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1 From the School of Optometry and the 2 Division of Public Health Biology and Epidemiology of the School of Public Health, University of California, Berkeley; and the 3 School of Optometry, University of Montreal, Quebec, Canada.
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Abstract |
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METHODS. The Berkeley Contact Lens Extended Wear Study (CLEWS) was a randomized, concurrently controlled clinical trial in which more than 200 subjects in EW with rigid gas-permeable (RGP) lenses were observed for 1 year. After adapting to EW, subjects were randomized to either medium or high oxygen-permeable (Dk) RGP lenses and underwent clinical assessments, keratometry, and corneal pachometry at 3-month intervals.
RESULTS. The ONSR was directly related to lens Dk (P = 0.01) and exhibited substantial variability across subjects. The probability of remaining free of complications over time was not significantly lower for subjects with a mild ONSR compared with those with greater edema (P = 0.84). The risk of development of keratopathy was not significantly related to the ONSR (relative risk = 1.00).
CONCLUSIONS. The corneal ONSR is not a good predictor of ocular complications in 1 year of RGP EW. Lenses that cause little or no corneal edema are not necessarily safer for overnight wear.
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Introduction |
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The likely connection between hypoxic dose and risk of contact lens–associated keratopathy (CLAK) has prompted researchers to monitor corneal swelling response as a means of assessing the impact of closed-eye contact lens wear on the cornea. There are several possible pathways by which corneal swelling can occur in overnight lens wear. If the oxygen transmissibility of a lens is inadequate to maintain normal corneal metabolism, lactate accumulates, creating an osmotic imbalance that causes the cornea to swell. The mechanical effects of a contact lens may include disruption of the epithelial cell layer, which could allow increased fluid uptake in the stroma. Corneal edema has also been linked to epithelial cytochrome P450 metabolites of arachidonic acid, in a rabbit model of closed-eye hydrogel lens wear.15 16
In addition to the known pathways leading to edema in closed-eye lens wear, other considerations have contributed to the use of the corneal swelling response as a quantitative measure of the impact of contact lens wear. The corneal overnight swelling response (ONSR) is directly related to hypoxic dose yet varies considerably among lens wearers, thereby reflecting individual differences in sensitivity to hypoxic exposure.17 18 19 20 In addition, edema due to contact lens wear is known to be associated with changes in corneal morphology and physiology such as polymegethism and pleomorphism of the endothelial cell layer,21 22 corneal striae,17 23 and impaired epithelial barrier function.24 Although swelling of the cornea occurs naturally (e.g., during sleep) and thus is unlikely to pose a risk for complications directly, it does provide a clear indication of hypoxic stress and may also reflect adverse changes in corneal morphology and physiology in response to contact lens wear. For these reasons, it has become widely accepted that the degree of corneal swelling provides an indication of the impact of overnight contact lens wear on the cornea and hence is likely to be related to the risk of ocular complications.
Previous studies have suggested that for safe overnight wear, a contact lens should not induce more than approximately 8% swelling if the cornea is to recover to a normal level during day wear.8 In current practice, most clinicians considering the prescription of lenses for EW have come to expect contact lens manufacturers to provide corneal swelling data, and the US Food and Drug Administration (FDA) requires overnight swelling results from manufacturers as part of the approval process for EW lenses.18 The majority of studies addressing the clinical effects of contact lens wear also report corneal swelling data, and there are numerous statements in the literature to the effect that reduced corneal swelling response is a feature of "safer" lenses, and that monitoring corneal swelling can help to ensure the patient’s safety in EW.13 18 19 25 26 27 28 It has been generally assumed that contact lenses that induce greater overnight corneal swelling pose a greater risk for development of keratopathy, and conversely that complications are less likely with lenses that induce little or no swelling. Although indirect evidence from many sources supports this assumption, to our knowledge there has not been a rigorous, longitudinal evaluation of corneal swelling response as a predictor of risk for CLAK.
The Berkeley Contact Lens Extended Wear Study (CLEWS) provides an opportunity to test this hypothesis directly. CLEWS was a randomized, concurrently controlled clinical trial in which 201 subjects were observed for 1 year of EW with rigid gas-permeable (RGP) lenses in a wide range of FDA-approved oxygen transmissibilities (Dk/t). In this article we use the clinical observations and corneal swelling data from CLEWS to estimate the risk of complications associated with the subject-specific edematous response to contact lens–induced hypoxia. The CLEWS data also permit us to examine more closely the assumption that ONSR can be used as a measure of contact lens safety for EW.
