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Physiologic Changes of the Cornea with Contact Lens Wear

Liesegang, Thomas J. M.D.

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From the Department of Ophthalmology, Mayo Clinic, Jacksonville, Florida.

Accepted May 30, 2001.

Address correspondence to Dr. Thomas J. Liesegang, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, U.S.A.

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Abstract

Purpose. This article reviews the corneal changes resulting from the hypoxia that occurs during sleep and specifically during contact lens wear.

Methods. Discussion includes a literature review and observations regarding the changes to the corneal epithelium, stroma, and endothelium that take place during sleep and wearing of contact lenses made from different materials.

Results. Hypoxia and hypercapnia cause significant changes to the corneal epithelium, stroma, and endothelium. Some of these changes can also be seen following the sleep cycle. Epithelial changes include decreased metabolic rate, morphologic changes, microcysts, changes in junctional integrity, decreased corneal sensation, and pannus formation. Stromal changes include stromal edema, stromal acidosis, neovascularization, and changes in corneal shape and, ultimately, corneal thinning. Endothelial changes include bleb formation, polymegethism, changes in endothelial cell density, and possible changes in endothelial function.

Conclusions. There are 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.

Contact lenses interact mechanically with the cornea and modify the physiologic processes of corneal tissue. These changes may lead to reduced corneal function. 1 It is necessary to differentiate corneal changes that are physiologically acceptable from those that are pathologic. Clinicians, biochemists, engineers, and vision scientists have performed countless research studies to understand the etiology of these changes in order to enhance the safety of contact lens wear.

Changes in the cornea caused by contact lenses can be divided according to the structures affected (tear film, epithelium, stroma, endothelium) or according to the causes. The major consequence of contact lens wear is chronic hypoxia, with corresponding hypercapnia. 2,3 Other consequences include tear film instability, allergy and toxicity, mechanical effects, inflammation and infection, and desiccation, as outlined by Bruce and colleagues. 4 Alternatively, these adverse events can be grouped into hypoxia-mediated events, immune events, mechanical events, and osmotic events, 5 but these categories are not mutually exclusive.

The physiologic changes differ among the various contact lens materials (polymethylmethacrylate [PMMA], rigid gas-permeable [RGP], soft hydrogel, silicone, and silicone hydrogel) and among various patterns of wear (daily, conventional, extended, overnight). Because individuals differ in susceptibility, these corneal changes are not uniformly present, although patterns emerge.

This article reviews the normal consequences of the prolonged closed-eye state and the superimposed consequences from contact lens wear, particularly those due to hypoxia and hypercapnia. Tear film instability, allergy and toxicity, or mechanical effects resulting from contact lens wear also contribute to some of these effects but are difficult to separate and will not be specifically addressed. The new silicone hydrogel contact lens may overcome some of these complications.

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PHYSIOLOGIC CHANGES DUE TO PROLONGED EYELID CLOSURE

The preferred environment for the eye is created by an alternating period of opening and closing. Prolonged eyelid closure from any cause triggers a cascade of biochemical, cellular, and microbial events, culminating in inflammation, hypoxia, and dry-eye states. 6,7

In the closed-eye environment, the partial pressure of oxygen as a percentage of oxygen in the atmosphere at the corneal surface is reduced from 21% to approximately 8%. Prolonged eye closure induces tear stasis, decreased tear volume, decreased oxygen tension, increased carbon dioxide, a shift to an acidic pH, corneal edema, corneal endothelial bleb response, increased corneal temperature, decreased acetylcholine, and decreased corneal sensitivity. 8 Analysis of the tear constituents in the closed eye confirms that a subclinical inflammatory condition exists under an eyelid during sleep. 9 There are increases in total tear protein, secretory IgA, and serum albumin; there is activation of complement and plasminogen, production of chemokines, recruitment of polymorphonuclear cells (PMNs), and release of highly reactive substances such as elastase and collagenase. Other major reflex tear components, such as lysozyme, lactoferrin, and tear-specific prealbumin, 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 of oxygen (Po2) of approximately 155 mm Hg and a partial pressure of carbon dioxide (Pco2) of near zero mm Hg 4 (Table 1). In the anterior chamber, Po2 is estimated to be 55 mm Hg, and Pco2 is estimated to be 40 mm Hg. 4 There is normally a flow of oxygen onto the anterior corneal surface and an efflux of CO2 from the surface.

Table 1
Table 1
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When the eye is closed, the Po2 in the palpebral conjunctival capillaries is approximately 60 mm Hg, 12 one third that of the pressure of the open eye. The Po2 decreases to approximately 40 mm Hg at the corneal surface because of corneal oxygen consumption; this results in only a small oxygen flux onto the anterior surface of the cornea. When the eye is closed, the palpebral conjunctiva has a Pco2 similar to that of the aqueous humor, and the resulting concentration gradient is negligible. Many investigators have observed significant individual variations in the levels of open-eye and closed-eye responses to the hypoxia. Contributing factors may include individual differences in corneal and crystalline lens oxygen requirements, endothelial structure and function, tear chemistry, lid action, lens pumping, and physiologic lagophthalmos. During sleep, the decrease in tear and stromal pH and the increase in corneal temperature and tear osmolality may affect corneal oxygen levels.

Mandell and Fatt 13 were the first to report an increase in corneal thickness (without contact lenses) during sleep, later measured to be approximately 4%. Because of the osmotic stromal response to the change in tear evaporation, the cornea returns to a baseline thickness within 1 hour of eye opening and continues thinning throughout the day.

Wearing soft contact lenses on an extended-wear basis mimics prolonged and exaggerated eye closure. Corneal swelling during continuous wear of hydrogel contact lens material also is cyclic, reaching approximately 12% overnight and 4% during the day. Zantos and Holden 14 reported that the overnight swelling response decreases with greater duration of continuous soft contact lens wear.

Uncomplicated daily wear of soft contact lenses does not appear to alter total protein or concentrations of secretory IgA and complement. Sleeping in contact lenses, however, increases the levels of total protein, secretory IgA, and complement to a greater degree than sleeping without contact lenses. 15

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HYPOXIA AND HYPERCAPNIA FROM CONTACT LENS WEAR

Fitting a contact lens on the eye leads to a significant reduction in the oxygen supply to the cornea, in the range of 8% to 15%, depending on the gas permeability of the lens material used. The 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 is given as Dk, where D is the diffusion coefficient of the material and k is the solubility coefficient of the material, and it is generally expressed as a whole number × 10−9 (cm × mL O2/s × mL × mm Hg). Oxygen transmissibility depends directly on this rate of flow and is inversely related to the average thickness of the lens (L). 16 Thus, oxygen transmissibility is given as Dk/L, and the higher the Dk value, the more permeable the lens is to oxygen.

The Po2 required by the human cornea for normal function is 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 least 75 Dk/L. Extended-wear soft contact lenses need a Dk/L of 75 to 89 to avoid inducing edema. 18,19 In open-eye conditions, the 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 extended-wear lenses do not meet these requirements. Another way of looking at this is to define the minimum oxygen percentage needed at the corneal surface to prevent corneal edema; this is approximately 10% to 13%, compared with the normal 21%. 18 Tear pumping is a supplementary route for providing oxygen to the cornea. Investigators have found that there is a 10% to 20% volume exchange per blink under an RGP contact lens, compared with only a 1% volume exchange per blink under a soft contact lens. 20

CO2 transmissibility is directly related to O2 transmissibility. The Pco2 in the anterior cornea varies depending on the transmissibility of the contact lens, increasing to a maximum of approximately 40 mm Hg with PMMA lenses. During eye closure, corneal Pco2 is always approximately 40 mm Hg because this is the tension at the palpebral vasculature. 21

If the oxygen decreases below a critical level, the cornea shifts to anaerobic glycolysis using the Embden-Meyerhof pathway, in which glucose is broken down to pyruvate and then to lactate. Because lactate does not diffuse rapidly out of the cornea, the consequence of decreased aerobic metabolism is stromal lactate accumulation. Hypoxia thus creates a lowered epithelial metabolic rate, an increase in epithelial lactate production, and an acidic shift in stromal pH. The degree of stromal acidosis varies, depending on the O2 transmissibility of the lens (i.e., Dk/L) and the buildup of CO2 under the lens.

