Mucin balls Ð Part 2

Using a corneal confocal microscope, Craig et al8 reported that mucin balls display a highly reflective core with a more poorly reflective, apparently translucent, outer layer. The diameter of the central core relative to the outer coating varied among mucin balls. This bilayered appearance was confirmed by the same authors using phase-contrast microscopy of mucin balls obtained from the back surface of lenses removed from the eye.
The name 'mucin balls' infers that these entities are composed primarily of tear mucins (mucins are the glycoprotein components of mucus and vary greatly in molecular size). Millar et al15 analysed mucin balls using light microscopic histochemistry, scanning electron microscopy, electron microscopic elemental analysis and confocal microscopy. They demonstrated that mucin balls are PAS positive, which indicates that glycoproteins are a major component. Lipids and bacteria were not detected. Millar et al15 concluded that mucin balls were made exclusively of collapsed mucin.

Pathogenesis of mucin ball formation
Within minutes of lens insertion, mucin ball formation begins at the interface of the posterior lens surface and the pre-corneal tear film. Sweeney et al7 suggest that mucin balls are more prominent in the superior quadrant of the cornea beneath the resting position of the upper eyelid. The mucinous layer of the tear film, along with some lipid components, is apparently 'rolled up' into discrete elements. At first, the resultant mucin balls are small in size and appear as an assortment of scattered debris in the form of individual deposits or small clumps of material. They remain fixed in position after a blink, which suggests that mucin balls are somehow fixed to, or partially embedded in, the epithelium (Figure 1).
With continuing lens wear, the mucin balls increase in size and some become deeply embedded in the epithelium, probably because of the force of the lens (Figure 2). At this point, slit-lamp examination using indirect retro-illumination reveals two forms of refractile elements. Those that display reversed illumination are the mucin balls that lie in the aqueous phase of the tear film. Those that display unreversed illumination are a either mucin balls buried deeper in the epithelial surface or fluid-filled pits created by mucin balls that subsequently became dislodged through blinking. These illumination effects are observed both with and without the lens on the eye (Figure 3). As stated previously, both mucin balls and fluid-filled pits stain with fluorescein and their appearance under fluorescent light is identical.
After prolonged periods of lens wear, some of the mucin balls become so large that they cannot maintain their spherical shape and collapse inwardly. This results in a doughnut appearance, with a flat centre and tyre-like annulus around the rim.1 A small, circular island of material can sometimes be observed in the centre of the collapsed mucin ball (Figure 4). It is unclear why mucin balls should collapse in this way, rather than the more intuitive scenario of the near-spherical mucin balls simply becoming flattened into a disciform shape.

Consequential pathology
Ladage et al10 were able to replicate the formation of mucin balls in a rabbit model, and observed Ki-67-positive stromal cells immediately beneath indentations that reached the epithelial basement membrane. This indicates that active proliferation of stromal cells was stimulated focally. These authors also noted a local increase in keratocyte density immediately beneath deep mucin balls. Stromal keratocytes do not divide unless stimulated to do so, which led Ladage et al10 to conclude that the Ki-67-positive stromal cells represent either dividing keratocytes or activated fibroblasts.
From a theoretical standpoint, clinicians ought to be concerned about the formation of mucin balls inasmuch as they represent a compromise of the mucus phase of the pre-corneal tear film. For example, Fleiszig et al16 demonstrated the critical importance of the mucus phase in preventing the attachment of potentially pathogenic bacteria to the corneal surface. In the absence of a properly formed mucus layer, which may occur as a result of extensive mucin ball formation, bacteria are more likely to attach to the cornea and establish an infection.
Aside from the protective function of mucus, potentially pathogenic organisms are more likely to establish an infectious process if there is a breach of the corneal epithelium. Fonn et al1 and Pritchard et al17 observed that fluorescein does not generally penetrate into the epithelium, which they suggest indicates that this corneal layer is not breached as a result of mucin ball formation. However, inspection of images of fluorescein staining in patients who have extensive mucin ball formation (Figure 5) reveals a diffuse halo of staining around some mucin balls, suggestive of a corneal breach.
Concerns that the above factors could lead to an increased occurrence of infectious keratitis among silicone hydrogel contact lens wearers can be allayed because early indications are that the incidence of sight-threatening corneal ulceration with silicone hydrogel lenses is low.
Fonn et al1 and Pritchard et al17 reported the case of a patient who demonstrated extensive mucin ball formation. This patient, who was using silicone hydrogel lenses on an extended wear basis, also presented with an acute red eye reaction, an asymptomatic epithelial defect (with rapid diffusion of fluorescein into the stroma), two further instances of asymptomatic infiltrates and symptoms of dryness over an 18-month period. These adverse events may have been coincidental to the appearance of mucin balls in this patient.
Mucin balls may cause a slight, though temporary, irregularity in the corneal surface that could reduce its wettability if present as a chronic condition.2 Aside from this, mucin balls do not seem to compromise ocular integrity. As discussed previously, mucin balls are not associated with increased corneal inflammation, corneal staining (apart from that staining directly attributable to the mucin balls) or conjunctival redness,2,7,9 and patients who display mucin balls do not experience discomfort or reduced vision.2,7,9

