CARNT, NICOLE BOptom; JALBERT, ISABELLE OD, PhD, FAAO; STRETTON, SERINA PhD; NADUVILATH, THOMAS PhD; PAPAS, ERIC PhD
Sodium fluorescein staining of the cornea is regularly used to assess corneal integrity during contact lens wear. Asymptomatic corneal staining associated with toxicity to lens care solutions is common and usually manifests as extensive, low-grade punctate staining without any associated symptoms.1–5 Although any compromise to the corneal surface can place lens wearers at risk of more serious sequelae, the mild and transient nature of solution toxicity has led to the suggestion that, in most cases, it is clinically insignificant and does not require cessation of lens wear.6,7
“No-rub” multipurpose lens care solutions have become very popular since they were first introduced, and clinical experience, along with several clinical studies,5,8 have shown them to be safe and effective for the majority of wearers when used with conventional hydrogel lens materials. However, with silicone hydrogel lenses, there is increasing evidence that certain combinations of “no-rub” multipurpose lens care solutions and silicone hydrogel lens types are associated with solution-based corneal staining,6,7,9–12 despite wearers successfully using the same solution with conventional low-Dk hydrogel lenses. This apparent incompatibility between some lens care solutions and silicone hydrogels is of concern because of the recent surge in interest in silicone hydrogel daily wear (DW) and the expected increase in the number of these lens wearers in the near future.13 In general, it is the active ingredient that is implicated in toxicity staining with silicone hydrogels,6,7,11,12 but the same silicone hydrogel material can react differently with different formulations of the same active ingredient, suggesting that this interaction may be a contributor to corneal staining.11 Although most of the toxicity staining with silicone hydrogel lenses is mild and asymptomatic, some combinations can lead to toxic staining of sufficient severity to result in discontinuation from lens wear.7 In severe cases, the pattern of solution-based corneal staining can be atypical, and is more concentrated in the peripheral cornea.7
To date, no studies have found an association between toxicity staining with soft contact lenses (SCLs) and any signs and symptoms.6,7 One study has shown a potential association between solution-based corneal staining and increased levels of lower palpebral papillae;4 however, the severity of papillae was less than slight (<grade 2, 0 to 4 scale), and no other significant physiological associations were reported. Some preliminary evidence investigating the impact of multipurpose solutions in non-lens-wearers indicates that the solutions themselves may affect the changes in corneal epithelial cell turnover that occurs during contact lens wear14 and may result in weaker barrier function;15 however, the implications for these effects are unknown. To our knowledge, no studies have examined whether a relationship exists between solution toxicity staining and corneal inflammation during contact lens wear. Our purpose in this study was to explore the possibility of such an association by conducting a retrospective analysis of several nonrandomized clinical trials in which a range of predominantly silicone hydrogel lens types were worn in combination with several different lens care solutions.
MATERIALS AND METHODS
Records of 609 DW subjects enrolled in several nonrandomized interventional clinical trials of spherical SCL wear at the Institute for Eye Research (IER), Sydney, Australia between May 2004 and November 2005 were analyzed retrospectively. Subjects were recruited from the general Sydney population. To be eligible for clinical trials subjects had to be at least 18 years old, need correction in both eyes and be correctable to at least 20/40 (6/12) distance visual acuity with spherical hydrogel contact lenses, have no ocular or systemic clinical findings that would prevent safe contact lens wear, and have stable and distortion-free keratometric readings at the first visit. Exclusion criteria were active corneal infection; acute or subacute inflammation or infection of the anterior chamber; any eye disease, injury, or abnormality of the cornea, conjunctiva, or eyelids that would affect contact lens wear; dry eye or low corneal sensitivity; any systemic disease or use of medication that may affect the eye or be exaggerated by lens wear; monocular subjects or those with a history of refractive surgery. Subjects were not dispensed contact lenses if a successful lens fit was not achieved, if visual acuity with contact lenses was <20/40 (6/12), or if they were dissatisfied with their vision or comfort at the baseline visit.
All procedures were conducted in accordance with the institution’s Ethics Committee and the Helsinki Declaration of 1975, as revised in 1983. Subjects were advised of any potential adverse reactions and signed a record of informed consent before enrolment.
