occurred in all three zones. The papules in the localized GPC associated with silicone hydrogels usually occur in zones 2 and 3 (but can also be seen in zone 1), which is similar to the pattern seen with rigid contact lens wearers [21].

Epidemiology

Although GPC can occur with any type of contact lens, it is most often associated with wearing soft lenses. In a study of 221 patients, 85% were wearing soft contact lenses, whereas 15% were wearing rigid lenses [22]. The onset of GPC seems to occur sooner with soft lenses than rigid lenses. Allansmith and colleagues [2] reported an average interval of 10 months for the development of GPC in soft lens wearers, compared with an average of 8.5 years for wearers of rigid lenses. In a study of 221 patients with GPC, however, those wearing soft daily wear contact lenses had been wearing the same brand of lenses for an average of 19.9 months, whereas the patients wearing rigid gas-permeable lenses averaged 21.6 months before developing GPC, and patients wearing polymethyl methacrylate lenses wore them for longer than 90 months [22]. If one considers the total time that patients had been wearing lenses, soft daily wear contact lens patients wore their soft lenses (a variety of brands) an average of 87.4 months before being diagnosed with GPC, patients wearing rigid gas-permeable lenses had worn their lenses an average of 129.8 months, and polymethyl methacrylate wearers averaged 205.5 months of lens wear. This study confirmed the impression that the development of GPC does occur sooner in wearers of soft lenses than in those with rigid lenses (silicone hydrogels were not involved in this study). The study also reported that the signs and symptoms associated with GPC seemed to be more severe in soft lens wearers than in rigid gas-permeable lens wearers [22].

Because GPC is believed to have an immunologic basis, researchers have studied the occurrence of other atopic conditions in patients with GPC. The estimated frequency of hay fever and allergic rhinitis in the general population is considered to be 15% to 20%; reported studies have varied on the incidence of allergies in patients with GPC. Friedlaender [5] reported an incidence of 12%, whereas Donshik [22] reported an incidence of over 26%. In addition, patients with allergies seem to have more severe signs and symptoms of GPC than patients who do not have allergies [22]. The presence or absence of other allergic conditions does not seem to have any e ect, however, on the ultimate management of patients with GPC or their ability to continue to contact lens wear [22].

The US Food and Drug Administration has divided soft contact lenses into four groups based on water content and ionic properties of the lens material. There is some debate as to whether silicone hydrogel lenses should have a separate classification, but as of this writing they are currently sorted

into several of the existing groups. All types and brands of soft lenses have been associated with the occurrence of GPC. When a large study compared the various lens groups to determine the relationship between lens group and the development of GPC, the contact lenses in Food and Drug Administration group 1 (low water content, nonionic lenses) and group 4 (high water content, ionic lenses) seem to be similar in the severity of the signs and symptoms, and the length of time to onset of GPC. When group 1 contact lenses were compared with group 3 (low water content, ionic lenses), however, patients wearing group 3 contact lenses were found to have more severe signs and symptoms and a shorter time to onset of GPC [22]. The relatively small number of patients in group 2 lenses in this study prevented meaningful comparison with the other groups.

The incidence of GPC among silicone hydrogel contact lens wearers is probably equal to or less than with HEMA-based contact lenses. Silicone hydrogel contact lens wearers, however, are more likely to develop localized GPC than generalized GPC. Contact lens wearers who develop localized GPC seem to have milder symptoms than those associated with generalized GPC. Lens discomfort, blurred vision, secretions, itching, lens awareness, and the need to clean lenses were reported less often in patients with localized GPC compared with patients with generalized GPC. In addition, the incidence of unilateral GPC was greater in localized GPC patients, whereas bilateral GPC was greater in patents that developed generalized GPC. In a study of 124 patients who developed GPC while wearing silicone hydrogels contact lenses, the mean time in lenses before developing GPC was similar for the localized and generalized forms of GPC; and somewhat less than the time reported for HEMA-based hydrogels [21].

Histopathology

When the histopathology of GPC patients is studied, it must be remembered that even asymptomatic lens wearers can have histologic and morphologic changes of the upper tarsal conjunctiva [23,24]. In patients with GPC, however, the changes in the tarsal conjunctiva are more severe [25].

Although studies have found the concentration of inflammatory cells in the conjunctival epithelium of patients with GPC (44,000/mm3) is similar to that found in normal individuals (55,000/mm3) [26], there is a definite di erence in the distribution of the various types of inflammatory cells. In normal conjunctival tissue, neutrophils and lymphocytes are present only in the epithelium and the substantia propria, whereas mast cells and plasma cells are present in the substantia propria but not in the epithelium. Basophils and eosinophils are not normally found in either the epithelium or the substantia propria. Conjunctival biopsies from patients with GPC, however, found mast cells in the epithelium, and eosinophils were found in the epithelium and substantia propria. Basophils were also found in the epithelium and substantia propria.