Contact lens wear therefore produces corneal hypoxia and accumulation of CO2, both of which cause acidosis. 22 The pH of the epithelium, stroma, and aqueous humor decreases significantly with contact lens wear when the Dk/L is less than 100. Hypoxia causes substantial effects on the epithelium and stroma but has limited or no direct effects on the endothelium and aqueous humor. Carbon dioxide accumulation causes significant acidosis in all compartments measured. Most of the acidosis occurs in the anterior layers of the cornea and results from retardation of the normal carbon dioxide efflux. Corneal acidosis promotes endothelial polymegethism, epithelial microcysts, corneal edema, striate lines, infiltrative keratitis, and microbial keratitis.

After prolonged corneal hypoxia, there is depletion of the glycogen reserves of the cornea, diminished adenosine triphosphate (ATP), and ultimately a slowing of the water transport system in the endothelium. The combined effects of the accumulation of lactic acid in the stroma and a decrease in the pumping action of the endothelium result in increased corneal edema.

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Epithelial Effects of Hypoxia

The effects of hypoxia and hypercapnia on the epithelium include a decreased epithelial metabolic rate with decreased oxygen uptake, lactate accumulation, acidic shift, decreased ion pumping, reduction in cell synthesis with enzyme shifts, and possible changes in DNA and RNA. The clinically observed correlates include morphologic changes, microcysts, compromise in junctional integrity, epithelial defects, neovascularization, and decreased corneal sensation (Table 2). The compromised junctional integrity is accompanied by diminished electrical potential and reduced adhesion. 8 In the short term, this can manifest clinically as epithelial erosions, edema, ulceration, and warpage; and long-term manifestations include formation of microcysts, bullae, vacuoles, thinning with vascularization, increased fragility, and decreased sensitivity. Effects on epithelial function include abnormal metabolism and decreased sensation. The effects on epithelial structure include reduced nerve density, edema, epithelial thinning, abnormal cell shapes, and microcysts.

Table 2
Table 2
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Epithelial Metabolic Rate Reduction

With extended-wear soft contact lenses, the epithelial metabolism is reduced because of a 15% decrease in oxygen uptake. The technique of redox fluorometry confirms the reduced epithelial metabolic rate, and other studies confirm the reduced mitotic rate of the basal epithelial cells. Short-term contact lens wear causes a temporary decrease in corneal oxygen flux; long-term wear causes a sustained reduction. 23 The decreased metabolic rate affects the epithelial physiology, the cellular junctional integrity, and the cellular reserves of glycogen. Glycogen becomes depleted, cell synthesis is reduced, and corneal sensation is decreased. Lactate accumulates between basal cells, causing a decrease in pH, and there is an increase in intercellular spaces manifest as “Sattler veil.” There is no intracellular edema, and the epithelium actually thins by approximately 6%. With decreased pumping ability, increased permeability of the epithelial cells can result in dehydration. The synthesis of cytochrome P-450 arachidonic metabolites causes an inflammatory response. 24 In the rabbit model of extended-wear soft contact lenses, Ren and colleagues 25 found increased limbal epithelial stem-cell proliferation, with a concomitant decrease in the proliferation of basal epithelial cells. They hypothesized that increased stem-cell activity is a compensatory mechanism for decreased central basal cell activity and may lead to a depletion of the stem-cell reservoir.

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Epithelial Morphology Changes

Wide-field color specular microscopy has been used to monitor surface epithelial morphology during extended wear of conventional hydrogel lenses and to identify changes in epithelial barrier function. 26,27 Suppression of mitotic activity and of the exfoliation rate in the corneal epithelium with soft contact lens wear results in a decrease in the number of superficial cells and a flattening of the underlying cells. 28 A shift in size toward larger surface cells occurs, also indicative of a reduced exfoliation rate and possibly contributed to by the relatively stagnant post-lens tear film and the dampening effect of the lens on blink-mediated shear forces from eyelid movement.

With extended-wear soft contact lenses, 26 the mean corneal epithelial cell size is affected most. Because these mature cells have fewer microvilli and less mucin, more sites are available for possible bacterial adhesion. This also results in epithelial thinning, decreased corneal oxygen flux, epithelial microcysts, and increased fragility of the epithelial layer. Because of the basal-cell flattening and the decrease in the number and thickness of epithelial cells with extended-wear soft contact lenses, the epithelium is thinned by 6% on average. Hypoxia delays apoptosis, or programmed cell death, and results in the retention of the superficial cells. The epithelial thickness is reduced to nearly one third its normal thickness in areas of contact lens bearing. A layer of wing cells is absent, and the basal cells are compressed. 29 There is an increase in rate of cell mitosis in these lens-bearing areas. The thickness returns to normal within a short time after discontinuation of contact lens wear. 30 Tsubota and co-workers 31 demonstrated that corneal epithelial cell size increases linearly with increasing overnight wear and overall duration of hydrogel lens extended wear (Fig. 1).

Fig. 1
Fig. 1
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Changes in tear film during overnight contact lens wear increase epithelial permeability, leading to further increases in epithelial dehydration. Although most tissues swell with hypoxia, the corneal epithelium becomes thinner. Redistribution of cellular water apparently occurs, leading to local changes in the refractive index that give rise to the Sattler veil. 32,33 The Sattler veil is a corneal haze in which halos appear around lights. The condition occurs without changes in epithelial thickness and without uptake of water. It is caused by an increase in light scatter at the level of the corneal epithelium. Epithelial edema causes more forward scattering of light than stromal edema and thus has a more profound effect on vision—sometimes termed “epithelial bedewing.” Other terms describing this hypoxia-induced corneal edema include “corneal misting”34 and “central circular clouding.”35 The Sattler veil seems to result from an increase in the intercellular spaces of the epithelium during hypoxia, which may be due to an increase in lactate concentration, with a corresponding decrease in pH, between basal cells. Sattler veil is distinct from microcysts. With RGP or PMMA contact lenses, the change usually occurs under the 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.

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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 metabolism. 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 persons who do not wear contact lenses, the number is small, usually less than 10 microcysts.

Epithelial microcysts are usually asymptomatic. Zantos 36 and others proposed that hypoxia was the primary cause, although this hypothesis does not explain microcyst location in the midperipheral region of the cornea. Microcysts tend to conform to an arcuate pattern in the lower pupillary margin. They are seen in areas of contact lens bearing and also may be related to epithelial trauma and inadequate lens movement, with pockets of cellular debris. Staining is observed when microcysts break on the surface, although this usually has no effect on vision. With extended-wear contact lenses, epithelial microcysts usually increase in number and size over a period of weeks, until they reach a steady state. The increase in numbers of microcysts after discontinuing contact lens wear is due to the return of normal epithelial metabolism, with more encapsulated cellular matter brought to the surface before being eliminated. 30 The presence of microcysts correlates with a reduced epithelial mitotic rate and an increase in the regeneration time of the epithelium (Fig. 2). Impaired cellular synthesis and waste removal are features related to this altered metabolism.

Fig. 2
Fig. 2
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Pathologic examination of microcysts shows degenerated epithelial cells (apoptotic cells), probably from dysfunction of the basal cells of the epithelium, with cellular degeneration and lysis. 37 Microcysts probably form in the basal epithelium and are transported anteriorly as the epithelium grows in that direction. They appear to be caused by metabolic stress and the altered growth pattern of the epithelium due to the direct and indirect effects of hypoxia or hypercapnia.

Microcysts may resolve with an increase in the oxygen transmissibility of the contact lens, a decrease in overnight wear of an extended-wear lens, or a change from a soft lens to a rigid lens. Switching to a disposable extended-wear lens or changing solutions is not likely to be effective.

