The CLAO Journal 28(1): 12–27, 2002 © 2002 Lippincott Williams & Wilkins, Inc.

Physiologic Changes of the Cornea with Contact

Lens Wear
Thomas J. Liesegang, M.D.

Purpose. This article reviews the corneal changes resulting from events,5 but these categories are not mutually exclusive.
the hypoxia that occurs during sleep and specifically during The physiologic changes differ among the various contact lens
contact lens wear. Methods. Discussion includes a literature re- materials (polymethylmethacrylate [PMMA], rigid gas-permeable
view and observations regarding the changes to the corneal epi- [RGP], soft hydrogel, silicone, and silicone hydrogel) and among
thelium, stroma, and endothelium that take place during sleep and various patterns of wear (daily, conventional, extended, over-
wearing of contact lenses made from different materials. Results.
night). Because individuals differ in susceptibility, these corneal
Hypoxia and hypercapnia cause significant changes to the corneal
epithelium, stroma, and endothelium. Some of these changes can changes are not uniformly present, although patterns emerge.
also be seen following the sleep cycle. Epithelial changes include This article reviews the normal consequences of the prolonged
decreased metabolic rate, morphologic changes, microcysts, closed-eye state and the superimposed consequences from contact
changes in junctional integrity, decreased corneal sensation, and lens wear, particularly those due to hypoxia and hypercapnia. Tear
pannus formation. Stromal changes include stromal edema, stro- film instability, allergy and toxicity, or mechanical effects result-
mal acidosis, neovascularization, and changes in corneal shape ing from contact lens wear also contribute to some of these effects
and, ultimately, corneal thinning. Endothelial changes include bleb but are difficult to separate and will not be specifically addressed.
formation, polymegethism, changes in endothelial cell density, and The new silicone hydrogel contact lens may overcome some of
possible changes in endothelial function. Conclusions. There are
these complications.
multiple and significant corneal changes resulting from hypoxia
and hypercapnia. These changes vary with the specific lens style.
The high-oxygen-permeable contact lenses recently introduced
may overcome some of these problems. PHYSIOLOGIC CHANGES DUE TO PROLONGED
Key Words: Blebs—Contact lenses—Endothelium—Hypercap- EYELID CLOSURE
nia—Hypoxia—Microcysts—Neovascularization—Polymegethism—
Stromal acidosis—Stromal edema. The preferred environment for the eye is created by an alternat-
ing period of opening and closing. Prolonged eyelid closure from
any cause triggers a cascade of biochemical, cellular, and micro-
bial events, culminating in inflammation, hypoxia, and dry-eye
Contact lenses interact mechanically with the cornea and modify states.6,7
the physiologic processes of corneal tissue. These changes may In the closed-eye environment, the partial pressure of oxygen as
lead to reduced corneal function.1 It is necessary to differentiate a percentage of oxygen in the atmosphere at the corneal surface is
corneal changes that are physiologically acceptable from those that reduced from 21% to approximately 8%. Prolonged eye closure
are pathologic. Clinicians, biochemists, engineers, and vision sci- induces tear stasis, decreased tear volume, decreased oxygen
entists have performed countless research studies to understand the tension, increased carbon dioxide, a shift to an acidic pH, corneal
etiology of these changes in order to enhance the safety of contact edema, corneal endothelial bleb response, increased corneal tem-
lens wear. perature, decreased acetylcholine, and decreased corneal sensitiv-
Changes in the cornea caused by contact lenses can be divided ity.8 Analysis of the tear constituents in the closed eye confirms
according to the structures affected (tear film, epithelium, stroma, that a subclinical inflammatory condition exists under an eyelid
endothelium) or according to the causes. The major consequence during sleep.9 There are increases in total tear protein, secretory
of contact lens wear is chronic hypoxia, with corresponding
IgA, and serum albumin; there is activation of complement and
hypercapnia.2,3 Other consequences include tear film instability,
plasminogen, production of chemokines, recruitment of polymor-
allergy and toxicity, mechanical effects, inflammation and infec-
phonuclear cells (PMNs), and release of highly reactive substances
tion, and desiccation, as outlined by Bruce and colleagues.4 Alter-
such as elastase and collagenase. Other major reflex tear compo-
natively, these adverse events can be grouped into hypoxia-medi-
nents, such as lysozyme, lactoferrin, and tear-specific prealbumin,
ated events, immune events, mechanical events, and osmotic
remain static.10 Eyelid closure also increases the microbial load on
the conjunctiva and lid margins.11
When the eye is open, the cornea is exposed to a partial pressure
Accepted May 30, 2001. of oxygen (Po2) of approximately 155 mm Hg and a partial
From the Department of Ophthalmology, Mayo Clinic, Jacksonville,
Florida.
pressure of carbon dioxide (Pco2) of near zero mm Hg4 (Table 1).
Address correspondence to Dr. Thomas J. Liesegang, Mayo Clinic, 4500 In the anterior chamber, Po2 is estimated to be 55 mm Hg, and
San Pablo Road, Jacksonville, FL 32224, U.S.A. Pco2 is estimated to be 40 mm Hg.4 There is normally a flow of

12
 PHYSIOLOGIC CHANGES OF THE CORNEA WITH CONTACT LENS WEAR 13

TABLE 1. Ocular Environment in the Closed and Open Eye expressed as a whole number ⫻ 10⫺9 (cm ⫻ mL O2/s ⫻ mL ⫻
Variable Closed Eye Open Eye
mm Hg). Oxygen transmissibility depends directly on this rate of
flow and is inversely related to the average thickness of the lens
Cornea (pH) 7.39 7.55
Tears (pH) 7.25 7.45
(L).16 Thus, oxygen transmissibility is given as Dk/L, and the
Temperature (°C) 36.2 34.50 higher the Dk value, the more permeable the lens is to oxygen.
Tonicity (% NaCl) 0.89 0.97 The Po2 required by the human cornea for normal function is
O2 (mm Hg) 61.00 155.00
CO2 (mm Hg) 55.00 0.0 considered to be at least 75 mm Hg,17,18 and therefore the oxygen
transmissibility necessary to avoid hypoxia in the closed eye is at
Modified from Vajdic CM, Holden BA. Extended-wear contact
lenses. In: Hamano H, Kaufman HE, eds. The Physiology of the
least 75 Dk/L. Extended-wear soft contact lenses need a Dk/L of
Cornea and Contact Lens Applications. New York, Churchill Living- 75 to 89 to avoid inducing edema.18,19 In open-eye conditions, the
stone 1987:101–148; with permission. corneal oxygen demand requires a Dk/L of at least 20, and
daily-wear soft contact lenses should have a Dk/L of 20 to 34 to
avoid inducing edema.18,19 Most thick or high-powered lenses or
oxygen onto the anterior corneal surface and an efflux of CO2 from extended-wear lenses do not meet these requirements. Another
the surface. way of looking at this is to define the minimum oxygen percentage
When the eye is closed, the Po2 in the palpebral conjunctival needed at the corneal surface to prevent corneal edema; this is
capillaries is approximately 60 mm Hg,12 one third that of the approximately 10% to 13%, compared with the normal 21%.18
pressure of the open eye. The Po2 decreases to approximately 40 Tear pumping is a supplementary route for providing oxygen to the
mm Hg at the corneal surface because of corneal oxygen consump- cornea. Investigators have found that there is a 10% to 20%
tion; this results in only a small oxygen flux onto the anterior volume exchange per blink under an RGP contact lens, compared
surface of the cornea. When the eye is closed, the palpebral with only a 1% volume exchange per blink under a soft contact
conjunctiva has a Pco2 similar to that of the aqueous humor, and lens.20
the resulting concentration gradient is negligible. Many investiga-
CO2 transmissibility is directly related to O2 transmissibility.
tors have observed significant individual variations in the levels of
The Pco2 in the anterior cornea varies depending on the transmis-
open-eye and closed-eye responses to the hypoxia. Contributing
sibility of the contact lens, increasing to a maximum of approxi-
factors may include individual differences in corneal and crystal-
mately 40 mm Hg with PMMA lenses. During eye closure, corneal
line lens oxygen requirements, endothelial structure and function,
Pco2 is always approximately 40 mm Hg because this is the
tear chemistry, lid action, lens pumping, and physiologic lagoph-
tension at the palpebral vasculature.21
thalmos. During sleep, the decrease in tear and stromal pH and the
If the oxygen decreases below a critical level, the cornea shifts
increase in corneal temperature and tear osmolality may affect
to anaerobic glycolysis using the Embden-Meyerhof pathway, in
corneal oxygen levels.
which glucose is broken down to pyruvate and then to lactate.
Mandell and Fatt13 were the first to report an increase in corneal
Because lactate does not diffuse rapidly out of the cornea, the
thickness (without contact lenses) during sleep, later measured to
consequence of decreased aerobic metabolism is stromal lactate
be approximately 4%. Because of the osmotic stromal response to
accumulation. Hypoxia thus creates a lowered epithelial metabolic
the change in tear evaporation, the cornea returns to a baseline
rate, an increase in epithelial lactate production, and an acidic shift
thickness within 1 hour of eye opening and continues thinning
in stromal pH. The degree of stromal acidosis varies, depending on
throughout the day.
the O2 transmissibility of the lens (i.e., Dk/L) and the buildup of
Wearing soft contact lenses on an extended-wear basis mimics
CO2 under the lens.
prolonged and exaggerated eye closure. Corneal swelling during
Contact lens wear therefore produces corneal hypoxia and
continuous wear of hydrogel contact lens material also is cyclic,
accumulation of CO2, both of which cause acidosis.22 The pH of
reaching approximately 12% overnight and 4% during the day.
the epithelium, stroma, and aqueous humor decreases significantly
Zantos and Holden14 reported that the overnight swelling response
with contact lens wear when the Dk/L is less than 100. Hypoxia
decreases with greater duration of continuous soft contact lens
causes substantial effects on the epithelium and stroma but has
wear.
limited or no direct effects on the endothelium and aqueous humor.
Uncomplicated daily wear of soft contact lenses does not appear
Carbon dioxide accumulation causes significant acidosis in all
to alter total protein or concentrations of secretory IgA and
compartments measured. Most of the acidosis occurs in the ante-
complement. Sleeping in contact lenses, however, increases the
rior layers of the cornea and results from retardation of the normal
levels of total protein, secretory IgA, and complement to a greater
carbon dioxide efflux. Corneal acidosis promotes endothelial poly-
degree than sleeping without contact lenses.15
megethism, epithelial microcysts, corneal edema, striate lines,
infiltrative keratitis, and microbial keratitis.
HYPOXIA AND HYPERCAPNIA FROM CONTACT After prolonged corneal hypoxia, there is depletion of the
LENS WEAR glycogen reserves of the cornea, diminished adenosine triphos-
phate (ATP), and ultimately a slowing of the water transport
Fitting a contact lens on the eye leads to a significant reduction system in the endothelium. The combined effects of the accumu-
in the oxygen supply to the cornea, in the range of 8% to 15%, lation of lactic acid in the stroma and a decrease in the pumping
depending on the gas permeability of the lens material used. The action of the endothelium result in increased corneal edema.
oxygen permeability of a contact lens is described in terms of the
rate of oxygen flow through a given area of the material. This rate Epithelial Effects of Hypoxia
is given as Dk, where D is the diffusion coefficient of the material The effects of hypoxia and hypercapnia on the epithelium
and k is the solubility coefficient of the material, and it is generally include a decreased epithelial metabolic rate with decreased oxy-

