Giant (mechanically induced) Papillary Conjunctivitis (GPC), the severe form of mechanically induced papillary conjunctivitis, may be secondary to a variety of mechanical stimuli of the tarsal conjunctiva. Since GPC is predominantly associated with the use of contact lenses (CLs), the disease is also referred to as contact lens-induced papillary conjunctivitis (CLPC).
GPC is an inflammatory condition seen in upper tarsal conjunctiva, initially reported by Spring in 1974 (Spring TF, Reaction to hydrophilic lenses, Med J Aust 1974; 1:449-50). A papillary reaction, similar to the one with allergic conjunctivitis, occurs in soft contact lens wearers. Allansmith and colleagues further detailed the syndrome, suggesting that it may be immunologic in origin, with the proteinaceous deposits on the contact lenses, serving as the antigen (Allansmith MR, Korb DR, Greiner JV, et. al. Giant papillary conjunctivitis in contact lens wearers. Am J Ophthalmol 1977; 83:697-708).
GPC, a non-infectious inflammatory disorder was originally named for the presence of giant papillae (1.0mm or greater in diameter) along the upper tarsal surface. However, papillae measuring 0.3mm or greater are now considered abnormal and a feature of this condition.
GPC is most often associated with wearing soft (hydro-gel) contact lenses, though it can occur with any type of contact lens. The contact lens type, material, wearing schedule, cleaning process and length of time lenses have been worn contribute to the severity of the disease, with soft lens wearers suffering from more severe manifestations of disease than counterparts in rigid gas-permeable (RGP) lenses. Silicone hydro-gel lenses also appear to have similar effects with prolonged use. Incidence among extended wearers is supposed to be higher than the daily wearers of soft lenses.
With an increased frequency of contact lens replacement from more than four weeks to a period less than that, the incidence of GPC reduces. Both sexes develop GPC. GPC may be more aggressive in children who wear contact lenses.
The condition has also been reported in patients with:-
– Ocular dermoids.
– Ocular prosthesis.
– Exposed sutures/ knots following ocular procedures (such as monofilament nylon sutures).
– Extruded scleral buckles.
– Glaucoma filtering blebs.
– Corneal surface irregularity.
– Exposed corneal deposits.
– Tissue adhesives.
– Even elevated corneal scars.
Dry eye is a common association, especially with contact lens wearer.
A related phenomenon is the so called ‘mucus fishing syndrome’, when, in a variety of underlying anterior segment disorders, patients develop or exacerbate a chronic papillary reaction due to repetitive manual removal of mucus. Giant papillae can also be seen in other conditions such as vernal keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC).
One study suggests that patients who suffer from allergies seem to have more severe signs and symptoms of GPC. Significant correlation between GPC and other forms of allergy like rhinitis, hay fever and environmental allergy were found. Giant papillary conjunctivitis can follow seasonality similar to that of environmental allergies.
Because of the high prevalence of GPC in contact lens wearers, every patient who wears contact lens should be considered potential candidate for GPC.
Many contact lens wearers consider their symptoms as normal discomfort associated with contact lens use. Symptoms may be worse after lens removal. Often, in early disease, these symptoms may be out of proportion to the clinical findings.
GPC patients may have variety of symptoms in eye, such as:
– Burning sensation.
– Foreign body sensation.
– Increased mucus secretion, particularly on awakening in the morning (especially at the inner canthus).
– Decreased contact lens tolerance.
– Excessive contact lens movement.
– Blurring of vision.
– Ptosis (drooping of upper eyelid).
– Bloody tears (very rare).
The antigens responsible for giant papillary conjunctivitis are not yet identified.
The initiating event is believed to be antigenic stimulus and/or mechanical irritation of the upper palpebral (lid) conjunctiva, perhaps by a contact lens surface or edge or deposit, followed by histological changes in the tissue (mast cell de-granulation and secondary inflammatory cascade). This leads to conjunctivitis and further tissue changes and increasing inflammatory markers in the tears.
Debris on the surface of contact lenses may be a cause as well as a result, leading to inflammation that causes more lens deposits to form, leading to further inflammation.
Poor cleaning, thick or rough contact lens edges, heat sterilisation and extended wearing time favour the development of giant papillary conjunctivitis.
First-generation silicone hydro-gel contact lenses may be more prone to GPC development, perhaps because of their mechanical stiffness or higher propensity for lipid deposition. Silicone hydro-gel lenses tend to induce more local GPC, whereas soft (hydro-gel) lenses tend to induce more generalised GPC reactions in upper palpebral conjunctiva.