Management
The obvious strategy to prevent mucin ball formation, should this be the aim of the clinician, is to refit the patient with a lens type that is not made from silicone hydrogel materials. However, patients are likely to be highly motivated to wear silicone hydrogel lenses because of their comfort and convenience when used for continuous wear.
In patients who wear silicone hydrogel lenses, mucin ball formation can be minimised by:

Optimising lens fit Ð flat-fitting lenses are thought to exacerbate mucin ball formation2,6,9
Advising the patient to use lubricating drops after waking and before sleep2,6
Advising the patient to adopt a shorter wearing schedule (such as removing the lenses once every six nights instead of 30 nights).2

Prognosis
After lens removal, those mucin balls not embedded in the epithelium are blinked away rapidly. The residual 'embedded' mucin balls, and the fluid-filled pits generally resolve in a matter of hours.2 In severe cases, embedded mucin balls may remain in the epithelium for up to seven days.1 Mucin balls reform again if silicone hydrogel lens wear is recommenced.

Differential Diagnosis
Clinicians need to be able to differentiate mucin balls Ð and the fluid-filled epithelial pits they cause Ð from other phenomena induced by contact lenses that occur at or near the ocular surface, such as epithelial microcysts, epithelial vacuoles, epithelial bullae and dimple veiling.
Microcysts and mucin balls are similar in size. Microcysts can be observed, using optic section illumination with a slit-lamp biomicroscope, to be within the epithelium and to display reversed illumination. Therefore, unlike mucin balls, microcysts do not stain with fluorescein. However, microcysts that are breaking through the epithelial surface do stain with fluorescein and may be indistinguishable from mucin balls.
Epithelial vacuoles reside within the epithelium, display unreversed illumination and do not stain with fluorescein. Epithelial bullae are similar to vacuoles, but are more oval in shape, and have an irregular and indistinct border. Fluid-filled epithelial pits induced by mucin balls also display unreversed illumination, but unlike fluid vacuoles, they do stain with fluorescein.
Dimple veiling induced by contact lenses refers to the formation of fluid-filled pits in the epithelial surface as a result of pressure from individual air bubbles trapped beneath rigid contact lenses (and to a lesser extent in soft lenses). The epithelial depressions ('dimples') fill with the aqueous phase of the tear film, stain with fluorescein and display unreversed illumination; as such, they may be indistinguishable in appearance from fluid-filled epithelial pits induced by mucin balls. Dimple veiling tends to occur in clustered regions, which correspond to areas of loose lens fitting that can support the existence of large air bubbles. Thus, the type of lens (ie, a poorly fitting rigid lens versus a silicone hydrogel lens) is likely to be a key factor in differentiating these otherwise similar phenomena.
A summary of the features that differentiate the conditions described above is given in Table 1.