Subjects were assigned one of a range of commercially available lens types (Table 1) to be worn bilaterally, for 3 months of DW, with monthly disposal. One of several marketed lens care solutions was allocated in each case, and subjects were instructed to rinse the lenses on removal, disinfect overnight, and insert the lenses directly from the lens care solution. Lens care solutions used included one hydrogen peroxide-based solution (AOSEPT ClearCare, CIBA Vision, Duluth, GA) and three multipurpose lens care solutions (OPTI-FREE Express, Alcon, Fort Worth, TX; ReNu MoistureLoc, Bausch & Lomb, Rochester, NY; AQuify Multipurpose Solution, CIBA Vision, Duluth, GA). Unit dose saline solution (sodium chloride 0.9%, AstraZeneca) was given to each subject as an in-eye lubricant to be used as required.
In addition to the baseline visit, subjects were examined at 2 weeks, 1 and 3 months. Appointments were randomly conducted throughout the day. At each visit, subjects’ compliance with wear schedule and lens care regimen was confirmed. Subjects were encouraged to return for unscheduled visits if any unusual subjective symptoms or signs occurred. As a number of investigators were involved in the examinations, all took part in a preliminary, and ongoing, training program that ensured concordance among observers. Investigators were not masked to the lens type-solution combination used by each subject.
Observations were made using a slit-lamp biomicroscope (Zeiss SL-120, Germany) with a range of magnification and illumination. Limbal and bulbar redness were assessed with diffuse white light at low to moderate magnification (10× to 16×), and corneal and conjunctival observations were made with direct and indirect white light at moderate to high magnification (16× to 40×). Limbal and bulbar redness were graded from 0 to 4 (using 0.5 steps), where 0 = none, 1 = very slight, 2 = slight, 3 = moderate, and 4 = severe.16
Corneal infiltrative events (CIEs) were diagnosed using the Sweeney et al.17 clinical characterization scheme of CIEs with SCL wear. This separates adverse events into severe (microbial keratitis); symptomatic [contact lens-induced peripheral ulcer (CLPU), contact lens-induced red eye (CLARE), infiltrative keratitis (IK)]; and asymptomatic [asymptomatic infiltrative keratitis (AIK), asymptomatic infiltrates (AI)]. A summary of key signs and symptoms is provided in Table 2.
Corneal staining with sodium fluorescein (Fluorets BP 1 mg, Chauvin Pharmaceuticals) moistened with 1 drop of sterile, unit dose saline was assessed with a cobalt blue filter in the illumination system and a yellow fluorescein enhancement filter (Kodak Wratten No.12) over the objective lens.18 The presence of staining was recorded within 5 min of fluorescein instillation to minimize diffusion to surrounding tissues. The cornea was divided into five areas (one central, four peripheral) as previously described19 and toxic solution-based staining was defined as diffuse punctate staining in at least four out of five areas. Typical toxic staining patterns included diffuse punctate staining of the entire cornea, or denser annular staining in the periphery. This latter presentation was defined as staining in corneal areas 2 to 5, with none in the central area, or as staining 0.5 units (graded on a 0 to 4 scale,16 where 0 = none and 4 = severe) greater in areas 2 to 5 than in the central cornea. As diagnosis of micropunctate toxic staining can sometimes be difficult, where necessary, an immediate second opinion was sought from another investigator to confirm or deny the presence of toxic staining.
If toxic staining was detected without symptoms, subjects resumed their lens wear schedule without any treatment. Subjects presenting with mild symptoms or other signs, such as redness or infiltrates, were temporarily discontinued from lens wear if appropriate, and were instructed to rinse their lenses with unit dose saline before they were re-inserted. Subjects were re-assessed at the next visit.
Data from all subjects who commenced DW were analyzed. Incidence rates of toxic staining were computed using the first event of a subject-eye from scheduled follow-up visits at 2 weeks, 1 months and 3 months of wear. Incidence rates of infiltrative events were computed from scheduled and unscheduled follow-up visits occurring within the 3 months study period. Incidence was reported as a rate per 100 subject-eye months.
Demographic factors of subjects with and without toxic staining were compared using the Fisher exact test, χ2, or t test, depending on whether the variable was binary, categorical or continuous.
The rates of infiltrative events were compared between eyes with and without toxic staining, or with and without limbal redness ≥grade 2.0, using Fisher exact test. The strength of any association between infiltrative events and toxic staining or previous events of limbal redness was determined using an odds ratio and its 95% confidence interval. The reported odds ratio can be stated as the ratio of the odds in favor of an infiltrative event among those exposed when compared with unexposed. Statistical significance was determined at the 95% level of confidence. A scatter plot was used to display the association of rates of toxic staining with infiltrative events of various lens-solution groups. Spearman’s correlation was used to determine the association between the incidence of toxic staining and corneal inflammation for specific solution-lens type combinations. Data were analyzed using SPSS v12.