It must also be remembered that although the inflammatory cell density is similar in normal conjunctiva and conjunctiva from GPC patients, the total conjunctival mass for GPC patients is twice that found in normal individuals. This increase in tissue mass is seen clinically as the thickening of the conjunctiva and the formation of papules. Individuals with GPC also have double the total number of inflammatory cells compared with individuals without GPC [23].

The histologic appearance of conjunctiva from patients with GPC is very similar to that seen in vernal conjunctivitis, lending support for an immunologic basis for GPC [27,28]. Di erences have been found, however, in inflammatory markers in the tears. Tear histamine levels in patients with vernal conjunctivitis are markedly elevated, averaging four times higher than those associated with GPC [29]. Histamine is released predominantly from the mast cells, which are slightly more numerous in vernal conjunctivitis than in GPC, although the di erence is not statistically significant [27]. Studies have also found that the percentage of degranulated mast cells is similar in the epithelium and stroma in patients with vernal conjunctivitis and GPC [26,30]. It is possible that the measured di erences in histamine levels in GPC and vernal conjunctivitis are related to a di erence in either the presence of histaminase or in the mechanism that controls histamine release. Two types of mast cells with di erent neutroprotease composition, MCt and MCtc, have been reported [31–34]. The MCt cells contain tryptase, but not chymase, and their granules are characterized by discrete scrolls. This is the predominant mast cell in the alveoli of the lung and the small intestines, and they seem to be dependent on the presence of functional T lymphocytes. The MCtc mast cells contain both tryptase and chymase and are not dependent on T lymphocytes for normal growth. MCtc cells are the predominant type in the skin and small intestinal submucosa, and their granules are characterized by grading and lattice substructures.

The normal conjunctival epithelium is devoid of mast cells, whereas the substantia propria contains an average of 11,054/mm3. The predominant mast cell in normal conjunctival tissue is the MCtc cells (mast cells containing tryptase and chymase) [35]. In patients with allergic conjunctivitis, and in asymptomatic wearers of soft contact lenses, mast cells are found in the substantia propria but not in the epithelium. Patients with vernal conjunctivitis and GPC have mast cells present in both the epithelium and substantia propria, but in patients with vernal conjunctivitis, MCt mast cells are present in the substantia propria and they are not found in patients with GPC or allergic conjunctivitis. This contrast may help explain the clinical di erence between these two conditions.

Elevated levels of other inflammatory markers are found in the tears of patients with GPC. Tear immunoglobulins, specifically IgE, IgG, and in the more severe cases IgM, have been found in the tears of patients with active GPC [17]. These tear immunoglobulins are locally produced by the external eye and are not elevated in an asymptomatic contact lens wearer. The

levels seen in GPC patients are related to the severity of symptoms, and after contact lens wear has been discontinued and the inflammation resolves, the tear immunoglobulins levels in patients with GPC return to normal levels within 1 to 2 weeks, despite the persistence of the tarsal papillary reaction [17]. Levels of complement factors, including C3, Factor B, and C3 anaphylatoxin, are also elevated in tears of GPC patient [36]. Decay-accelerating factor, a complement regulatory protein that inhibits C3 amplification convertase, is decreased in patients with GPC and may be responsible for enhancing complement activation [37]. Tear lactoferrin levels are increased in GPC patients, whereas tear lysozyme levels seem to remain normal [38,39]. The elevated levels of tear immunoglobulins and inflammatory mediators, which are also found in vernal conjunctivitis, further support an immunologic cause of GPC.

Eotaxin, a chemokine that attracts eosinophils, is elevated in patients with contact lens–induced GPC. The levels are correlated with the severity of the papillary reaction. Because eosinophils are important cells in allergic reactions, their presence in GPC is additional evidence of an immunologic cause of GPC, and may play a role in papillary formation [40]. It is interesting to note, however, that eotaxin levels were not found to be elevated in chronic GPC secondary to ocular prosthesis [41].

Neutrophilic chemotactic factor (NCF) has been detected in the tears of GPC patients at 15 times the level found in the tears of normal individuals. Asymptomatic contact lens wearers also have elevated levels of NCF, but the levels are only three times higher than normal levels [42]. NCF is released from injured conjunctival tissue, and the factor released is not related to interleukin-1, complement compound C5a, or leukotriene B4 [43]. When injected into normal tarsal conjunctiva of rabbits, NCF can create tarsal injection and a papillary reaction that is similar to that seen in GPC (Fig. 8). Histologic analysis of the conjunctiva from these rabbits

Fig. 8. Upper tarsal conjunctiva of rabbit after injection of neutrophilic chemotactic factor. A papillary reaction can be observed.