References
1 Fonn D, Pritchard N and Dumbleton K. Factors affecting the success of silicone hydrogels. In: Silicone Hydrogels. The Rebirth of Continuous Wear Contact Lenses, 2000.Ed Sweeney DF, p214Ð234. (Oxford: ButterworthÐHeinemann).
2 Dumbleton K, Jones L, Chalmers R, et al. Clinical characterisation of spherical post-lens debris associated with Lotrafilcon high-Dk silicone lenses. CLAO J, 2000; 26, 186Ð92.
3 Fleming C, Austen R and Davies S. Pre-corneal deposits during soft contact lens wear. Optom Vis Sci, 2000; 71, 152SÐ153S.
4 Tan J, Keay L and Jalbert I. Tear microspheres (TMSS) with high Dk lenses. Optom Vis Sci, 1999; 76S, 226.
5 Bourassa S and Benjamin WJ. Transient corneal surface 'microdeposits' and associated epithelial surface pits occurring with gel contact lens extended wear. Int Contact Lens Clin, 1988; 15, 338Ð340.
6 Tan J, Keay L, Jalbert I, et al. Mucin balls with wear of conventional and silicone hydrogel contact lenses. Optom Vis Sci, 2003; 80, 291Ð297.
7 Sweeney DF, Keay L, Jalbert I, et al. Clinical performance of silicone hydrogel lenses. In: Silicone Hydrogels. The Rebirth of Continuous Wear Contact Lenses, Ed. Sweeney DF, p. 90Ð149. (Oxford: ButterworthÐHeinemann), 2000.
8 Craig JP, Sherwin T, Grupcheva CN and McGhee CN. An evaluation of mucin balls associated with high-Dk silicone hydrogel contact lens wear. Adv Exp Med Biol, 2002; 506, 917Ð923.
9 Morgan PB and Efron N. Comparative clinical performance of two silicone hydrogel contact lenses for continuous wear. Clin Exp Optom, 2002; 85, 183Ð192.
10 Ladage PM, Petroll WM, Jester JV, et al. Spherical indentations of human and rabbit corneal epithelium following extended contact lens wear, CLAO J, 2002; 28, 177Ð180.
11 Nichols J and King-Smith E. In-vivo thickness of the pre- and post-lens tear film and silicone hydrogel contact lenses measured by interferometry. Optom Vis Sci, 2001; 78, 51S.
12 Bron AJ, Tripathi RC and Tripathi BJ. Wolff's Anatomy of the Eye and Orbit, 1997, Eighth Edition. (London: Chapman & Hall Medical).
13 Naduvilath TJ. Statistical Modelling of Risk Factors Associated with Soft Contact Lens-Related Corneal Infiltrative Events. PhD Thesis, 2003. (Newcastle: University of Newcastle).
14 Lai YC and Friends GD. Surface wettability enhancement of silicone hydrogel lenses by processing with polar plastic molds. J Biomed Mater Res, 1997; 35, 349Ð356.
15 Millar TJ, Papas EB, Ozkan J, et al. Clinical appearance and microscopic analysis of mucin balls associated with contact lens wear. Cornea, 2003; 22, 740Ð745.
16 Fleiszig SM, Zaidi TS, Ramphal R and Pier GB. Modulation of Pseudomonas aeruginosa adherence to the corneal surface by mucus. Infect Immunol, 1994; 62, 1799Ð1804.
17 Pritchard N, Jones L, Dumbleton K and Fonn D. Epithelial inclusions in association with mucin ball development in high-oxygen permeability hydrogel lenses. Optom Vis Sci, 2000; 77, 68Ð72.

Professor Nathan Efron is director of Eurolens Research, UMISTUsing a corneal confocal microscope, Craig et al8 reported that mucin balls display a highly reflective core with a more poorly reflective, apparently translucent, outer layer. The diameter of the central core relative to the outer coating varied among mucin balls. This bilayered appearance was confirmed by the same authors using phase-contrast microscopy of mucin balls obtained from the back surface of lenses removed from the eye.
The name 'mucin balls' infers that these entities are composed primarily of tear mucins (mucins are the glycoprotein components of mucus and vary greatly in molecular size). Millar et al15 analysed mucin balls using light microscopic histochemistry, scanning electron microscopy, electron microscopic elemental analysis and confocal microscopy. They demonstrated that mucin balls are PAS positive, which indicates that glycoproteins are a major component. Lipids and bacteria were not detected. Millar et al15 concluded that mucin balls were made exclusively of collapsed mucin.