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14 T.J. LIESEGANG

TABLE 2. Epithelial Changes Due to Hypoxia and Hypercapnia

from Contact Lens Wear
Metabolic rate decreased
Morphologic changes
Microcysts
Compromised junctional integrity
Epithelial defects
Neovascularization
Decreased corneal sensation

gen uptake, lactate accumulation, acidic shift, decreased ion pump-

ing, reduction in cell synthesis with enzyme shifts, and possible
changes in DNA and RNA. The clinically observed correlates
include morphologic changes, microcysts, compromise in junc-
tional integrity, epithelial defects, neovascularization, and de- FIG. 1. Changes in corneal epithelial cell size over time, as mea-
creased corneal sensation (Table 2). The compromised junctional sured by surface specular microscopy, in patients wearing soft
contact lenses on a daily-wear (DWSCL) versus an extended-wear
integrity is accompanied by diminished electrical potential and
basis (EWSCL). (Modified from Tsubota K, Hata S, Toda I, et al.
reduced adhesion.8 In the short term, this can manifest clinically as Increase in corneal epithelial cell size with extended wear soft
epithelial erosions, edema, ulceration, and warpage; and long-term contact lenses depends on continuous wearing time. Br J Ophthal-
manifestations include formation of microcysts, bullae, vacuoles, mol 1996;80:144 –147; with permission.)
thinning with vascularization, increased fragility, and decreased
sensitivity. Effects on epithelial function include abnormal metab- dampening effect of the lens on blink-mediated shear forces from
olism and decreased sensation. The effects on epithelial structure eyelid movement.
include reduced nerve density, edema, epithelial thinning, abnor- With extended-wear soft contact lenses,26 the mean corneal
mal cell shapes, and microcysts. epithelial cell size is affected most. Because these mature cells
have fewer microvilli and less mucin, more sites are available for
Epithelial Metabolic Rate Reduction possible bacterial adhesion. This also results in epithelial thinning,
With extended-wear soft contact lenses, the epithelial metabo- decreased corneal oxygen flux, epithelial microcysts, and in-
lism is reduced because of a 15% decrease in oxygen uptake. The creased fragility of the epithelial layer. Because of the basal-cell
technique of redox fluorometry confirms the reduced epithelial flattening and the decrease in the number and thickness of epithe-
metabolic rate, and other studies confirm the reduced mitotic rate lial cells with extended-wear soft contact lenses, the epithelium is
of the basal epithelial cells. Short-term contact lens wear causes a thinned by 6% on average. Hypoxia delays apoptosis, or pro-
temporary decrease in corneal oxygen flux; long-term wear causes grammed cell death, and results in the retention of the superficial
a sustained reduction.23 The decreased metabolic rate affects the cells. The epithelial thickness is reduced to nearly one third its
epithelial physiology, the cellular junctional integrity, and the normal thickness in areas of contact lens bearing. A layer of wing
cellular reserves of glycogen. Glycogen becomes depleted, cell cells is absent, and the basal cells are compressed.29 There is an
synthesis is reduced, and corneal sensation is decreased. Lactate increase in rate of cell mitosis in these lens-bearing areas. The
accumulates between basal cells, causing a decrease in pH, and thickness returns to normal within a short time after discontinua-
there is an increase in intercellular spaces manifest as “Sattler tion of contact lens wear.30 Tsubota and co-workers31 demon-
veil.” There is no intracellular edema, and the epithelium actually strated that corneal epithelial cell size increases linearly with
thins by approximately 6%. With decreased pumping ability, increasing overnight wear and overall duration of hydrogel lens
increased permeability of the epithelial cells can result in dehy- extended wear (Fig. 1).
dration. The synthesis of cytochrome P-450 arachidonic metabo- Changes in tear film during overnight contact lens wear increase
lites causes an inflammatory response.24 In the rabbit model of epithelial permeability, leading to further increases in epithelial
extended-wear soft contact lenses, Ren and colleagues25 found dehydration. Although most tissues swell with hypoxia, the cor-
increased limbal epithelial stem-cell proliferation, with a concom- neal epithelium becomes thinner. Redistribution of cellular water
itant decrease in the proliferation of basal epithelial cells. They apparently occurs, leading to local changes in the refractive index
hypothesized that increased stem-cell activity is a compensatory that give rise to the Sattler veil.32,33 The Sattler veil is a corneal
mechanism for decreased central basal cell activity and may lead haze in which halos appear around lights. The condition occurs
to a depletion of the stem-cell reservoir. without changes in epithelial thickness and without uptake of
water. It is caused by an increase in light scatter at the level of the
Epithelial Morphology Changes corneal epithelium. Epithelial edema causes more forward scatter-
Wide-field color specular microscopy has been used to monitor ing of light than stromal edema and thus has a more profound
surface epithelial morphology during extended wear of conven- effect on vision—sometimes termed “epithelial bedewing.” Other
tional hydrogel lenses and to identify changes in epithelial barrier terms describing this hypoxia-induced corneal edema include “cor-
function.26,27 Suppression of mitotic activity and of the exfoliation neal misting”34 and “central circular clouding.”35 The Sattler veil
rate in the corneal epithelium with soft contact lens wear results in seems to result from an increase in the intercellular spaces of the
a decrease in the number of superficial cells and a flattening of the epithelium during hypoxia, which may be due to an increase in
underlying cells.28 A shift in size toward larger surface cells lactate concentration, with a corresponding decrease in pH, be-
occurs, also indicative of a reduced exfoliation rate and possibly tween basal cells. Sattler veil is distinct from microcysts. With
contributed to by the relatively stagnant post-lens tear film and the RGP or PMMA contact lenses, the change usually occurs under the

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 PHYSIOLOGIC CHANGES OF THE CORNEA WITH CONTACT LENS WEAR 15

area of the contact lens. With soft contact lenses, the edema is
more diffuse and usually less prominent, and a Sattler veil is not
visible.