Of the 609 subjects enrolled in the clinical trials, toxic staining was detected in 77 subjects (n = 142 eyes). Of the number of eyes with toxic staining, 62% occurred as diffuse staining across the whole cornea (Fig. 1) and 38% occurred as an annular ring of diffuse staining in the periphery (Fig. 2). There were no differences in demographic characteristics between subjects with toxic staining and the unaffected control subjects, and more than 85% of subjects completed the studies (Table 3).
The types of CIEs detected were similar between eyes with toxic staining and unaffected control eyes. Both asymptomatic (n = 21) and symptomatic infiltrative events (n = 14) were observed in the two groups. Infiltrative keratitis was the only symptomatic CIE observed.
For all lens types, CIEs were 3 times more likely to occur in eyes in which toxic staining was detected 6.7% (9/134) compared with unaffected control eyes 2.3% (24/1049) (odds ratio 3.08, p = 0.008, 95% CI 1.40 to 6.76). Considering silicone hydrogel lenses in isolation did not significantly alter the calculated odds ratio (3.04, 95% CI 1.37 to 6. 71).
When data were analyzed by subject rather than by eye, the association was similar, with CIEs being 3.6-times more likely to occur in subjects with toxic staining (11.4%, 8/70) compared with unaffected control subjects (3.5%, 18/513; odds ratio 3.55, p = 0.008, 95% CI 1.48 to 8.50). The rate of CIEs in eyes in which clinically important levels of limbal redness (≥grade 2.0) had previously been detected was 2.2% (10/462) compared to the rate in unaffected eyes of 1.4% (10/701). Previous events of limbal redness ≥grade 2.0 were not associated with CIEs (odds ratio 1.53, p = 0.364, 95% CI 0.63 to 3.70).
When symptomatic and asymptomatic CIEs were analyzed separately, the odds ratio for the association between the incidence of asymptomatic events and toxic staining increased and was greater than the odds ratio for the association between symptomatic events and toxic staining (Table 4). However, the confidence intervals for these odds ratios overlapped slightly, rendering the interpretation of differences in association between toxic staining and symptomatic and asymptomatic CIEs inconclusive.
Similarly, when the association between CIEs and the type of toxic staining was analyzed further, the odds ratio for the association between the incidence of corneal inflammation and diffuse toxic staining per eye was greater than that between corneal inflammation and peripheral staining (Table 5), although once again, the confidence intervals for these two odds ratios overlapped.
When the association between toxic staining and CIEs was analyzed for individual combinations of lens type and contact lens solution, it was found that the rate of CIEs tended to increase as the rate of toxic staining increased for specific lens type-solution combinations (Spearman’s rho = 0.558, p = 0.025, n = 16). The peroxide-based solution consistently resulted in the lowest rates of toxic staining and corneal inflammation, regardless of lens type (Fig. 3).
This study demonstrates that corneal inflammation is 3 times more likely to occur in contact lens wearing eyes experiencing toxic staining than those that do not, and that limbal redness is not a predictor of such corneal inflammation. Although the inflammatory events described in the present study tended to be mild and mostly asymptomatic, they were most often seen at scheduled visits, which occurred more frequently than is likely in general practice. Had lens wear not been interrupted, it is possible that more severe symptoms and signs may have resulted, particularly for symptomatic events. In circumstances in which subjects were observed to have redness, discomfort, or signs of inflammation, investigators had the option of either temporarily discontinuing lens wear or introducing saline rinses before lens insertion. In both cases, the interventions would tend to reduce the impact of lens care solutions on the ocular environment, with the result that the interpretation of any association between the two is likely to be conservative.
Although this study did not demonstrate a causal relationship between toxic staining and corneal inflammation, it is consistent with other studies that have indicated an association between corneal staining and corneal infiltrates. Naduvilath et al.20 examined the predictive factors for symptomatic infiltrative events (CLPU, CLARE, or IK) among 677 subjects wearing conventional hydrogel or silicone hydrogel lenses enrolled in several 1-year extended wear studies. A range of factors were found to be associated with symptomatic corneal infiltrates with bacterial contamination of lenses the most significant. However, corneal staining was listed together with suboptimal lens fit and higher levels of deposits as being associated with infiltrative keratitis (IK). Szczotka-Flynn et al.21 examined the association between corneal staining and the occurrence of corneal infiltrates in 317 subjects wearing a silicone hydrogel lens on a continuous wear basis for 3 years. In this study, the probability of developing corneal infiltrates was low, but was significantly greater in those subjects with a previous event of corneal staining (seven-fold higher risk). Taken together with the present work, these studies suggest a link between corneal disruption and low-grade corneal inflammation. Further confirmatory investigations as well as studies are needed to better understand the mechanisms involved.
