Ocular allergy

THE JOURNAL

OF

ALLERGY AND

CLINICAL

IMMUNOLOGY NUMBER 5

VOLUME 76

Continuing

Medical

Education

This continuing medical education self-assessment is sponsored by The American Academy of Allergy Immunology.

program and

Ocular allergy Mitchell

H. Friedlaender,

M.D. San Fruncisco, Calif.

It should come as no surprise to the allergist that the eye is a frequent target of allergic reactions. In fact, ocular allergy is one of the most frequent clinical problems encountered by the allergist and ophthalmologist alike. The vast majority of ocular allergy affects the conjunctiva, the mucous membraneof the eye. Therefore, we usually speak of ocular allergy and allergic conjunctivitis synonymously. There are, however, several types of allergic conjunctivitis. The largest group is associatedwith environmental allergens and is the ocular component of allergic rhinoconjunctivitis. A smaller group is associated with atopic dermatitis, and is usually referred to as uropic kerutoconjunctivitis. An unusual syndrome,occurring mainly in children and having impressiveallergic features, is vernal keruroconjunctivitis. The popularity of contact lenses has spawned another category of ocular allergy, known as GPC. The exact etiology of this condition is of considerable interest to ophthalmologists, their patients, and contact lens manufacturers. Ophthalmologiststend to be “treaters” of disease,and when patients complain, eyedropsare generally prescribed. This tendency has led to a variety Supported by National Institutes of Health Research Grant EY 02502. Reprint requests: M. H. Friedlaender, M.D., S-315 Francis 1. Proctor Foundation, University of California, San Francisco, CA 94143.

XIGPC: GiantpaprllaryconJunctlvltls of contact allergic reactions causedby a wide variety of medications and their preservatives. The importance of ocular allergy is due more to its frequency than to its severity. From the ophthalmologist’s perspective, ocular allergy is rarely a blinding disease, although some cases of atopic and vernal keratoconjunctivitis have produced severe cornea1 scarring and loss of vision. From the allergist’s point of view, the red, itchy eyes of allergic conjunctivitis are quite common and often do not require evaluation by an ophthalmologist. From the patient’s point of view, the symptomsof ocular allergy are usually mild but moderately annoying. When the condition is seasonal, patients usually learn to live with their symptoms. Others may experience year-round symptoms, and occasionally, the ocular features are the most prominent part of the allergic patient’s disease.This is often true in patients with vernal keratoconjunctivitis and atopic keratoconjunctivitis. Contact lens patients present a challenging and emotional problem to the treatmentof ocular allergic disease. Such patients are often very determined to wear their lenses under almost any circumstance. Their reasonsare often psychologic and related to the 645

646

Friedlaender

FIG. 1. Structure

of the eye.

and heavily populated wrth mast ceila;. ‘The corne:;~ itself, which forms a transparent “watch crystal’ L~~PI the pigmented iris, is not covered by c~~~~.~u~~ct~~~ ;md is avascular under normal circumstances. Tears are produced in the lacrimal @rd. locueed in the orbit just above the lateral aspect oj’ the e:yir. Sometimes the iacrimai gland tissue can bc observed in the upper con.junctivai fomix. beneath the upper lids. IIl~munoglobulin-producing plasma cells hav< been identified in the lacrimal gland. and cievated levels of IgE are found in the allergic patient in ihc gland and in the tears. The pigmented tissue of the eye. :biso called thr uveul ttwt, is highly vascular and contains large numbers of mast cells. In fact. the choroid has one of rhe highest densities of mast cells of ani’ tissue HI the body. Even in pathologic conditions, these mast ~~11s do not appear to degranulate. and it ;\ mre that WC consider

cosmetic and convenience aspect of contact lenses. It may be difficult to wean these patients away from contact lenses, even in the face of sight-threatening complications. As in other medical specialties, ove~edication is a sjgnificant problem in ophth~mology. The indiscriminate use of antibiotics, antivirals, and anti-inflammatory agents has led to a high incidence of contact allergic reactions in routine ophthalmic practice. It is often difficult to pinpoint the allergen in patients using a variety of medications or solutions and also difficult to separate the toxic from the allergic components. The use of thimerosal as a preservative in eye drops and contact lens solutions has been partially responsible for the high incidence of contact allergy in patients with and without previous ocular inflammation. STRUCTURE (FIG. 1)

AND FUNCTION

OF THE EYE

The eye is surrounded by the bony orbit of the skull and is protected from environmental insults by the eyelids. The inner aspect of the eyelids and the front part of the globe is lined by a mucous membrane, the conjunctiva. The conjunctiva is highly vascular and contains mucous-producing goblet cells in its epithelium. Beneath the epi~elium, the stroma is composed of blood vessels and loose connective tissue. Mast ceils are found throughout the conjunctival stroma, often associated with small blood vessels, and are believed to participate in the ocular allergic reaction, The conjunctiva is loosely adherent to the globe but strongly adherent to the ~~~~~~, the junction of the cornea and sdera. The limbal area is highly vascular

uveitis

to be “allergic”

in the usual

~nsc

of the word

The ocular immune

response

The eye resists foreign substances through a variety of specific and nonspecific defense mechanisms. Like other parts of the body. the eye is constantly exposed to a flood of microorganisms but is capable of warding off most of these with little or no alteration of its structure or function. Much of the natural resistance of the eye depends on the anatomic and physiologic properties of its external structures--the lids, tears. conjunctiva . and cornea. Lids The lids have the obvious function of protecting the eye from trauma and foreign material through the blink mechanism. The action of the cilia also sweep away small particles. The lids keep the eye lubricated with tears and help to sweep foreign substances from the eye and into the tear drainage. The skin of the eyelids has the same properties as skin elsewhere. The loose a~angement of connective tissue in the eyelids promotes impressive lid edema in response to immediate or delayed allergic reactions. The lids possess a number of glands, the secretions of which bring to the tear film a number of antimicrobial substances such as lysozyme. lactofetrin, and immu~ogIobu~in. AU the major immunoglobulin classes except fgD have been detected in human tears. 1gA is the major immunoglobulin in tears, and as in other external secretions, it is the I Is dimeric variety containing secretory piece that predominates.’ IgG is usually present in small amounts, whereas igM is only rarely found<’ IgE is detectable by radioimmunoassay, ’ and this im-