Epithelial Microcysts
Epithelial microcysts do not occur immediately with either daily
or extended-wear contact lenses and usually take 2 to 3 months to
appear. Occasionally they appear after relatively short periods of
disposable contact lens wear. After cessation of lens wear, the
microcysts increase in number before they disappear within 2 to 3
months.30,36
Epithelial microcysts are another sign of altered epithelial me-
tabolism.23 Epithelial microcysts were first observed in PMMA
lens wearers but also occur frequently with soft contact lenses, and
especially with extended wear. The occurrence of intraepithelial
cysts is a useful and reliable clinical indicator of a disorder of
epithelial cell growth from chronic corneal hypoxic compromise.
Although, for unclear reasons, epithelial microcysts also occur in FIG. 2. Changes in epithelial oxygen uptake, thickness, and num-
ber of microcysts after cessation of long-term wear of high-water
persons who do not wear contact lenses, the number is small, content hydrogel contact lenses, compared with control eye data
usually less than 10 microcysts. (dashed line). (Modified from Holden BA, Sweeney DF, Vannas A, et
Epithelial microcysts are usually asymptomatic. Zantos36 and al. Effects of long-term extended contact lens wear on the human
others proposed that hypoxia was the primary cause, although this cornea. Invest Ophthalmol Vis Sci 1985;26:1489 –1501; with permis-
hypothesis does not explain microcyst location in the midperiph- sion).
eral region of the cornea. Microcysts tend to conform to an arcuate
pattern in the lower pupillary margin. They are seen in areas of produce epithelial damage is measured with the esthesiometer and
contact lens bearing and also may be related to epithelial trauma demonstrated by fluorescein staining.38 Fragility is also manifested
and inadequate lens movement, with pockets of cellular debris. by decreases in corneal electrical potential, punctate staining,
Staining is observed when microcysts break on the surface, al- epithelial abrasion, and an increased risk of microbial infection.
though this usually has no effect on vision. With extended-wear The reduction in epithelial adhesion correlates with a decrease in
contact lenses, epithelial microcysts usually increase in number hemidesmosome synthesis.39 Suggested mechanisms of the prob-
and size over a period of weeks, until they reach a steady state. The lems with epithelial adhesion include a mechanical deformation of
increase in numbers of microcysts after discontinuing contact lens basal cell shape or a hypoxia-induced increase in intracellular
wear is due to the return of normal epithelial metabolism, with calcium. There is a reduction in epithelial healing rate, probably
more encapsulated cellular matter brought to the surface before from reduced ATP production. Contact lens wear induces corneal
being eliminated.30 The presence of microcysts correlates with a swelling and an epithelial inflammatory response related to the
reduced epithelial mitotic rate and an increase in the regeneration synthesis of the cytochrome P-450 arachidonic acid metabolites
time of the epithelium (Fig. 2). Impaired cellular synthesis and 12(R) hydroxyeicosatetraenoic acid (12 R HETE) and 8(R) hy-
waste removal are features related to this altered metabolism. droxy-hexadecatrienoic acid (8 R HHDTrE).24,40 Time-dependent
Pathologic examination of microcysts shows degenerated epi- epithelial increases in the production of these metabolites correlate
thelial cells (apoptotic cells), probably from dysfunction of the directly with the corneal inflammatory response, and the inflam-
basal cells of the epithelium, with cellular degeneration and ly- matory response can be reduced by their inhibition. 12 R HETE is
sis.37 Microcysts probably form in the basal epithelium and are a sodium-potassium ATP inhibitor and is a vasodilatory, chemo-
transported anteriorly as the epithelium grows in that direction. tactic, and angiogenic factor.
They appear to be caused by metabolic stress and the altered Using rabbit corneas, Imayasu et al41 showed that the Dk/L of
growth pattern of the epithelium due to the direct and indirect extended-wear contact lenses correlates with increased surface cell
effects of hypoxia or hypercapnia. desquamation and increased binding of Pseudomonas aeruginosa.
Microcysts may resolve with an increase in the oxygen trans- This effect occurred regardless of whether soft or RGP contact
missibility of the contact lens, a decrease in overnight wear of an lenses were worn, implicating oxygen transmissibility rather than
extended-wear lens, or a change from a soft lens to a rigid lens. other factors, such as lens fit, in compromising the cornea and
Switching to a disposable extended-wear lens or changing solu- enhancing the risk of infection. Solomon42 found that higher
tions is not likely to be effective. infection rates in rabbits correlated with the amount of corneal
edema, which is related to oxygen transmissibility. In humans,
Compromised Junctional Integrity and Epithelial Defects Fleiszig et al43 reported that exfoliated cells from extended-wear
The maintenance of the electrical potential between the tear film soft contact lens wear bind more P. aeruginosa than those from
and the aqueous humor depends in part on superficial epithelial daily-wear contact lens wearers; hypoxia was the suspected cause.
tight junctions between the corneal epithelial cells. Contact lens Chronic hypoxia alone, however, is not the sole explanation
wear may compromise junctional integrity by loosening the epi- because corneal infections do not commonly develop in patients
thelial tight junctions, thus separating the corneal epithelial cells. wearing PMMA lenses. The interaction with the closed eye during
The increase in epithelial fragility can be measured with the contact lens wear is probably also an important mechanism. Early
Cochet-Bonnet esthesiometer; the minimum pressure required to studies with high-Dk materials suggested that such materials may

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16 T.J. LIESEGANG

reduce the epithelial barrier function defects and hold promise of the endothelial vascular cells and determine the direction of
eliminating this problem.44 growth.
Epithelial abrasions are attributed to low oxygen transmissibility This response to contact lens wear has been described variously
of the contact lens, with loosening of intercellular tight junctions as vascularization, neovascularization, limbal hyperemia, vessel
and separation of corneal epithelial cells. Superficial punctate penetration, vasoproliferation, vascular pannus, or vascular re-
keratitis is a common complication of contact lens wear attributed sponse. It is a normal (albeit undesirable) vascular response to
to hypoxia that results in the desquamation of stressed surface contact lens wear, and some vascular response occurs with almost
cells. Superficial punctate keratitis appears as pits in the epithelial all contact lenses. There are several steps in the neovascularization
surface and leads to the premature shedding of small groups of process: (1) Limbal hyperemia, a dilatation of existing limbal
cells45; it is commonly seen in association with the corneal capillaries, is reversible and is common with hydrogel soft contact
hypoxia from overwear of PMMA or extended-wear soft contact lenses worn overnight but can also occur with any tightly fitting
lenses. Although hypoxia is a frequent etiologic factor, superficial contact lens; (2) superficial neovascularization (pannus) is the
punctate keratitis also may occur for many other reasons, including progression of limbal hyperemia and the penetration of vessels into
solution toxicity, edema, lens deposits, lens care products, lens fit, the superficial cornea; (3) deep stromal neovascularization results
lens surface or edge irregularities, foreign bodies, improper lens from chronic hypoxia that may progress to an active inflammatory
insertion or removal, tear film disruption, and accumulated meta- or fibrovascular deep pannus; and (4) there may be an intracorneal
bolic waste products. The compromised epithelial integrity related hemorrhage.
to hypoxia and other osmotic or mechanical factors increases the Limbal vessel dilatation has been identified as the initial clinical
likelihood of bacterial adherence. sign in corneal vascularization. Chronic limbal vessel dilatation
Vital stains can demonstrate the loss of the corneal epithelial could provide an active vascular plexus adjacent to the cornea on
integrity. Rose bengal, trypan blue, methylene blue, fluorexon, and which stimuli promoting vessel growth could act. Although cor-
neal vascularization has been reported during extended wear of
bromthymol blue have been used, but fluorescein is the most
disposable and conventional lenses, quantitative and comparative
commonly used stain for contact lens evaluation.3 The defects can
data are lacking. Because hypoxia is believed to be one of the
be superficial, moderate, or deep (into the stroma). There are
major causal factors of vascularization, the extent of corneal
punctate stains, diffuse stains, linear stains, and dimple stains
vascularization with disposable and conventional contact lenses of
(indentations in the surface). Defects also may develop in individ-
similar oxygen transmissibility would be expected to be similar.
uals who do not wear contact lenses (especially with age), but most
New contact lenses with high oxygen transmissibility are promis-
cases occur with RGP contact lenses and, to a lesser degree, with
ing developments for reducing these stimuli of vessel dilatation
soft contact lenses. Staining seen at the 3- and 9-o’clock positions
and growth.
results from reduced or incomplete blinking habits. Arcuate stain-
The prevalence of neovascularization is low with RGP or
ing occurs because of a poorly polished intermediate lens zone or
PMMA contact lenses, more common with daily-wear soft contact
edge; and dimpling occurs in tight-fitting areas. lenses, higher with extended-wear soft contact lenses, and very
A classification of epithelial defects caused by contact lenses high with aphakic extended-wear lenses. Neovascularization is
has been proposed by Watanabe.46 Variations include (1) superfi- more common with soft contact lenses than with microcorneal
cial punctate keratitis, which can be diffuse or involve the lower, lenses because the soft contact lens covers the entire cornea.
3- and 9-o’clock, or upper cornea; (2) linear (arcuate or Additionally, the tear film beneath the soft contact lens is mini-
pseudodendritic) complications; and (3) plane complications (in- mized because of the relatively tight fit required to keep the lens in
filtration, epithelial edema, erosion, ulcer, and neovascularization). position. Vascularization is always greater in the superior limbus
Most of these epithelial complications occur with PMMA (73%) and is directly related to lens oxygen transmissibility. It is espe-
and RGP (33%) lenses but can be seen with soft contact lenses cially common with large and thick contact lenses and results in
(15%–22%) or with disposable soft contact lenses (3%). The major development of new corneal vessels in up to 20% of wearers.49
causes of these epithelial defects include insufficient oxygen The vascularization associated with RGP lenses is caused by
supply, mechanical stimulation, and local inadequate tear film. continual 3- and 9-o’clock staining; the incidence of neovascular-
Epithelial adhesion to the basement membrane is also reduced ization is low, related most often to limbal coverage by an
with extended wear of contact lenses.47 Overwear can result in eccentrically riding contact lens or persistent overwear.50
sloughing of the epithelium adherent to the posterior surface of the Vascular regression occurs after lens removal, leaving “ghost
contact lens; this can cause a circular hole in the epithelium that vessels” in the cornea. Occasionally, intrastromal opacities can
may take weeks to heal. RGP lenses have been demonstrated to occur, consisting of lipid droplets and inflammatory cells adjacent
induce tear-film instability associated with damage to the ocular- to the blood vessels in the deep stroma near the Descemet mem-
surface epithelium and mucin layer.48 In RGP wearers, abnormally brane. Although these opacities are caused by inflammatory cells,
shortened conjunctiva break-up time produces ocular surface dam- the cooperation of stromal keratocytes is necessary.
age, demonstrated as 3- and 9-o’clock staining. No single theory can account for corneal neovascularization;
rather, several factors may contribute.51 Proposed theories take the
Neovascularization following aspects into account: metabolic factors (hypoxia, lactic
Neovascularization (angiogenesis) is produced as a response to acid, edema, stromal softening); angiogenic suppression (necessity
a metabolic or an angiogenic factor by mature existing blood of substances that inactivate the normally present angiogenic
vessels. New vessels form from existing vascular endothelium that inhibitors); vasostimulation (locally generated or introduced vaso-
retains the capacity to revert to primitive vascular mesenchyme. stimulatory factors such as free cellular elements, humoral com-
Vasostimulatory factors initiate new growth by a direct effect on ponents, epithelial cell factors, or extrinsic factors); and neural