Pathogenesis of mucin ball formation
Within minutes of lens insertion, mucin ball formation begins at the interface of the posterior lens surface and the pre-corneal tear film. Sweeney et al7 suggest that mucin balls are more prominent in the superior quadrant of the cornea beneath the resting position of the upper eyelid. The mucinous layer of the tear film, along with some lipid components, is apparently 'rolled up' into discrete elements. At first, the resultant mucin balls are small in size and appear as an assortment of scattered debris in the form of individual deposits or small clumps of material. They remain fixed in position after a blink, which suggests that mucin balls are somehow fixed to, or partially embedded in, the epithelium (Figure 1).
With continuing lens wear, the mucin balls increase in size and some become deeply embedded in the epithelium, probably because of the force of the lens (Figure 2). At this point, slit-lamp examination using indirect retro-illumination reveals two forms of refractile elements. Those that display reversed illumination are the mucin balls that lie in the aqueous phase of the tear film. Those that display unreversed illumination are a either mucin balls buried deeper in the epithelial surface or fluid-filled pits created by mucin balls that subsequently became dislodged through blinking. These illumination effects are observed both with and without the lens on the eye (Figure 3). As stated previously, both mucin balls and fluid-filled pits stain with fluorescein and their appearance under fluorescent light is identical.
After prolonged periods of lens wear, some of the mucin balls become so large that they cannot maintain their spherical shape and collapse inwardly. This results in a doughnut appearance, with a flat centre and tyre-like annulus around the rim.1 A small, circular island of material can sometimes be observed in the centre of the collapsed mucin ball (Figure 4). It is unclear why mucin balls should collapse in this way, rather than the more intuitive scenario of the near-spherical mucin balls simply becoming flattened into a disciform shape.

Consequential pathology
Ladage et al10 were able to replicate the formation of mucin balls in a rabbit model, and observed Ki-67-positive stromal cells immediately beneath indentations that reached the epithelial basement membrane. This indicates that active proliferation of stromal cells was stimulated focally. These authors also noted a local increase in keratocyte density immediately beneath deep mucin balls. Stromal keratocytes do not divide unless stimulated to do so, which led Ladage et al10 to conclude that the Ki-67-positive stromal cells represent either dividing keratocytes or activated fibroblasts.
From a theoretical standpoint, clinicians ought to be concerned about the formation of mucin balls inasmuch as they represent a compromise of the mucus phase of the pre-corneal tear film. For example, Fleiszig et al16 demonstrated the critical importance of the mucus phase in preventing the attachment of potentially pathogenic bacteria to the corneal surface. In the absence of a properly formed mucus layer, which may occur as a result of extensive mucin ball formation, bacteria are more likely to attach to the cornea and establish an infection.
Aside from the protective function of mucus, potentially pathogenic organisms are more likely to establish an infectious process if there is a breach of the corneal epithelium. Fonn et al1 and Pritchard et al17 observed that fluorescein does not generally penetrate into the epithelium, which they suggest indicates that this corneal layer is not breached as a result of mucin ball formation. However, inspection of images of fluorescein staining in patients who have extensive mucin ball formation (Figure 5) reveals a diffuse halo of staining around some mucin balls, suggestive of a corneal breach.
Concerns that the above factors could lead to an increased occurrence of infectious keratitis among silicone hydrogel contact lens wearers can be allayed because early indications are that the incidence of sight-threatening corneal ulceration with silicone hydrogel lenses is low.
Fonn et al1 and Pritchard et al17 reported the case of a patient who demonstrated extensive mucin ball formation. This patient, who was using silicone hydrogel lenses on an extended wear basis, also presented with an acute red eye reaction, an asymptomatic epithelial defect (with rapid diffusion of fluorescein into the stroma), two further instances of asymptomatic infiltrates and symptoms of dryness over an 18-month period. These adverse events may have been coincidental to the appearance of mucin balls in this patient.
Mucin balls may cause a slight, though temporary, irregularity in the corneal surface that could reduce its wettability if present as a chronic condition.2 Aside from this, mucin balls do not seem to compromise ocular integrity. As discussed previously, mucin balls are not associated with increased corneal inflammation, corneal staining (apart from that staining directly attributable to the mucin balls) or conjunctival redness,2,7,9 and patients who display mucin balls do not experience discomfort or reduced vision.2,7,9

Management
The obvious strategy to prevent mucin ball formation, should this be the aim of the clinician, is to refit the patient with a lens type that is not made from silicone hydrogel materials. However, patients are likely to be highly motivated to wear silicone hydrogel lenses because of their comfort and convenience when used for continuous wear.
In patients who wear silicone hydrogel lenses, mucin ball formation can be minimised by:

Optimising lens fit Ð flat-fitting lenses are thought to exacerbate mucin ball formation2,6,9
Advising the patient to use lubricating drops after waking and before sleep2,6
Advising the patient to adopt a shorter wearing schedule (such as removing the lenses once every six nights instead of 30 nights).2

Prognosis
After lens removal, those mucin balls not embedded in the epithelium are blinked away rapidly. The residual 'embedded' mucin balls, and the fluid-filled pits generally resolve in a matter of hours.2 In severe cases, embedded mucin balls may remain in the epithelium for up to seven days.1 Mucin balls reform again if silicone hydrogel lens wear is recommenced.