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Methods |
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Measurement Procedures and Analysis Variables
Pachometry measurements were taken to assess both the ONSR with
the study lenses and the recovery of the cornea to open-eye steady
state (OESS) thickness after experimentally induced edema. We used a
modified Haag-Streit optical pachometer equipped with small
light–emitting diodes to improve the patient’s fixation and
alignment. The instrument and calibration techniques have been
described previously.31
Baseline overnight swelling measurements were made after the first successful week of EW adaptation, during which all subjects wore the same high-Dk lenses, but before randomization to the study lenses. Subjects reported for baseline (pre-randomization) measurements after discontinuing all lens wear for 1 week. The ONSR was also assessed 1 week after randomization, and at the 3-, 6-, 9-, and 12-month study visits. For these post-randomization visits, subjects slept with lenses on for 4 to 6 nights before the ONSR assessment and reported to the laboratory wearing the lenses.
For the baseline ONSR assessment, afternoon (PM) OESS corneal thickness measurements were taken on each eye a minimum of 4 hours after awakening. Subjects were instructed to place a patch over the right eye before sleep that night that was not removed until 1 to 2 minutes before pachometry readings began the following morning (AM). An identical procedure was used in all post-randomization ONSR visits, except that subjects wore their lenses until immediately before the PM measurements and reinserted them immediately after, keeping their lenses on for overnight patching. Subjects failing to attend the AM visit or who did not keep the eye patched correctly until reaching the laboratory were rescheduled for the next available AM visit. If the subject was unable to reschedule within 1 week of the PM visit, then both the PM and AM visits were rescheduled.
The baseline (i.e., pre-randomization, no lens) ONSR reflects the normal physiological swelling that occurs when the eyes are closed in sleep. Because randomized subjects reported for follow-up visits with the assigned study lenses in place, the uncorrected ONSR (ONSRuc) includes the combined effects of the closed-eye state and contact lens-induced hypoxia. We also used a corrected ONSR (ONSRc) by subtracting the baseline ONSR (closed-eye, no lens) from the post-randomization ONSR (closed-eye, with lens) readings. The ONSRc thus reflects the actual overnight swelling response to the lenses, over and above the normal swelling occurring during sleep. Although the corrected ONSRc variable is preferred, in that it more accurately reflects the swelling response to the lens, this correction has not been widely employed, and therefore we present analyses using both variables for comparison with previous studies.
The recovery of the cornea from experimentally induced edema was assessed at baseline (before randomization), after discontinuing lens wear for 1 week. For the corneal recovery assessment, low-Dk stress lenses were inserted in both eyes, and the subject lay supine with eyes closed for 1 hour to induce corneal edema. The lenses were then removed and pachometry measurements were taken throughout the day as the cornea recovered to OESS thickness. The eye to be measured first was randomly selected for each subject. We employed a nonlinear model of corneal recovery32 from which we obtained estimates of the swelling response to the stress lens and the late-afternoon OESS thickness. For analysis, we use the stress lens swelling response (SLSR), expressed in percentage increase over OESS thickness, which provides another measure of the subject-specific reaction to hypoxia at baseline, and as such may be a predictor of subsequent keratopathy in EW.
In this article we examine each of these corneal swelling response variables as a predictor of initial onset of CLAK. For analysis CLAK is defined as a suite of adverse ocular responses, including moderate to severe grades of 17 possible slit lamp findings (e.g., microcysts, corneal staining, infiltrates, striae), substantial changes in corneal curvature or refractive error, unresolvable pain-related symptoms, persistent lens binding, or multiple concurrent slit lamp findings. This definition of CLAK was based on survey responses from six optometrists not associated with CLEWS who were asked to indicate for each adverse condition the level of severity they thought would require intervention (e.g., changing lens parameters, prescribing medications, discontinuing lens wear). We elected to use this composite outcome because the incidence of any specific, serious complication (e.g., corneal ulcer) was very low or null over 1 year of RGP EW, and the majority of complications that did arise were diagnosed early and successfully treated by CLEWS clinicians. It is of interest to determine whether this composite CLAK outcome can be predicted, because it reflects the earliest signs of adverse response to lens wear, unacceptable ocular health, and conditions that may seriously threaten vision unless identified and treated by a clinician. An in-depth discussion of the criteria for defining CLAK has been presented previously.30
Statistical Methods
The relationships between ONSR and lens Dk and Dk/t were
analyzed using a mixed model approach (SAS Proc Mixed; SAS, Cary,
NC).33
We employed mixed effects analysis of variance
models with fixed effects for time in EW after randomization, hypoxic
dose expressed as Dk or Dk/t, and hypoxia–time interactions plus a
single subject-level random effect. In our mixed models we specified a
compound symmetric covariance structure and assumed a common covariance
in the repeated measurements on a subject and independence between
subjects.
