Article Date: 5/1/2013

Are Corneal Staining and Infiltrative Keratitis Related?

Are Corneal Staining and Infiltrative Keratitis Related?

A review of research considers whether there is a link between these two complex entities.

images Dr. Srinivasan is a research assistant professor at the Centre for Contact Lens Research (CCLR), School of Optometry and Vision Science, University of Waterloo, Canada. Over the past three years, CCLR has received research support or honoraria from the following companies: Alcon, Allergan, AMO, B+L, CooperVision, Essilor, Inspire, Johnson & Johnson, Menicon, OcuSense, and Visioneering. Dr. Srinivasan is not a paid consultant and does not serve on an advisory board or own shares in any optometric company.

By Sruthi Srinivasan, PhD, BSOptom, FAAO

For almost half a century, eyecare professionals have used vital stains to detect ocular surface abnormalities. Rose bengal, lissamine green, and sodium fluorescein (NaFl) are the three most commonly used vital dyes to visualize these surface abnormalities.

When it comes to the cornea, NaFl is one of the main clinical diagnostic tools used to assess the integrity of its surface. “Corneal staining,” also referred to as “corneal hyperfluorescence” (Kim, 2000; Korb et al, 2008; 2010; Efron, 2012) is best visualized using a yellow barrier filter in addition to a cobalt blue excitation filter, especially to view subtle changes.

Understanding Corneal Staining

Although corneal staining has been researched widely, the underlying mechanisms are not clearly understood. The amount of NaFl dye, the location of its instillation on the eye, and the time between dye instillation and evaluation of staining can differ across eyecare practices and research sites. There is no consensus-based standardized grading scale that is globally accepted for corneal staining evaluation, which adds another dimension to this issue. Hence, understanding corneal staining is a hot topic in research and in clinical practice. Many are especially interested in staining associated with contact lens wear using certain contact lens and care solution combinations.

The scope of this article is to probe further into the etiology of corneal staining and to examine any evidence of a link between corneal staining and the occurrence of corneal inflammation in contact lens wear.

A recently published review article by Efron (2012) discusses some of the potential cellular mechanisms that may be involved in corneal surface hyperfluorescence. Some of the commonly described mechanisms are uptake by dead (Machado et al, 2009) or damaged (Wilson et al, 1995) cells, ingress around cells where there is a loss of epithelial cell junction integrity (Machado et al, 2009), and surface pooling (Tabery 1992). NaFl corneal staining/hyperfluorescence is also a normal physiological phenomenon due to desquamation (Kikkawa, 1972; Feenstra and Tseng, 1992; Wilson et al, 1995; Thinda et al, 2010; and others). Other clinicians and researchers have also reported about NaFl corneal staining, mechanisms, and use as a vital dye (Ward, 2008; Morgan and Maldonado-Codina, 2009).

Corneal staining occurs in contact lens wearers and in non-lens wearers, albeit at different frequencies. The frequency of staining in non-lens wearers ranges from 4 percent to 79 percent (Korb and Korb, 1970; Caffery and Josephson, 1991; Josephson and Caffery, 1992; Schwallie et al, 1997). It is often clinically associated with a poor tear film and is typically minimal in degree (less than grade 1).

In contact lens wearers, the frequency of staining typically ranges between 30 percent and 55 percent (Begley et al, 1996; Nichols et al, 2002). Patients are often clinically asymptomatic, and the inferior region of the cornea is often the most affected (<grade 2). Only 5 percent to 10 percent have exhibited staining greater than grade 2. Contact lens-related staining can result from hypoxia, dehydration, solution toxicity, foreign body, or trauma. Of all the aforementioned conditions, solution-induced corneal staining has gained significant interest among researchers and clinicians.

Corneal staining is relatively common in soft contact lens wearers. Nichols et al (2002) studied a group of 500 hydrogel contact lens wearers and found corneal staining in 55.7 percent of the study population. Moderate-to-severe staining was seen in 8 percent of the study population. Moderate-to-severe staining was associated with noncompliance, annual contact lens replacement, and lens power. Staining was associated with lens care noncompliance, use of rewetting drops, and annual contact lens replacement.

Solution-Induced Corneal Staining

Although solution-induced corneal staining (SICS) has been studied widely in the literature, its clinical relevance is still controversial. SICS is a generic term that describes corneal staining caused by lens care solutions; more recently, the observation has been termed preservative-associated transient hyperfluorescence (PATH) (Bright et al, 2012; Efron, 2012). This new theory has been proposed to explain the mechanism behind SICS. It states that the fluorescein viewed is not true corneal staining as we traditionally think of it but rather is a fluorescein/contact lens/preservative/epithelial cell binding phenomenon. The theory proposes that the preservative from a multipurpose care solution (MPS) can leach out of the contact lenses and transiently bind to the cell membrane of the corneal epithelial cells. When fluorescein is subsequently instilled, it binds to the MPS preservative that is accumulating at the ocular surface (Ikeda et al, 1984; Bright et al, 2012). However, contrary to this concept, a recently published case report demonstrated that SICS is visible without NaFl as well as in the presence of NaFl, rose bengal, and lissamine green (Maldonado-Codina et al, 2013).