In patients with GPC, there is increase in numbers of inflammatory cells like neutrophils, lymphocytes, mast cells, plasma cells eosinophils and basophils in conjunctival epithelium and substantia propria. These findings, along with elevation of cytokines and chemokines in the tear film of GPC patients, suggest a possible allergic mechanism for the development of disease. Locally produced tear immunoglobulin (e.g. IgE, IgG, and even IgM in severe cases) are also found to be elevated in the tears of GPC patients, with the degree of elevation correlated to the severity of symptoms. With discontinuation of lens wear and resolution of the signs and symptoms, these tear immunoglobulin levels return to normal.
The proteinaceous deposits on the lens surface have been cited as the possible nidus for the development of inflammation and thus, the papillae associated with GPC. Even with the best cleaning regimens involving enzymatic treatment, a residual coating still exists, and as new coating material is constantly built on the surface of the lens, the overall lens coating increases. The lens type and material also affect the rate and amount of accumulation of protein coating.
The nature of these deposits is similar in patients with and without GPC. However, those affected with GPC generally have more coating on their contact lenses. Immunoglobulin G, A and M (IgG, IgA and IgM) are also found in the protein deposit on GPC-associated contact lenses.
Mechanical hypothesis, is supported by the association between GPC and inert objects, such as cyanoacrylate adhesives, exposed sutures and scleral buckle elements, ocular dermoids and orbital prosthesis. It is postulated that the irritation produced by lens damages conjunctival epithelial cells, and causes release of chemotactic factors (e.g. neutrophil chemotactic factor). It is suggested that a combination of direct trauma and the resulting inflammation cascade can stimulate a hypersensitivity reaction to lens-bound antigens.
Diagnosis of GPC is generally made by thorough history and careful clinical observation.
GPC shares morphologic and histologic similarities with VKC, but is best differentiated from this and other immunologically based conjunctival inflammation by the associated clinical history (e.g. contact lens wear, surgical intervention).
A careful and selective history is necessary to elicit the reports of symptoms that many may consider normal discomfort associated with contact lens use.
A history of systemic allergy also help to predict which of the contact lens users may end up with GPC.
Slit-lamp (bio-microscopic) examination by an eye-specialist is required for the diagnosis.
The bio-microscopic finding of normal tarsal conjunctiva, include a vascular arcade of fine, radiating vessels running perpendicular to the lid margin and a smooth, moist and pink surface. This has been termed a ‘satin’appearance. Generally, the surface is devoid of papillae, or there may be a fine, fairly uniform papillary appearance detectable after the instillation of fluorescein dye and examination with cobalt-blue filter. These papillae, if present, are often smaller than 0.3 mm in size. Non-specific signs of inflammation, such as thickening of the tarsal conjunctiva with mild hyperaemia, may be noted in early cases. In addition, bulbar conjunctival injection, superior corneal pannus, and corneal opacities may also be found on examination. As the disease progresses, non-uniform papillary changes develop, and finally giant papillae are seen, defined as a papillary reaction greater than 0.3 mm.
Allansmith divided superior tarsal surface into three zones. Zone 1 is located proximally along the uppermost edge of tarsal plate, zone 3 is located distally adjacent to the lid margin, with zone 2 in between. Papillae associated with soft contact lens-related GPC first appear in zone 1 and progress to zone 2 and 3.This pattern is reversed in GPC related to rigid gas permeable (RGP) contact lens wear. Papillae associated with RGP contact lenses are typically seen in zone 3, adjacent to the lid margin or distal half of the lid. These papillae are usually fewer in number and flattened in appearance. The topographic difference between GPC associated with large diameter soft contact lenses and small diameter RGP lenses is most probably related to mechanical or immunological stimulus for GPC. The conjunctiva is affected in sequential manner as the disease progresses. In the early stages, there is hyperaemia of the conjunctiva, with partial loss of the vascular pattern of conjunctiva. The papillae size is around 0.3mm. With progression of the disease there is more congestion of the tarsal surface with loss of vascular pattern. In severe cases, the tarsal plate is thickened with total obscuration of the vascular pattern. This stage may be associated with sub-conjunctival scarring.
Characterisation of the size and location of the papillae is helpful in correlating clinical findings with patient symptoms. Delineation of the upper tarsal plate into three zones, as well as two areas medially and laterally, can be useful to the clinician in determining whether findings are within the normal variance or whether it represents disease. For example, large papillae in the junctional or transitional zone are not considered pathologic and should be disregarded in the assessment of the upper tarsal conjunctiva.