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Compromised Junctional Integrity and Epithelial Defects

The maintenance of the electrical potential between the tear film and the aqueous humor depends in part on superficial epithelial tight junctions between the corneal epithelial cells. Contact lens wear may compromise junctional integrity by loosening the epithelial tight junctions, thus separating the corneal epithelial cells. The increase in epithelial fragility can be measured with the Cochet-Bonnet esthesiometer; the minimum pressure required to produce epithelial damage is measured with the esthesiometer and demonstrated by fluorescein staining. 38 Fragility is also manifested by decreases in corneal electrical potential, punctate staining, epithelial abrasion, and an increased risk of microbial infection. The reduction in epithelial adhesion correlates with a decrease in hemidesmosome synthesis. 39 Suggested mechanisms of the problems with epithelial adhesion include a mechanical deformation of basal cell shape or a hypoxia-induced increase in intracellular calcium. There is a reduction in epithelial healing rate, probably from reduced ATP production. Contact lens wear induces corneal swelling and an epithelial inflammatory response related to the synthesis of the cytochrome P-450 arachidonic acid metabolites 12(R) hydroxyeicosatetraenoic acid (12 R HETE) and 8(R) hydroxy-hexadecatrienoic acid (8 R HHDTrE). 24,40 Time-dependent epithelial increases in the production of these metabolites correlate directly with the corneal inflammatory response, and the inflammatory response can be reduced by their inhibition. 12 R HETE is a sodium-potassium ATP inhibitor and is a vasodilatory, chemotactic, and angiogenic factor.

Using rabbit corneas, Imayasu et al 41 showed that the Dk/L of extended-wear contact lenses correlates with increased surface cell desquamation and increased binding of Pseudomonas aeruginosa. This effect occurred regardless of whether soft or RGP contact lenses were worn, implicating oxygen transmissibility rather than other factors, such as lens fit, in compromising the cornea and enhancing the risk of infection. Solomon 42 found that higher infection rates in rabbits correlated with the amount of corneal edema, which is related to oxygen transmissibility. In humans, Fleiszig et al 43 reported that exfoliated cells from extended-wear soft contact lens wear bind more P. aeruginosa than those from daily-wear contact lens wearers; hypoxia was the suspected cause. Chronic hypoxia alone, however, is not the sole explanation because corneal infections do not commonly develop in patients wearing PMMA lenses. The interaction with the closed eye during contact lens wear is probably also an important mechanism. Early studies with high-Dk materials suggested that such materials may reduce the epithelial barrier function defects and hold promise of eliminating this problem. 44

Epithelial abrasions are attributed to low oxygen transmissibility of the contact lens, with loosening of intercellular tight junctions and separation of corneal epithelial cells. Superficial punctate keratitis is a common complication of contact lens wear attributed to hypoxia that results in the desquamation of stressed surface cells. Superficial punctate keratitis appears as pits in the epithelial surface and leads to the premature shedding of small groups of cells 45; it is commonly seen in association with the corneal hypoxia from overwear of PMMA or extended-wear soft contact lenses. Although hypoxia is a frequent etiologic factor, superficial punctate keratitis also may occur for many other reasons, including solution toxicity, edema, lens deposits, lens care products, lens fit, lens surface or edge irregularities, foreign bodies, improper lens insertion or removal, tear film disruption, and accumulated metabolic waste products. The compromised epithelial integrity related to hypoxia and other osmotic or mechanical factors increases the likelihood of bacterial adherence.

Vital stains can demonstrate the loss of the corneal epithelial integrity. Rose bengal, trypan blue, methylene blue, fluorexon, and bromthymol blue have been used, but fluorescein is the most commonly used stain for contact lens evaluation. 3 The defects can be superficial, moderate, or deep (into the stroma). There are punctate stains, diffuse stains, linear stains, and dimple stains (indentations in the surface). Defects also may develop in individuals who do not wear contact lenses (especially with age), but most cases occur with RGP contact lenses and, to a lesser degree, with soft contact lenses. Staining seen at the 3- and 9-o’clock positions results from reduced or incomplete blinking habits. Arcuate staining occurs because of a poorly polished intermediate lens zone or edge; and dimpling occurs in tight-fitting areas.

A classification of epithelial defects caused by contact lenses has been proposed by Watanabe. 46 Variations include (1) superficial punctate keratitis, which can be diffuse or involve the lower, 3- and 9-o’clock, or upper cornea; (2) linear (arcuate or pseudodendritic) complications; and (3) plane complications (infiltration, epithelial edema, erosion, ulcer, and neovascularization). Most of these epithelial complications occur with PMMA (73%) and RGP (33%) lenses but can be seen with soft contact lenses (15%–22%) or with disposable soft contact lenses (3%). The major causes of these epithelial defects include insufficient oxygen supply, mechanical stimulation, and local inadequate tear film.

Epithelial adhesion to the basement membrane is also reduced with extended wear of contact lenses. 47 Overwear can result in sloughing of the epithelium adherent to the posterior surface of the contact lens; this can cause a circular hole in the epithelium that may take weeks to heal. RGP lenses have been demonstrated to induce tear-film instability associated with damage to the ocular-surface epithelium and mucin layer. 48 In RGP wearers, abnormally shortened conjunctiva break-up time produces ocular surface damage, demonstrated as 3- and 9-o’clock staining.

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Neovascularization

Neovascularization (angiogenesis) is produced as a response to a metabolic or an angiogenic factor by mature existing blood vessels. New vessels form from existing vascular endothelium that retains the capacity to revert to primitive vascular mesenchyme. Vasostimulatory factors initiate new growth by a direct effect on the endothelial vascular cells and determine the direction of growth.

This response to contact lens wear has been described variously as vascularization, neovascularization, limbal hyperemia, vessel penetration, vasoproliferation, vascular pannus, or vascular response. It is a normal (albeit undesirable) vascular response to contact lens wear, and some vascular response occurs with almost all contact lenses. There are several steps in the neovascularization process: (1) Limbal hyperemia, a dilatation of existing limbal capillaries, is reversible and is common with hydrogel soft contact lenses worn overnight but can also occur with any tightly fitting contact lens; (2) superficial neovascularization (pannus) is the progression of limbal hyperemia and the penetration of vessels into the superficial cornea; (3) deep stromal neovascularization results from chronic hypoxia that may progress to an active inflammatory or fibrovascular deep pannus; and (4) there may be an intracorneal hemorrhage.

Limbal vessel dilatation has been identified as the initial clinical sign in corneal vascularization. Chronic limbal vessel dilatation could provide an active vascular plexus adjacent to the cornea on which stimuli promoting vessel growth could act. Although corneal vascularization has been reported during extended wear of disposable and conventional lenses, quantitative and comparative data are lacking. Because hypoxia is believed to be one of the major causal factors of vascularization, the extent of corneal vascularization with disposable and conventional contact lenses of similar oxygen transmissibility would be expected to be similar. New contact lenses with high oxygen transmissibility are promising developments for reducing these stimuli of vessel dilatation and growth.

The prevalence of neovascularization is low with RGP or PMMA contact lenses, more common with daily-wear soft contact lenses, higher with extended-wear soft contact lenses, and very high with aphakic extended-wear lenses. Neovascularization is more common with soft contact lenses than with microcorneal lenses because the soft contact lens covers the entire cornea. Additionally, the tear film beneath the soft contact lens is minimized because of the relatively tight fit required to keep the lens in position. Vascularization is always greater in the superior limbus and is directly related to lens oxygen transmissibility. It is especially common with large and thick contact lenses and results in development of new corneal vessels in up to 20% of wearers. 49 The vascularization associated with RGP lenses is caused by continual 3- and 9-o’clock staining; the incidence of neovascularization is low, related most often to limbal coverage by an eccentrically riding contact lens or persistent overwear. 50

Vascular regression occurs after lens removal, leaving “ghost vessels” in the cornea. Occasionally, intrastromal opacities can occur, consisting of lipid droplets and inflammatory cells adjacent to the blood vessels in the deep stroma near the Descemet membrane. Although these opacities are caused by inflammatory cells, the cooperation of stromal keratocytes is necessary.