Certain care solution and contact lens combination incompatibilities are highlighted in the literature (Jones et al, 2002; Garofalo et al, 2005). These incompatibilities have been described as SICS (Carnt et al, 2007; Papas et al, 2007; Andrasko and Ryen, 2008; Fonn et al, 2010). SICS generally results in either a lack of or minimal associated signs and/or symptoms.

Corneal Infiltrates

Definitions The term “infiltrate” refers to any material that has passed into the spaces of tissues or cells. This may include fluids, cells, or other substances (natural or foreign substances in excess) (Anderson, 2003). Contact lens lens-related inflammation is characterized by white blood cells (WBCs), usually polymorphonuclear (PMN) leukocytes, invading the corneal stroma (infiltrates) (Dartt, 2010). Infiltrative keratitis (IK) refers to an inflammation of the corneal tissue caused in part by or due to the presence of infiltrates. IK is a typically unilateral (but can present bilaterally) inflammatory reaction of the cornea characterized by anterior stromal or subepithelial infiltration. The epithelium may or may not be involved. It is often noticed in the periphery or in the midperiphery of the cornea. Infiltrates are small and can be multiple. There is no anterior chamber involvement (Efron, 2006).

Other definitions of infiltrates have appeared in the literature. Millodot et al (2002) defined infiltrates as “small, hazy, greyish areas (focal or diffuse) located in the cornea, typically near the limbus. The adjacent conjunctiva is usually hyperemic. They appear as a result of corneal inflammation, reaction to solution preservatives and some contact lens wear (especially extended wear) which causes prolonged hypoxia.” Dartt’s definition of infiltrates was as follows: “The infiltrates appear as small, usually round, opaque lesions (focal) or dispersed in a haze (diffuse). Usually limbal and bulbar redness accompanies the infiltrates. Epithelial damage can be present. Inflammation can be as a result of mechanical trauma but more often results from toxic reactions to bacteria.” (Dartt, 2010).

Clinical Appearance and Classification Clinical presentation of corneal inflammation ranges from mild, self-limiting focal infiltrates to those associated with microbial keratitis (MK). Corneal infiltrative events (CIEs) are most commonly classified as either “sterile” or “microbial” (Stein et al, 1988; Poggio et al, 1989; Cheng et al, 1999; Sharma et al, 2002) and by their severity (Aasuri et al, 2003; Efron et al, 2005).

Sterile (non-infectious) corneal infiltrates have the appearance of small, round, hazy greyish-white opacities (focal or diffuse). The opacities are composed of inflammatory cells (PMN in particular). The size can range from less than 0.5mm to 1.5mm in diameter (Robboy et al, 2003). The infiltrates are often situated peripherally (but can be located anywhere in the cornea), and they may be associated with limbal hyperemia (Dumbleton, 2002; Sankaridurg et al, 2004; Willcox et al, 2004) and may be graded based on size, number, severity, and area affected (Josephson and Caffery, 1979; Cutter et al, 1996). They may be sub-epithelial or deeper, in the anterior stroma. Symptoms, if present, may include mild-to-moderate irritation, which is often described as a foreign body sensation, mild redness, lacrimation, photophobia, and occasionally mild discharge (Dumbleton, 2002; Sankaridurg et al, 2004; Willcox et al, 2004). In the absence of symptoms, they are often referred to as “asymptomatic infiltrative keratitis” (AIK) or “asymptomatic infiltrates” (AI) and also occur in non-contact lens wearers (Sweeney et al, 1996; Hickson and Papas, 1997; Sankaridurg et al, 2003). Gram-positive exotoxins have been found on or near the lid margin in cases of IK (Sankaridurg et al, 2000; Willcox et al, 2004).

Other classification approaches have been used. Sweeney et al (2003) have classified infiltrates according to their clinical sub type as follows: “clinically significant and symptomatic,” “clinically insignificant and asymptomatic,” and “serious and symptomatic.” MK falls under the category of “serious and symptomatic.” Contact lens-induced peripheral ulcer (CLPU), contact lens-induced acute red eye (CLARE), and IK are categorized as “clinically significant and symptomatic,” whereas AI and AIK are categorized as “clinically insignificant and asymptomatic.”

There is a considerable overlap between the clinical presentation of MK, CLPU, CLARE, and IK. There is certainly some difficulty in clinically differentiating these entities (microbial or ulcerative) with absolute certainty (Efron and Morgan, 2006).

What Are the Risk Factors?

A history of a previous CIEs is associated with a higher risk for developing corneal infiltrates in silicone hydrogel wearers (McNally et al, 2003; Dumbleton et al, 2000). Lens bacterial bioburden (discussed below), poor hygiene (hand washing) (Dart et al, 2008; Radford et al, 2009), and overnight wear (Morgan et al, 2005; Radford et al, 2009; Chalmers et al, 2012), are also some of the risk factors.