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 PHYSIOLOGIC CHANGES OF THE CORNEA WITH CONTACT LENS WEAR 17

FIG. 3. Proposed contributions of corneal epithelium-derived ei-

cosanoids to hypoxia-induced ocular inflammation. (From Mieyal FIG. 4. Comparative rates of sensory loss among three types of
PA, Bonazzi A, Jiang H, et al. The effect of hypoxia on endogenous contact lenses during 12 hours of wear. (Modified from Millodot M.
corneal epithelial eicosanoids. Invest Opthalmol Vis Sci 2000;41: Effect of the length of wear of contact lenses on corneal sensitivity.
2170 –2176; with permission.) Acta Ophthalmol 1976;54:721–730; with permission.)
to normal in a few hours after short-term contact lens wear.53,54
control (mediation of the vascular response to contact lens wear by Eyelid closure during sleep also causes a reduction in corneal
contact lens-induced changes to corneal neurology). Another way sensitivity.55
of categorizing stimuli that can promote vessel penetration into the Long-term wear of contact lenses causes a more pronounced
normally avascular cornea includes nutritional, inflammatory, me- loss of sensation that is more persistent. There are individual
chanical, traumatic, and toxic factors. One or all of these stimuli variations, and sensitivity tends to return with cessation of contact
are present during contact lens wear, particularly overnight wear. lens wear. Decreased sensation is milder with soft contact lenses
Whatever classification system is used, the most important factor and the return of sensation is more rapid, compared with PMMA
is contact lens-induced tissue hypoxia, which induces corneal lenses. Extended wear results in pronounced decreases, but recov-
edema and stromal softening. The additional mechanical injury to ery can occur. After 5 to 7 years of wear, sensation may be
the epithelium results in the release of enzymes, migration of permanently decreased with PMMA lenses, and the situation is
inflammatory cells into this site, and release of vasostimulatory possibly similar with soft contact lens wear.
agents causing vessels to grow in that direction. Corneal hypoesthesia is thought to be an adaptation to chronic
Soft contact lens-induced hypoxia has been shown to stimulate hypoxia, to decreased corneal pH, or to mechanical stimulation
the metabolism of arachidonic acid by a nicotinamide adenine and is correlated with levels of acetycholine.10 It does not appear
dinucleotide phosphate (NADPH)– cytochrome P-450 monooxy- to be a consequence of edema. The specific end mechanism may
genase, hydroxyeicosatrienoic acid (12 R HETrE), a proinflamma- be related to acetycholine concentrations or choline acetyltrans-
tory and angiogenic factor (Fig. 3).52 Biologic actions of this factor ferase, the enzyme responsible for the synthesis of acetycholine.
result in an increase in barrier permeability, vasodilatation, poly- Epithelial acetylcholine is a neurotransmitter to corneal nerves and
morphonuclear chemotaxis, and vascular endothelial cell mitogen- is decreased in hypoxia. There is also a suggestion of a lack of
esis. Routine contact lens wear is associated with inflammatory trophic function for the ciliary nerves in the maintenance of
reactions and, even in asymptomatic patients, can induce release of epithelial properties.49 A hypoxia-induced decrease in neural
some proinflammatory cytokines, including interleukins 6 and 8. transmission or neural damage or a sensory adaptation to mechan-
Hypoxia creates an environment in which epithelial cyclooxygen- ical stimulation also may occur. Contact lenses appear less likely
ase activity is severely suppressed, whereas metabolizing activity to affect corneal sensation if oxygen transmissibility is high, and
of cytochrome P-450-arachidonic acid or 12-lipoxygenase is main- most studies support the concept that hypoesthesia depends on the
tained or enhanced. The 12 R HETE produced by the corneal epithelial oxygen tension level.56 Corneal sensation may be a more
epithelium acts intracellularly to promote corneal edema, whereas sensitive test than refraction, keratometry, or pachometry for
12 R HETrE acts in a paracrine manner to initiate an inflammatory monitoring the status of corneal health during contact lens
cascade that can elicit neutrophil chemotaxis and neovasculariza- wear.10,56 Considerable individual variation exists, with many
tion of the cornea.52 unknown factors, however.

Corneal Hypoesthesia
Contact lens wear is associated with a decrease in corneal
STROMAL EFFECTS OF HYPOXIA
sensation, as measured by esthesiometry. Corneal touch thresholds The short-term effects of hypoxia and hypercapnia on the
differ with the various types of contact lens (Fig. 4). Within 1 day, stroma include stromal acidosis, edema, and striae. Long-term
those wearing PMMA contact lenses experience a 200% increase, effects include stromal thinning, infiltrates, neovascularization,
soft contact lens wearers experience a 50% increase, and those and corneal shape alterations8 (Table 3).
wearing high-water content extended-wear soft contact lenses
experience a 10% increase of touch thresholds. Stromal Acidosis
Decreased corneal sensation is not usually associated with RGP During contact lens wear, the stroma undergoes a decrease in pH
or any high-oxygen transmissible contact lenses. Sensation returns from the effects of metabolic and respiratory acidosis occurring in

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18 T.J. LIESEGANG

TABLE 3. Stromal Changes Due to Hypoxia and Hypercapnia The contact lens restricts oxygen at the anterior corneal surface.
from Contact Lens Wear Hypoxia decreases ATP production by the usual aerobic break-
Stromal acidosis down of glucose in the corneal epithelium. This causes a compen-
Stromal edema satory shift to the Embden-Meyerhof anaerobic glycolytic pathway
Stromal thinning
Neovascularization in epithelial cells. Smelser and Chen58 found increased corneal
Corneal shape alterations lactate concentrations after corneal hypoxia. Klyce59 observed the
connection between increased corneal lactate values and the ob-
served swelling of the stroma during contact lens wear. Because
the epithelium and diffusing into the stroma (Fig. 5). Metabolic
lactate cannot penetrate the superficial epithelium, all the newly
acidosis is caused by the accumulation of stromal lactic acid
formed lactate accumulates between epithelial cells, subsequently
during anaerobic metabolism. Respiratory acidosis is caused by the
diffuses posteriorly into the stroma, across the endothelium, and
accumulation of carbon dioxide (hypercapnia) because the gas-
finally is washed out into the aqueous humor. Additionally, lactic
impermeable contact lens precludes normal efflux of carbon diox-
ide. Thus, both hypercapnia and hypoxia lead to stromal acidosis.4 acid creates an osmotic load that is balanced by increased move-
Corneal epithelial and aqueous acidification during contact lens ment of water into the stroma. The sudden influx of water cannot
wear in rabbits appears similar to the stromal acidification mech- be matched by the removal of water from the stroma by the
anism in humans, and this animal model has been used in several endothelial pump. Therefore, although the stromal edema appears
studies.57 to be entirely due to lactate accumulation from hypoxia, the
In closed-eye conditions, the normal pH of the human corneal decreased stromal pH (stromal acidosis) is a result of both hypoxia
stroma is similar to that of blood (7.39) because of diffusion of and hypercapnia. This stromal acidosis also reduces the deswelling
CO2 from the palpebral conjunctiva into the cornea.4 Under response that occurs after corneal insult.
open-eye conditions, the human stromal pH increases by 0.15 to Contact lens hypoxia may correlate with the activity of lactate
7.55. It may decrease by as much as 0.25 during wear of soft dehydrogenase (LDH) in the cornea.60 With RGP wear, the LDH
contact lens of nearly zero oxygen transmissibility. Wearing thick, isozyme appears to switch from the aerobic type to the anaerobic
low-water content soft contact lenses can produce a stromal pH of type and return to normal over time. Tear LDH concentrations may
7.15. Under closed-eye conditions, hypercapnia is always present, provide a method for ongoing assessment of the tolerance of the
with or without contact lens wear. Thus, the degree of corneal ocular surface to contact lens wear.60
hypoxia in contact lens wear is the only significant variable in A contradictory study showed that chronic RGP contact lens
stromal acidosis. wear is associated with altered glucose-lactate metabolism in the

FIG. 5. Mechanism of pH reduction during contact lens wear. (A) Normal eye. Metabolic production
of lactate and hydrogen ions by the epithelium is at its basal rate because oxygen is readily available.
Carbon dioxide rapidly diffuses down a steep concentration gradient from aqueous to tears. (B) Open
eye with contact lens. Epithelial oxygen and possibly aqueous Po2 are reduced, which stimulates
lactate production (osmotically causing corneal swelling) and hydrogen ion production. Additionally,
CO2 efflux from the cornea is impeded, leading to higher stromal Pco2 which, when hydrated,
produces a hydrogen and a bicarbonate ion. Thus, the effects of hypoxia and hypercapnia on stromal
pH are additive. In the closed lens-wearing eye, epithelial Po2 is decreased and corneal Pco2 is
increased further because conjunctival Po2 ⬇ 55 mm Hg and Pco2 ⬇ 38 mm Hg. (From Bonanno JA,
Polse KA. Effect of rigid contact lens oxygen transmissibility on stromal pH in the living human eye.
Ophthalmology 1987;94:1305–1309; with permission.)