No single theory can account for corneal neovascularization; rather, several factors may contribute. 51 Proposed theories take the following aspects into account: metabolic factors (hypoxia, lactic acid, edema, stromal softening); angiogenic suppression (necessity of substances that inactivate the normally present angiogenic inhibitors); vasostimulation (locally generated or introduced vasostimulatory factors such as free cellular elements, humoral components, epithelial cell factors, or extrinsic factors); and neural control (mediation of the vascular response to contact lens wear by contact lens-induced changes to corneal neurology). Another way of categorizing stimuli that can promote vessel penetration into the normally avascular cornea includes nutritional, inflammatory, mechanical, traumatic, and toxic factors. One or all of these stimuli are present during contact lens wear, particularly overnight wear. Whatever classification system is used, the most important factor is contact lens-induced tissue hypoxia, which induces corneal edema and stromal softening. The additional mechanical injury to the epithelium results in the release of enzymes, migration of inflammatory cells into this site, and release of vasostimulatory agents causing vessels to grow in that direction.

Soft contact lens-induced hypoxia has been shown to stimulate the metabolism of arachidonic acid by a nicotinamide adenine dinucleotide phosphate (NADPH)–cytochrome P-450 monooxygenase, hydroxyeicosatrienoic acid (12 R HETrE), a proinflammatory and angiogenic factor (Fig. 3). 52 Biologic actions of this factor result in an increase in barrier permeability, vasodilatation, polymorphonuclear chemotaxis, and vascular endothelial cell mitogenesis. Routine contact lens wear is associated with inflammatory reactions and, even in asymptomatic patients, can induce release of some proinflammatory cytokines, including interleukins 6 and 8. Hypoxia creates an environment in which epithelial cyclooxygenase activity is severely suppressed, whereas metabolizing activity of cytochrome P-450-arachidonic acid or 12-lipoxygenase is maintained or enhanced. The 12 R HETE produced by the corneal epithelium acts intracellularly to promote corneal edema, whereas 12 R HETrE acts in a paracrine manner to initiate an inflammatory cascade that can elicit neutrophil chemotaxis and neovascularization of the cornea. 52

Fig. 3
Fig. 3
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Corneal Hypoesthesia

Contact lens wear is associated with a decrease in corneal sensation, as measured by esthesiometry. Corneal touch thresholds differ with the various types of contact lens (Fig. 4). Within 1 day, those wearing PMMA contact lenses experience a 200% increase, soft contact lens wearers experience a 50% increase, and those wearing high-water content extended-wear soft contact lenses experience a 10% increase of touch thresholds.

Fig. 4
Fig. 4
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Decreased corneal sensation is not usually associated with RGP or any high-oxygen transmissible contact lenses. Sensation returns to normal in a few hours after short-term contact lens wear. 53,54 Eyelid closure during sleep also causes a reduction in corneal sensitivity. 55

Long-term wear of contact lenses causes a more pronounced loss of sensation that is more persistent. There are individual variations, and sensitivity tends to return with cessation of contact lens wear. Decreased sensation is milder with soft contact lenses and the return of sensation is more rapid, compared with PMMA lenses. Extended wear results in pronounced decreases, but recovery can occur. After 5 to 7 years of wear, sensation may be permanently decreased with PMMA lenses, and the situation is possibly similar with soft contact lens wear.

Corneal hypoesthesia is thought to be an adaptation to chronic hypoxia, to decreased corneal pH, or to mechanical stimulation and is correlated with levels of acetycholine. 10 It does not appear to be a consequence of edema. The specific end mechanism may be related to acetycholine concentrations or choline acetyltransferase, the enzyme responsible for the synthesis of acetycholine. Epithelial acetylcholine is a neurotransmitter to corneal nerves and is decreased in hypoxia. There is also a suggestion of a lack of trophic function for the ciliary nerves in the maintenance of epithelial properties. 49 A hypoxia-induced decrease in neural transmission or neural damage or a sensory adaptation to mechanical stimulation also may occur. Contact lenses appear less likely to affect corneal sensation if oxygen transmissibility is high, and most studies support the concept that hypoesthesia depends on the epithelial oxygen tension level. 56 Corneal sensation may be a more sensitive test than refraction, keratometry, or pachometry for monitoring the status of corneal health during contact lens wear. 10,56 Considerable individual variation exists, with many unknown factors, however.

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STROMAL EFFECTS OF HYPOXIA

The short-term effects of hypoxia and hypercapnia on the stroma include stromal acidosis, edema, and striae. Long-term effects include stromal thinning, infiltrates, neovascularization, and corneal shape alterations 8 (Table 3).

Table 3
Table 3
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Stromal Acidosis

During contact lens wear, the stroma undergoes a decrease in pH from the effects of metabolic and respiratory acidosis occurring in the epithelium and diffusing into the stroma (Fig. 5). Metabolic acidosis is caused by the accumulation of stromal lactic acid during anaerobic metabolism. Respiratory acidosis is caused by the accumulation of carbon dioxide (hypercapnia) because the gas-impermeable contact lens precludes normal efflux of carbon dioxide. Thus, both hypercapnia and hypoxia lead to stromal acidosis. 4 Corneal epithelial and aqueous acidification during contact lens wear in rabbits appears similar to the stromal acidification mechanism in humans, and this animal model has been used in several studies. 57

Fig. 5
Fig. 5
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In closed-eye conditions, the normal pH of the human corneal stroma is similar to that of blood (7.39) because of diffusion of CO2 from the palpebral conjunctiva into the cornea. 4 Under open-eye conditions, the human stromal pH increases by 0.15 to 7.55. It may decrease by as much as 0.25 during wear of soft contact lens of nearly zero oxygen transmissibility. Wearing thick, low-water content soft contact lenses can produce a stromal pH of 7.15. Under closed-eye conditions, hypercapnia is always present, with or without contact lens wear. Thus, the degree of corneal hypoxia in contact lens wear is the only significant variable in stromal acidosis.

The contact lens restricts oxygen at the anterior corneal surface. Hypoxia decreases ATP production by the usual aerobic breakdown of glucose in the corneal epithelium. This causes a compensatory shift to the Embden-Meyerhof anaerobic glycolytic pathway in epithelial cells. Smelser and Chen 58 found increased corneal lactate concentrations after corneal hypoxia. Klyce 59 observed the connection between increased corneal lactate values and the observed swelling of the stroma during contact lens wear. Because lactate cannot penetrate the superficial epithelium, all the newly formed lactate accumulates between epithelial cells, subsequently diffuses posteriorly into the stroma, across the endothelium, and finally is washed out into the aqueous humor. Additionally, lactic acid creates an osmotic load that is balanced by increased movement of water into the stroma. The sudden influx of water cannot be matched by the removal of water from the stroma by the endothelial pump. Therefore, although the stromal edema appears to be entirely due to lactate accumulation from hypoxia, the decreased stromal pH (stromal acidosis) is a result of both hypoxia and hypercapnia. This stromal acidosis also reduces the deswelling response that occurs after corneal insult.

Contact lens hypoxia may correlate with the activity of lactate dehydrogenase (LDH) in the cornea. 60 With RGP wear, the LDH isozyme appears to switch from the aerobic type to the anaerobic type and return to normal over time. Tear LDH concentrations may provide a method for ongoing assessment of the tolerance of the ocular surface to contact lens wear. 60

A contradictory study showed that chronic RGP contact lens wear is associated with altered glucose-lactate metabolism in the 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 independent of lens-oxygen transmissibility and may thus represent a prolonged mechanical effect of contact lens wear itself.

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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 stroma by a sodium-potassium-ATPase and bicarbonate ion pump. Both an endothelial pump-leak and a minor epithelial pump-leak occur. During sleep, edema occurs in every human cornea, with an increase in thickness of 4%, whereas on waking, a reduction in thickness occurs. Superimposing a contact lens adds to this fluctuation in corneal thickness, which is related to hypoxia. Stromal edema occurs because of a break in epithelial or endothelial barriers, a reduction in pump function (mainly endothelial), or an increase in osmotic activity (imbibition pressure) of the stromal compartment.

