Signs and Symptoms
Atopy is a genetic predisposition to develop an allergic reaction.1 Systemic examples include allergic rhinitis and atopic dermatitis. The ocular correlate is atopic conjunctivitis. Patients with atopic keratoconjunctivitis (AKC) invariably have a personal or family history of allergic disease.2 This may include atopic dermatitis, asthma, hayfever, food allergies and/or urticaria.2-4 Patients are usually male, older than 20 years, with the peak incidence occurring between ages 30 and 50.2–5 The condition is variable, with exacerbations and remissions; a large number of patients never seek medical care.6 The disease has a reputation of provoking more symptoms during the winter months.2–7
Symptoms associated with AKC consist of bilateral itching with associated hyperlacrimation. Patients may also complain of a stringy or ropy mucoid discharge.2-5 Eyelid swelling may be substantial, with burning eyelids and periocular skin. Inspection of the eyelids reveals characteristically scaly, indurated and wrinkled skin, with the possibility of fissure development at the lateral canthi associated with chronic ocular rubbing and epiphora.2–7
Biomicroscopically, there will be pronounced conjunctival hyperemia and edema, as well as tarsal papillae. Gelatinous limbal papillae and Horner-Trantas dots (i.e., collections of degenerated epithelial cells and eosinophils), considered pathognomonic for vernal keratoconjunctivitis, may also be seen in advanced cases.2–7 Notable corneal involvement may also be encountered, including punctate keratitis, persistent epithelial erosions, “shield ulcers;” mucus plaque formation, corneal pannus and neovascularization.2,8 The associated corneal involvement may represent the primary inflammatory process, or can be secondary to disrupted tear chemistry and lid function.
The chronic inflammation associated with AKC has the capacity to impart cicatricial changes within the conjunctiva and cornea.8 Subepithelial conjunctival fibrosis, symblepharon (with subsequent entropion), corneal lipid deposition and pannus are not uncommon.7-9 Primary corneal ectasias, such as keratoconus and pellucid marginal degeneration, may also occur in association with AKC. These corneal changes occur secondary to chronic mechanical stress, which produces associated astigmatic changes and scarring with subsequent visual impairment. Interestingly, cataract development is also possible in AKC. Anterior subcapsular opacities (sometimes called “shield cataracts”) are thought to result from the complications of atopic inflammation.4,7,9 Keratoconus has been associated with eyelid rubbing in atopic patients.
Atopy is the predisposed allergic reaction via the elevated production of immunoglobulin E upon exposure to an environmental antigen that is either inhaled or ingested.1 AKC is believed to manifest elements of both Type I and Type IV hypersensitivity reactions.10 Type I represents an immediate or anaphylactic reaction by the innate immune system secondary to an exposure that the body has been preprogrammed to eradicate. It involves the sudden degranulation of mast cells local to the region of exposure mediated by IgE antibodies.2 This is the response seen in acute allergic conjunctivitis.
A Type IV reaction, also known as a delayed or cell-mediated hypersensitivity reaction, involves the slower adaptive immune system. Here, plasma cells, B-cells, T-lymphocytes and associated lymphokines respond following multiple exposures to varying loads of the antigen. Type IV reactions include contact dermatitis and phlyctenulosis. The measurement of released tear-specific inflammatory markers, such as histamine, tryptase, interleukins (IL-4, IL-5) and eotaxin, may be useful in confirming the diagnosis and monitoring ocular allergy.11 New technologies such as multiplex bead assays, membrane-bound antibody array and proteomic techniques are being used to characterize and quantify the distribution of a wide range of these bioactive proteins in tears.11
Histopathologic evaluation of conjunctival samples from patients with AKC reveals elevated levels of mast cells, lymphocytes, eosinophils and basophils.2,3 Mast cell degranulation, which is seen in acute forms of ocular allergy, initiates the release of histamine, chymase, tryptase and heparin; these mediators are responsible for vasodilation, increased collagenase activity and early fibrinogenesis.8,11 In addition, degranulation of eosinophils releases numerous toxic/inflammatory proteins, such as eosinophil cationic protein, eosinophil peroxidase, and eosinophil-derived neurotoxin.9,11 These proteins not only induce cicatricial changes in the conjunctiva; they have also been shown to cause cytotoxic disruption in corneal epithelial cells, suggesting a possible mechanism for the extensive corneal pathology seen in chronic AKC.8,13 Matrix metalloproteinase is another eosinophil product associated with fibrosis and scarring.