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 PHYSIOLOGIC CHANGES OF THE CORNEA WITH CONTACT LENS WEAR 19

cornea and the aqueous humor. Increased concentrations of lactate

were found in the epithelium, but decreased lactate concentrations
were found in the stroma and aqueous humor, for lenses with a low
Dk/L.61 No increase in epithelial lactate concentration, however,
was observed in a study of a hyper-oxygen transmissible test lens
(Dk/L ⫽ 125); thus, these lenses remain promising.44 These
authors suggest that increased stromal lactate accumulation cannot
account for persistent stromal edema in chronic extended wear of
RGP lenses. They suggest that this effect appears to be indepen-
dent of lens-oxygen transmissibility and may thus represent a
prolonged mechanical effect of contact lens wear itself.

Stromal Edema
The cornea is 78% water, and the stroma constitutes 90% of the
thickness of the cornea, with a tendency to imbibe water. In the
pump-leak model of the endothelium, water is moved out of the FIG. 6. The relationship between corneal edema and lens oxygen
performance showing the Holden-Mertz criterion of 87 Dk/L units
stroma by a sodium-potassium-ATPase and bicarbonate ion pump.
for avoiding edema during overnight lens wear. (From Brennan N,
Both an endothelial pump-leak and a minor epithelial pump-leak Efron N. What to expect with new high-Dk soft extended wear
occur. During sleep, edema occurs in every human cornea, with an lenses. Contact Lens Spectrum Suppl 1999;August:4s– 8s; with
increase in thickness of 4%, whereas on waking, a reduction in permission.)
thickness occurs. Superimposing a contact lens adds to this fluc-
tuation in corneal thickness, which is related to hypoxia. Stromal the lens and may represent the prolonged mechanical effect of lens
edema occurs because of a break in epithelial or endothelial wear itself.
barriers, a reduction in pump function (mainly endothelial), or an With extended-wear soft contact lenses, the increase in stromal
increase in osmotic activity (imbibition pressure) of the stromal thickness occurs significantly more in the center than in the
compartment. periphery because of hypoxia. With current soft contact lenses and
Measurement of central corneal swelling is the most commonly RGP lenses, unadapted patients usually have daytime corneal
edema of 1% to 6% and nighttime edema of 10% to 15%, as
used short-term index of the physiologic compatibility of a contact
measured on awakening. With extended-wear lenses, overnight
lens, because a change in corneal thickness is inversely related to
edema averages 10% to 12%. If the soft contact lens water content
the average oxygen transmissibility of the contact lens.62 The
is increased to the maximum, it is possible to maintain normal
response begins within half an hour after contact lens insertion and
corneal thickness, at least during the day. After weeks of soft
generally peaks within 3 hours. The degree of corneal edema
contact lens wear, the pattern of daytime thinning of the cornea is
associated with long-term contact lens wear appears to decrease
also reduced, possibly from adaptation.
with time. The swelling response to contact lens wear is generally
Extended wear of RGP lenses usually induces less central
presented as a population mean; however, there is significant
edema than extended wear of soft hydrogel contact lenses. Other
variation among individuals.
factors that influence corneal thickness, such as reflex hypotonic
When the oxygen tension of the anterior part of the eye is tearing or a long-term physical thinning of the stroma, however,
restricted by contact lens wear, this provokes a change in epithelial can introduce an artifact into measurements of corneal thickness,
cellular lactate production rate. The principal drainage route for in long-term contact lens wearers. The degree of corneal swelling
lactate is across the stroma through the endothelium into the induced by contact lenses varies markedly among individuals, and
aqueous humor. Lactate is a well-dissociated acid; thus, it is adaptation is a confounding variable. With RGP lenses, as the
principally present in the stroma as its sodium salt. The presence oxygen transmissibility is increased to 90 to 100 Dk/L units, the
of stromal sodium lactate has an osmotic effect. The change in increased thickness becomes difficult to detect, and there is no
stromal water content due to the osmotic (imbibition) pressure of detectable clinical gain with Dk/L values in excess of these values
the lactic acid in turn determines the thickness of the stroma. The (Fig. 6).
degree of stromal thickness observed in anoxia can be wholly Striae and folds that appear during overnight contact lens wear
accounted for theoretically by the changes in lactate levels. Factors are a function of the oxygen transmissibility of the lens and the
other than hypoxia contribute to corneal edema, including temper- oxygen uptake rate of the cornea. Grades of edema can be
ature, humidity, osmolality, carbon dioxide of the tears and cornea, assigned.2 Posterior striae indicate an acute change in corneal
mechanical effects, and inflammation, but these effects are prob- thickness. Striae occur at 5% to 7% stromal edema and represent
ably minimal.8 Klyce59 proved by complex mathematical models fluid separation of vertically arranged collagen fibrils in the pos-
and by laboratory techniques that anoxia provokes stromal swell- terior stroma. Zantos and Holden63 measured the average critical
ing. The combination of hypoxia and excess carbon dioxide may level of stromal swelling for the appearance of striae at 4.5% for
be the most significant contribution.8 Alternatively, however, vertical and 3.8% for horizontal striae. The folds appear as black
studies on RGP extended wear and stromal swelling in rabbits61 lines in the posterior stroma, observed if 10% to 15% stromal
found that increased stromal lactate accumulation from contact swelling is present, and represent physical buckling of the poste-
lens wear could not account for persistent stromal edema with rior stromal layers of the Descemet membrane. There is an alter-
chronic extended wear of RGP lenses. These authors thought that ation to the topography of the endothelial layer as seen in specular
stromal edema may be independent of oxygen transmissibility of reflection. Haze appears at 15% stromal edema and represents an

