Treatment of Allergic Eye Disease

Amy T. Kelmenson, Naveen K. Rao and Michael B. Raizman

Introduction

Ocular allergies are a common group of disorders that can be debilitating for patients and, at times, challenging for physicians to diagnose and treat. For the purpose of developing an appropriate treatment strategy, it can be useful to conceptually divide ocular allergies into six categories: seasonal allergic conjunctivitis (SAC), perennial allergic conjunctivitis (PAC), vernal keratoconjunctivitis (VKC), atopic keratoconjunctivitis (AKC), giant papillary conjunctivitis (GPC), and contact allergic conjunctivitis (CAC).

SAC is the most prevalent form of ocular allergy and is often accompanied by seasonal allergic rhinitis. Its seasonal incidence is closely tied to the cyclic release of environmental plant-derived airborne allergens. PAC is more likely to occur year-round, though most patients also experience seasonal exacerbations, and is thought to be caused by indoor allergens, such as animal dander and dust mites. Both SAC and PAC can cause significant morbidity, but rarely cause permanent visual impairment. VKC is a less common, self-limited variant of ocular allergy, that can present with unique corneal and conjunctival manifestations, described elsewhere in this text. AKC is a chronic condition associated with atopic dermatitis or eczema, often in individuals with a history of atopy. Both VKC and AKC are primary conjunctival disorders that can cause secondary corneal scarring and therefore, can be vision-threatening. Giant papillary conjunctivitis (GPC) is a reversible condition, most commonly associated with chronic mechanical irritation from contact lenses, exposed sutures, or prostheses. CAC occurs after sensitization to ocular medications and their preservatives.¹

This chapter will focus on treatment of ocular allergic disease. The following sections address avoidance, medical therapy, and surgical therapy of ocular allergies. A brief review of new and experimental treatment modalities is included as well.

Avoidance

Avoiding known allergen triggers is critical to prevent or ameliorate the symptoms of ocular allergies. Many patients are aware of their allergen triggers, but in some cases allergy testing can be helpful. Possible strategies for avoiding allergens include, staying indoors during high pollen counts, using air conditioners and air filters in the home and car, keeping windows closed, and washing hair and clothes after being outdoors. Patients with perennial allergic conjunctivitis may benefit from covering bedding with plastic covers, removing carpets, and avoiding pets. At a minimum, pets should not be allowed in the bedroom. When eyes itch, the natural response is to rub. The temporary relief of itching achieved from rubbing is negated by a more exuberant inflammatory response.² Eye rubbing may bring large quantities of allergens in direct contact with the conjunctiva from the hands and may mechanically disrupt cell membranes, resulting in further release of inflammatory mediators.^2,3 The inflammation, in turn, may result in an itch – rub cycle that is difficult to break. In addition, chronic eye rubbing has been associated with the development of keratoconus. Encouraging patients to stop rubbing their eyes should be a fundamental goal. Cool artificial tears may provide some relief by diluting both inflammatory mediators and allergens on the ocular surface. Cool compresses and ice packs to the eyelids may reduce swelling and provide some additional relief. For many patients, non-medical treatments alone are not sufficient.¹

Treatment of concurrent lid margin disease can be problematic, particularly in the case of AKC. Warm compresses, eyelids scrubs, and eyelid massage, mainstays of treatment for meibomian gland dysfunction and blepharitis, can exacerbate the chronic inflammation in AKC. Patients should be discouraged from using moisture on the lids, as this can worsen the eczematous changes of the lid skin, such as redness, thickening, and development of fissures. Instead, the use of dry warm compresses is preferred. Any subsequent lid massage should be limited to gentle pressure over the meibomian glands, rather than a vigorous back-and-forth motion. Adjunct use of oral tetracyclines, such as doxycycline or minocycline, and nutritional supplements, such as fish oil and flaxseed oil, can also be helpful.

Medical Therapy

When choosing a medical therapy for allergic conjunctivitis, it is important to remember that the efficacy of an individual medication will vary between patients. As discussed below, each medical therapy targets different mediators in the inflammatory cascade for allergic conjunctivitis (Figs 17.1, 17.2). Selection of an antiallergy medication should be based on the severity, symptoms and projected duration of a patient’s allergic disease. For example, a patient with a severe allergic response may initially benefit from a topical corticosteroid, while a patient with moderate symptoms from complex allergies or who requires extended treatment, may do well with mast cell stabilizers or dual-action agents (mast cell stabilizer/antihistamine). Topical medications are listed in Table 17.1.

Table 17.1

Topical Medications for the Treatment of Allergic Conjunctivitis

(From Mishra GP, Tamboli V, Jwala J, et al. Recent patents and emerging therapeutics in the treatment of allergic conjunctivitis. Recent Pat Inflamm Allergy Drug Discov 2011;5:26–36.)

Figure 17.1 Mast cell activation pathways. (Adapted from: Mishra GP, Tamboli V, Jwala J, et al. Recent Patents and Emerging Therapeutics in the Treatment of Allergic Conjunctivitis. Recent Pat Inflamm Allergy Drug Discov 2011;5:26–36.)

Figure 17.2 When activated, mast cells in the conjunctiva and eyelid release preformed mediators of inflammation from their granules and newly synthesized mediators from their cell membranes via the arachidonic acid cascade. (From Raizman MB. Update on Ocular Allergy. Focal Points Clinical Modules for Ophthalmologists 1994;12:1.)