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Ocular allergy

647

munoglobulin may be increased in patients suffering from allergic disorders of the external eye.4 Tear immunoglobulins appear to be produced by plasma cells within the lacrimal gland, whereas secretory component is produced by the acinar epithelial cells of the gland.’ Complement is also found in human tears, although its relationship to specific ocular disease is still unknown. Conjunctiva Normal structure and function. The normal conjunctiva forms a natural barrier to invasion by exogenous substances. Inflammatory cells present from the time of birth have been studied in several animal species.6 The quantity of leukocytes appears to increase with age and antigenic exposure. The normal human conjunctiva contains an extraordinary number of infiltrative, inflammatory cells, among which lymphocytes, plasma cells, and neutrophils are found.’ No doubt, many of the inflammatory cells normally present in the conjunctiva are engaged in phagocytosis and in processing antigen for its elimination and for the individual’s immunologic memory. The epithelial cells of the conjunctiva may also participate in phagocytosis.’ The normal palpebral conjunctiva varies a great deal in its surface morphology from a satin-smooth appearance to a uniform or nonuniform papillary appearance.’ Papillae represent collections of nonspecific inflammatory cells and tissue elements that are bound closely to the tarsal plate or the limbus. Follicles may also be observed in the normal conjunctiva, especially in the lower fomix. These are not related to disease and are especially common in childhood. Conjunctival follicles represent tightly packed collections of lymphocytes in various stages of development. Lymphocyte aggregates containing mature and immature lymphocytes are found just below the epithelium in the conjunctiva of adult rabbits after 10 weeks of age.” The conjunctiva is endowed with several other nonspecific protective mechanisms. Constant epithelial turnover and a cool temperature caused by tear evaporation may serve a protective function. In addition, certain unknown factors make the conjunctiva usually resistant to certain viruses (such as those that cause the common cold) but highly susceptible to the gonococcus and the agent of inclusion conjunctivitis. In contrast, the nasal mucosa is highly susceptible to cold viruses and yet resistant to the gonococcus. The prominent vascularity of the conjunctiva and the frequently observed dilation of its vessels suggest that the exchange of substances across the vessel walls is a fun-

FIG. 2. Small to moderate size papillae tarsal conjunctiva in an atopic patient.

(bumps) on upper

damental response of the conjunctiva to noxious substances. Pathologic responses. The conjunctiva can undergo a variety of morphologic changes in response to microorganisms, toxins, and various antigens. The type of response depends largely on the nature of the stimulus. Hyperemia occurs in response to physical stimuli such as wind, sun, smoke, allergens, toxins, and infectious agents. A brilliant red appearance suggests a bacterial conjunctivitis, whereas a “milky” appearance suggests allergic conjunctivitis. The latter appearance is caused by an obscuration of blood vessels by conjunctival edema. Tearing often accompanies hyperemia and may be increased by transudation across blood vessel walls. Exudation is observed in all types of acute conjunctivitis. A purulent exudate is characteristic of bacterial conjunctivitis, whereas a stringy exudate is more often observed in allergic conjunctivitis. Drooping of the upper eyelid (pseudoptosis) may be due to increased weight of the lid from cellular infiltration and edema. Chemosis, or edema of the conjunctiva, is often associated with an acute allergic response as well as several other types of conjunctivitis. Papillary hypertrophy occurs when inflammatory cells accumulate within the conjunctiva, causing it to heap up in mounds that are bound to the tarsal plate by strong connective tissue fibrils. A tuft of vessels forms in the substance of the papilla and branches over it like the spokes of an umbrella. When the papillae are small, the conjunctiva frequently has a smooth, velvety appearance as in bacterial conjunctivitis. In allergic conditions, such as vernal and atopic keratoconjunctivitis (Fig. 2), the papillae of the upper tarsus may be larger, flattopped, polygonal, and milky in appearance. These papillae may also form at the limbus where they appear as gelatinous excrescences.

648

Friedlaender

FIG. 3. Follicular fection.

conjunctivitis

caused

by chlamydial

in-

Follicles are characteristic of viral and chlamydial infections (Fig. 3) and also of toxic conjunctivitis caused by application of certain topical medications. When follicles are located on the upper palpebral conjunctiva or at the limbus, they are strongly suggestive of chlamydial disease. Those follicles located in the lower fomix or at the lateral margin of the upper tarsus are of limited diagnostic value. The follicle is rounded, whitish-gray in color, and avascular, although small blood vessels may encircle it. Conjunctival scrapings are often helpful in determining the etiology of an inflammatory response.” A predominantly neutrophilic reaction is characteristic of fungal infections and all but two bacterial infections (Branhamella catarrhalis and Moraxella). Several diseases of unknown etiology also produce a neutrophi1 response, including erythema multiforme and Reiter’s syndrome. Eosinophils are characteristic features of allergic inflammation. Mast cells may also be observed, especially in vernal keratoconjunctivitis. Mononuclear cells predominate in conjunctival scrapings from patients with viral conjunctivitis, whereas neutrophils are observed in response to chlamydial infections. Humoral immune responses. All five immunoglobulins are routinely found in the human conjunctiva.” Most are present in the subepithelial tissue, and almost none are found in the epithelium. Immunoglobulinproducing plasma cells are not routinely identified in the perilimbal conjunctiva with the use of immunofluorescent techniques. ” Immediate hypersensitivity reactions have been studied in the guinea pig conjunctiva after systemic sensitization with normal rabbit serum. l4 Topical conjunctival challenge produces edema, hyperemia, and infiltration by a large number of eosinophils and neutrophils. Both IgE and IgG homocytotropic antibody can be demonstrated in serum, and when these are passively transferred to nor-