Measurement of central corneal swelling is the most commonly used short-term index of the physiologic compatibility of a contact lens, because a change in corneal thickness is inversely related to the average oxygen transmissibility of the contact lens. 62 The response begins within half an hour after contact lens insertion and generally peaks within 3 hours. The degree of corneal edema associated with long-term contact lens wear appears to decrease with time. The swelling response to contact lens wear is generally presented as a population mean; however, there is significant variation among individuals.

When the oxygen tension of the anterior part of the eye is restricted by contact lens wear, this provokes a change in epithelial cellular lactate production rate. The principal drainage route for lactate is across the stroma through the endothelium into the aqueous humor. Lactate is a well-dissociated acid; thus, it is principally present in the stroma as its sodium salt. The presence of stromal sodium lactate has an osmotic effect. The change in stromal water content due to the osmotic (imbibition) pressure of the lactic acid in turn determines the thickness of the stroma. The degree of stromal thickness observed in anoxia can be wholly accounted for theoretically by the changes in lactate levels. Factors other than hypoxia contribute to corneal edema, including temperature, humidity, osmolality, carbon dioxide of the tears and cornea, mechanical effects, and inflammation, but these effects are probably minimal. 8 Klyce 59 proved by complex mathematical models and by laboratory techniques that anoxia provokes stromal swelling. The combination of hypoxia and excess carbon dioxide may be the most significant contribution. 8 Alternatively, however, studies on RGP extended wear and stromal swelling in rabbits 61 found that increased stromal lactate accumulation from contact lens wear could not account for persistent stromal edema with chronic extended wear of RGP lenses. These authors thought that stromal edema may be independent of oxygen transmissibility of the lens and may represent the prolonged mechanical effect of lens wear itself.

With extended-wear soft contact lenses, the increase in stromal thickness occurs significantly more in the center than in the periphery because of hypoxia. With current soft contact lenses and RGP lenses, unadapted patients usually have daytime corneal edema of 1% to 6% and nighttime edema of 10% to 15%, as measured on awakening. With extended-wear lenses, overnight edema averages 10% to 12%. If the soft contact lens water content is increased to the maximum, it is possible to maintain normal corneal thickness, at least during the day. After weeks of soft contact lens wear, the pattern of daytime thinning of the cornea is also reduced, possibly from adaptation.

Extended wear of RGP lenses usually induces less central edema than extended wear of soft hydrogel contact lenses. Other factors that influence corneal thickness, such as reflex hypotonic tearing or a long-term physical thinning of the stroma, however, can introduce an artifact into measurements of corneal thickness, in long-term contact lens wearers. The degree of corneal swelling induced by contact lenses varies markedly among individuals, and adaptation is a confounding variable. With RGP lenses, as the oxygen transmissibility is increased to 90 to 100 Dk/L units, the increased thickness becomes difficult to detect, and there is no detectable clinical gain with Dk/L values in excess of these values (Fig. 6).

Fig. 6
Fig. 6
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Striae and folds that appear during overnight contact lens wear are a function of the oxygen transmissibility of the lens and the oxygen uptake rate of the cornea. Grades of edema can be assigned. 2 Posterior striae indicate an acute change in corneal thickness. Striae occur at 5% to 7% stromal edema and represent fluid separation of vertically arranged collagen fibrils in the posterior stroma. Zantos and Holden 63 measured the average critical level of stromal swelling for the appearance of striae at 4.5% for vertical and 3.8% for horizontal striae. The folds appear as black lines in the posterior stroma, observed if 10% to 15% stromal swelling is present, and represent physical buckling of the posterior stromal layers of the Descemet membrane. There is an alteration to the topography of the endothelial layer as seen in specular reflection. Haze appears at 15% stromal edema and represents an advanced form of striae, with gross separation of collagen fibers through the full thickness of the stroma.

Holden and Mertz 18 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 approximately 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 in a 12% loss of ability to recover.

A corneal stress test for extended wear 42 has been suggested. Measuring corneal swelling after 1 night of wearing extended-wear soft contact lenses may identify those patients whose corneas are at risk for significant oxygen deprivation during overnight contact lens wear. Corneal swelling of 5% or less seems to indicate that the cornea can tolerate 7 nights of extended wear.

The corneal edema varies with the material and design of the contact lens. PMMA causes swelling in the area covered by the contact lens (steeper in that area), whereas the soft contact lens affects the entire cornea (with less effect on corneal topography or power), 66 and the Sattler veil is generally absent in soft contact lens wearers. The anoxic swelling may subside over time, although the reasons are unknown. Wearers of PMMA contact lenses show three types of response 67: (1) Some individuals may demonstrate maximum stromal swelling of 2% to 4% during the first day of wear but no swelling after 2 weeks of wear; these individuals have adequate levels of tear exchange and corneal oxygenation and suffer only from changes in tear osmolarity. (2) Other PMMA wearers may have a maximum swelling of 5% to 8% during the first days of wear, with a decrease to a lower level after 2 weeks of wear; these individuals are usually able to wear contact lenses, but any further problem is superimposed on the initial problem of swelling, and contact lens wear becomes intolerable. (3) Some individuals may have greater than 8% stromal swelling and are unable to wear the contact lenses beyond 6 hours the first day. In the third group, oxygenation is inadequate, and this level of response is usually provoked by a grossly tight fit; wearing time is restricted, and problems are more common in this group because they are always at risk for overwear syndrome.

Because swelling is a function of the ability of the lens material to transmit gases, lens thickness and water content are important criteria in soft contact lens wear. Large variability in patients exists, although the following observations have been made: (1) thick hydrogen lenses provoke more stromal swelling than thin lenses; (2) the extent of swelling declines with time; (3) the extent of swelling rarely exceeds the maximum amount that can be provoked by anoxia alone (8%); (4) the use of thin lenses causes, on average, less than 1% stromal swelling; and (5) swelling is much greater with extended wear of soft contact lenses, which results in increased levels of corneal thickness during periods of sleep.

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Stromal Thinning

Whereas stromal edema is an acute response to contact lens wear, stromal thinning is a chronic pathophysiologic change in patients who have worn contact lenses for years. Thinning by 2% may be a sequela of chronic stromal edema correlated with degeneration and possible death of stromal keratocytes. 68 Immediately after contact lens removal, the stromal thinning is masked by superimposed edema; the thinning becomes apparent only 2 days after cessation of contact lens wear (Fig. 7). Less stromal thinning is associated with a thinner initial stroma, lower epithelial oxygen uptake rate, and less endothelial polymegethism before lens wear. Unlike the recovery of the epithelium, recovery of the stroma from chronic edema is slow. Both stromal edema and a subsequent 4.8% reduction in stromal thickness were recorded with long-term extended wear of hydrogel lenses. 30 Continuation of stromal thinning was reported up to 6 months after cessation of contact lens wear.

Fig. 7
Fig. 7
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The causes of corneal thinning probably involve the losses of stromal keratocytes and mucopolysaccharide. 68 Chronic edema induces morphologic changes in the stromal keratocytes, manifesting as functional changes in the ability of these cells to synthesize collagen, glycoproteins, and proteoglycans. Another possible cause is dissolution of stromal tissue, perhaps due to the effects of lactic acid on the stromal mucopolysaccharide ground substance. 8 Stromal keratocytes lose their ability to synthesize new stromal tissue because of hypoxia and the indirect effects of chronic induced-tissue acidosis due to accumulation of lactic acid and carbonic acid. Confocal microscopic examination of extended-wear soft contact lens patients showed reduced stromal keratocyte density. 69 Additive mechanisms include hypoxic, cytokine-mediated, or mechanical effects. Hyper-reflective keratocyte nuclei were also reported. 70 With confocal microscopy, a new type of chronic stromal change also was observed, with highly reflective panstromal microdot deposits in the corneal stroma. 71 This deposition is more common with long-term wear of contact lenses and more common with soft lenses than with RGP lenses. This condition may be an early stage of corneal disease, but its clinical significance is unknown. No data are yet available comparing the effects of conventional and disposable contact lenses on stromal thickness during long-term wear. 72

A study with the Orbscan (Orbscan Inc., Salt Lake City, UT) topography system 73 showed that the mean corneal thickness in the center and in eight peripheral areas was significantly reduced by approximately 30 to 50 μm in long-term soft contact lens wearers compared with noncontact lens wearing control subjects.