Bio-microscopic findings may also be helpful, as the location and appearance of the papillae are associated with the type and material of the lens. Soft contact lens wearers often exhibit a generalised papillary response, whereas those wearing rigid gas-permeable lenses or silicone hydro-gels manifest papillae in a more localised fashion. Soft lens wearers usually form papillae nearest the upper margin of the tarsal plate and progress to diffuse involvement, whereas rigid lens wearers and those using silicone hydro-gel lenses develop papillae near the lid margin and persist in a more localised pattern.
In addition, other associated signs and symptoms can aid in the diagnosis of GPC. These signs and symptoms are often classified into four stages:
Stage 1, or Preclinical disease: Minimal mucous discharge is usually noted upon awakening, and patients may have occasional itching after lens removal. Examination of the lens reveals a mild protein coating. The tarsal conjunctiva may appear normal, or exhibit mild hyperaemia with normal vascular structures.
Stage 2, or Mild disease: There is increased mucous production along with itching, increased lens awareness and marked coating of the contact lens. Blurring of vision may occur. Mild to moderate injection of the tarsal conjunctiva is seen with some loss of normal vascular pattern (i.e. superficial vessels are typically obscured, but deeper vessels are still visible). The papillary reaction noted on examination may show variability in terms of the size of the papillae. Some of the papillae measure 0.3 mm or greater at this stage, and can best be detected upon examination with cobalt-blue filter after instillation of fluorescein dye.
Stage 3, or Moderate disease: Itching and mucous formation, along with lens coating, are more prominent, and patients often have difficulty with lens tolerance and keeping the lens clean. Increased lens awareness and excessive lens movement with blinking results in fluctuating vision and reduction in lens wear time. The tarsal conjunctiva shows marked thickening and injection, with obscuration of normal vascular pattern. The papillae increases in both size and number, and the papillae appear more elevated secondary to changes in the underlying tissue (e.g. sub-conjunctival fibrosis and thickening).
Stage 4, or severe disease: Patients are often unable to wear their lenses at all, with intense discomfort and cloudy vision upon initial insertion of the lens. There is excessive lens movement and poor centration of the contact lens. Increased mucous secretion is also seen, often to the point where the eyelids are stuck together in the morning. The normal vascular pattern is completely obscured, and the papillae have enlarged to size of 1 mm or greater. There may be sub-conjunctival scarring and fluorescein staining of the apices of papillae.
It is important to note that, although these stages can aid in the characterisation of the disease, patient presentation is often variable. Some patients may have minimal complaints but exhibit marked inflammatory changes on the tarsal conjunctiva; in contrast, patients with severe symptoms may present with only mild or early tarsal changes. Also, despite GPC is often noted bilaterally, the clinical findings may be grossly asymmetric. In some cases, the disparity between eyes is easily explained (e.g. poor lens fit), but in other cases, no specific reason is determined.
Thus signs of GPC are:
– Increased mucous discharge. Increased mucous discharge in GPC is because of increased surface area and thickness of epithelium with a resultant increase in total number of goblet cells. There is also increased mucous secretion by non-goblet epithelial cells.
– Substantial CL protein deposits may be present.
– Excessive CL mobility due to upper lid capture.
– Superior tarsal hyperaemia and papillae; by definition, ‘giant’ papillae are > 1.0 mm in diameter, but the clinical syndrome of mechanically induced papillary conjunctivitis commonly features only fine/medium papillae, particularly in early or mild disease.
– Focal apical ulceration and whitish scarring may develop on larger papillae.
– Ptosis may occur, mainly as a result of irritative spasm and tissue laxity secondary to chronic inflammation.
The pathognomonic sign of disease is papillae formation on the upper tarsal conjunctiva. Presence of papillae larger than 0.3 mm in association with presence of the symptoms is diagnostic of GPC.
Histological/ Immuno-histochemical studies:
Neutrophils and lymphocytes are present in the epithelium and substantia propria of normal conjunctival tissue. Mast cells and plasma cells are also present, though they are sequestered to the substantia propria. In patients with GPC, these cells increase in number and are often found throughout the epithelium and the substantia propria, and are found in conjunction with other inflammatory cells, such as basophils and eosinophils. Elevation of cytokines and chemokines in the tear film of GPC patients, suggest a possible allergic mechanism for the development of disease. Locally produced tear immunoglobulin (e.g. IgE, IgG, and even IgM in severe cases) are also elevated in the tears of GPC patients.
The proteinaceous deposits on the lens surface have been cited as the possible nidus for the development of inflammation and thus, the papillae associated with GPC. The lens type and material also affect the rate and amount of accumulation of protein coating.