Survival analysis methods were employed to assess the risk of complications associated with the level of corneal swelling. Many CLEWS subjects with pachometry data were observed for varying periods up to 12 months without development of an adverse condition. For example, a subject may have moved from the area, may have been unwilling to continue the time commitment required by the study, or may have been terminated for noncompliance (unrelated to any problem wearing the study lenses). These subjects provided censored observations and contributed less than 12 subject-months at risk for CLAK.
To account for censoring, the probability of remaining free of complications over time was estimated using the Kaplan-Meier method (Proc LIFETEST; SAS).33 Kaplan-Meier provides a nonparametric estimate of the survival function, which gives the probability of surviving at least to a specified time without experiencing an adverse event. In using this method, we assume that survival and censoring times are independent and that the probability of survival is constant within each time interval in which a complication was observed. Subjects were stratified by level of corneal swelling, and the Kaplan-Meier survival curves for the strata were compared by log-rank test. The relative risk of keratopathy associated with the level of corneal swelling response was derived from Cox proportional hazards regression models (Proc PHREG; SAS33 ). Cox proportional hazards models provide an estimate of the hazard function, which gives the instantaneous risk of development of a complication at a specified time, given survival to that time. A ratio of the hazard estimates for two different levels of corneal swelling provides a measure of the relative risk of complications associated with the swelling response. The Cox approach takes censoring of observations into account and assumes that the hazard rates in two strata are related by a multiplicative constant.
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Results |
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Subjects, Treatment, and Outcomes
Because pachometry measurements were taken on nonrandom subsets of
the larger CLEWS subject group, it was necessary to ensure that
subjects with pachometry data did not differ substantially between Dk
groups in their baseline demographic and ocular characteristics. The
average age of CLEWS subjects was 23 years, there were approximately
56% males and 44% females, Caucasian and Asian North Americans
accounted for approximately 75% of the ethnic makeup, and refractive
errors averaged approximately 2.75 diopters in the direction of myopia.
For the CLEWS subjects with pachometry measurements, we found no
clinically important differences between the two Dk groups in these
baseline characteristics, nor did the pachometry subgroups differ from
the larger CLEWS subject group from which they were selected. We may
therefore conclude that any apparent group differences in outcomes we
find will not be due to confounding by these variables and that our
corneal swelling results will be generally applicable to the larger
CLEWS study population.
With the medium- and high-Dk lenses used in CLEWS, two distinct levels of oxygen would be available to the cornea if all other lens parameters were held constant. However, the amount of oxygen reaching the cornea is more closely related to Dk/t, which is a function of the permeability of the material and the thickness of the lens. Because study lenses of varying central thickness were made to achieve the correct vertex power for each subject, there was a resultant range of Dk/t across subjects within each Dk group. The histogram shown in Figure 1 reveals a bimodal distribution of Dk/t with a clear separation between the two Dk groups. Because the distributions of Dk/t in the two study groups are completely disjoint, we may conclude that the subjects in the medium- and high-Dk groups participating in pachometry measurements received distinctly different hypoxic doses.
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17% above OESS, on average).
Baseline overnight swelling was approximately 2.3% in both groups,
whereas post-randomization overnight swelling was greater on average in
the medium-Dk group for all the ONSR variables. The first
ONSRc taken shortly after randomization was 4.8%
for the medium-Dk group on average with subjects ranging from 0% to
14%, whereas the high-Dk group averaged 2.4%
ONSRc with corneas in individual subjects
swelling from 0% to 9%. The first uncorrected
ONSRuc averaged 6.6% with corneal swelling
ranging from 1% to 17%, and 5.1% with corneal swelling ranging from
0% to 10% in the medium- and high-Dk groups, respectively. ONSR
readings began after the stress lens measurement was discontinued from
the CLEWS trial, and many subjects had already completed part of the
12-month follow-up period before ONSR data collection began. Therefore,
not all subjects with uncorrected post-randomization
ONSRuc (n = 75) had an
ONSRc corrected for baseline (n =
33).
