Article Date: 9/1/2007

Corneal Staining: The IER Matrix Study
CORNEAL STAINING

Corneal Staining: The IER Matrix Study

Researchers followed patients for three months wear in each of 16 lens care/silicone hydrogel lens combinations to assess staining and its significance.

By Nicole Carnt, BOptom (Hons); Mark D.P. Willcox, PhD; Vicki Evans, PhD, BOptom; Thomas J. Naduvilath, PhD; Daniel Tilia, BOptom (Hons), MOptom; Eric B. Papas, PhD, BSc, MCOptom, DipCL; Deborah F. Sweeney, BOptom, PhD, FAAO; & Brien A. Holden, PhD, DSc, OAM

Ms. Carnt is a senior research optometrist at the International Clinical Trials Centre for the Institute for Eye Research, Sydney, Australia.
Prof. Willcox is a professor at School of Optometry and Vision Science, University of New South Wales, chief scientific officer of the Institute for Eye Research and executive director of Science and Core Capabilities of the Vision CRC, Sydney, Australia.
Dr. Evans is head of Clinical Research at the International Clinical Trials Centre for the Institute for Eye Research, Sydney, Australia.
Dr. Naduvilath is a biostatistician and clinical database manager at the Institute for Eye Research, Sydney, Australia.
Mr. Tilia is a research optometrist at the International Clinical Trials Centre for the Institute for Eye Research, Sydney, Australia, part-time clinical supervisor at the School of Optometry and Vision Science, University of New South Wales, and works part-time in private practice.
Dr. Papas is executive director of Research and Development at the Institute for Eye Research and Vision Cooperative Research Centre in Sydney.
Prof. Sweeney is the chief executive officer of the Vision Cooperative Research Centre and holds executive roles in the International Society for Contact Lens Research, The Keratoprosthesis (KPro) Study Group and the International Association of Contact Lens Educators.
Prof. Holden is scientia professor of the University of New South Wales, chief executive officer of the Institute for Eye Research, deputy CEO and director of commercialization of Vision CRC, executive chair of the International Centre for Eyecare Education and executive chair of Optometry Giving Sight.

Silicone hydrogel lenses are capturing an ever-increasing share of the contact lens market because of their capacity to reduce or eliminate the clinical signs of hypoxia. This benefit has proven equally popular among practitioners prescribing for daily wear as it has among those prescribing for extended or continuous wear schedules.

The increasing use of silicone hydrogel lenses for daily wear also partly reflects recent research findings indicating that silicone hydrogels have not substantially reduced the risk of overnight wear-induced microbial keratitis (MK).

Lens Care and Silicone Hydrogels

The growth in use of silicone hydrogel lenses for daily wear requires practitioners and the industry to revisit the issues related to daily lens care. Care system design has tried to achieve a balance between consumer convenience (ease of use), patient comfort, microbial efficacy and unwanted effects of lens care system components on the lens and the eye. In recent times this balance has tipped largely in favor of convenience and comfort rather than of safety and efficacy — at the cost of some serious recent failures in antimicrobial efficacy.

Structurally, silicone hydrogel contact lenses are more complex than conventional hydrogels because of the incorporation of various hydrophobic, highly oxygen-permeable components such as silicone in various forms, some fluorine species as well as components and treatments used to improve lens wettability. It's likely, therefore, that lens care solutions will interact differently with the various silicone hydrogel lenses than they do with conventional hydrogel lenses in which the water within the lens acts as a reservoir for chemicals.

With silicone hydrogel lenses, we must consider the type and size of preservative molecule as well as the interaction of ingredients, such as buffers, chelating agents, surfactants and isotonicity agents, with the bulk and surface of the lens. Neither the lens/solution interactions nor the efficacy of the lens care solution are predictable according to preservative type and concentration alone.

It's critical, therefore, to understand how contact lens solution products interact with all of the different silicone hydrogel materials and that practitioners receive scientifically valid guidance on which combinations are the most efficacious and benign.

Silicone Hydrogel Interactions Various attempts have been made to predict the clinical outcome of using different combinations of lens care products and silicone hydrogel contact lenses. The most widely publicized of these is the Andrasko Staining Grid (www.staininggrid.com). The Grid is based on results obtained by soaking a lens overnight in a particular solution and then recording the average percent of corneal staining (by area) after two hours of wear the following day with that combination. Itoi has published an alternative grid (www.staininggrid-japan.com). Carnt et al (2007) have taken prediction a step further by examining the relationship between lens careinduced corneal staining and corneal inflammation.

The Institute for Eye Research Matrix Study: Methods and Materials

The data we report in this paper are derived from groups of approximately 40 patients who were followed for three months of wear in each of 16 lens care/silicone hydrogel lens combinations — approximately 640 patient-care/lens combinations in total. Clinicians saw the patients a total of four times in the study: at baseline, two weeks, one month and three months.

Study lenses included Acuvue Advance and Acuvue Oasys (Vistakon), PureVision (Bausch & Lomb) and O2Optix (CIBA Vision).