The nature of these deposits is similar in patients with and without GPC. Those affected with GPC generally have more coating on their contact lenses. Immunoglobulin G, A and M (IgG, IgA and IgM) are also found in the protein deposits on GPC-associated contact lenses.
GPC should be differentiated from conditions such as:
– Allergic conjunctivitis.
– Viral conjunctivitis.
– Bacterial conjunctivitis.
– Chlamydial genitourinary infections.
– Congenital ptosis.
Management should be carried out under medical supervision.
Other cause of conjunctival papillae should be excluded, as well as CL intolerance due to other causes, such as a reaction to lens cleaning solutions and dry eyes.
GPC treatment is directed at reducing or eliminating any mechanical stimulation and lens coating from the contact lenses or modulating the immune response to the antigenic proteins on the lens surface. Depending on the severity of disease, several or all of the strategies for reducing lens coating or mechanical stimulation may need to be employed.
The ultimate goal in managing patients with GPC is to allow them to continue wearing their contact lenses.
Individuals utilising daily disposable lenses have not been reported to develop GPC.
Removal of the stimulus:
– Measures adopted to reduce exposure to the antigenic proteins on the contact lens:
- CL wear should be discontinued for several weeks and the current lenses replaced. For mild-moderate disease, this may be adequate for resolution. In severe CLPC a longer interval without lens wear may be needed.
- Decreasing the lens wear time.
- Changing design of the contact lens.
- Changing the lens material.
- Shortening contact lens replacement interval.
– Assessment of the status and fit of an ocular prosthesis.
– Replacement of ocular prosthesis by a new prosthesis (preferably coated with bio-compatible material- biocoat).
– Removal of other underlying causes, such as exposed sutures or a scleral buckle.
– Partial excision, revision with non-penetrating drainage surgery or glaucoma drainage device implantation for filtering bleb.
– Cessation of contact lens wear, substituting spectacles or refractive surgery, may be necessary for severe or refractory disease.
Ensure effective cleaning of CL or ocular prosthesis:
– Changing the type of CL solution, particularly discontinuation of preservative-containing preparations. Cleaning, rinsing and storage solutions containing preservatives such as thiomersal and chlorhexidine should be discarded.
– Switching to monthly, then daily disposable CL, if the condition persists after renewing non-disposable lenses.
– Rigid lenses carry a lesser risk of CLPC, probably because they are easier to clean effectively.
– Regular (at least weekly) use of contact lens protein removal tablets (enzyme cleaning).
– Ocular prosthesis: Ocular prosthesis should be cleaned with detergent and polished.
– Cold compresses: Cold compresses help in improving symptoms.
Medications such as mast cell stabilisers and topical corticosteroids may be needed to control immune reaction.
Drug therapy includes:
– Topical artificial tears: Artificial tears provide lubrication and help to wash away the environmental allergens and lens debris.
– Topical combined vasoconstrictor and antihistamine: Topical combined vasoconstrictor and antihistamine like antazoline (antihistamine) with xylometazoline (vasoconstrictor) may offer relief in some cases.
– Topical mast cell stabilisers: Mast cell stabilisers should be non-preserved in patients wearing soft contact lens, or can be instilled when the lenses are not in the eye, with a delay of perhaps half an hour after drop instillation prior to lens insertion. Most can be continued long-term if necessary. Examples are cromolyn sodium, lodoxamide, nedocromil and pemirolast. Cromolyn sodium in early GPC, particularly when combined with meticulous lens hygiene, gives relief of foreign body sensation, dryness, congestion, mucus production and in papillary size.
– Topical selective second-generation H1-blocking antihistamines: Topical selective H1 receptor blockers are better than vasoconstrictors alone or in combination with non-specific anti-histamine eye-drops, in controlling signs and symptoms. The group contains drugs like emedastine and levocabastine. Topical second-generation H1 antihistamines are much more selective, and thus significantly reduce the occurrence of adverse drug reactions, such as drowsiness/ sedative action, dry eye and dry mouth.
– Selective H1-blocking antihistamines and topical mast cell stabilisers (Dual acting drugs): Agents such as azelastine, epinastine, bepotastine, olopatadine and ketotifen have both mast cell-stabilising and anti-histamine properties. These agents have a relatively rapid onset of action. Topical antihistamine and mast cell stabiliser combination solution may offer a pharmacologic adjunctive treatment. Combined antihistamine/mast cell stabilisers generally suffice without exposing the patient to the known risks of topical corticosteroids. Most patients do not require more aggressive treatment.
– Non-steroidal anti-inflammatory drugs (NSAIDs): Non-steroidal anti-inflammatory preparations like ketorolac and diclofenac may improve symptoms. Combining one of these with a mast cell stabiliser is an effective regimen in some patients.