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Hypoxic Dose and Corneal Swelling Response
Before assessing the risk of keratopathy associated with the level
of corneal edema, we want to confirm that the ONSR represents a
subject-specific physiological reaction to hypoxic stress and thus may
be useful as a predictor of CLAK. In this section we verify that the
ONSR was directly related to hypoxic dose and exhibited variability
among our subjects and that repeated ONSR measurements before initial
onset of CLAK did not systematically change over time.
Figure 2 shows the trend in pre-CLAK ONSRc (corrected for baseline), stratified by Dk group. The ONSRc was significantly greater in the medium-Dk group (P = 0.01) when adjusted for time in EW and group–time interactions, indicating that overnight corneal swelling is directly related to the oxygen permeability (Dk) of the lens in our subjects. There was no significant time effect on ONSRc (P = 0.52), which suggests that our subjects did not adapt (i.e., show a systematic increase or decrease in swelling response) to continued hypoxic exposure over time. There was no significant interaction between time in EW and Dk (P = 0.76), suggesting that the ability of our subjects’ corneas to adapt to hypoxic exposure over time was not dependent on the level of hypoxia. With no interaction term, the fixed-effects parameter estimates and their standard errors changed only slightly. Similar results were found for pre-CLAK ONSRuc (uncorrected), with a significant Dk group effect (P = 0.05) and no significant time effect (P = 0.63) or group-time interaction (P = 0.84).
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Corneal Swelling Response and Keratopathy
Table 2
shows, for each corneal swelling variable, the number of subjects in
each group that had a CLAK event before 12 months or were censored
before initial onset of CLAK for reasons unrelated to lens wear. The
majority of subjects in both Dk groups had at least one adverse event
during the 12-month EW follow-up period, although only one subject with
medium-Dk lenses who had persistent lens adherence was forced to
completely discontinue lens wear. In all other cases, the complication
was treated successfully and lens wear was eventually resumed. The most
commonly observed adverse conditions included redness and staining of
the conjunctiva, central and peripheral corneal staining, infiltrates,
striae, endothelial polymegethism, persistent lens adherence, and
reported symptoms of red eye, foreign-body sensation, and general
discomfort or pain. Most of these complications were observed across Dk
groups, with the exception of striae, infiltrates, and polymegethism,
which occurred mostly in the medium-Dk group. There were no indications
of microbial keratitis, neovascularization, or corneal ulcers in any of
our subjects, primarily because of early diagnosis of adverse
conditions and intervention by CLEWS clinicians.
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Cox proportional hazards models allowed us to estimate the relative risk of development of a complication associated with the level of corneal swelling. Table 3 shows the estimated risk ratios and 95% risk limits associated with a 1% increase in the first post-randomization ONSRc and ONSRuc. A risk ratio equal to 1 would indicate no difference in risk of CLAK with increased corneal swelling, whereas a risk ratio of more than 1.00 reflects a higher risk predicted by greater corneal swelling. The risk ratios shown in Table 3 are very close to (and not significantly different from) 1.00, as were the risk ratios obtained using the other three corneal swelling variables, both as independent predictors and as adjustments to the effects of hypoxic dose (Dk/t). Table 3 also shows that the risk of keratopathy was not significantly greater with corneal swelling above a threshold of 8% for ONSRuc or 5.7% for ONSRc. The 95% risk limits permit us to rule out all but fairly minor elevations in risk of keratopathy associated with increases in corneal swelling. For example, an 8% increase in ONSRuc results in a relative risk of 1.00, with an upper limit of approximately 1.76. In this case a modest elevation in risk for high levels of swelling is within the upper confidence limit and thus cannot be completely ruled out; however, our best estimate is still that there is no increased risk.
