I, Morgan P, Efron N. Confocal microscopic appearance and thickness of the cornea following extended wear contact lenses: a study with neophytes. Optom. Vis. Sci. 2001;78(12s):199.
4. Zantos SG, Holden BA. Ocular changes associated with continuous wear of contact lenses. Aust J Optom 1978;61:418-426.
5. Klyce SD. Stromal lactate accumulation can account for corneal oedema osmotically following epithelial hypoxia in the rabbit. J Physiol 1981;321:49-64.
6. Fullard RJ, Carney LG. Human tear enzyme changes as indicators of the corneal response to anterior hypoxia. Acta Ophthalmologica 1985;63(6):678-83.
7. Madigan MC, Holden BA, Kwok LS. Extended wear of contact lenses can compromise corneal epithelial. Current Eye Research 1987;6(10):1257-60.
8. Ren DH, Petroll WM, Jester JV, Ho-Fan J, Cavanagh HD. The relationship between contact lens oxygen permeability and binding of Pseudomonas aeruginosa to human corneal epithelial cells after overnight and extended wear. CLAO J 1999;25:80-100.
9. Yamamoto K, Ladage PM, Ren DH, Li L, Petroll WM, Jester JV, et al. Effects of low and hyper Dk rigid gas permeable contact lenses on Bcl-2 expression and apoptosis in the rabbit corneal epithelium. CLAO Journal|CLAO (Contact Lens Association of Ophthalmologists) Journal 2001;27(3):137-43.
10. Lemp MA, Gold JB. The effects of extended-wear hydrophilic contact lenses on the human corneal epithelium. American Journal of Ophthalmology 1986;101(3):274-7.
11. Bourne W. The effect of long-term contact lens wear on the cells of the cornea. CLAO J 2001;27(4):225-30.
12. Lambert SR, Klyce SD. The origins of Sattler's veil. American Journal of Ophthalmology 1981;91(1):51-6.
13. Wilson G, Fatt I. Thickness of the corneal epithelium during anoxia. American Journal of Optometry & Physiological Optics 1980;57(7):409-12.
14. Bergmanson JP, Ruben CM, Chu LW. Epithelial morphological response to soft hydrogel contact lenses. British Journal of Ophthalmology|The British Journal of Ophthalmology 1985;69(5):373-9.
15. O'Leary DJ, Wilson G, Henson DB. The effect of anoxia on the human corneal epithelium. American Journal of Optometry & Physiological Optics 1981;58(6):472-6.
16. Uniacke CA, Hill RM. The depletion course of epithelial glycogen with corneal anoxia. Archives of Ophthalmology 1972;87(1):56-9.
17. Lowther GE, Hill RM. Recovery of the corneal epithelium after a period of anoxia. American Journal of Optometry & Archives of American Academy of Optometry 1973;50(3):234-41.
18. Uniacke CA, Augsburger A, Hill RM. Epithelial swelling with oxygen insufficiency. American Journal of Optometry & Archives of American Academy of Optometry 1971;48(7):565-8.
19. Fonn D, Wang J, Simpson T. Topographical thickness of the epithelium and total cornea using optical coherence tomography. Invest Ophthalmol Vis Sci 2000;41(S675).
20. Harris M, Mandell R. Contact lens adaptation: osmotic theory. Am J Ophthalmol 1969;46:196-202.
21. Fonn D, du Toit R, Situ P, Vega JA, Simpson T, Chamlers R. Apparent sympathetic response of contralateral nonlens wearing eyes after overnight lens wear in the fellow eye. [ARVO Abstract]. Invest Ophthalmol Vis Sci 1998;39:S336.
22. Covey M, Sweeney DF, Terry RL, Sankaridurg PR, Holden BA. Hypoxic effects on the anterior eye of high Dk soft contact lens wearers are negligible. Optom Vis Sci 2001;78:95-99.
23. Keay L, Sweeney DF, Jalbert I, Skotnitsky C, Holden BA. The microcyst response to high Dk/t silicone hydrogel contact lenses. Optom Vis Sci 2000;77:582-585.
24. Ren DH, Yamamoto K, Ladage PM, Molai M, Li L, Petroll WM, et al. Adaptive effects of 30-night wear of hyper-O(2) transmissible contact lenses on bacterial binding and corneal epithelium: a 1-year clinical trial. Ophthalmology 2002;109(1):27-39; discussion 39-40.
25. Stapleton F, Kasses S, Bolis S, Keay L. Short term wear of high Dk soft contact lenses does not alter corneal epithelial cell size or viability. Br J Ophthalmol 2001;85:143-146.


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