It has been suggested that inherent feedback mechanisms that normally regulate the allergic response may be impaired in atopic disorders, resulting in continuous T-cell activation.11,12 Research has identified several specific genes that may be responsible supporting the strong role of family history in atopic disease.12
In the mildest forms, AKC is a seasonal nuisance disease. It can be treated easily with palliative methods (tears, cold compresses, lubricants) and mild topical anti-allergy medications (vasoconstrictors, antihistamine/mast cell stabilizers). Oral non-sedating antihistamines can be used to concurrently manage accompanying non-ocular and adnexal symptoms.14 When possible, the patient should be instructed to avoid the environmental and chemical agents that are known to provoke the process.
In more severe cases, AKC can induce chronic debilitating symptoms along with tissue destruction capable of permanently affecting function.2,8 Topical non-steroidal anti-inflammatory drugs (NSAIDs) can also be used to mitigate signs and symptoms.15 Here, dosage and length of use must be monitored. Documented cases of keratolysis have been reported associated with increased frequency of administration and extended use.16,17
Because the pathology of AKC involves inflammation, topical corticosteroids may be required to suppress an aggressive inflammatory response. Prednisolone acetate 1% and difluprednate emulsion 0.05% are topical ophthalmic steroids that can be prescribed for chronic forms of the disorder. While they are effective agents, consideration must be given for intraocular pressure elevation with chronic use. Loteprednol etabonate 0.5% is a potent topical steroid with a reputation for having less propensity to raise IOP, though this response may occur with chronic use. It should be considered as an option for patients who require long-term corticosteroid therapy with close observation.18,19
The dosing of topical steroids should vary depending on the individual case; QID-Q2H for severe cases, with BID-QD dosing for cases requiring long-term maintenance. In cases demonstrating raised IOP where the topical therapy must be continued, aqueous suppressants can be added. Finally, topical steroids used for less than two weeks generally can be discontinued without tapering. In cases that induce the formation of corneal shield ulcer, topical cycloplegia and broad-spectrum antibiotic prophylaxis should be added.2
Patients with AKC who are inadequately controlled with topical corticosteroids or those who experience negative sequelae warranting discontinuation of steroids may require topical or systemic immunomodulatory therapy (oral, sublingual or subcutaneous routes).20-26 Topical cyclosporine may be an effective alternative in this situation; it has been shown to specifically inhibit T-lymphocyte proliferation while imparting direct inhibitory effects on eosinophil and mast-cell activation.20,21 Early research using cyclosporine 2% in maize oil demonstrated a distinct benefit.22 However, clinical studies involving 0.05% cyclosporine emulsion have shown mixed results.20-25 Oral steroids are only considered in non-responsive situations.
Atopic dermatitis involving the lids, in addition to palliative treatments and oral antihistamines, may require corticosteroid creams or ointments. Options include over-the-counter hydrocortisone 10%, fluorometholone ointment, triamcinolone acetonide 0.1% or clobetasone butyrate 0.05%. The immediate satisfaction topical steroids can produce encourages patients to use them liberally or without consulting a professional. This relapsing behavior by the patient is sometimes known as “topical steroid addiction.” Since topical steroids can raise IOP and thin the dermis, patients must be educated that unapproved use is not a sound strategy. In lieu of steroids, topical tacrolimus 0.1% ointment (Protopic, Astellas Pharma) has demonstrated equivalent safety and efficacy in a head-to-head clinical study.26,27
• Patients using topical steroids for long periods of time should also be monitored for glaucoma and cataractogenesis.
• It is important to distinguish between AKC and vernal keratoconjunctivitis (VKC). VKC is seen in younger males (age three to 25 years) and has a tendency to become exacerbated during warmer months and in warmer climates.
• AKC must also be differentiated from contact eyelid dermatitis. Contact dermatitis presents with acute, pitting edema (that can be pushed in), erythema and pronounced itching of the adnexa. Corneal and conjunctival involvement is rare and signals additional toxic exposure.
• Topical NSAIDs can provide analgesia in the management of AKC but the dosage and length of use must monitored as keratolysis has been associated with increased or prolonged regimens.
• Oral antihistamines have diminished bioavailability to the ocular tissues; however, their positive effect on the adnexa mandates consideration in AKC treatment.
• Consultation and comanagement with an allergist, dermatologist and corneal surgeon should be considered in patients with ongoing or worsening exacerbations.
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