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Discussion |
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Do these results completely invalidate the use of overnight corneal swelling as a measure of contact lens safety? First, it must be kept in mind that our results apply to the specific conditions obtaining in CLEWS, and inferences cannot necessarily be drawn to substantially different study populations, lens types other than RGP, different Dk/t ratings, longer observation periods, or other wearing schedules (e.g., daily wear). Second, although corneal swelling was not associated with our composite keratopathy outcome, it is possible that distinguishing metabolically related complications such as striae and endothelial polymegethism from the mechanical effects of the lens on the ocular surface would reveal a stronger predictive relationship. However, because the CLEWS incidence rates for specific complications with 1 year of RGP wear were very low, such a detailed analysis would require further study with larger sample sizes or longer observation periods. Third, there are two facets to the use of corneal swelling as a diagnostic measure for the safety of overnight lens wear, and the CLEWS data permit us to adequately address only one of them. Ideally, a diagnostic such as corneal swelling should possess both specificity and sensitivity relative to the outcome of interest—that is, both a low rate of false positives (i.e., substantial edema but no complications) and a low rate of false negatives (i.e., complications without substantial edema). In this analysis, corneal swelling had poor sensitivity as a risk measure, because a large number of subjects who did not display greater corneal swelling nevertheless developed complications. However, because the majority of subjects in both Dk groups had at least one adverse event of some sort, we did not have a substantial control group without complications and therefore cannot draw definitive conclusions about the specificity of corneal swelling to CLAK cases. In other words, we cannot reliably estimate the rate of false positives, because so few subjects remained free of complications.
In spite of these analytical limitations, it is clear that measuring overnight corneal swelling on a single occasion in a small group of subjects is of little use in assessing the safety of RGP lenses for overnight wear. Although it is not known whether greater corneal swelling is specific to lenses that pose a higher risk of keratopathy, we have shown in this article that the swelling response to overnight lens wear has poor sensitivity and many subjects who do not display greater edema will nevertheless develop lens-related complications. It is possible that lenses that result in substantially greater overnight swelling pose a greater risk for keratopathy (although we cannot tell from the CLEWS data); however, a lower ONSR does not imply a lesser risk for complications or a safer contact lens.
Although the usefulness of corneal swelling in predicting keratopathy appears to be limited, some means of reliably assessing the safety of a lens for EW is clearly needed. Several alternative measures of risk are suggested by recent studies, such as epithelial permeability,14 34 35 rate of tear exchange under the contact lens,36 37 38 and profiles of contact lens movement over the ocular surface.36 39 40 Evaluation of fluorescein staining patterns and bacterial culture from eye wash samples may also contribute predictive information. It is interesting that all these assessments reveal differences between RGP and soft contact lens (SCL) EW, because many serious types of complications associated with SCL (e.g., corneal ulcer) are observed in the absence of corneal edema,41 whereas no such adverse responses were observed, even among our medium-Dk RGP subjects whose corneas swelled substantially. This suggests that tear exchange and hypoxic or mechanical effects on the corneal epithelium could be more closely related to the mechanisms of keratopathy than the corneal edema induced by increased lactate concentration and thus may prove to be better predictors of keratopathy (perhaps in conjunction with oxygen ratings and/or corneal swelling in some cases).
In summary, it is clear that the degree of contact lens–induced corneal swelling is not a good predictor of risk for development of keratopathy in overnight wear, at least for RGP lenses in the FDA-approved range of Dk/t. In assessing the safety of RGP lenses for EW, the degree of induced corneal swelling need not be considered a major risk factor, except possibly in cases in which lenses tend to induce extreme edematous reactions in some subjects. Statements in the past literature (scientific, educational, promotional, and regulatory) relating to lens safety or risk of complications that have been based partly on overnight corneal swelling results must be viewed with these limitations in mind.
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Acknowledgements |
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Footnotes |
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Submitted for publication May 2, 2001; revised July 31, 2001; accepted August 17, 2001.
Commercial relationships policy: N.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be marked
"advertisement" in accordance with 18 U.S.C. 
1734
solely to indicate this fact.
Corresponding author: Andrew D. Graham, School of Optometry, University of California, Berkeley, CA 94720-2020. agraham{at}spectacle.berkeley.edu
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References |
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This article has been cited by other articles:
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  R. Martin, V. de Juan, G. Rodriguez, R. Cuadrado, and I. Fernandez Measurement of Corneal Swelling Variations without Removal of the Contact Lens during Extended Wear Invest. Ophthalmol. Vis. Sci., July 1, 2007; 48(7): 3043 - 3050. [Abstract] [Full Text] [PDF]
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