Signs and Symptoms
Allergic conjunctivitis is the most common manifestation of ocular allergy, affecting between 20% and 40% of the US population.1-11 Acute allergic conjunctivitis describes the abrupt and immediate response seen in sensitized individuals after exposure to a particular allergen or sensitizing agent. Two main forms are recognized: seasonal allergic conjunctivitis (SAC), which coincides with pollen blooms such as ragweed, and perennial (or persistent) allergic conjunctivitis (PAC), in which exposure may occur at any time throughout the year (e.g., allergies to animal dander or dust mite feces).4,5 In the majority of cases, allergic conjunctivitis is a bilateral phenomenon, although the presentation may be asymmetric.
The ocular allergic response involves a constellation of signs and symptoms, all of which may vary in intensity. Itching remains the hallmark symptom; tearing is also an exceedingly common complaint, particularly after rubbing the eyes in response to itching.1-7 More severe reactions may prompt complaints of ocular burning, foreign body sensation or photophobia, though these are relatively rare in acute disease.1
Clinical evaluation reveals variable conjunctival hyperemia and chemosis. Ocular discharge is watery, though mucous may accumulate in the fornices or collect on the lash margin in the form of “crusts,” especially during sleep. Eversion of the eyelids may reveal a fine papillary response, particularly along the upper tarsal plate. Externally, the eyelids may be red, swollen and edematous, with a pseudoptosis in pronounced cases. If questioned, the patient will often reveal a personal or family history of allergic disease.
Clinical signs of infection (e.g., fever, pharyngitis, palpable preauricular lymph nodes) are notably absent in allergic conjunctivitis. While patients with seasonal allergy may suffer from concurrent symptoms of rhinitis, post-nasal drip or sinus congestion, these should not be mistaken for evidence of viral or bacterial infection.3 Likewise, the eyes will display no mucopurulent discharge or follicular response. Microbial cultures or assays for viral proteins (e.g., AdenoPlus, Nicox) will be consistently negative.
The allergic response is classically considered to be an over-reaction of the body’s immune system to substances perceived as foreign (allergens), despite the fact that said substances are not inherently pathogenic.4 This response can be innate or acquired.
The key component of the ocular allergic response is the mast cell; these are widely distributed throughout the body, especially in connective tissue and mucosal surfaces, particularly the conjunctiva.1 Immunoglobulin (IgE and IgG) receptors, which are sensitized to specific allergens, are expressed on mast cell surfaces. When allergens are encountered at the cellular level, an antigen-antibody response ensues, in turn triggering mast cell degranulation; this process releases pre-formed proinflammatory mediators and spurs the secretion of chemokines and cytokines.4,8
The primary chemical mediator released during degranulation is histamine, which is responsible for increased vascular permeability, vasodilation, bronchial contraction and increased secretion of mucous.12 Heparin, chymase and tryptase are likewise released from mast cells, as well as several chemotactic factors.
Degranulation also stimulates the production of newly formed mediators through the activation of phospholipase-A2 on membrane phospholipids, releasing arachidonic acid and platelet-activating factor. Arachidonic acid is further degraded via the cyclooxygenase pathway to form, among other chemicals, prostaglandins and thromboxanes, and—via the lipoxygenase pathway—leukotrienes.8,10 These newly formed mediators drive the inflammatory reaction and incite recruitment and activation of additional inflammatory cells, leading to what has come to be known as the “late phase” of the allergic response.
The late-phase reaction typically commences approximately six hours following sustained mast cell degranulation.8,9 T-lymphocyte activation and infiltration of the conjunctival mucosa by eosinophils, basophils, neutrophils and macrophages are the hallmark of the late phase.9
Leukocytic infiltration is not necessarily inherent to all cases of acute allergic conjunctivitis (usually only in the more severe presentations); in fact, the late-phase response is much more characteristic of chronic allergic disorders like atopic and vernal keratoconjunctivitis, which constitute less than 2% of cases seen in clinical practice.1,5
The management of ocular allergic reactions is primarily aimed at reducing symptomology and quelling any significant inflammation while attempting to discover, remove and avoid the offending agent, although this may not always be possible or practical. Nonpharmaceutical measures such as artificial tear solutions and cold compresses are often used for mild cases of allergic conjunctivitis, or as adjunctive therapy to more traditional management.11,13,14 Artificial tear solutions provide a barrier function, serving to flush or dilute antigens from the ocular surface while soothing and lubricating the irritated ocular surface. While these are typically recommended to be used as needed, the clinician must be cognizant of the cumulative effect of preservatives in hypersensitive allergy patients; therefore, preservative-free artificial tears should be used whenever possible.15
Cold compresses and topical decongestants help to produce vasoconstriction, reducing hyperemia, chemosis and other symptoms by inhibiting the release of the inflammatory cells into the tissues from the vasculature. Numerous decongestant solutions (containing one of the following: naphazoline, antazoline, tetrahydrozaline, phenylephrine) are available as over-the-counter preparations, either alone or in combination with a mild topical antihistamine (e.g., pheniramine maleate or antazoline phosphate).