FIG. 4. Severe epithelial keratitis tetracaine anesthetic eyedrops,

caused by chronrc use u+

ma1 guinea pigs, conjunctival hypersensittvity can hi: demonstrated by topical challenge. I4 Antihistamines, disodium cromoglycate, and steroids do not modify the clinical signs. but they do inhibit the neutrophii and eosinophil response. I5 Immediate hypersensitivity reactions can be elicited in the guinea pig conjunctiva after intravitreal, intradermal, or even topical sensttization with protein antigens.” A model of type i hypersensitivity has been developed by’ injecting ;I:% caris suum or ‘Toxocara canis into the vitreous of the guinea pig eye. A brisk IgE antibody response occurs in the aqueous humor.” When pollens arc instilled into the conjunctival sac of inbred atopic dogs. conjunctival injection and edema appear within 5 minutes. * Cellular immune responses. Delayed hypersenrr.tivity reactions can be elicited in the guinea pig conjunctiva by use of simple chemicals such as oxazo-, lone. Ix The conjunctival response contains predominantly mononuclear cells. but a large number of eosinophils can also be observed. A reaction that 1s widely believed to represent delayed hypersensitivity in the conjunctiva is the phlyctenule, a transient. nod,ular lesion observed in response to a variety of ml-crobial agents. Both B- and T-lymphocytes have been identified in the human conjunctiva and lacrimal gland in patients with phlyctenular keratoconjunctivitis and Sjogren’s syndrome.” B cells are generally found in higher numbers but are more concentrated in the central follicles, whereas ‘T cells are found mainly in peripheral follicles and scattered throughout the tissue. Cornea Normal structure andjiunction. The cornea has long been a favorite site for immunologic study because of *Friedlaender MH, Frick OL: Unpublished observations

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FIG. 5. Trantas’ dots (small white dots) at limbus in patient with vernal keratoconjunctivitis.

its transparency and its lack of blood vessels. Lymphatic drainage is also lacking except when new blood vessels grow into the central cornea. The cornea is considered a “privileged site,” and cornea1 transplants survive with little or no anti-inflammatory therapy in animals and in man. Antigens and other substances that enter the cornea from the bloodstream must enter from the limbus and diffuse into the cornea. This appears to prevent large molecules such as IgM from entering the central cornea.” Cellular elements can enter the cornea through limbal blood vessels, and many types of cornea1 inflammation are accompanied by a great outpouring of cells from these vessels.2o Mast cells are found at the limbus in most animal species20in association with the limbal blood vessels. The function of these cells is not known, although it has been suggested that they may regulate the tone or other functions of the limbal vessels. Pathologic responses EPITHELIAL KERATITIS.Epithelial keratitis may accompany a wide variety of insults to the external eye including allergy, infection, drugs, other chemicals, and ultraviolet light. The distribution of the keratitis and the presence of other ocular findings may provide a clue to its etiology. Drug toxicity or drug allergy are among the most common causes of epithelial keratitis ( Fig. 4). In vernal keratoconjunctivitis a central epithelial keratitis may be an early sign of cornea1 complications from this allergic condition. Epithelial keratitis may also accompany contact sensitivity to a wide variety of ocular medications, including neomycin, idoxuridine, atropine, and its derivatives, thimerosal, and certain topical anesthetics. TRANTAS DOTS. Trantas’ dots are white, chalky deposits found at the limbus (Fig. 5) and are observed in patients with atopic and vernal conjunctivitis. They are composed of large numbers of eosinophils and are

Ocular allergy

FIG. 6. Marginal infiltrates sociated with staphylococcal

FIG. 7. Wessely in the cornea.

in the peripheral blepharitis.

ring caused by antigen-antibody

cornea

649

as-

reaction

transient. Their presence usually correlates with the activity of the allergic disease. MARGINAL INFILTRATES.Marginal or catarrhal corneal infiltrates form near the limbus (Fig. 6) and are usually associated with bacterial infections, particularly those caused by staphylococci. A clear interval is present between the infiltrate and the adjacent limbal tissues. The lesions last 4 to 14 days and heal without treatment. They are most commonly observed at the 10, 2, 4, and 8 o’clock positions, possibly because of contact between the cornea and the Staphylococcusinfected lids. They are usually considered to be the result of an antibody-mediated reaction to bacterial antigens or exotoxins, the most frequent being those of Staphylococcus aureus. The characteristic location and appearance of the catarrhal infiltrates probably depend on the optimal concentration of antigen and antibody being present 1 or 2 mm inside the limbal blood vessels. WESSELYRINGS.These ring-shaped infiltrates (Fig. 7) form in the cornea1 stroma and are concentric with the limbus.2’ They develop after intracomeal injection

.I, ALLERtit

650 Friedlaender

FIG. 8. Phlyctenule at the limbus.

of antigens, after infectious cornea1 ulcers, after endotoxin injection, and after bee stings of the cornea. These comeal rings are considered to be due to an antigen-antibody interaction in the cornea, presumably resulting from outwardly diffusing antigen meeting and reacting with antibody diffusing inward from the limbus. This may be viewed as similar to the Ouchterlony gel diffusion test for antigen-antibody interaction with the cornea acting as a gel. PHLYCTENULES.Phlyctenules are small, nodular lesions that occur for the first time at the limbus (Fig. 8) but may subsequently occur on the conjunctiva or cornea. Toward the end of their lo- to 14-day course, they typically ulcerate and leave a triangular scar. They are most commonly associated with staphylococcal infections or tuberculosis, but they can also be observed after infections with Candida albicans, Coccidioides immitis, and certain nematodes.” Phlyctenules are believed to be due to a delayed hypersensitivity mechanism, and indeed it has been demonstrated that phlyctenules can be produced experimentally by topical challenge in animals made hypersensitive to tuberculin” and Staphylococcus.“‘! Other pathologic responses of the cornea Cellular infiltration of the cornea1 stroma leads to a gray or white appearance of the cornea. This is usually due to a combination of cellular infiltration and edema. Some infectious agents, especially adenovirus, are accompanied by small, multifocal infiltrates containing viral antigen and inflammatory cells. These generally disappear with topical corticosteroid therapy, at least temporarily. The ingrowth of blood vessels into the cornea1 stroma is observed in a wide variety of conditions, and the pathogenesis of this process has been the subject of intensive study. Necrosis of cornea1 cells is usually a potent stimulus for cornea1 vascularization. Recent interest has centered on the relationship between inflammatory cells, particularly neutrophils, and cornea1 vascularization.25. I6