Differential Diagnosis
Clinicians need to be able to differentiate mucin balls Ð and the fluid-filled epithelial pits they cause Ð from other phenomena induced by contact lenses that occur at or near the ocular surface, such as epithelial microcysts, epithelial vacuoles, epithelial bullae and dimple veiling.
Microcysts and mucin balls are similar in size. Microcysts can be observed, using optic section illumination with a slit-lamp biomicroscope, to be within the epithelium and to display reversed illumination. Therefore, unlike mucin balls, microcysts do not stain with fluorescein. However, microcysts that are breaking through the epithelial surface do stain with fluorescein and may be indistinguishable from mucin balls.
Epithelial vacuoles reside within the epithelium, display unreversed illumination and do not stain with fluorescein. Epithelial bullae are similar to vacuoles, but are more oval in shape, and have an irregular and indistinct border. Fluid-filled epithelial pits induced by mucin balls also display unreversed illumination, but unlike fluid vacuoles, they do stain with fluorescein.
Dimple veiling induced by contact lenses refers to the formation of fluid-filled pits in the epithelial surface as a result of pressure from individual air bubbles trapped beneath rigid contact lenses (and to a lesser extent in soft lenses). The epithelial depressions ('dimples') fill with the aqueous phase of the tear film, stain with fluorescein and display unreversed illumination; as such, they may be indistinguishable in appearance from fluid-filled epithelial pits induced by mucin balls. Dimple veiling tends to occur in clustered regions, which correspond to areas of loose lens fitting that can support the existence of large air bubbles. Thus, the type of lens (ie, a poorly fitting rigid lens versus a silicone hydrogel lens) is likely to be a key factor in differentiating these otherwise similar phenomena.
A summary of the features that differentiate the conditions described above is given in Table 1.

References
1 Fonn D, Pritchard N and Dumbleton K. Factors affecting the success of silicone hydrogels. In: Silicone Hydrogels. The Rebirth of Continuous Wear Contact Lenses, 2000.Ed Sweeney DF, p214Ð234. (Oxford: ButterworthÐHeinemann).
2 Dumbleton K, Jones L, Chalmers R, et al. Clinical characterisation of spherical post-lens debris associated with Lotrafilcon high-Dk silicone lenses. CLAO J, 2000; 26, 186Ð92.
3 Fleming C, Austen R and Davies S. Pre-corneal deposits during soft contact lens wear. Optom Vis Sci, 2000; 71, 152SÐ153S.
4 Tan J, Keay L and Jalbert I. Tear microspheres (TMSS) with high Dk lenses. Optom Vis Sci, 1999; 76S, 226.
5 Bourassa S and Benjamin WJ. Transient corneal surface 'microdeposits' and associated epithelial surface pits occurring with gel contact lens extended wear. Int Contact Lens Clin, 1988; 15, 338Ð340.
6 Tan J, Keay L, Jalbert I, et al. Mucin balls with wear of conventional and silicone hydrogel contact lenses. Optom Vis Sci, 2003; 80, 291Ð297.
7 Sweeney DF, Keay L, Jalbert I, et al. Clinical performance of silicone hydrogel lenses. In: Silicone Hydrogels. The Rebirth of Continuous Wear Contact Lenses, Ed. Sweeney DF, p. 90Ð149. (Oxford: ButterworthÐHeinemann), 2000.
8 Craig JP, Sherwin T, Grupcheva CN and McGhee CN. An evaluation of mucin balls associated with high-Dk silicone hydrogel contact lens wear. Adv Exp Med Biol, 2002; 506, 917Ð923.
9 Morgan PB and Efron N. Comparative clinical performance of two silicone hydrogel contact lenses for continuous wear. Clin Exp Optom, 2002; 85, 183Ð192.
10 Ladage PM, Petroll WM, Jester JV, et al. Spherical indentations of human and rabbit corneal epithelium following extended contact lens wear, CLAO J, 2002; 28, 177Ð180.
11 Nichols J and King-Smith E. In-vivo thickness of the pre- and post-lens tear film and silicone hydrogel contact lenses measured by interferometry. Optom Vis Sci, 2001; 78, 51S.
12 Bron AJ, Tripathi RC and Tripathi BJ. Wolff's Anatomy of the Eye and Orbit, 1997, Eighth Edition. (London: Chapman & Hall Medical).
13 Naduvilath TJ. Statistical Modelling of Risk Factors Associated with Soft Contact Lens-Related Corneal Infiltrative Events. PhD Thesis, 2003. (Newcastle: University of Newcastle).
14 Lai YC and Friends GD. Surface wettability enhancement of silicone hydrogel lenses by processing with polar plastic molds. J Biomed Mater Res, 1997; 35, 349Ð356.
15 Millar TJ, Papas EB, Ozkan J, et al. Clinical appearance and microscopic analysis of mucin balls associated with contact lens wear. Cornea, 2003; 22, 740Ð745.
16 Fleiszig SM, Zaidi TS, Ramphal R and Pier GB. Modulation of Pseudomonas aeruginosa adherence to the corneal surface by mucus. Infect Immunol, 1994; 62, 1799Ð1804.
17 Pritchard N, Jones L, Dumbleton K and Fonn D. Epithelial inclusions in association with mucin ball development in high-oxygen permeability hydrogel lenses. Optom Vis Sci, 2000; 77, 68Ð72.