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Corneal Shape Alterations

Contact lens wear can result in corneal distortion or warpage. Multiple other terms have been used in the literature to describe these changes, including “indentation,” “steepening,” “flattening,” “sphericalization,” “imprinting,” and “wrinkling.” These changes are predictable to the extent that contact lenses can be used to reduce the cone protrusion in keratoconus and in orthokeratology, which is the controversial practice of fitting progressively flatter, reversed-geometry tight-fitting RGP lenses, with the aim of flattening the cornea to reduce myopia.

Videokeratopographic mapping techniques reveal that all forms of contact lens wear are capable of inducing changes in corneal topography. Topographic abnormalities were detected in 75% of corneas with PMMA lens wear, 57% with RGP lens wear, 31% with daily-wear soft lenses, and 23% with extended-wear soft lenses, compared with 8% of normal corneas without contact lens wear. 74 These changes can cause spectacle blur or contact lens decentration. Generally, contact lenses with high oxygen transmissibility induce little warpage. 75 Corneal topographic changes with contact lenses have been reviewed by Ruiz-Montenegro et al. 74 Significant changes occur with RGP contact lenses and occasionally with daily-wear or extended-wear soft contact lenses. Many different topographic patterns can result from contact lens wear, but most involve flattening in areas of lens bearing. The changes correlate with the resting position of the RGP or PMMA lenses and entail flattening beneath the decentered contact lens and possible adjacent steepening, usually detectable only with computer-assisted topographic analysis. Changes also occur in the overall curvature; and central clouding occurs initially with PMMA lenses, with induced central steeping and myopia. 76 With PMMA lenses, a central flattening occurs later, with reduction in myopia. RGP lenses have the same effect but to a lesser extent, which is proportional to the oxygen transmissibility of the contact lens.

Changes in corneal asymmetry also take place with contact lens wear. The surface asymmetry index (SAI), a quantitative measure of the radial symmetry of the four central videokeratoscope mires surrounding the vertex of the cornea, is higher with PMMA, RGP, and extended-wear soft contact lenses. In addition, there are changes in corneal regularity. The surface regularity index (SRI) is a measure of central and paracentral corneal irregularity derived from the summation of fluctuations in corneal power that occur along semimeridians of the 10 central videokeratoscope mires. The SRI is high with PMMA and RGP lenses, and occasionally also with soft lenses.

Corneal wrinkling may manifest with the appearance of a series of deep parallel grooves in the cornea that give the impression of a wrinkled cornea. 77 There may be signs of corneal indentation, in which the impression of the contact lens edge is evident on the cornea. Other patterns can occur, including central irregular astigmatism, radial asymmetry, changes in the axis of astigmatism, and reversal of the normal pattern of progressive flattening from the center to the periphery.

When PMMA lenses first became available, the main problems encountered were central corneal clouding, 3- and 9-o’clock staining, and corneal distortion. 8 Approximately 30% of PMMA lens wearers manifest corneal distortion that can be clinically significant. 78 Distortion (warpage) with PMMA lenses is caused by a combination of central corneal edema (due to hypoxia) plus superimposed mechanical pressure from the contact lens or the eyelid on the softened cornea, and also by mucus binding beneath the rigid lens. Metabolic factors such as oxygen tension may also contribute. The central cornea steepens with PMMA wear. Such steepening may be more than the circadian changes that have been observed, 79 in which the cornea flattens again during periods of sleep after PMMA lens wear, although baseline curvature is not achieved before the next period of lens wear. Over the first year of PMMA lens wear, the induced corneal steepening gradually decreases and the cornea may eventually become flatter than its prefit value. 49 The curvature changes are more apparent in the horizontal than in the vertical meridian. 80,81 Changes are less marked with soft contact lenses, which induce a slight corneal flattening in the first 2 or 3 weeks, followed by a period of relative steepening.

Although changes in corneal shape and reduction of refractive error are touted as permanent effects in the practice of orthokeratology, cessation of PMMA lens wearing is followed by large fluctuations in corneal shape and refractive error. The myopia of most subjects eventually returns to prelens-wear levels. 82 The induced changes in corneal topography and refractive state may remain unpredictable, and with long-term wear, this molding effect may lead to loss of regularity, resolving power, and visual function. The prognosis varies and depends on magnitude and duration of lens-induced deformation forces. The cornea usually returns to its original shape over months, but sometimes the changes are irreversible. Changes in shape are less common with soft contact lenses and usually require corneal topography examination to detect or monitor.

The Orbscan topography system 73 demonstrated that the mean corneal thickness was significantly reduced in long-term soft contact lens wear by 30 to 50 μm, compared with normal eyes without contact lenses. There was no correlation between central thickness and the degree of myopia detected. Corneal curvature was significantly steeper in the eyes wearing soft contact lenses than in normal eyes. No difference in mean corneal astigmatism was noted. The SRI and SAI were significantly greater in the contact lens wearers than in the control group. The authors concluded that long-term soft contact lens wear (average of 13 years) appears to decrease the entire corneal thickness and to increase the corneal curvature and surface irregularity. This may be caused by thinning of the epithelium and stroma due to chronic edema of the stroma and biochemical changes. Alternatively, it may be related to chronic exposure to a hyperosmotic tear film or to increased apoptosis of keratocytes and epithelial cells from chronic microtrauma and hypoxia. The increased curvature could be a contact lens-induced ectasia (similar to forme fruste keratoconus).

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ENDOTHELIAL EFFECTS OF HYPOXIA

The additive effects of hypoxia and hypercapnia alter the stroma. This induction of stromal acidosis has both short-term and long-term ramifications for endothelial function. Initial contact lens wear causes transient endothelial blebs and folds. Chronic hypoxia disturbs endothelial cell stability and produces polymegethism, pleomorphism, bedewing, guttata, and possibly cell death (Table 4). Endothelial polymegethism is a relatively permanent effect of inadequate oxygen permeability 8 and is prevalent with all contact lenses. The coefficient of variation for cell size is high with all types except RGP lenses. The effect on endothelial function appears to be minimal, although the functional reserve at times of stress may be reduced.

Table 4
Table 4
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Endothelial Blebs

Before 1977, the endothelium was thought to be immune to the effects of contact lenses because it received its nourishment from the aqueous. Zantos and Holden, 83 however, noted that the endothelial mosaic undergoes a dramatic alteration within minutes of insertion of a contact lens, especially when the oxygen transmissibility of the lens is low. Endothelial blebs appear as black, nonreflecting areas in the endothelial mosaic and as an increase in separation between cells. Blebs consist of endothelial swelling, with subsequent changes in the contours of cell membranes. 72 Initially, this appears as if cells had fallen off the posterior surface of the cornea. The phenomenon is observed within minutes after insertion of the lens, peaks at 20 to 30 minutes, and subsides to low levels after 45 to 60 minutes, with only a few blebs visible at other times. Due to adaptation, the response is reduced with continual contact lens wear.

Blebs can be produced by contact lens wear combined with anoxia or by passing a nitrogen gas mixture containing 10% carbon dioxide and 21% oxygen through a goggle. Because the gas mixture does not produce stromal swelling (there is no hypoxia), the common factor is the production of stromal acidosis. Thus, blebs resulting from contact lens wear appear to be a consequence of hypoxic acidosis and an accumulation of carbon dioxide because of a diffusion barrier, rather than because of hypoxia per se. 84 The carbonic and lactic acids may alter the physiologic status of the environment surrounding the endothelial cells; this induces changes in membrane permeability or pump activity, resulting in net movement of water into endothelial cells, with resultant development of blebs. Both endothelial blebs and stromal acidosis occur faster with hypercapnia than with hypoxia. The intracellular endothelial pH is the common factor.

Pathologic examination of blebs shows edema of the nuclear endothelial cells, with intracellular fluid vacuoles and fluid space between cells. 85 There is localized edema of groups of endothelial cells, which bulge toward the aqueous.