iCLiN. IMMUNOL, WIVEMBER ‘985

A heat labile fraction isolated from nemrophils ha>, been implicated as a possible vasculogenic factor.” HUMORALIMMUNERESPONSES.ExceptforIgM, all immunoglobulins and albumin can routinely be dem onstrated in the cornea by direct immunofluorc~cence.” Most of the immunoglobulin is concentrated in the stroma. Large molecules, including IgM, maq sometimes be found in the corneas of older individuals, presumably caused by an increased permeabilit> of the limbal blood vessels with increasing age. ii “ir one time it was believed that the cornea could nc11 support a typical Arthus reaction. since this phenon;enon requires blood vessels damaged by antigen-ail” tibody complexes and inflammatory iomponenits. More recently, several investigators ha; i: dcmor:strated that in fact the cornea can suppc)n aotrgzr!antibody reactions and that damage can result tt: ~JOI-neal collagen fibrils even in the absence of corncal vascularization.‘” When protein antigens arc injected into the rabbit cornea, a biphasic reaction occurs. ’ The early phase (3 to 5 days) in which crmcal i.iouding occurs is believed to be a manifestation of delayed hypersensitivity. A later stage t7 to 14 days) ih ckrxacterized by the Wessely phenomenon and IS acc’ompanied by the precipitation of immune complexes ~1 the cornea. CELLIXAK IMMUNE RESPONSES. After irljection of a protein antigen into the guinea pig cornea, a cellular reaction occurs around the limbal blood vessels and in the peripheral cornea. A mononuclear response prcdominates: however. basophils, eosinophils, and II~LI trophils are also observed.“’ Such reactions bear a similarity to cutaneous basophil hypersensitivity m the skin. Classic delayed hypersensitivity reactions, characterized by a massive infiltration ot mononuclear cells. is observed when mycobacterial adjuvants are used during sensitization TYPES OF ALLERGIC CONJUNCTIVITIS Allergic forms of conjunctivitis are very common in ophthalmic practice. Although many cases are seasonal, a large number of patients have year-round symptoms. Furthermore, allergic conjunctivitis related to topical medications, solutions. and contact lenses are being observed with increasing frequency. Although vernal keratoconjunctivitis and atopic keratoconjunctivitis make up a small percentage of a!lergic conjunctivitis patients, these two forms arc the most debilitating and the most difficult ones to treat. Allergic

rhinoconjunctivitis

The conjunctiva. like the nasal mucosa, can be atfected in allergies to airborne pollens, animal dander, and other environmental antigens. The most important

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Ocular allergy 651

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allergens vary from one location to another, but the symptoms and signs appear to be similar throughout the world. Very often, symptoms are not severe enough to precipitate a visit to the allergist or the ophthalmologist. For patients who seek help, some may not require treatment, and others may simply avoid certain allergens. Ocular features. Symptoms usually consist of lowgrade ocular and periocular itching, tearing, burning, stinging, photophobia, redness, and watery discharge. Redness and itching appear to be the most consistent symptoms. Although symptoms persist throughout the allergy season, they are subject to exacerbations and remissions depending on the weather and the patient’s activities. Symptoms are generally worse when the weather is warm and dry. Cooler temperatures and rain tend to alleviate symptoms. Although itching is generally mild, it can occasionally be very severe and patients may rarely be incapacitated by their symptoms. The conjunctiva usually demonstrates mild or moderate edema and injection (Fig. 9). The combination of these two features causes a pinkish or milky appearance of the conjunctiva. Because the conjunctival blood vessels are partially obscured, they are best evaluated with a slit lamp microscope. Occasionally, chemosis is so marked that it is obvious without magnification. If edema is severe, patients will also demonstrate periorbital edema. This is more prominent around the lower lids because of gravity. Ecchymoses, or the “allergic shiner,” has also been described in allergic patients and is believed to be the result of impaired venous return from the skin and subcutaneous tissues.3’ A proper diagnosis can generally be made by taking a careful history. More often than one would guess, patients are not aware that they are allergic until symptoms develop during a severe allergy season. Scratch or prick tests are helpful in establishing a definite diagnosis. lnstillation of an offending pollen into the conjunctival sac will also reproduce the typical symptoms of hay fever conjunctivitis.32 However, this type of conjunctival testing is rarely necessary. Scraping the conjunctival surface to detect eosinophils is a very helpful diagnostic test. The procedure is done by placing a drop of topical anesthetic, such as tetracaine hydrochloride, 0.5%, in the lower conjunctival sac. The anesthetic takes effect within 10 seconds. With the use of a platinum spatula, the inner surface of the lower lid is gently scraped several times. The material is then spread on a microscope slide. The slide is stained with Giemsa or one of the other common reagents. Slides are examined for the presence of eosinophils or eosinophil granules. Eosino-

FIG. 9. Allergic

conjunctivitis

caused by animal

dander.

phils are not found ordinarily in conjunctival scrapings from nonallergic individuals. The presence of even one eosinophil or eosinophil granule is considerable evidence in favor of a diagnosis of allergic conjunctivitis.33 The absence of eosinophils should not rule out a diagnosis of allergy. Eosinophils are often present in the deeper layers of the conjunctiva and may be absent or undetectable in the upper layers. The frequency of eosinophils in the conjunctival scrapings from patients with allergic conjunctivitis may vary from 20% to 80% depending on the patient population, the chronicity of the allergic condition, and the persistence of the examiner.33s34 Treatment. Antihistamines may be administered systemically to relieve allergic symptoms. They may only partially relieve ocular symptoms, and patients often complain of side effects such as drowsiness and dryness of the eyes, nose, and mouth. Antihistamines such as antazoline and pheniramine are available as eyedrops and are usually combined with a topical vasoconstrictor such as naphazoline hydrochloride. These antihistamine/vasoconstrictor eyedrops are useful in treating mild allergic conjunctivitis. Most are used four times a day, and the side effects are minimal. They whiten the eyes by constricting the conjunctival blood vessels. They also relieve itching in most patients.35 Disodium cromoglycate (Opticrom, 4%; Fisons Corp., Bedford, Mass.) has recently become available as an eyedrop preparation in the United States. This drug, which stabilizes mast cells, has been a useful addition to the other drugs available for treating allergic conjunctivitis. Several studies have indicated the therapeutic value of cromolyn in allergic conjunctivitis.36. 37 Usually, 10 to 14 days of treatment are necessary before optimal relief is obtained. Occasionally, patients notice improvement within 24 to 48 hours. Cromolyn is most useful for relief of mild and moderate symptoms of allergic conjunctivitis. More