Professor Nathan Efron is director of Eurolens Research, UMISTUsing a corneal confocal microscope, Craig et al8 reported that mucin balls display a highly reflective core with a more poorly reflective, apparently translucent, outer layer. The diameter of the central core relative to the outer coating varied among mucin balls. This bilayered appearance was confirmed by the same authors using phase-contrast microscopy of mucin balls obtained from the back surface of lenses removed from the eye.
The name 'mucin balls' infers that these entities are composed primarily of tear mucins (mucins are the glycoprotein components of mucus and vary greatly in molecular size). Millar et al15 analysed mucin balls using light microscopic histochemistry, scanning electron microscopy, electron microscopic elemental analysis and confocal microscopy. They demonstrated that mucin balls are PAS positive, which indicates that glycoproteins are a major component. Lipids and bacteria were not detected. Millar et al15 concluded that mucin balls were made exclusively of collapsed mucin.

Pathogenesis of mucin ball formation
Within minutes of lens insertion, mucin ball formation begins at the interface of the posterior lens surface and the pre-corneal tear film. Sweeney et al7 suggest that mucin balls are more prominent in the superior quadrant of the cornea beneath the resting position of the upper eyelid. The mucinous layer of the tear film, along with some lipid components, is apparently 'rolled up' into discrete elements. At first, the resultant mucin balls are small in size and appear as an assortment of scattered debris in the form of individual deposits or small clumps of material. They remain fixed in position after a blink, which suggests that mucin balls are somehow fixed to, or partially embedded in, the epithelium (Figure 1).
With continuing lens wear, the mucin balls increase in size and some become deeply embedded in the epithelium, probably because of the force of the lens (Figure 2). At this point, slit-lamp examination using indirect retro-illumination reveals two forms of refractile elements. Those that display reversed illumination are the mucin balls that lie in the aqueous phase of the tear film. Those that display unreversed illumination are a either mucin balls buried deeper in the epithelial surface or fluid-filled pits created by mucin balls that subsequently became dislodged through blinking. These illumination effects are observed both with and without the lens on the eye (Figure 3). As stated previously, both mucin balls and fluid-filled pits stain with fluorescein and their appearance under fluorescent light is identical.
After prolonged periods of lens wear, some of the mucin balls become so large that they cannot maintain their spherical shape and collapse inwardly. This results in a doughnut appearance, with a flat centre and tyre-like annulus around the rim.1 A small, circular island of material can sometimes be observed in the centre of the collapsed mucin ball (Figure 4). It is unclear why mucin balls should collapse in this way, rather than the more intuitive scenario of the near-spherical mucin balls simply becoming flattened into a disciform shape.