Toxic staining was observed with all lens type and solution combinations tested, with the lowest rates of toxic staining and corneal inflammation occurring with hydrogen peroxide-based solutions. To standardize study conditions, all lenses were replaced monthly, irrespective of manufacturers’ recommendation. This inevitably meant that some types were worn for longer than would be expected in practice; however, these were not associated with a higher risk of toxic staining or corneal inflammatory events. So far as silicone hydrogel lenses are concerned, several studies have now shown that specific combinations of materials and a range of multipurpose solutions are associated with toxic staining,6,7,9–12,22 but it is not clear whether it is the antimicrobial ingredient or other components of the solution formulations that is responsible for the corneal staining observed. When first marketed, it was thought that the high molecular weight preservatives in multipurpose solution formulations would not penetrate the lens surface. However, analysis of silicone hydrogel lenses presoaked with several of the antimicrobial agents used in lens care solutions such as polyquaternium-1, polyhexamethylene biguanide, or alexidine indicates that these compounds can adsorb and be released from the surface of lenses.23,24 A possible etiology for the association between toxic staining and corneal inflammation is that subclinical damage weakens the ability of the corneal surface to resist microbial, lens-related, or environmental challenges, which if left undetected may ultimately lead to an inflammatory event. Several studies using animal models have shown that lens care solutions or the preservatives they contain can adversely affect the corneal epithelium,25–27 and preliminary evidence in human subjects14 indicates that contact lens solutions can impair corneal homeostasis, which may lead to weaker barrier function.15 Conversely, scanning confocal microscopy of rat cornea after exposure to PHMB-soaked contact lenses has revealed no overt detectable changes in corneal morphology, despite greater punctate staining in eyes wearing PHMB-soaked lenses compared with control eyes.28 These conflicting reports clearly indicate that more investigation is required to better understand the nature of toxic staining during lens wear and any potential causal relationship with corneal inflammation.
Previous studies have shown that toxic staining is most likely to be observed within 2 to 4 h after lenses have been inserted and is less likely to be observed after longer wearing time.6 As visits were scheduled at the subject’s convenience rather than soon after lens insertion, it is possible that this study underestimated the incidence of toxic staining. In future studies, it may be prudent to schedule at least one follow-up appointment about 2 h after lenses have been inserted, and this would certainly be recommended as a desirable approach for clinicians seeking to maximize their chances of observing such staining events. It was noted that 12 subjects presented with toxic staining in only one eye. The reason for this finding is currently unclear. No association was found with lens type, solution type, or subject characteristics; however given the low numbers involved, this was not unexpected.
The majority of inflammatory events that occurred in this study were mild and asymptomatic; however, the potential for more serious sequelae suggests that practitioners should take a conservative approach when managing their patients. The practical implications of these data are that practitioners cannot rely on observing obvious levels of limbal redness as an indicator of low level corneal infiltrates and that all daily lens wearers should be routinely examined with sodium fluorescein together with suitable excitation and barrier filters to enhance detection of any potential staining. Observations should take place preferably within about 2 h of lens insertion. If significant corneal staining is detected, alternative solution or lens type combinations ought to be investigated to reduce or eliminate the general level of staining and to lower the risk of potential episodes of corneal inflammation.
This study was supported by the Australian Federal Government through the Cooperative Research Centre Scheme, and in part by CIBA Vision.
Data from this study were presented previously at the Association for Research in Vision and Ophthalmology Annual Meeting, April 30 – May 4, 2006, Ft Lauderdale, FL.
Vision CRC is an Australian Commonwealth funded cooperative research center and under its conditions of funding Vision CRC is required to commercialize its research. As part of that commercialization activity, Vision CRC receives royalty income from the sale of silicon hydrogel contact lenses sold by Bausch & Lomb and CIBA Vision. The Institute for Eye Research (IER) is a not for profit research corporation that is a core participant in Vision CRC and its employees are entitled to benefit from such royalties.
Institute for Eye Research
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Sydney, NSW 2052, Australia
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