The solutions included Clear Care (CIBA; disinfecting agent hydrogen peroxide), Aquify MPS (CIBA; disinfecting agent polyhexmethylene biguanide [PHMB]), Opti-Free Express (Alcon Laboratories Inc; disinfecting agent polyquaternium-1 [Polyquad]) and Opti-Free Replenish (Alcon; disinfecting agent myristamidopropyl dimethylamine [Aldox]).

Figure 1. Diffuse staining spread over most of the cornea. If severe, there can be linear areas of coalescent punctate staining.

Figure 2. Peripheral staining, usually a continuous paralimbal/limbal annulus. We considered staining peripheral when the average extent of staining in the peripheral corneal zones was more than 0.5 of a unit higher than the central zone.

An ethics committee approved the study and all subjects underwent informed consent in accordance with the Declaration of Helsinki.

Clinicians asked patients to wear their lenses for a minimum of six hours per day, five days per week. The maximum hours per day and days per week weren't restricted as long as patients didn't sleep in their lenses overnight. The age, refractive error, corneal curvature, gender and lens wear experience of the patients was representative of the typical contact lens population. Patients replaced all lenses monthly with the exception of the lens/solution combinations specified as two-week replacement in Table 1. Clinicians saw patients at any time during the day between 8 a.m. and 7 p.m. with the vast majority seen at early morning and late afternoon. We masked neither clinicians nor patients as to the identity of the lenses or solutions.

All subjective and objective performance measures were collected by clinicians who participated in an ongoing training program to ensure grading consistency for all clinical variables. They graded corneal staining on a 0 to 4 modified IER Grading Scale for extent (0 = none, 1 = ≤5 percent, 2 = 6 percent to 15 percent, 3 = 16 percent to 30 percent and 4 = >30 percent) in each of five zones of the cornea. In addition, clinicians indicated the presence of solution-induced corneal staining according to the following definition:

Solution-induced Corneal Staining (SICS): diffuse punctate staining (extent grade 1 and above) in at least four of the five regions (central, superior, inferior, nasal and temporal) of the cornea. Conjunctival staining extending from the limbus to the lens edge may also be present. There are normally two presentations of this type of staining: diffuse and peripheral (Figures 1 and 2). Figures 3 and 4 show differential diagnoses of peripheral SICS from dehydration staining and limbal transition pooling.

Figure 3. Dehydration staining, located mainly inferiorly and contributed to by to partial blinking and lagophthalmos. It may also occur in the superior cornea adjacent to the upper lid margin due to an unstable tear meniscus. It generally presents in bands and is located in the mid-peripheral cornea.

Figure 4. Limbal transition pooling. Circumferentially arranged radial spokes of fluorescein pooling at the anterior edge of the limbal transition zone occurs in some patients.

Results

Table 1 reports the IER Matrix Study data. The rates presented indicate the percentage of patients who had SICS per month during the first three months of wear of a particular lens/solution combination.

The overall rate of SICS for all patients in the 16 cells was 4.9 percent. As the distribution of the overall rate was normal, the 50 percent confidence limit was ±1.4 percent (0.67 x the standard error) from the overall rate. Rates for lens/solution combinations in the upper quartile of the overall rate (above 6.3 percent) are colored orange, and rates in the lower quartile (below 3.5%) are green. Rates in the inner two quartile ranges (between 3.5 percent and 6.3 percent) are yellow.

Table 1. IER Matrix Study data (percent of patients per month).

Seventy-three percent of the cases were bilateral. The majority of eyes (61 percent) exhibited diffuse staining, with 39 percent exhibiting peripheral staining. The likelihood of peripheral SICS was not infiuenced by lens type. Twenty-three percent of patients presented with diffuse staining SICS in one eye and peripheral SICS in the other eye.

Discussion

Hydrogen Peroxide Hydrogen peroxide caused far less corneal staining with silicone hydrogels than did any of the multipurpose solutions (MPS) (for all lens types combined, p<0.001). The virtual absence of any SICS when using a peroxide care system with any of the silicone hydrogels suggests that it's the method of choice to avoid this type of corneal insult.

Lenses

  1. PureVision demonstrated statistically significant staining with all care systems except hydrogen peroxide. (PureVision versus other lens types with MPS, p<0.001).
  2. Acuvue Advance had the lowest frequency of staining for MPS compared to all other lens types (p<0.001).

Multipurpose Solutions

  1. The Opti-Free products (Opti-Free Express/Replenish) were in higher quartile ranges than were peroxide and Aquify MPS for both Acuvue Oasys and O2Optix.
  2. Opti-Free Replenish was also in higher quartile ranges than Opti-Free Express for Acuvue Oasys and O2Optix.
  3. Aquify MPS was in the higher quartile range for PureVision.

Differences From the Andrasko Staining Grid

The difficulty in comparing information from the IER Matrix Study and the Andrasko Staining Grid is that the Andrasko Grid reports a mean area of the cornea affected after two hours exposure while the IER data is incidence from a clinical study over three months (Table2).