Consequential pathology
Ladage et al10 were able to replicate the formation of mucin balls in a rabbit model, and observed Ki-67-positive stromal cells immediately beneath indentations that reached the epithelial basement membrane. This indicates that active proliferation of stromal cells was stimulated focally. These authors also noted a local increase in keratocyte density immediately beneath deep mucin balls. Stromal keratocytes do not divide unless stimulated to do so, which led Ladage et al10 to conclude that the Ki-67-positive stromal cells represent either dividing keratocytes or activated fibroblasts.
From a theoretical standpoint, clinicians ought to be concerned about the formation of mucin balls inasmuch as they represent a compromise of the mucus phase of the pre-corneal tear film. For example, Fleiszig et al16 demonstrated the critical importance of the mucus phase in preventing the attachment of potentially pathogenic bacteria to the corneal surface. In the absence of a properly formed mucus layer, which may occur as a result of extensive mucin ball formation, bacteria are more likely to attach to the cornea and establish an infection.
Aside from the protective function of mucus, potentially pathogenic organisms are more likely to establish an infectious process if there is a breach of the corneal epithelium. Fonn et al1 and Pritchard et al17 observed that fluorescein does not generally penetrate into the epithelium, which they suggest indicates that this corneal layer is not breached as a result of mucin ball formation. However, inspection of images of fluorescein staining in patients who have extensive mucin ball formation (Figure 5) reveals a diffuse halo of staining around some mucin balls, suggestive of a corneal breach.
Concerns that the above factors could lead to an increased occurrence of infectious keratitis among silicone hydrogel contact lens wearers can be allayed because early indications are that the incidence of sight-threatening corneal ulceration with silicone hydrogel lenses is low.
Fonn et al1 and Pritchard et al17 reported the case of a patient who demonstrated extensive mucin ball formation. This patient, who was using silicone hydrogel lenses on an extended wear basis, also presented with an acute red eye reaction, an asymptomatic epithelial defect (with rapid diffusion of fluorescein into the stroma), two further instances of asymptomatic infiltrates and symptoms of dryness over an 18-month period. These adverse events may have been coincidental to the appearance of mucin balls in this patient.
Mucin balls may cause a slight, though temporary, irregularity in the corneal surface that could reduce its wettability if present as a chronic condition.2 Aside from this, mucin balls do not seem to compromise ocular integrity. As discussed previously, mucin balls are not associated with increased corneal inflammation, corneal staining (apart from that staining directly attributable to the mucin balls) or conjunctival redness,2,7,9 and patients who display mucin balls do not experience discomfort or reduced vision.2,7,9

Management
The obvious strategy to prevent mucin ball formation, should this be the aim of the clinician, is to refit the patient with a lens type that is not made from silicone hydrogel materials. However, patients are likely to be highly motivated to wear silicone hydrogel lenses because of their comfort and convenience when used for continuous wear.
In patients who wear silicone hydrogel lenses, mucin ball formation can be minimised by:

Optimising lens fit Ð flat-fitting lenses are thought to exacerbate mucin ball formation2,6,9
Advising the patient to use lubricating drops after waking and before sleep2,6
Advising the patient to adopt a shorter wearing schedule (such as removing the lenses once every six nights instead of 30 nights).2

Prognosis
After lens removal, those mucin balls not embedded in the epithelium are blinked away rapidly. The residual 'embedded' mucin balls, and the fluid-filled pits generally resolve in a matter of hours.2 In severe cases, embedded mucin balls may remain in the epithelium for up to seven days.1 Mucin balls reform again if silicone hydrogel lens wear is recommenced.