652

J ALLERGY

Friedlaender

FIG. 10. Staphylococcal

blepharitis

in an atopic

patient.

severe cases may require the addition of topical corticosteroids. Unlike corticosteroids, cromolyn has minimal ocular side effects. An acute chemotic reaction to cromolyn has been reported in two patients,‘*. w but like the side effects in the treatment of asthma,4” cromolyn side effects are rare. An extra benefit of cromolyn eye drops is the relief of nasal symptoms caused by the drainage of tear fluid into the nasal passages. Corticosteroids may be extremely effective in relieving symptoms of allergic rhinitis, but since the disease is a chronic, recurrent, benign condition, these drugs should be used only in extreme situations. Topical steroids are associated with glaucoma, cataract formation, and infections of the cornea and conjunctiva.” Therefore, they should be used with the greatest caution, and preferably, the patient should be monitored by an ophthalmologist. Under no circumstances should patients be allowed to use corticosteroid eyedrops without medical supervision, nor should they be given prescriptions for unlimited refills. Atopic

keratoconjunctivitis

The skin of the eyelids can be affected in atopic dermatitis just as the skin elsewhere can be affected. There are some unique ocular features of atopic dermatitis that make this condition interesting and challenging from the ophthalmologist’s point of view. Ocular features. Erythematous and exudative lesions may be found on the eyelid skin. In later stages crusting and scaling can occur. Secondary staphylococcal blepharitis requiring treatment may also develop (Fig. 10). In fact, Staphylococcus aureus can be cultured from the eyelids of a high percentage of atopic patients.42 The conjunctiva may demonstrate hyperemia, chemosis, and filamentous discharge. Less commonly, giant papillary hypertrophy may be observed on the palpebral conjunctiva. Trantas’ dots can sometimes be observed at the limbus, especially

FIG. 11. Keratoconus

CLIN. iMMUNCJ1.. YOVEMBER 1985

in an atopic patient

superiorly. Atopic keratoconjunctivitis may persist for many years, and occasionally, the ocular component of this disease may be the predominant feature These severe cases demonstrate tremendous photophobla. redness, and tearing. Many have difficulty opening their eyes outdoors and are constantly bothered by ocular irritation, itching, and discharge. In iong standing disease there may be significant conjunctivai scarring. This can be manifested as stellate scars, most visible on the upper palpebral conjunctiva. Rarely. shrinkage of the fomices can occur. Punctate staining of the cornea can be demonstrated by putting a drop of fluorescein in the eye, and it the disease is severe, scarring and vascularization of the cornea may occur. Keratoconus (Fig. 11) is an unusual cone-shaped ectasia of the cornea that !s sometimes associated with atopic dermatitis. In one series, ” 16% of keratoconus patients had atopic dermatitis, and an additional 16% had other forms of cutaneous inflammation. It has been suggested, aithough it has not been proved, that local irritation of the eyelids caused by eczema or hay fever may lead to excessive eye rubbing. This. coupled with a congenitally thinned and weakened cornea, may lead to the development of keratoconus, Atopic cataracts have been described as a compli-cation of atopic dermatitis.“” The incidence has bt-n estimated at 8% to 10%. They are observed mainly in the severe chronic forms of the disease. especially in children and young adults. Atopic cataracts usually appear at least 10 years after the onset of skin involvement. Once a cataract is detected. however, it may evolve rapidly into complete opacification withm 6 months. These cataracts are frequently bilateral, and involvement may be symmetric. Occasionally, a unilateral cataract is observed. Classically, atopic cararacts have a shieldlike opacification affecting the anterior cortex (Fig. 12). Frequently, the cataract begins

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Ocular allergy

FIG. 12. Atopic

cataract.

as a posterior subcapsular opacity. Since this form of cataract is identical to the one induced by corticosteroids, it may be impossible to determine if the cataract was caused by the treatment or the disease. Spontaneous retinal detachment is believed to be more common in patients with atopic dermatitis than in the general population.45, 46This would appear to be a rare complication of ocular allergic disease. Treatment. Topical corticosteroids may be used for short periods of time; however, their long-term usage should be avoided. Some success has been obtained with 4% cromolyn eyedrops. Often, supplemental topical steroids must be used, especially during periods of heightened disease activity. If an inciting antigen can be identified, it should be eliminated. The eyelid lesions should be treated like atopic skin lesions elsewhere on the body. Surgery for atopic cataracts should not be undertaken lightly since complications, including hemorrhage, retinal detachment, iridocyclitis, and cornea1 edema can occur. Keratoconus can be treated successfully with contact lenses or, in advanced cases, by cornea1 transplantation. Vernal keratoconjunctivitis Vernal keratoconjunctivitis is a bilateral and often severe disease, occurring mainly in children and associated with climatic factors. It is characterized by a stringy mutinous discharge and giant papillae of the upper palpebral conjunctiva (Fig. 13). Many features of vernal keratoconjunctivitis suggest an allergic etiology. Patients with vernal keratoconjunctivitis frequently have a history of atopic disease such as hay fever, atopic eczema, or asthma.47 Sometimes, a history of atopy can be elicited only in a member of the patient’s family. Increased levels of IgE can be detected in the tears of patients with vema1,48.49 and even when the

FIG. 13. Vernal

keratoconjunctivitis

653

with giant papillae.