The bleb response is universal among contact lens wearers within 10 minutes after insertion, but there is variation in response. The blebs also occur during sleep and can be observed on awakening. 86 To a similar extent, blebs occur with conventional and disposable contact lenses of similar oxygen transmissibility, but their occurrence is minimal or absent with silicone elastomer contact lenses. There is also an increase in the number of blebs in the late evening in patients with extended-wear soft contact lenses. The overall number of blebs can be seen to decrease over the initial 8 days of extended wear. Despite their dramatic clinical appearance, blebs are asymptomatic and are thought to be of little clinical significance; they represent a short-term as well as long-term adaptation of the endothelium. 87

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Polymegethism

Polymegethism refers to a greater-than-normal variation of corneal endothelial cell size, resulting in a layer of large and small cells. The degree of endothelial polymegethism is measured by the coefficient of variation of endothelial cell size, a dimensionless ratio calculated by dividing the standard deviation of the areas of the cells in a defined field by the arithmetic mean of the areas of all cells in that field. For endothelial cells, polymorphism (or pleomorphism) refers to variations in cell shape distinct from the classical, uniform six-sided endothelial cell appearance. Pleomorphism can be defined as an increase in the proportion of nonhexagonal cells on the monolayer and usually accompanies polymegethism.

Polymegethism is a normal phenomenon of aging but is accelerated with contact lens wear correlates with hypoxia. MacRae et al 88 and, recently, Lee et al 89 reported an association between significant increases in endothelial polymegethism and pleomorphism and reduction in endothelial cell density. MacRae and colleagues hypothesized that polymegethism and pleomorphism precede reduced cell density because all three features were observed in long-term wearers. Polymegethism has been observed and quantified with daily- and extended-wear soft, RGP, and PMMA contact lenses and with age. Only the silicone elastomer contact lens, which has high gas permeability, does not lead to significant endothelial polymegethism. The degree of polymegethism was shown to correlate with duration of contact lens wear and degree of hypoxia by many but not all investigators. Extended wear of contact lenses appears to produce a more rapid increase in the coefficient of variation of endothelial cell size than daily wear. Recovery from contact lens-induced endothelial polymegethism is slow, and the condition may be irreversible, even after cessation of contact lens wear. This condition is unique because other corneal changes induced by contact lenses usually disappear with cessation of wear. Sibug et al, 90 however, reported a trend toward reduced polymegethism 5 years after cessation of contact lens wear. In another study, 91 the endothelial polymegethism was still present even 7 years after cessation of PMMA contact lens wear.

The cause of polymegethism is not yet clear. Connor and Zagrod 92 theorized that the causes of polymegethism involve a hypoxia-induced reduction in ATP levels and changes in the concentration of extracellular and intracellular calcium. Alternatively, corneal stromal acidosis may be an etiologic factor. 22 Polymegethism is one of the features of the corneal exhaustion or fatigue syndrome. 93,94 This syndrome is thought to represent endothelial dysfunction brought on by chronic contact lens-induced hypoxia and acidosis. Whether the morphologic changes in the endothelium in polymegethism are a result of changes in cell size or a redistribution of cell mass is in dispute. 95,96 Regardless of the cause, an irregular mosaic is inherently unstable, because adjacent cells with similar dimensions best maintain the barrier function of the endothelium. 97

When the cornea is exposed to 12 R HETE and 8 R HHDTrE, changes similar to those seen with contact lens-induced hypoxia occur, including edema, neovascularization, and endothelial polymegethism. 40 An underlying mechanism of polymegethism is related to the ability of 12 R HETE to inhibit the sodium-potassium ATPase of the endothelial pump. Repeated endothelial exposure to 12 R HETE and 8 R HHDTrE due to the diffusion of these eicosanoids (which results from the corneal epithelial inflammatory response to contact lens wear) causes endothelial cell swelling and a permanent change in the cellular cytoskeleton, leading to endothelial polymegethism.

The consequences of endothelial polymegethism are unclear. The condition may be benign, although polymegethism appears to be linked to corneal hydration control. Hydration control can be tested by inducing corneal edema and then recording the exponential rate of corneal deswelling. 98 Deswelling after induced edema is considerably slower in PMMA contact lens wearers than in non-contact lens wearers. An impaired functional reserve was demonstrated in a study that showed increased endothelial permeability and an increased endothelial pump rate in patients with polymegethism associated with wearing extended-wear soft contact lenses. 99 Endothelial polymegethism may adversely affect the ability of the cornea to reduce edema after surgical stress, a concern specifically for surgical patients. 97,100,101 Rao et al 97 showed that patients with polymegethism take longer to recover from corneal edema induced by cataract surgery. Slow corneal deswelling has been associated with polymegethism in the young and the elderly. 102

The pathologic basis of polymegethism is debated. Although the endothelial cells have clearly changed in shape, the volume of each cell may remain constant because the cells have become reoriented in three-dimensional space 96 (Fig. 8). An oblique reorientation of the lateral walls of endothelial cells occurs in contact lens wearers with some intercellular and intracellular edema. Endothelial cytoskeletal F-actin has abnormal patterns that may contribute to polymegethism and may be the result of constant stress in cell volume regulation. 103 No damage was evident on examination of the ultrastructure of the organelles of endothelial cells. 96

Fig. 8
Fig. 8
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Endothelial Cell Density

Although polymorphism and pleomorphism are well-known consequences of contact lens wear, most studies have been unable to confirm a change in endothelial cell density with contact lens wear 18,30,88,101,104–111; however, there have been a few isolated reports of endothelial cell loss. 112 MacRae et al 88 reported low endothelial cell density in a subgroup of PMMA lens wearers. PMMA wearers showed advanced polymegethism and pleomorphism 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 endothelial cell density. A subset of approximately 10% of PMMA lens wearers show these changes.

Using age-matched controls (not following individual patients), Setala and co-workers 113 also noted a lower endothelial cell density. In this study, mean endothelial cell density in contact lens wearers was minimally lower, and the mean coefficient of variation differed significantly from normal in all contact lens wearers. Very low mean endothelial cell density was observed in some patient populations of contact lens wearers and was seen only in contact lens wearers. A recent study by Lee et al 89 also found a significant change in the coefficient of variation of cell size and a decrease in cell density among long-term soft contact lens wearers. Thus, some studies suggest that there may be a subset of PMMA and soft contact lens wearers who react with high pleomorphism and polymegethism and also a decrease in endothelial cell density.

The morphologic change in endothelial cell density is speculated to be an indicator of cell stress due to chronic hypoxia; therefore, polymegethism and pleomorphism may be signs of premature cell death. This appears related to the type of contact lens. For example, Setala et al 113 found minimal or no endothelial morphologic changes with RGP and silicone lenses. These authors suggested that long duration of contact lens wear affects cell densities, especially after 25 years. Corneas with low cell density may remain clear unless stressed by conditions such as contact lens wear, surgical procedures, or age. Although these endothelial changes have not been shown to be reversible after cessation of contact lens wear, Sibug et al 90 believed that the changes might be slowly reversible.

Wiffen and colleagues 114 showed that endothelial cell density was significantly higher centrally than peripherally in normal subjects without contact lenses but not in contact lens wearers. The coefficient of variation of cell area was higher peripherally than centrally for both normal controls and contact lens wearers, but contact lens wearers had significantly higher coefficients of variation than controls in both the center and the periphery. The central cornea has more hexagonal cells than the peripheral cornea in both normals and contact lens wearers: the percentage of hexagonal cells is less in both the center and periphery in contact lens wearers compared with normals. These authors conclude that contact lens wear causes a mild redistribution in endothelial cell density from the central to the peripheral cornea. Other authors have found increased central endothelial cell density with RGP lens wear. 115

In patients newly fitted with fluorocarbon RGP contact lenses, the coefficient of variation of cell area increased within 2 months and continued to increase over the next 3 years, 116 and this correlated with the oxygen transmissibility of the lenses. The endothelial cell density was decreased at 2 and 3 years, but corneal thickness did not change. In older contact lens wearers who switched to RGP fluorocarbon contact lenses, after 3 years there were no significant changes in any morphologic values, except that corneal thickness was decreased significantly. The authors concluded that, although oxygen transmissibility was improved with the fluorocarbon lens, polymegethism was still induced within 2 months by these contact lenses, and morphologic changes stemming from previous contact lens wear did not improve during 3 years of daily wear of these RGP lenses. These contact lens changes do not occur in patients wearing silicone lenses, which are highly permeable to oxygen.