Differential Diagnosis
Clinicians need to be able to differentiate mucin balls Ð and the fluid-filled epithelial pits they cause Ð from other phenomena induced by contact lenses that occur at or near the ocular surface, such as epithelial microcysts, epithelial vacuoles, epithelial bullae and dimple veiling.
Microcysts and mucin balls are similar in size. Microcysts can be observed, using optic section illumination with a slit-lamp biomicroscope, to be within the epithelium and to display reversed illumination. Therefore, unlike mucin balls, microcysts do not stain with fluorescein. However, microcysts that are breaking through the epithelial surface do stain with fluorescein and may be indistinguishable from mucin balls.
Epithelial vacuoles reside within the epithelium, display unreversed illumination and do not stain with fluorescein. Epithelial bullae are similar to vacuoles, but are more oval in shape, and have an irregular and indistinct border. Fluid-filled epithelial pits induced by mucin balls also display unreversed illumination, but unlike fluid vacuoles, they do stain with fluorescein.
Dimple veiling induced by contact lenses refers to the formation of fluid-filled pits in the epithelial surface as a result of pressure from individual air bubbles trapped beneath rigid contact lenses (and to a lesser extent in soft lenses). The epithelial depressions ('dimples') fill with the aqueous phase of the tear film, stain with fluorescein and display unreversed illumination; as such, they may be indistinguishable in appearance from fluid-filled epithelial pits induced by mucin balls. Dimple veiling tends to occur in clustered regions, which correspond to areas of loose lens fitting that can support the existence of large air bubbles. Thus, the type of lens (ie, a poorly fitting rigid lens versus a silicone hydrogel lens) is likely to be a key factor in differentiating these otherwise similar phenomena.
A summary of the features that differentiate the conditions described above is given in Table 1.

References
1 Fonn D, Pritchard N and Dumbleton K. Factors affecting the success of silicone hydrogels. In: Silicone Hydrogels. The Rebirth of Continuous Wear Contact Lenses, 2000.Ed Sweeney DF, p214Ð234. (Oxford: ButterworthÐHeinemann).
2 Dumbleton K, Jones L, Chalmers R, et al. Clinical characterisation of spherical post-lens debris associated with Lotrafilcon high-Dk silicone lenses. CLAO J, 2000; 26, 186Ð92.
3 Fleming C, Austen R and Davies S. Pre-corneal deposits during soft contact lens wear. Optom Vis Sci, 2000; 71, 152SÐ153S.
4 Tan J, Keay L and Jalbert I. Tear microspheres (TMSS) with high Dk lenses. Optom Vis Sci, 1999; 76S, 226.
5 Bourassa S and Benjamin WJ. Transient corneal surface 'microdeposits' and associated epithelial surface pits occurring with gel contact lens extended wear. Int Contact Lens Clin, 1988; 15, 338Ð340.
6 Tan J, Keay L, Jalbert I, et al. Mucin balls with wear of conventional and silicone hydrogel contact lenses. Optom Vis Sci, 2003; 80, 291Ð297.
7 Sweeney DF, Keay L, Jalbert I, et al. Clinical performance of silicone hydrogel lenses. In: Silicone Hydrogels. The Rebirth of Continuous Wear Contact Lenses, Ed. Sweeney DF, p. 90Ð149. (Oxford: ButterworthÐHeinemann), 2000.
8 Craig JP, Sherwin T, Grupcheva CN and McGhee CN. An evaluation of mucin balls associated with high-Dk silicone hydrogel contact lens wear. Adv Exp Med Biol, 2002; 506, 917Ð923.
9 Morgan PB and Efron N. Comparative clinical performance of two silicone hydrogel contact lenses for continuous wear. Clin Exp Optom, 2002; 85, 183Ð192.
10 Ladage PM, Petroll WM, Jester JV, et al. Spherical indentations of human and rabbit corneal epithelium following extended contact lens wear, CLAO J, 2002; 28, 177Ð180.
11 Nichols J and King-Smith E. In-vivo thickness of the pre- and post-lens tear film and silicone hydrogel contact lenses measured by interferometry. Optom Vis Sci, 2001; 78, 51S.
12 Bron AJ, Tripathi RC and Tripathi BJ. Wolff's Anatomy of the Eye and Orbit, 1997, Eighth Edition. (London: Chapman & Hall Medical).
13 Naduvilath TJ. Statistical Modelling of Risk Factors Associated with Soft Contact Lens-Related Corneal Infiltrative Events. PhD Thesis, 2003. (Newcastle: University of Newcastle).
14 Lai YC and Friends GD. Surface wettability enhancement of silicone hydrogel lenses by processing with polar plastic molds. J Biomed Mater Res, 1997; 35, 349Ð356.
15 Millar TJ, Papas EB, Ozkan J, et al. Clinical appearance and microscopic analysis of mucin balls associated with contact lens wear. Cornea, 2003; 22, 740Ð745.
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Professor Nathan Efron is director of Eurolens Research, UMIST