mean level of IgE in tears is not significantly greater than in control subjects, the serum levels are significantly elevated.48 In patients with vernal keratoconjunctivitis, it has been demonstrated that IgA, IgD, and IgE are synthesized locally by conjunctival plasma cells in a ratio of approximately 4: 1 : 2, respectively. Histologically, the conjunctiva contains many eosinophils, plasma cells, and fixed tissue mast cells. Eosinophils and mast cells can also be demonstrated by scraping the conjunctiva with a platinum spatula. Additional histologic features have recently been described, including the presence of basophils, microvascular alterations of endothelial cells, and deposition of fibrin.5” Other histologic features of vernal keratoconjunctivitis include infiltration by lymphocytes and neutrophils and epithelial invasion by mast cells and eosinophils. Ocular features. Vernal keratoconjunctivitis begins in the prepuberty years and is more common in male than female subjects. After the age of 20 years, the incidence in the two sexes is about the same. The peak incidence is between the ages of 11 and 13 years, and the disease is rare after the age of 30 years, Vernal keratoconjunctivitis is more common in warm climates than in temperate zones and is rarely observed in cold climates. Because of its geographic pattern, heat and other physical factors have been believed to contribute to the pathogenesis of the disease. Patients complain of extreme itching and a ropy, mucous discharge. The hallmark of vernal keratoconjunctivitis is the presence of giant papillae on the palpebral conjunctiva. These papillae are polygonal and flattopped and contain tufts of capillaries. The conjunctiva has a milky appearance, and many fine papillae may be present on the lower palpebral conjunctiva. A pseudomembrane may be present in severe cases (Maxwell-Lyon sign). Cornea1 findings include superficial cornea1 ulcers

664

.!. ALLERGY

Friedlaender

FIG. 14. Cornea1 plaque

in vernal

keratoconjunctivitis.

and plaquelike deposits in the anterior cornea (Fig. 14). These findings contain mucous and many compacted layers of epithelial cells. Trantas’ dots may be found at the limbus, especially during heightened disease activity. Other cornea1 complications include diffuse epithelial keratitis and an arcuslike deposit that may be adjacent to limbal papillae. The limbal form of vernal keratoconjunctivitis (Fig. 15) is characterized by several gelatinous swellings at the limbus. This may be associated with a variable amount of giant papillae on the upper tarsal conjunctiva. This form of vernal keratoconjunctivitis is more common among races with dark skin. Treatment. Vernal keratoconjunctivitis is a self-limited disease that runs a 5- to IO-year course. Treatment should be conservative and aimed at relieving symptoms without producing serious iatrogenic side effects. Topical and systemic corticosteroids are frequently used in treating this condition. Although they decrease symptoms, they do not significantly affect the cornea1 complications or shorten the duration of the disease. Corticosteroids may also be associated with serious side effects. A short course of topical steroids is useful in breaking the inflammatory cycle. Their use should be supplemented with vasoconstrictors, cold compresses, ice packs, and climatotherapy. Having the patient move to a cool, moist climate or sleep in a cool or air-conditioned room may produce marked relief of symptoms in many cases. Recently, cromolyn eye drops have been used topically in a 1% to 4% solution with good results.“~52 This drug reduces itching, hyperemia, and mucous discharge. The giant papillae may remain large for months or years despite therapy. Yet symptoms are markedly improved. Often, supplemental topical corticosteroids are required for satisfactory relief of symptoms. Hyposensitization therapy with grass pollens and

FIG. 15. Limbal vernal ings at the limbus.

with arcuslike

depost

!:L!N. IMMUNC)L. WVEMBER 19BS

Note WS:

other antigens may be helpful in some mcidence~ but in general has not been rewarding. The cornea1 plaques are usually resistant to medtcal therapy, and usually, they must be surgically w moved.“3 These plaques may be associated with some scarring and may lead to a permanent reduction in the patient’s vision. GPC A condition similar in appearance to vernal keratoconjunctivitis is observed in contact lens wearers and has become known as GPC.“’ This condition (Fig. 16) is observed mostly in individuals who wear soti contact lenses, but it has been observed in hard contact lens wearers and in people who wear ocular prostheses after an eye has been enucleated.” In most cases the papillae are not really giant, and the upper tarsal conjunctiva has a red, fine papillary response. Trantas’ dots have been reported? however, these are rare in GPC. The etiology of GPC is unclear. There may be some predisposition among allergic patients; however, this is difficult to prove. The offending antigen could be the contact lens polymer, deposits on the surface of the lens, or chemicals in the contact lens solutions. Treatment. It is easy to treat GPC by stopping con tact lens wear. Many patients will not accept this aitemative and are tenaciously attached to their contact lenses. It may be possible to continue contact lens wear if the patient’s wearing time is reduced. but usually symptoms persist. Prescribing a new contact lens is often very helpful but only temporarily. Some success has been obtained by switching to a different contact lens material, such as silicone. Improvement has also been reported with cromolyn eye drops.“’ Many contact lens cleaning and wetting solutions contain thimerosal, and this has been implicated in contact

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Ocular allergy

FIG. 16. GPC associated

with contact

lens wear.

lens intolerance. It may be helpful to use a nonthimerosal cleaner, and unpreserved saline can be used if patients are cautious about their hygiene. Symptoms of GPC include redness, burning, itching, pain, and discharge. Patients with such symptoms find it difficult to wear their contact lenses more than a few hours at a time. This produces considerable visual and emotional problems for many people, and a great deal of time and effort can be expended in trying to eliminate the signs and symptoms of this condition. Contact

allergy

The eye is a frequent site of involvement in contact dermatitis.58 Ocular preparations containing neomycin sulfate, atropine and its derivatives, and thimerosal are effective sensitizers. A typical victim of “conjunctivitis medicamentosa” is the patient who is treated for a “red eye.” Eyedrops are prescribed, and symptoms begin to improve. The medication is continued for one reason or another, and the eye starts to become redder. More eyedrops, or sometimes a different eyedrop, is used, and a vicious cycle of inflammation is begun. It becomes difficult to tell whether the conjunctivitis is related to the original disease or the medication. Usually, the best treatment is to stop all eyedrops, observe the patient in a few days, and perform cultures and conjunctival scrapings. The skin of the eyelids may be red, edematous, and ulcerated (Fig. 17). Conjunctivitis characterized by a papillary response, pronounced vasodilatation, chemosis, and watery discharge may be present. In severe cases a keratitis can develop and is typified by small to large epithelial defects and cornea1 opacities. Some of the most severe responses are associated with topical anesthetics (Fig. 4). Some long standing cases have also occurred with glaucoma medications.59

FIG. 17. Contact allergy (conjunctivitis related to pilocarpine eyedrops.