– Topical corticosteroids: Topical steroids like fluorometholone or loteprednol may be used. Topical steroids can be used for the acute phase of resistant cases, particularly those where effective removal of the stimulus is difficult, as in bleb-related disease.
Short-term low-potency topical corticosteroid used concurrently with combined antihistamine/mast cell stabiliser (dual-acting drugs) is a more effective treatment than mono-therapy with either separately.
There is no role of long-term usage of topical steroids in treatment due to associated complications (development of cataract, glaucoma or superadded infections).
– Immune-modulator drugs: Immune-modulator drug such as tacrolimus ointment is found to be comparable to fluorometholone in efficacy without the side effects of corticosteroids in the treatment of GPC. (http://reference.medscape.com/medline/abstract/22821643).
Topical tacrolimus ointment for severe GPC cases, refractory to conventional therapy, appears to be effective alternative treatment (http://reference.medscape.com/medline/abstract/18216583).
Immune response modulation for GPC mainly focuses on topical therapy, most commonly mast cell stabilisers and loteprednol. Mast cell stabilisers may be used in patients with moderate to severe GPC that suffered a recurrence of symptoms despite changes in the contact lens design or polymer. The use of steroids, such as loteprednol, has been found to reduce the presence of papillae, itching, and lens intolerance. However, chronic treatment with a steroid is generally not recommended in these cases.
A combination of the two options seems most appropriate for initiating treatment for the patient suffering from GPC.
For stage 1, more frequent observation (e.g. 4-6 month follow-up) may be all that is required, as these individuals are generally asymptomatic but will be predisposed to developing GPC.
Treatment for stage 2 to stage 3 should begin with discontinuation of contact lenses for about 2-4 weeks, with re-evaluation of the conjunctiva and refit with frequent replacement of contact lenses. These can range from daily disposables lenses to lenses that are replaced every 2 weeks. For those changing their lenses every 1-2 weeks, a lens cleaning regimen utilising a hydrogen peroxide (disinfection by hydrogen peroxide appears to be least likely to further traumatise the conjunctiva)based cleaner is preferred. If there is return of symptoms despite a change in the lens type and polymer, discontinue the lenses for another 2-4 weeks, refit with a daily disposable lens (or RGP lens) and add a mast cell stabiliser. These patients should generally be re-evaluated 3-4 times in a year.
For severe, or stage 4 disease, discontinuation of contact lens wear may be required for at least 4 weeks, along with refitting the contact lens with either a daily disposable or RGP lens. Check for the resolution of associated findings of corneal and apical papillary staining. The appearance and size of the papillae may not change during the course of treatment for severe GPC. If the associated inflammatory signs have resolved, then attempts to refit the patient with a new lens may have a greater success rate. If the patient is refitted with a daily wear contact lens and replaces the lens in an interval of 4 weeks or less, the rate of developing GPC reduces.
If there is no response and signs and symptoms persist, one may have to consider discontinuing contact lens use.
– Refractive surgery: Refractive surgery such as laser-assisted in-situ keratomileusis (LASIK) may be considered in patients who refuse conservative management. This helps in avoiding contact lenses.
Therapeutic effect is evidenced by:
– Return of contact lens tolerance.
– Decreased mucous in tears.
– Suppression of ocular itching.
– Decreased hyperaemia of tarsal conjunctiva.
– Decreased inflammation of giant papillae.
Amelioration of symptoms is more important than clinical signs in assessment of therapeutic effect.
Overall prognosis of giant papillary conjunctivitis is good. About 80% of patients may return to comfortable contact lens wear with appropriate management.
Giant papillary conjunctivitis has been a common cause of temporary and permanent contact lens intolerance.
The eyelids in some patients may return to their normal appearance following resolution of GPC, whereas in others, lid retain small, white-capped scars of giant papillae for long periods, sometimes indefinitely.
Patients should be educated about the chronic nature of disease and its clinical symptoms (e.g. Itching of eyes, mucous discharge and contact lens intolerance). Patient should be advised to present within a week of any relapsing symptoms. Patient should understand appropriate contact lens cleaning and follow-up care.
Preventive methods adopted to reduce the prevalence of GPC among users of hydro-gel contact lenses are:
– Increased frequency of contact lens replacement.
– Decreased wear time.
– Hydrogen peroxide disinfection.
– Timely appropriate professional supervision.
– Rigorous cleaning measures (particularly with enzyme tablets).
Increased enzyme cleaning of rigid lenses also appears to be prophylactic.