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20 T.J. LIESEGANG

advanced form of striae, with gross separation of collagen fibers

through the full thickness of the stroma.
Holden and Mertz18 reported that an oxygen value of 12%
(compared with the normal 21% at sea level) is required to avoid
stromal edema for daily wear of contact lenses; and 18% is
required for extended-wear lenses.64 Therefore, a Dk/L of approx-
imately 70 to 90 was required for extended wear, and a Dk/L of 34
was required for daily wear.
Corneal acidosis also reduces corneal hydration control as
measured by the rate at which the thickness of the cornea decreases
exponentially after an increased hydration load.65 The relation
between recovery and corneal pH is relatively unchanged for pH in
the physiologic range but decreases notably when pH is below the
physiologic range (7.4 –7.65). The deswelling rate is different for
soft and RGP contact lenses and for patients with no previous
contact lens wear. Years of contact lens wear could possibly result
FIG. 7. Decrease in stromal thickness of the lens-wearing eye after
in a 12% loss of ability to recover.
cessation of lens wear, indicating true edema, apparent edema, and
A corneal stress test for extended wear42 has been suggested. stromal thinning versus control eye data (dashed line). (Modified
Measuring corneal swelling after 1 night of wearing extended- from Holden BA, Sweeney DF, Vannas A, et al. Effects of long-term
wear soft contact lenses may identify those patients whose corneas extended contact lens wear on the human cornea. Invest Ophthal-
mol Vis Sci 1985;26:1489 –1501; with permission.)
are at risk for significant oxygen deprivation during overnight
contact lens wear. Corneal swelling of 5% or less seems to indicate Stromal Thinning
that the cornea can tolerate 7 nights of extended wear. Whereas stromal edema is an acute response to contact lens
The corneal edema varies with the material and design of the wear, stromal thinning is a chronic pathophysiologic change in
contact lens. PMMA causes swelling in the area covered by the patients who have worn contact lenses for years. Thinning by 2%
contact lens (steeper in that area), whereas the soft contact lens may be a sequela of chronic stromal edema correlated with
affects the entire cornea (with less effect on corneal topography or degeneration and possible death of stromal keratocytes.68 Imme-
power),66 and the Sattler veil is generally absent in soft contact diately after contact lens removal, the stromal thinning is masked
lens wearers. The anoxic swelling may subside over time, although by superimposed edema; the thinning becomes apparent only 2
the reasons are unknown. Wearers of PMMA contact lenses show days after cessation of contact lens wear (Fig. 7). Less stromal
three types of response67: (1) Some individuals may demonstrate thinning is associated with a thinner initial stroma, lower epithelial
maximum stromal swelling of 2% to 4% during the first day of oxygen uptake rate, and less endothelial polymegethism before
wear but no swelling after 2 weeks of wear; these individuals have lens wear. Unlike the recovery of the epithelium, recovery of the
adequate levels of tear exchange and corneal oxygenation and stroma from chronic edema is slow. Both stromal edema and a
suffer only from changes in tear osmolarity. (2) Other PMMA subsequent 4.8% reduction in stromal thickness were recorded
wearers may have a maximum swelling of 5% to 8% during the with long-term extended wear of hydrogel lenses.30 Continuation
first days of wear, with a decrease to a lower level after 2 weeks of stromal thinning was reported up to 6 months after cessation of
of wear; these individuals are usually able to wear contact lenses, contact lens wear.
but any further problem is superimposed on the initial problem of The causes of corneal thinning probably involve the losses of
swelling, and contact lens wear becomes intolerable. (3) Some stromal keratocytes and mucopolysaccharide.68 Chronic edema
individuals may have greater than 8% stromal swelling and are induces morphologic changes in the stromal keratocytes, manifest-
ing as functional changes in the ability of these cells to synthesize
unable to wear the contact lenses beyond 6 hours the first day. In
collagen, glycoproteins, and proteoglycans. Another possible
the third group, oxygenation is inadequate, and this level of
cause is dissolution of stromal tissue, perhaps due to the effects of
response is usually provoked by a grossly tight fit; wearing time is
lactic acid on the stromal mucopolysaccharide ground substance.8
restricted, and problems are more common in this group because
Stromal keratocytes lose their ability to synthesize new stromal
they are always at risk for overwear syndrome.
tissue because of hypoxia and the indirect effects of chronic
Because swelling is a function of the ability of the lens material induced-tissue acidosis due to accumulation of lactic acid and
to transmit gases, lens thickness and water content are important carbonic acid. Confocal microscopic examination of extended-
criteria in soft contact lens wear. Large variability in patients wear soft contact lens patients showed reduced stromal keratocyte
exists, although the following observations have been made: (1) density.69 Additive mechanisms include hypoxic, cytokine-medi-
thick hydrogen lenses provoke more stromal swelling than thin ated, or mechanical effects. Hyper-reflective keratocyte nuclei
lenses; (2) the extent of swelling declines with time; (3) the extent were also reported.70 With confocal microscopy, a new type of
of swelling rarely exceeds the maximum amount that can be chronic stromal change also was observed, with highly reflective
provoked by anoxia alone (8%); (4) the use of thin lenses causes, panstromal microdot deposits in the corneal stroma.71 This depo-
on average, less than 1% stromal swelling; and (5) swelling is sition is more common with long-term wear of contact lenses and
much greater with extended wear of soft contact lenses, which more common with soft lenses than with RGP lenses. This con-
results in increased levels of corneal thickness during periods of dition may be an early stage of corneal disease, but its clinical
sleep. significance is unknown. No data are yet available comparing the

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 PHYSIOLOGIC CHANGES OF THE CORNEA WITH CONTACT LENS WEAR 21

effects of conventional and disposable contact lenses on stromal When PMMA lenses first became available, the main problems
thickness during long-term wear.72 encountered were central corneal clouding, 3- and 9-o’clock stain-
A study with the Orbscan (Orbscan Inc., Salt Lake City, UT) ing, and corneal distortion.8 Approximately 30% of PMMA lens
topography system73 showed that the mean corneal thickness in wearers manifest corneal distortion that can be clinically signifi-
the center and in eight peripheral areas was significantly reduced cant.78 Distortion (warpage) with PMMA lenses is caused by a
by approximately 30 to 50 ␮m in long-term soft contact lens combination of central corneal edema (due to hypoxia) plus
wearers compared with noncontact lens wearing control subjects. superimposed mechanical pressure from the contact lens or the
eyelid on the softened cornea, and also by mucus binding beneath
Corneal Shape Alterations the rigid lens. Metabolic factors such as oxygen tension may also
Contact lens wear can result in corneal distortion or warpage. contribute. The central cornea steepens with PMMA wear. Such
Multiple other terms have been used in the literature to describe steepening may be more than the circadian changes that have been
these changes, including “indentation,” “steepening,” “flattening,” observed,79 in which the cornea flattens again during periods of
“sphericalization,” “imprinting,” and “wrinkling.” These changes sleep after PMMA lens wear, although baseline curvature is not
are predictable to the extent that contact lenses can be used to achieved before the next period of lens wear. Over the first year of
reduce the cone protrusion in keratoconus and in orthokeratology, PMMA lens wear, the induced corneal steepening gradually de-
which is the controversial practice of fitting progressively flatter, creases and the cornea may eventually become flatter than its prefit
reversed-geometry tight-fitting RGP lenses, with the aim of flat- value.49 The curvature changes are more apparent in the horizontal
tening the cornea to reduce myopia. than in the vertical meridian.80,81 Changes are less marked with
Videokeratopographic mapping techniques reveal that all forms soft contact lenses, which induce a slight corneal flattening in the
of contact lens wear are capable of inducing changes in corneal first 2 or 3 weeks, followed by a period of relative steepening.
topography. Topographic abnormalities were detected in 75% of Although changes in corneal shape and reduction of refractive
corneas with PMMA lens wear, 57% with RGP lens wear, 31% error are touted as permanent effects in the practice of orthokera-
with daily-wear soft lenses, and 23% with extended-wear soft tology, cessation of PMMA lens wearing is followed by large
lenses, compared with 8% of normal corneas without contact lens fluctuations in corneal shape and refractive error. The myopia of
wear.74 These changes can cause spectacle blur or contact lens most subjects eventually returns to prelens-wear levels.82 The
decentration. Generally, contact lenses with high oxygen transmis- induced changes in corneal topography and refractive state may
sibility induce little warpage.75 Corneal topographic changes with remain unpredictable, and with long-term wear, this molding effect
contact lenses have been reviewed by Ruiz-Montenegro et al.74 may lead to loss of regularity, resolving power, and visual func-
Significant changes occur with RGP contact lenses and occasion- tion. The prognosis varies and depends on magnitude and duration
ally with daily-wear or extended-wear soft contact lenses. Many of lens-induced deformation forces. The cornea usually returns to
different topographic patterns can result from contact lens wear, its original shape over months, but sometimes the changes are
but most involve flattening in areas of lens bearing. The changes irreversible. Changes in shape are less common with soft contact
correlate with the resting position of the RGP or PMMA lenses and lenses and usually require corneal topography examination to
entail flattening beneath the decentered contact lens and possible detect or monitor.
adjacent steepening, usually detectable only with computer-as- The Orbscan topography system73 demonstrated that the mean
sisted topographic analysis. Changes also occur in the overall corneal thickness was significantly reduced in long-term soft
curvature; and central clouding occurs initially with PMMA contact lens wear by 30 to 50 ␮m, compared with normal eyes
lenses, with induced central steeping and myopia.76 With PMMA without contact lenses. There was no correlation between central
lenses, a central flattening occurs later, with reduction in myopia. thickness and the degree of myopia detected. Corneal curvature
RGP lenses have the same effect but to a lesser extent, which is was significantly steeper in the eyes wearing soft contact lenses
proportional to the oxygen transmissibility of the contact lens. than in normal eyes. No difference in mean corneal astigmatism
Changes in corneal asymmetry also take place with contact lens was noted. The SRI and SAI were significantly greater in the
wear. The surface asymmetry index (SAI), a quantitative measure contact lens wearers than in the control group. The authors con-
of the radial symmetry of the four central videokeratoscope mires cluded that long-term soft contact lens wear (average of 13 years)
surrounding the vertex of the cornea, is higher with PMMA, RGP, appears to decrease the entire corneal thickness and to increase the
and extended-wear soft contact lenses. In addition, there are corneal curvature and surface irregularity. This may be caused by
changes in corneal regularity. The surface regularity index (SRI) is thinning of the epithelium and stroma due to chronic edema of the
a measure of central and paracentral corneal irregularity derived stroma and biochemical changes. Alternatively, it may be related
from the summation of fluctuations in corneal power that occur to chronic exposure to a hyperosmotic tear film or to increased
along semimeridians of the 10 central videokeratoscope mires. The apoptosis of keratocytes and epithelial cells from chronic micro-
SRI is high with PMMA and RGP lenses, and occasionally also trauma and hypoxia. The increased curvature could be a contact
with soft lenses. lens-induced ectasia (similar to forme fruste keratoconus).
Corneal wrinkling may manifest with the appearance of a series
of deep parallel grooves in the cornea that give the impression of
ENDOTHELIAL EFFECTS OF HYPOXIA
a wrinkled cornea.77 There may be signs of corneal indentation, in
which the impression of the contact lens edge is evident on the The additive effects of hypoxia and hypercapnia alter the
cornea. Other patterns can occur, including central irregular astig- stroma. This induction of stromal acidosis has both short-term and
matism, radial asymmetry, changes in the axis of astigmatism, and long-term ramifications for endothelial function. Initial contact
reversal of the normal pattern of progressive flattening from the lens wear causes transient endothelial blebs and folds. Chronic
center to the periphery. hypoxia disturbs endothelial cell stability and produces poly-