655

medicamentosa)

Rubbing the eyes after handling soaps, detergents, or chemicals may provoke a contact dermatitis reaction. Allergic reactions to cosmetics affect primarily the eyebrows and upper lids because of the method of application. Mascara, eyebrow pencil, and face creams all may act as allergens. Nail polish can cause sensitization around the eye by the accidental touching of the area. Lip gloss and eye gloss cosmetics contain lanolin fractions that may also act as sensitizers. Diagnosis and treatment. A diagnosis of allergic contact sensitivity can be made by patch testing. More often, a different eyedrop, ointment, or contact lens solution is prescribed. For acute skin lesions cold compresses can be applied to the eyelids. Corticosteroids are rarely necessary; however, systemic corticosteroids are sometimes used in severe poison ivy dermatitis involving the eyes. For the conjunctivitis or keratitis associated with drugs, the best treatment is withdrawal of the drug and the substitution of an appropriate, nonirritating medication. New horizons in treatment. There is considerable interest among ophthalmologists and pharmaceutical companies in the development of new antiallergic and anti-inflammatory compounds that can be used safely in the eye. The frequency of allergic forms of conjunctivitis and the hazards associated with topical steroids have led to the need for these alternatives. Cromolyn has been a very useful addition to our therapeutic resources, but more potent agents are still being sought. There has been considerable interest in nonsteroidal anti-inflammatory drugs that inhibit the metabolites of arachidonic acid. None of these agents are available in the United States as eyedrops. A combination H,/H, blocker is currently being investigated, and other mast cell stabilizers are also being tested. Allergic conjunctivitis, unlike many ocular conditions, is rarely associated with permanent visual im-

656

.J ALLERGY

Friedlaender

pairment. It is, however, a common and extremely uncomfortable problem for those who are affected. Since many allergic conjunctivitis patients are observed by both the allergist and the ophthalmologist, it is important for both to recognize the hallmarks of allergic conjunctivitis and to understandthe different therapeutic alternatives for the managementof this condition.

18. 19.

20.

21.

REFERENCES 1. Bluestone R, Easty DL, Goldberg LS, et al: Lacrimal immunoglobulins and complement quantified by counter-immunoelectrophoresis. Br J Ophthalmol 59279, 1975 2. Chandler JW, Leder R, Kaufman HE, Caldwell JR: Quantitative determinations of complement components and immunoglobulins in tears and aqueous humor. Invest Ophthalmol 13:151, 1974 3. McClellan BH, Whitney CR, Newman LP. Allansmith MR: Immunoglobulins in tears. Am .I Ophthalmol 7689, 1973 4. Brauninger GE, Centifanto YM: Immunoglobu1in E in human tears. Am J Ophthalmol 72~558, 1971 5. Franklin RM, Kenyon KR, Tomasi TB Jr: Immunohistologic studies of human lacrimal gland: localization of immunoglobulins, secretory component, and lactoferrin. J Immunol I 10: 984, 1973 6. McMaster PRB Aronson SB, Bedford MJ: Mechanisms of the host response in the eye. IV. The anterior eye in germ-free animals. Arch Ophthalmol 77:392, 1967 7. Allansmith MR, Korb DR, Greiner JV, et al: Giant papillary conjunctivitis in contact lens wearers. Am J Ophthalmol 83:697. 1977 8. Zimianski MC, Dawson CR. Togni B: Epitheliai cell phagocytosis of Liste-rin monocyrogenes in the conjunctiva. Invest Ophthalmoi 13:623, 1974 9. Greiner JV, Covington HI, Allansmith MR: Surface morphology of the human upper tarsal conjunctiva. Am J Ophthalmol 83892, 1977 10. Axelrod AJ, Chandler JW: Morphologic characteristics of conjunctival-associated lymphoid tissue in the rabbit. Invest Ophthahnol Vis Sci 17(suppl):I82, 1978 1I. Kimura SJ, Thygeson P: The cytology of external ocular disease. Am J Ophthalmol 39:137, 1955 12. Allansmith MR, Hutchison D: Immunoglobulins in the conjunctiva. Immunology 12:225, 1967 13. Allansmith MR. Whitney CR, McClellan BH, Newman LP: Immunoglobulins in the human eye. Location, type, and amount. Arch Ophthalmol 89:36, 1973 14. Dwyer RS, Turk JL, Darougar S: Immediate hypersensitivity in the guinea pig conjunctiva. I. Characterization of the IgE and IgG antibodies involved. Int Arch Allergy Appl Immunol 46:910, 1974 IS. Dwyer RS, Darougar S, Jones BR: Immediate hypersensitivity in the guinea pig conjunctiva. II. Effect of treatment with antihistamines steroids and disodium cromoglycate. Mod Probl Ohthalmol 16:186, 1976 16. Hall JM, Pribnow JF, Meisler D, Friedlaender M, Schoenrock B: Immediate hypersensitivity in the guinea pig conjunctiva. Intravitreal and topical sensitization. Invest Ophthalmol Vis Sci 25:212. 1984 17. Donnelly JJ. Rockey JH, Soulsby EJL: Intraocular IgE anti-