These agents tend to be the preferred treatment modality for those patients who self-medicate their allergy symptoms. Unfortunately, such OTC preparations have been associated with significant tachyphylaxis and “rebound hyperemia,” as well as chronic follicular conjunctivitis and eczematoid blepharoconjunctivitis when used chronically.16,17 The consensus of most experts today is that products containing topical decongestants are not recommended, particularly given the array of other available options.13,15
The pharmacologic options for managing ocular allergy are exceedingly diverse. In fact, there are nearly as many commercially available topical medications for allergic conjunctivitis today as there are for glaucoma. Overall, five distinct classes or categories of topical drugs are recognized: (1) antihistamines, (2) mast cell stabilizers, (3) antihistamine/mast cell stabilizer combinations, (4) corticosteroids and (5) non-steroidal anti-inflammatory drugs (NSAIDs).
These medications are available only by prescription in the United States, with the exception of Zaditor, which was granted over-the-counter status in October 2006. In the wake of that approval, ketotifen has been released commercially under a variety of other trade names, including Alaway (Bausch + Lomb), Refresh Eye Itch Relief (Allergan), Claritin Eye (Schering-Plough), Zyrtec Itchy Eye Drops (McNeil Consumer Healthcare) and TheraTears Allergy Eye Itch Relief (Akorn).
In general, all of these medications are beneficial to a degree by themselves and also in combination. Topical antihistamines provide prompt symptomatic relief, but their effects can be short-lived—on the order of just four to six hours. Mast cell stabilizers prevent mast cell degranulation and hence attempt to decapitate the allergic response, but they lack the capacity to alleviate acute itching rapidly. In addition, mast cell stabilizers may take several days to a week to achieve full efficacy, and are best used with a preloading strategy to be effective before the exposure takes place. Antihistamine/mast cell stabilizer combinations provide the benefits of both of these categories and are by far the most common choice among eye care practitioners today; these drugs also have the advantage of BID dosing, except for Pataday and Lastacaft, the only topical allergy medications currently approved for once-daily dosing.15
Topical corticosteroids may serve to quell inflammation and offer relief to those patients with more severe cases of acute allergic conjunctivitis. While there are well-known risks associated with long-term corticosteroid use (e.g., cataractogenesis, glaucoma), short-term therapy with topical steroids can be extremely effective. Studies have shown Alrex to have an excellent safety profile in the treatment of ocular allergy, even with therapy of up to four years’ duration.18 Topical NSAIDs are likely the least effective option for ocular allergy, and should be considered a treatment of last resort.13 While NSAIDs may provide mild symptomatic relief, they do not directly address mast cell degranulation or the histamine response, and inhibit only a portion of the inflammatory cascade (i.e., that involving the prostaglandin cascade, not leukotriene effects).
In recent years, there has been a good deal of discussion regarding the use of nasal allergy preparations and their potential for alleviating ocular allergy symptoms. The literature does demonstrate that nasal corticosteroid sprays can have a direct and beneficial impact on ocular allergy.19-24 Studies have consistently shown that medications like Flonase (fluticasone propionate 0.05mg, GlaxoSmithKline), Veramyst (fluticasone furoate 0.0275mg, GlaxoSmithKline) and Nasonex (mometasone furoate 0.05mg, Merck) help to ameliorate concurrent ocular symptoms when used to treat nasal rhinitis.19-24 However, it is important to understand that topical ocular agents still offer faster, safer and more complete relief of ocular symptoms than any other form of therapy, as demonstrated in head-to-head studies for ocular itching, redness, chemosis and eyelid swelling associated with allergic conjunctivitis.25-27
Oral antihistamines are rarely required for the treatment of acute allergic conjunctivitis, unless there is associated rhinitis, sinusitis, urticaria or other manifestations of systemic allergy. Some of the older, over-the-counter antihistamines such diphenhydramine hydrochloride and chlorpheniramine maleate are effective, but can induce drowsiness and functional impairment.28 Loratadine, desloratadine, fexofenadine, cetirizine and levocetirizine are second-generation antihistamines; the sedative effect of these drugs is greatly diminished, though it is not entirely eliminated.29 In addition, all of these oral medications have the capacity for anticholinergic effects, causing dryness of the mucosal membranes of the mouth, nose and eyes.30
• When evaluating patients with presumed allergic conjunctivitis, pay special attention to the inferior fornix and medial canthus. In many cases, the caruncle and plica semiluminaris may demonstrate marked hyperemia or inflammation. This is presumably because of the accumulation of histamine-laden tears in the area of the lacrimal puncta. Also, eyelid eversion is recommended to evaluate the status of the superior tarsus to diagnostically assess the fine papillary response.
• In differentiating allergic conjunctivitis from other forms of ocular surface disease, an extremely helpful question may be, “What happens when you rub your eyes?” Most itchy surface disorders such as dry eye and blepharitis generally improve with digital manipulation, because it stimulates the flow of additional tears. However, rubbing in allergy can cause further degranulation of mast cells, releasing more histamine and other chemokines into the ocular tissues and resulting in greater symptomology.31 Hence, patients with true allergies almost always say that their symptoms worsen when they rub their eyes.
• Seasonal allergic conjunctivitis usually occurs around the same time each year, and may last for only a few weeks or months. Therefore, patients who present for their annual examination during other times of the year may go undiagnosed. It is important to ask not only whether the patient is experiencing symptoms at the time of the exam, but also if they ever suffer from red, itchy, watery eyes. The safety and efficacy of today’s medications allow for proactive prescribing, weeks to months before symptoms arise.
• Despite marketing efforts to the contrary, most allergy experts agree that topical ophthalmic medications are the best means to manage the symptoms of ocular allergy; nasal sprays are best for nasal symptoms, and oral antihistamines should be used as an adjunct to these therapies when necessary.
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