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22 T.J. LIESEGANG

TABLE 4. Endothelial Changes Due to Hypoxia and Hypercapnia ance, blebs are asymptomatic and are thought to be of little clinical
from Contact Lens Wear significance; they represent a short-term as well as long-term
Endothelial blebs adaptation of the endothelium.87
Polymegethism
Endothelial cell density change Polymegethism
Endothelial function change
Polymegethism refers to a greater-than-normal variation of
corneal endothelial cell size, resulting in a layer of large and small
megethism, pleomorphism, bedewing, guttata, and possibly cell cells. The degree of endothelial polymegethism is measured by the
death (Table 4). Endothelial polymegethism is a relatively perma- coefficient of variation of endothelial cell size, a dimensionless
nent effect of inadequate oxygen permeability8 and is prevalent ratio calculated by dividing the standard deviation of the areas of
with all contact lenses. The coefficient of variation for cell size is the cells in a defined field by the arithmetic mean of the areas of
high with all types except RGP lenses. The effect on endothelial all cells in that field. For endothelial cells, polymorphism (or
function appears to be minimal, although the functional reserve at pleomorphism) refers to variations in cell shape distinct from the
times of stress may be reduced. classical, uniform six-sided endothelial cell appearance. Pleomor-
phism can be defined as an increase in the proportion of nonhex-
Endothelial Blebs agonal cells on the monolayer and usually accompanies poly-
Before 1977, the endothelium was thought to be immune to the megethism.
effects of contact lenses because it received its nourishment from Polymegethism is a normal phenomenon of aging but is accel-
the aqueous. Zantos and Holden,83 however, noted that the endo- erated with contact lens wear correlates with hypoxia. MacRae et
thelial mosaic undergoes a dramatic alteration within minutes of al88 and, recently, Lee et al89 reported an association between
insertion of a contact lens, especially when the oxygen transmis- significant increases in endothelial polymegethism and pleomor-
sibility of the lens is low. Endothelial blebs appear as black, phism and reduction in endothelial cell density. MacRae and
nonreflecting areas in the endothelial mosaic and as an increase in colleagues hypothesized that polymegethism and pleomorphism
separation between cells. Blebs consist of endothelial swelling, precede reduced cell density because all three features were ob-
with subsequent changes in the contours of cell membranes.72 served in long-term wearers. Polymegethism has been observed
Initially, this appears as if cells had fallen off the posterior surface and quantified with daily- and extended-wear soft, RGP, and
of the cornea. The phenomenon is observed within minutes after PMMA contact lenses and with age. Only the silicone elastomer
insertion of the lens, peaks at 20 to 30 minutes, and subsides to low contact lens, which has high gas permeability, does not lead to
levels after 45 to 60 minutes, with only a few blebs visible at other significant endothelial polymegethism. The degree of polymegeth-
times. Due to adaptation, the response is reduced with continual ism was shown to correlate with duration of contact lens wear and
contact lens wear. degree of hypoxia by many but not all investigators. Extended
Blebs can be produced by contact lens wear combined with wear of contact lenses appears to produce a more rapid increase in
anoxia or by passing a nitrogen gas mixture containing 10% the coefficient of variation of endothelial cell size than daily wear.
carbon dioxide and 21% oxygen through a goggle. Because the gas Recovery from contact lens-induced endothelial polymegethism is
mixture does not produce stromal swelling (there is no hypoxia), slow, and the condition may be irreversible, even after cessation of
the common factor is the production of stromal acidosis. Thus, contact lens wear. This condition is unique because other corneal
blebs resulting from contact lens wear appear to be a consequence changes induced by contact lenses usually disappear with cessation
of hypoxic acidosis and an accumulation of carbon dioxide be- of wear. Sibug et al,90 however, reported a trend toward reduced
cause of a diffusion barrier, rather than because of hypoxia per polymegethism 5 years after cessation of contact lens wear. In
se.84 The carbonic and lactic acids may alter the physiologic status another study,91 the endothelial polymegethism was still present
of the environment surrounding the endothelial cells; this induces even 7 years after cessation of PMMA contact lens wear.
changes in membrane permeability or pump activity, resulting in The cause of polymegethism is not yet clear. Connor and
net movement of water into endothelial cells, with resultant de- Zagrod92 theorized that the causes of polymegethism involve a
velopment of blebs. Both endothelial blebs and stromal acidosis hypoxia-induced reduction in ATP levels and changes in the
occur faster with hypercapnia than with hypoxia. The intracellular concentration of extracellular and intracellular calcium. Alterna-
endothelial pH is the common factor. tively, corneal stromal acidosis may be an etiologic factor.22
Pathologic examination of blebs shows edema of the nuclear Polymegethism is one of the features of the corneal exhaustion or
endothelial cells, with intracellular fluid vacuoles and fluid space fatigue syndrome.93,94 This syndrome is thought to represent
between cells.85 There is localized edema of groups of endothelial endothelial dysfunction brought on by chronic contact lens-in-
cells, which bulge toward the aqueous. duced hypoxia and acidosis. Whether the morphologic changes in
The bleb response is universal among contact lens wearers the endothelium in polymegethism are a result of changes in cell
within 10 minutes after insertion, but there is variation in response. size or a redistribution of cell mass is in dispute.95,96 Regardless of
The blebs also occur during sleep and can be observed on awak- the cause, an irregular mosaic is inherently unstable, because
ening.86 To a similar extent, blebs occur with conventional and adjacent cells with similar dimensions best maintain the barrier
disposable contact lenses of similar oxygen transmissibility, but function of the endothelium.97
their occurrence is minimal or absent with silicone elastomer When the cornea is exposed to 12 R HETE and 8 R HHDTrE,
contact lenses. There is also an increase in the number of blebs in changes similar to those seen with contact lens-induced hypoxia
the late evening in patients with extended-wear soft contact lenses. occur, including edema, neovascularization, and endothelial poly-
The overall number of blebs can be seen to decrease over the initial megethism.40 An underlying mechanism of polymegethism is
8 days of extended wear. Despite their dramatic clinical appear- related to the ability of 12 R HETE to inhibit the sodium-