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body induced in guinea pigs with Ascaris suwn larvae. Inveki Ophthalmol Vis Sci 16:976, 1977 Friedlaender MH, Cyr R: Contact sensitivity in me gmnea 91% eye. Invest Ophthalmol Vis Sci I8(suppl):95, 1979 Belfort R Jr, Mendes NF: T- and B-lymphocytes in the humau conjunctiva and lacrimal gland. Invest Ophtbalmot Vi? Sci 17(suppl):182, 1978 Friedlaender MH, Dvorak HF: Morphology of delayed-type hypersensitivity reactions in the guinea pig cornea J Immunol 118:1558, 1977 Wessely K: Ueber anaphylaktische erscheinungen au der horrihaut. Munchen Med Wochenschr 58:1713, 1911 Thygeson P: Observations on nontuberculous phlyctenular keratoconjunctivitis. Tr Am Acad Ophth 58: 128. 1954 Weekers I.: L’exantheme de la conjonctivitc phylectenulaire envisage come une toxituberculide. Arch Ophthalmo! 29:2Y4. 1909 Funaishi S: Experimentelle untersuchungen uber die actialogie der phlyctaularaten augenentzundungen. Khn ‘vIonatshl :+;I. genheilkd 71:141, 1923 Inomata H, Smelser GK, Polack FM: Comeai ~ascularization in experimental uveitis and graft rejection. An electron microscopic study. Invest Ophthalmol 10:840, 1971 Klintworth GK: The contribution of morphology to our III:-derstanding of the pathogenesis of experimentally produced cornea1 vascularization. Invest Gphthalmol Vi? Sci l6:28 1 , 1977 Fromer CH. Klintworth GK: An evaluation of the role of leukocytes in the pathogenesis of experimentally induced corneai vascularization. III. Studies related to the vasoproliferative capability of polymorphonuclear leukocytes and lymphocytes Am J Pathol 82:157. 1976 Walton KW: Studies on the pathogenesis of cornea1 arcur ti)rmation. I. The human cornea1 arcus and its relation to atbentsclerosis as studied by immunofluorescence J Pathof I I I .2hi. 1973 Rahi AHS, Tripdthi RC: Anatomy of passive Arthus reaction in the cornea. A preliminary communication. Mod Probl Ophthalmol 16:155, 1976 Elliott JH, Flax MH, Leibowitz HMI: The limbal cellular infiltrate in experimental comeal hypersensitivity I. Morphologic studies after primary sensitization. Arch Ophthalmol 76:104, 1966 Marks MB: Stigmata of respiratory tract allerg;cs. Kalamazoo, Mich., 1977, Upjohn Co, p 12 Stegman R, Miller D: A human model of allergic conjunctivitis. Arch Ophthalmol 93: 1354, 1975 Friedlaender MH, Okumoto M. Kelley J: Diagnosis af allergic conjunctivitis. Arch Ophthalmol 102: 1198. 1984 Abelson MB, Madiwale N, Weson JH: ConJunctival eosins phila in allergic ocular disease. Arch Ophthalmol 101:SS5. 1983 Abelson MB. Allansmith MR, Friedlaender MH: Effects of topically applied ocular decongestant and antihistamine. Am J Ophthalmol 90:254. 1980 Greenbaum J, Cockcroft D, Hargreave FE, Dolovich J: Sodium cromoglycate in ragweed-allergic conjunctivitis. .I ALLERG\

CLIN IMMUNOI.59~437,1977 37. Friday GA, Biglan AW, Hiles DA, et al: Treatment of ragweedallergic conjunctivitis with cromolyn sodium 4% ophthalmic solution. Am J Ophthalmol 95: 169, I983 38. Ostler HB: Acute chemotic reaction to cromolyn. Arch Ophthalmol 100:412. 1982

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39. Ostler HB: Alpha, I-antitrypsin, and ocular sensitivity to cromoglycate. Lancet 1:1287, 1982 40. Settipane GA, Klein OE, Boyd GK, et al: Adverse reactions to cromolyn. JAMA 241:811, 1979 41. FriedlaenderMH: Corticosteroid therapy of ocular inflammation. Int Ophthalmol Clin 23:175, 1983 42. FriedlaenderMH, Masi RJ, Okumoto M, et al: Ocular microbial flora in immunodeficient patients. Arch Ophthalmol 98:1211, 1980 43. Copeman PWM: Eczema and keratoconus.Br Med J 2:977, 1965 44. Beetham WP: Atopic cataract. Arch Ophthalmol 24:21, 1940 45. Ingram RM: Retinal detachmentassociatedwith atopic dermatitis and cataract. Br J Ophthalmol 49:96, 1965 46. Coles RS, Lava1 J: Retinal detachmentsoccurring in cataract associatedwith neurodermatitis.Arch Ophthalmol48:30, 1952 47. FranklandAW, Easty D: Vernal keratoconjunctivitis: an atopic disease.Trans Ophthalmol Sot UK 91:479, 1971 48. Allansmith MR, Hahn GS, Simon MA: Tissue, tear, and serum IgE concentrationsin vernal conjunctivitis. Am J Ophthalmol 81:506, 1976 49. Brauninger GE, Centifanto YM: Immunoglobulin E in human tears. Am J Ophthalmol 72:558, 1971 50. Collin HB, Allansmith MR: Basophils in vernal conjunctivitis in humans:an electron microscopic study. Invest Ophthalmol 16:858, 1977

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51. Easty D, Rice NSC, JonesBR: Disodium cromoglycate(Intal) in the treatmentof vernal keratoconjunctivitis. Trans Ophthalmol Sot UK 91:491, 1971 52. Tabbara KF, Arafat NT: Cromolyn effects on vernal keratoconjunctivitis in children. Arch Ophthalmol 95:2184, 1977 53. Buckley RJ: Vernal keratopathy and its management.Tram Ophthalmol Sot UK. 101:234, 1981 54. Allansmith MR, Korb DR, Greiner JV, et al: Giant papillary conjunctivitis in contact lens wearers. Am J Ophthalmol 83:697, 1977 55. Meisler DM, KrachmerJH, GoekenJA: An immunopathologic study of giant papillary conjunctivitis associatedwith an ocular prosthesis.Am J Ophthalmol 92:368, 1981 56. Meisler DM, Zaret CR, Stock EL: Trantas’ dots and limbal inflammation associatedwith soft contact lens wear. Am J Ophthalmol 8966, 1980 57. Meisler DM, Berzina VJ, Krachmer JH: Cromolyn treatment of giant papillary conjunctivitis. Arch Ophthalmol 100:1608, 1982 58. Friedlaender MH: Allergy and immunology of the eye. New York, 1979, Harper & Row, pp 80-81 59. Mathias CGT, Maibach HI, Irvine A, Adler W: Allergic contact dermatitisto echothiophateiodide andphenylephrine.Arch Ophthalmol 97:286, 1979

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