The Andrasko Staining Grid has been proposed as a predictor of clinical performance. The main problem with this approach is that we have no confirmation that the two-hour result correlates with anything that happens with longer term wear. Though direct statistical comparisons are not possible with the two data sets because the Andrasko staining grid estimates the area of staining after two hours of wear and the IER Matrix reports percentages of patients who develop SICS, the categorical results (Table 3) allow some comparison.

Table 2. Differences between Andrasko Staining Grid and IER Matrix Study.

The Andrasko Staining Grid doesn't identify potentially problematic lens/solution combinations in the 'real' (clinical) world. Solutions that have compound and worsening effects over time can appear unreasonably benign with the Andrasko two-hour assessment than with longer term wear. For example, longer term wear with the Opti-Free solutions shows relatively poorer performance with Acuvue Oasys, O2Optix and PureVision lenses compared with two hours of wear (Table 4).

Table 3. Comparison of "findings" with Andrasko Staining Grid.

Different care systems used with the same silicone hydrogel lens produce different staining rates. Attempts to use short-term exposure testing to predict how lens/solution combinations will perform over clinically realistic time frames must be validated.

The Significance of Corneal Staining

Staining, Patient Discomfort and Adverse Events IER researchers Tilia (2006) and Carnt (2007) have shown that higher levels of SICS are associated with higher levels of contact lens discomfort and a three-times greater risk of corneal infiltrative events, respectively. Szczotka-Flynn (2007) found corneal staining increased the risk of the subsequent development of corneal infiltrates seven fold in silicone hydrogel continuous wear; however as this was almost exclusively a 30-night continuous wear study, the staining involved wasn't SICS.

Staining and MK Attempts have been made to associate, correlate and even propose a causal relationship between SICS and the occurrence of MK in individual patients. No evidence has yet appeared to establish any such association for any type of staining, whether solution-related or not.

In prospective clinical trials at the Institute for Eye Research in Sydney, Australia and at LV Prasad Eye Institute in India, 10 confirmed cases of lens-related MK have occurred to date (three in Sydney, seven in India). Five of the MK events occurred with low-Dk soft lens extended wear (EW); four were with silicone hydrogel EW or continuous wear (CW) and one with silicone hydrogel daily wear. The data in Figure 5 indicate that none of the patients who went on to have MK showed any consistent pattern or unusual period of high levels of staining of any type. The staining observed in the nine EW or CW MK patients wasn't SICS; however the data for these patients does illustrate, as Figure 5 shows, that corneal staining per se, regardless of the cause, isn't a precursor of MK.

The only case in Figure 5 of a daily wear silicone hydrogel MK was in the IER Matrix Study with Acuvue Oasys and Opti-Free Replenish. This particular patient (number 10 in Figure 5) didn't have SICS or other unusually high levels of corneal staining with this combination. As MK can occur with any lens/solution grouping, we should draw no conclusions from this one event.

Table 4. Differences in Solution Induced Corneal Staining — IER Matrix Study rates vs. Andrasko Staining Grid.

Research by Willcox, Choo and colleagues at the IER indicates that the only way to reliably trigger MK in a laboratory animal model is to physically penetrate the epithelium and Bowman's layer before loading in microorganisms. It's unlikely that even high levels of the type of staining caused by adverse lens/solution combinations causes enough corneal insult or damage to predispose to infection, but experimental evidence is needed to conclusively examine any such proposed relationship.

It's reasonable to expect that chronic SICS would have an effect on comfort and be associated with a higher level of infiltrates because it constitutes an on-going 'irritation' to the cornea. The suggestion that an association exists between staining and MK is at present unjustified. Convincing research in both the clinic and the laboratory is required to give this conjecture any credence.

Getting the Balance Right

Efforts to advance ease of use, on-eye comfort and biocompatibility of lens care solutions, though well-meaning, clearly needs to be better balanced with the fundamental purposes of lens care: microbial efficacy and safety. In general, the industry needs to be more respectful of both the efficiency and adaptability of microbial challenges and of the consequences of solution-lens-eye-environment interactions.

The fact that a relationship between SICS and MK hasn't been established doesn't mean that SICS shouldn't be eliminated. It should. While the results of longer term clinical studies, such as the IER Matrix, are useful in minimizing SICS by choosing the appropriate combination, currently the only way to virtually eliminate SICS with silicone hydrogel lenses is to use hydrogen peroxide disinfection. CLS

This study was funded by CIBA Vision, the Institute for Eye Research and The Australian Government through the Cooperative Research Centres scheme.

The tables and pictures defining SICS in this article are available on the IER Web site (www.ier.org.au).

For references, please visit www.clspectrum.com/references. asp and click on document #142.

Figure 5. Corneal staining levels in 10 contact lens wearers that went on to have microbial keratitis event.



Contact Lens Spectrum, Issue: September 2007