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Endothelial Function

To date, no direct link has been established between contact lens-induced acidosis and corneal function, although there is some indirect evidence. Long-term contact lens wear reduces endothelial functional reserve, as measured by the rate of corneal deswelling following lens-induced edema. This correlates with the duration and transmissibility of the contact lens worn. Other studies confirm that acute corneal swelling and deswelling rates are slowed in an acidic environment, implying that an acid environment may affect endothelial pumping or endothelial hydraulic activity.

Vannas et al 85 have suggested that monitoring the rate of decrease of corneal thickness after the induction of hypoxic corneal edema provides an assessment of endothelial pump function. Polse et al, 1 using the term “open-eye steady state,” developed a clinical method to measure overall endothelial function or corneal hydration control by inducing hypoxic corneal swelling with a contact lens and then measuring the rate of deswelling. Preliminary data 7 suggested that hypoxic exposure alters endothelial structure and reduces corneal function. Nieuwendaal et al, 98 using a similar method, found abnormally low rates of deswelling in long-term contact lens wearers.

Another approach was used by Carlson and co-workers, 104 who evaluated barrier function by measuring endothelial permeability to fluorescein. They found no difference between contact lens wearers and controls in corneal clarity, central corneal thickness, or endothelial response to fluorescein. Oxygen transmissibility, estimated underlying oxygen tension, and duration of contact lens wear did not correlate with any morphologic or functional endothelial variables. These authors concluded that long-term contact lens wear induces morphologic changes in the endothelium that may progress over time, but no functional abnormality was detected by the methods of anterior-segment fluorophotometry. In further studies Bourne et al 116 again found no statistically significant differences between contact lens wearers and controls in endothelial permeability, corneal deswelling, endothelial pump rate, or endothelial cell density, although contact lens wearers had significantly higher aqueous flow rate, coefficient of variation of cell area, and corneal autofluorescence than non-contact lens wearers.

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Corneal Exhaustion Syndrome

Sweeney 94 coined the term “corneal exhaustion syndrome” to characterize the sudden intolerance to contact lens wear with photophobia associated with a distorted endothelial mosaic and moderate to severe polymegethism. The condition involves contact lens intolerance with blurred vision, mire distortion, fluctuating changes in corneal curvature, and spectacle refraction after cessation of contact lens wear, as well as excessive open-eye edema response and moderate to severe endothelial changes. The effects on the endothelium appear to be long-term and possibly permanent.

Corneal exhaustion syndrome (contact lens failure after long-term wear) may be caused by endothelial dysfunction due to long-term hypoxia and acidosis. After years of contact lens wear, the endothelial function of regulating corneal hydration may be compromised to the point that the endothelium is no longer able to cope with the stresses imposed by contact lenses with low oxygen transmissibility. There must be an individual susceptibility to this rare syndrome.

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LESSONS FROM VARIOUS TYPES OF CONTACT LENS WEAR AND DIRECTIONS FOR THE FUTURE

Biochemical, cellular, and microbial changes occur in the closed-eye environment. The closed eye is a state of subclinical inflammation with an increase in tear protein, secretory IgA, serum albumin, complement and plasminogen, chemokines, and polymorphonuclear cells. This state may be beneficial against infection, but the addition of a contact lens may facilitate infection.

PMMA lenses present some unique problems. Daily wear of PMMA lenses induces approximately 6% central corneal edema 117 and frequent corneal warpage. This corneal stress may cause many unacceptable changes in corneal structure and function. Although some regression of endothelial polymegethism may occur after lens wear is discontinued, most changes appear to be irreversible. Endothelial polymegethism places the cornea at greater risk for surgical complications. 97,118 The corneal exhaustion syndrome is a rare problem that may occur in some patients with PMMA lenses. 93

Soft contact lenses initially were believed to supply enough oxygen to the cornea, 119 since Polse and Mandell 120 determined that only 2% oxygen was required to prevent corneal edema. Carney and Bailey 121 published the first paper questioning the adequacy of oxygen level supplied by a soft contact lens. The use of thick, soft lenses of low water content produced corneal edema, polymegethism, 107 myopic creep, 122 vascularization, 123 and occasionally the corneal exhaustion syndrome. 93,124

Extended-wear soft contact lenses generally do not provide sufficient oxygen to the eye. 14,125–128 In the Gothenberg (Sweden) study, 30 chronic hypoxia induced by extended wear of soft hydrogel lenses resulted in a 15% decrease in oxygen uptake rate, with 85% of patients producing microcysts. The epithelium thinned by 6%. The stroma was slightly edematous (2.5% of stromal thickness) while the patients were wearing the contact lenses, but when patients removed their contact lenses, the stroma was significantly thinner (2.3%) than before the contact lens wear. There was increased polymegethism in 95% of lens wearers, with a mean increase of 22%. 30 Sterile peripheral ulcers occurred in 1% in a 2-year prospective study. 8 Reduced oxygen with the closed lid plus extended wear of soft contact lenses caused problems of corneal swelling, epithelial microcysts, stromal and epithelial thinning, reduced epithelial mitosis rate, decreased damage threshold, stromal acidosis, endothelial polymegethism, decreased epithelial adhesion, increased epithelial cell size, and increased inflammatory activity in the epithelium.

The availability of disposable contact lenses led to a resurgence of the popularity of extended wear. Hypoxic, inflammatory, and infectious complications were soon documented, however, dispelling the belief that these lenses were the ultimate solution. Hypoxia still underlies most of the complications associated with hydrogel extended-wear soft contact lenses, and regular lens replacement of conventional or disposable contact lenses has no effect on this problem. All current hydrogel contact lenses create hypoxic stress, resulting in significant morphologic and functional corneal compromise. The hypoxia leads to increased anaerobic metabolism with stromal acidosis, overnight corneal swelling, residual daytime corneal edema, microcysts, vacuoles, striae, folds, blebs, and polymegethism. Controversy remains as to the relative incidence of corneal staining, neovascularization, sterile infiltrates, and infectious keratitis with disposable versus conventional extended-wear soft contact lenses.

Very thin, high-water content hydrogel soft contact lenses provide improved oxygen transmissibility but not to the level required to maintain normal epithelial aerobic metabolism. Additionally, these lenses can induce corneal desiccation, have inadequate durability, and are difficult to handle. Silicone elastomer contact lenses have yet to attain successful clinical performance in terms of surface chemistry, comfort, and maintenance of lens movement for any group of patients except aphakic infants and children. Other non-hydrogel materials with high oxygen permeability are currently being tested in clinical trials; however, corneal compromise is a function of both impaired oxygen supply and carbon dioxide accumulation in tissue. Therefore, adequate carbon dioxide transmissibility is another requirement. Maximizing contact lens oxygen transmissibility will not eradicate all the inflammatory and infectious events during overnight wear because the closed-eye environment cannot be overcome. Extended wear of current hydrogel polymers causes subtle long-term tissue changes that can have serious implications.

Newer soft materials with high oxygen transmissibility, anti-inflammatory and anti-infective components, and improved wettability ultimately are required to provide both safety and comfort during extended wear. 72 New lenses such as the silicone hydrogel and fluorosilicone hydrogel hybrid lenses are in trial and have the potential to overcome some of these physiologic limitations. They have very high oxygen transmissibility and, in early studies, did not raise the same issues of hypoxia. 44 True daily-wear disposable contact lenses may also overcome other issues with regard to contact lens safety but will remain expensive for many patients.

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Keywords:

Blebs; Contact lenses; Endothelium; Hypercapnia; Hypoxia; Microcysts; Neovascularization; Polymegethism; Stromal acidosis; Stromal edema

© 2002 The Contact Lens Association of Ophthalmologists, Inc.

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