Over-the-counter topical decongestants containing vasoconstrictors with or without antihistamines are generally well tolerated and effective for patients with mild allergic symptoms.4,5 Although the antihistamine component is weak, the vasoconstrictor component is very effective in reducing conjunctival hyperemia via alpha adrenoceptor stimulation. In the United States, either pheniramine or antazoline, the common antihistamines, is combined with naphazoline, a vasoconstrictor. Using these drops over time may result in tachyphylaxis, requiring patients to use the drops more frequently to obtain the same vasoconstrictor effect. Furthermore, discontinuation of vasoconstricting eyedrops may result in rebound hyperemia.⁶ Depending on the underlying condition, artificial tears, corticosteroid drops, or long-term therapy with mast cell stabilizers and/or immunotherapy may help alleviate dependence on the vasoconstricting eyedrops.⁶ Due to their mydriatic effect, topical decongestants are contraindicated in patients with narrow angles.

Antihistamines

Antihistamines are medications that target the H₁ histamine receptor. First-generation antihistamines block peripheral H₁ receptors, but also cross the blood – brain barrier and block central nervous system H₁ and cholinergic receptors as well. This produces the unwanted side effect of sedation. Nonselective topical antihistamines include pheniramine, antazoline, chlorpheniramine, and cyclizine.

Second-generation antihistamines do not cross the blood – brain barrier. They selectively block peripheral H₁ receptors, reducing the occurrence of sedation while still effectively treating allergic symptoms. These more potent topical antihistamines include levocabastine hydrochloride 0.05% and emedastine difumarate 0.05%. Most of the recent antihistamines have also been shown to have some mast cell stabilizing properties as well. Most topical antihistamines have a rapid onset of action, but have a short duration of action, requiring up to four times daily dosing. Selective antihistamines with mast cell stabilizing properties, such as olopatadine, azelastine, ketotifen, alcaftadine, epinastine, and bepotastine, have been shown to have a rapid onset but a longer duration of action when compared to the other topical antihistamines, lasting up to 16 hours.7–10 Because of the improved efficacy of combined antihistamine/mast cell stabilizers, the pure antihistamine drops have largely been replaced by combination drops.

Systemic therapy with oral antihistamines (diphenhydramine, carbinoxamine, clemastine, chlorpheniramine, brompheniramine, oxatomide, cetirizine, levocetirizine, loratadine, desloratidine, ketotifen, and fexofenadine) may be beneficial for perennial, vernal, or atopic allergic keratoconjunctivitis, given the chronicity of the disease and the potential for patients to become sensitized to preservatives in some commercial topical preparations. However, oral antihistamines are seldom used to treat isolated seasonal or perennial allergic conjunctivitis, but are frequently used to treat systemic allergy. They should be used with caution in patients with cardiac arrhythmias, or in combination with erythromycin, ketoconazole, itraconazole and troleandomycin. These medications may improve systemic symptoms, but ocular symptoms may worsen. Symptoms of dry eye may be induced or compounded by the propensity of antihistamines to reduce tear production. Topical antihistamines have muscarinic binding properties which, in theory, may also cause or worsen dry eye syndrome. The data on their effect on tear production are conflicting.¹¹ In general, there is little clinical evidence that topical antihistamines induce dryness. When oral antihistamines are needed to treat rhinitis, the addition of a topical antihistamine may help the ocular symptoms.

Mast Cell Stabilizers

Traditional mast cell stabilizers are thought to limit the flux of calcium across the mast cell membrane, thus preventing degranulation and release of vasoactive substances. Medications in this group include sodium cromoglycate 4%, lodoxamide tromethamine 0.1%, and the newer mast cell stabilizers: pemirolast potassium 0.1%, and nedocromil sodium 2%.

Given that these medications inhibit the release of histamine rather than block histamine receptors, they are better at preventing than treating allergic signs and symptoms. Their effects may not be seen until 2 to 5 days after initiation of therapy, while their maximum benefit is achieved 15 days after initiating therapy. Therefore, if patients have allergic symptoms during a defined season, they should begin these medications about 2 weeks prior to their allergy season and continue throughout the entire season. Mast cell stabilizers represent the mainstay of therapy for vernal and atopic keratoconjunctivitis. Nedocromil, originally thought to be just a mast cell stabilizing agent, is recognized to have multiple actions resulting in rapid relief of symptoms. These actions include antihistaminic (H₁ antagonist) effects, reduction of ICAM-1 expression, and inhibitory effects on eosinophils and neutrophils.¹²

Numerous studies have demonstrated the safety and effectiveness of cromolyn sodium, nedocromil, lodoxamide, and pemirolast, in treating signs and symptoms of vernal and seasonal allergic conjunctivitis.13–21 When comparing the older agents, lodoxamide is about 2500 times more potent than sodium cromoglycate in an animal model, although their efficacy in controlling the symptoms of allergic conjunctivitis is similar.²² A long-term comparison of nedocromil versus cromolyn sodium found that nedocromil 2% produced a more rapid and marked improvement in symptoms over cromolyn 2% and decreased the need for steroid rescue.²³ Lodoxamide 0.1% may have additional benefits over cromolyn sodium because it has been found to also have potential antieosinophil action.^16,24

Additional studies suggest that mast cell stabilizers may act through other mechanisms. Cromolyn sodium reportedly inhibits the chemotaxis, activation, degranulation, and cytotoxicity of neutrophils, eosinophils, and monocytes.16,25 Lodoxamide and cromolyn sodium may also have effects on Th2 cells, which have been implicated in the pathogenesis of VKC.²⁶ In some patients, mast cell stabilizing drops may be more effective for chronic therapy than dual-acting agents (antihistamine/mast cell stabilizing agents).