A retrospective study on contact lens wearers aged 8 to 33 years reported a highest risk for infiltrates in the 15- to 25-year-old age group, with a lower risk in the younger children (<15 years) (Chalmers et al, 2011). This study also showed no difference in risk of developing infiltrates with respect to gender or smoking. Morgan et al (2005) showed that males were at a greater risk of developing infiltrates. Other studies have shown smoking to be associated with a greater risk of developing corneal infiltrates in hydrogel lens wearers (Cutter et al, 1996) and silicone hydrogel lenses wearers (Morgan et al, 2005; Szczotka-Flynn et al, 2010). Chalmers et al (2007) in a one-year study of patients who wore contact lenses on a continuous wear schedule showed that lens wearers ≤25 years and >50 years of age had a higher risk of infiltrates. Ametropes of 5.00D or more were also at a greater risk (Chalmers et al, 2007).

A series of case reports discussed that a specific combination of a multipurpose solution and a silicone hydrogel contact lens material may be more likely to cause corneal infiltrates (Kislan and Hom, 2010; Kislan, 2011; Kislan, 2011; Shovlin, 2011). This conclusion was based on the reports of the case series. It was also reported that when the care system was changed to a hydrogen peroxide system, there was no recurrence of infiltrates (Sacco, 2011).

Is There a Link Between the Two Complex Entities—Staining and Infiltrative Events?

The mechanism and/or relationship between corneal staining and CIEs are poorly understood. There is no clear evidence as to whether there is an association between the two complex entities.

Carnt et al (2007) reported an association between toxic solution-related staining (SICS) and infiltrates. In this study involving 609 subjects, eyes that had exhibited toxic staining at another visit or visits were three times as likely to have developed infiltrates during the study. The same study also showed that peroxide-based solutions consistently resulted in the lowest rates of toxic staining and inflammation.

Another recent study by Carnt and coworkers (2009) reported the incidence of adverse events related to the use of varying silicone hydrogel contact lens and lens solution combinations. This study provided some initial evidence that lens type and care solution influence the incidence of adverse events among users of daily wear silicone hydrogel lenses. The rate of SICS varied significantly based on lens-solution combination, and most CIEs were observed during routine visits. This study also showed that a hydrogen peroxide-based care regimen exhibited the lowest incidence of CIEs and SICS.

Szczotka-Flynn et al (2007) reported that corneal staining at a previous visit was significantly associated with the development of an infiltrative event. This study was conducted on a sample of 317 subjects who wore silicone hydrogel contact lenses on a continuous wear basis. The lenses were worn for up to 30 nights and followed up for three years. The two factors that were significantly associated with the development of CIEs were staining and limbal redness.

A more recent study by Szczotka-Flynn (2010) showed that corneal staining is common during continuous wear of silicone hydrogel lenses, but it was not associated with the development of CIEs. The same study also concluded that more than 70 percent of the total risk of CIE in those who had substantial contact lens bioburden is attributable to this exposure. A review by Szczotka-Flynn and Chalmers (2013) reiterated the fact that the risk factor that best predicts the development of a contact lens-induced CIE is bacterial bioburden found on contact lenses and lid margins during wear. This review described the various risk factors and associations with CIEs reported across various studies. Bacterial contamination of not only contact lenses but also of lens storage cases is a significant risk factor in the development of corneal infiltrates during soft and silicone hydrogel contact lens wear (Willcox et al, 2011).

De la Jara and coworkers (2013) evaluated the SICS and CIEs of a single silicone hydrogel contact lens type used as both a daily disposable modality and as a reusable daily wear modality with multipurpose solutions and peroxide-based care solutions. The results of this study showed that participants who experienced CIEs had significantly less comfort on contact lens application compared to those who did not have a diagnosis of CIEs, but those who experienced CIEs reported no difference in comfort or dryness at the end of the day. Also, participants who experienced SICS reported significantly lower ratings for comfort at contact lens application and at the end of the day as well as dryness at the end of the day compared to those who did not have SICS. This study did not particularly evaluate the link between the two complex entities.

Jury Is Still Out

There does not appear to be a clear relationship between corneal staining and infiltrative keratitis. Although NaFl is used widely and is clinically accepted, there is a paucity of evidence-based research to fully support the mechanisms involved in the interaction of the ocular surface cells and the stain. Further work is required to clearly define methods of dye administration and evaluation techniques. It is unclear whether the infiltrates develop because of compromise to the epithelium that may/may not be indicated by corneal staining, or whether (an)other coexisting condition(s) causes infiltrates. We need to shine a light on this issue to understand the link between the two complex entities. Well-designed, controlled trials incorporating rigorous statistical approaches are required to recognize the link if one is present. CLS

For references, please visit and click on document #210.

Contact Lens Spectrum, Volume: 28 , Issue: May 2013, page(s): 34 - 37 55