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 PHYSIOLOGIC CHANGES OF THE CORNEA WITH CONTACT LENS WEAR 23

wear18,30,88,101,104 –111; however, there have been a few isolated

reports of endothelial cell loss.112 MacRae et al88 reported low
endothelial cell density in a subgroup of PMMA lens wearers.
PMMA wearers showed advanced polymegethism and pleomor-
phism compared with controls. Although their endothelial cell
density was not significantly different from that of controls, a
significantly greater percentage of contact lens wearers had low
endothelial cell density and were more likely to have severe
polymegethism and pleomorphism. The authors suggested that
polymegethism and pleomorphism lead to a reduced physiologic
reserve and are precursors to accelerated corneal endothelial cell
death. MacRae and associates used the term “contact lens-induced
endotheliopathy,” because these changes may represent pathologic
processes that may result in premature cell death and reduced
FIG. 8. Bergmanson’s theory of the development of endothelial endothelial cell density. A subset of approximately 10% of PMMA
polymegethism. Normal endothelium has interdigitated lateral sides
lens wearers show these changes.
and minimal separations between cells. Chronic anterior hypoxia
results in an oblique reorientation of the lateral wall of the endothe- Using age-matched controls (not following individual patients),
lial cell. Thus, a cell with a large anterior surface may have a small Setala and co-workers113 also noted a lower endothelial cell
posterior surface and vice versa. Consequently, cellular volume may density. In this study, mean endothelial cell density in contact lens
remain constant. (From Efron N. Contact Lens Complications. Ox- wearers was minimally lower, and the mean coefficient of varia-
ford, Butterworth-Heinemann 1999:193; with permission.)
tion differed significantly from normal in all contact lens wearers.
Very low mean endothelial cell density was observed in some
potassium ATPase of the endothelial pump. Repeated endothelial patient populations of contact lens wearers and was seen only in
exposure to 12 R HETE and 8 R HHDTrE due to the diffusion of contact lens wearers. A recent study by Lee et al89 also found a
these eicosanoids (which results from the corneal epithelial inflam- significant change in the coefficient of variation of cell size and a
matory response to contact lens wear) causes endothelial cell decrease in cell density among long-term soft contact lens wearers.
swelling and a permanent change in the cellular cytoskeleton, Thus, some studies suggest that there may be a subset of PMMA
leading to endothelial polymegethism. and soft contact lens wearers who react with high pleomorphism
The consequences of endothelial polymegethism are unclear. and polymegethism and also a decrease in endothelial cell density.
The condition may be benign, although polymegethism appears to The morphologic change in endothelial cell density is specu-
be linked to corneal hydration control. Hydration control can be lated to be an indicator of cell stress due to chronic hypoxia;
tested by inducing corneal edema and then recording the exponen- therefore, polymegethism and pleomorphism may be signs of
tial rate of corneal deswelling.98 Deswelling after induced edema premature cell death. This appears related to the type of contact
is considerably slower in PMMA contact lens wearers than in lens. For example, Setala et al113 found minimal or no endothelial
non-contact lens wearers. An impaired functional reserve was morphologic changes with RGP and silicone lenses. These authors
demonstrated in a study that showed increased endothelial perme- suggested that long duration of contact lens wear affects cell
ability and an increased endothelial pump rate in patients with densities, especially after 25 years. Corneas with low cell density
polymegethism associated with wearing extended-wear soft con- may remain clear unless stressed by conditions such as contact lens
tact lenses.99 Endothelial polymegethism may adversely affect the wear, surgical procedures, or age. Although these endothelial
ability of the cornea to reduce edema after surgical stress, a changes have not been shown to be reversible after cessation of
concern specifically for surgical patients.97,100,101 Rao et al97 contact lens wear, Sibug et al90 believed that the changes might be
showed that patients with polymegethism take longer to recover slowly reversible.
from corneal edema induced by cataract surgery. Slow corneal Wiffen and colleagues114 showed that endothelial cell density
deswelling has been associated with polymegethism in the young was significantly higher centrally than peripherally in normal
and the elderly.102 subjects without contact lenses but not in contact lens wearers. The
The pathologic basis of polymegethism is debated. Although the coefficient of variation of cell area was higher peripherally than
endothelial cells have clearly changed in shape, the volume of each centrally for both normal controls and contact lens wearers, but
cell may remain constant because the cells have become reoriented contact lens wearers had significantly higher coefficients of vari-
in three-dimensional space96 (Fig. 8). An oblique reorientation of ation than controls in both the center and the periphery. The central
the lateral walls of endothelial cells occurs in contact lens wearers cornea has more hexagonal cells than the peripheral cornea in both
with some intercellular and intracellular edema. Endothelial cy- normals and contact lens wearers: the percentage of hexagonal
toskeletal F-actin has abnormal patterns that may contribute to cells is less in both the center and periphery in contact lens wearers
polymegethism and may be the result of constant stress in cell compared with normals. These authors conclude that contact lens
volume regulation.103 No damage was evident on examination of wear causes a mild redistribution in endothelial cell density from
the ultrastructure of the organelles of endothelial cells.96 the central to the peripheral cornea. Other authors have found
increased central endothelial cell density with RGP lens wear.115
Endothelial Cell Density In patients newly fitted with fluorocarbon RGP contact lenses,
Although polymorphism and pleomorphism are well-known the coefficient of variation of cell area increased within 2 months
consequences of contact lens wear, most studies have been unable and continued to increase over the next 3 years,116 and this
to confirm a change in endothelial cell density with contact lens correlated with the oxygen transmissibility of the lenses. The

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24 T.J. LIESEGANG

endothelial cell density was decreased at 2 and 3 years, but corneal tion of contact lens wear, as well as excessive open-eye edema
thickness did not change. In older contact lens wearers who response and moderate to severe endothelial changes. The effects
switched to RGP fluorocarbon contact lenses, after 3 years there on the endothelium appear to be long-term and possibly perma-
were no significant changes in any morphologic values, except that nent.
corneal thickness was decreased significantly. The authors con- Corneal exhaustion syndrome (contact lens failure after long-
cluded that, although oxygen transmissibility was improved with term wear) may be caused by endothelial dysfunction due to
the fluorocarbon lens, polymegethism was still induced within 2 long-term hypoxia and acidosis. After years of contact lens wear,
months by these contact lenses, and morphologic changes stem- the endothelial function of regulating corneal hydration may be
ming from previous contact lens wear did not improve during 3 compromised to the point that the endothelium is no longer able to
years of daily wear of these RGP lenses. These contact lens cope with the stresses imposed by contact lenses with low oxygen
changes do not occur in patients wearing silicone lenses, which are transmissibility. There must be an individual susceptibility to this
highly permeable to oxygen. rare syndrome.

Endothelial Function LESSONS FROM VARIOUS TYPES OF CONTACT

To date, no direct link has been established between contact
LENS WEAR AND DIRECTIONS FOR THE FUTURE
lens-induced acidosis and corneal function, although there is some
indirect evidence. Long-term contact lens wear reduces endothelial Biochemical, cellular, and microbial changes occur in the
functional reserve, as measured by the rate of corneal deswelling closed-eye environment. The closed eye is a state of subclinical
following lens-induced edema. This correlates with the duration inflammation with an increase in tear protein, secretory IgA, serum
and transmissibility of the contact lens worn. Other studies confirm albumin, complement and plasminogen, chemokines, and poly-
that acute corneal swelling and deswelling rates are slowed in an morphonuclear cells. This state may be beneficial against infec-
acidic environment, implying that an acid environment may affect tion, but the addition of a contact lens may facilitate infection.
endothelial pumping or endothelial hydraulic activity. PMMA lenses present some unique problems. Daily wear of
Vannas et al85 have suggested that monitoring the rate of PMMA lenses induces approximately 6% central corneal edema117
decrease of corneal thickness after the induction of hypoxic cor- and frequent corneal warpage. This corneal stress may cause many
neal edema provides an assessment of endothelial pump function. unacceptable changes in corneal structure and function. Although
Polse et al,1 using the term “open-eye steady state,” developed a some regression of endothelial polymegethism may occur after
clinical method to measure overall endothelial function or corneal lens wear is discontinued, most changes appear to be irreversible.
hydration control by inducing hypoxic corneal swelling with a Endothelial polymegethism places the cornea at greater risk for
contact lens and then measuring the rate of deswelling. Preliminary surgical complications.97,118 The corneal exhaustion syndrome is a
data7 suggested that hypoxic exposure alters endothelial structure rare problem that may occur in some patients with PMMA lens-
and reduces corneal function. Nieuwendaal et al,98 using a similar es.93
method, found abnormally low rates of deswelling in long-term Soft contact lenses initially were believed to supply enough
contact lens wearers. oxygen to the cornea,119 since Polse and Mandell120 determined
Another approach was used by Carlson and co-workers,104 who that only 2% oxygen was required to prevent corneal edema.
evaluated barrier function by measuring endothelial permeability Carney and Bailey121 published the first paper questioning the
to fluorescein. They found no difference between contact lens adequacy of oxygen level supplied by a soft contact lens. The use
wearers and controls in corneal clarity, central corneal thickness, of thick, soft lenses of low water content produced corneal edema,
or endothelial response to fluorescein. Oxygen transmissibility, polymegethism,107 myopic creep,122 vascularization,123 and occa-
estimated underlying oxygen tension, and duration of contact lens sionally the corneal exhaustion syndrome.93,124
wear did not correlate with any morphologic or functional endo- Extended-wear soft contact lenses generally do not provide
thelial variables. These authors concluded that long-term contact sufficient oxygen to the eye.14,125–128 In the Gothenberg (Sweden)
lens wear induces morphologic changes in the endothelium that study,30 chronic hypoxia induced by extended wear of soft hydro-
may progress over time, but no functional abnormality was de- gel lenses resulted in a 15% decrease in oxygen uptake rate, with
tected by the methods of anterior-segment fluorophotometry. In 85% of patients producing microcysts. The epithelium thinned by
further studies Bourne et al116 again found no statistically signif- 6%. The stroma was slightly edematous (2.5% of stromal thick-
icant differences between contact lens wearers and controls in ness) while the patients were wearing the contact lenses, but when
endothelial permeability, corneal deswelling, endothelial pump patients removed their contact lenses, the stroma was significantly
rate, or endothelial cell density, although contact lens wearers had thinner (2.3%) than before the contact lens wear. There was
significantly higher aqueous flow rate, coefficient of variation of increased polymegethism in 95% of lens wearers, with a mean
cell area, and corneal autofluorescence than non-contact lens increase of 22%.30 Sterile peripheral ulcers occurred in 1% in a
wearers. 2-year prospective study.8 Reduced oxygen with the closed lid plus
extended wear of soft contact lenses caused problems of corneal
Corneal Exhaustion Syndrome swelling, epithelial microcysts, stromal and epithelial thinning,
Sweeney94 coined the term “corneal exhaustion syndrome” to reduced epithelial mitosis rate, decreased damage threshold, stro-
characterize the sudden intolerance to contact lens wear with mal acidosis, endothelial polymegethism, decreased epithelial ad-
photophobia associated with a distorted endothelial mosaic and hesion, increased epithelial cell size, and increased inflammatory
moderate to severe polymegethism. The condition involves contact activity in the epithelium.
lens intolerance with blurred vision, mire distortion, fluctuating The availability of disposable contact lenses led to a resurgence
changes in corneal curvature, and spectacle refraction after cessa- of the popularity of extended wear. Hypoxic, inflammatory, and

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 PHYSIOLOGIC CHANGES OF THE CORNEA WITH CONTACT LENS WEAR 25

infectious complications were soon documented, however, dispel- 8. Holden BA. The Glenn A. Fry Award lecture 1988: The ocular
ling the belief that these lenses were the ultimate solution. Hypoxia response to contact lens wear. Optom Vis Sci 1989;66:717–733.
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The CLAO Journal, Vol. 28, No. 1, 2002