SURVEY OF OPHTHALMOLOGY

VOLUME 24

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NUMBER 2

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SEPTEMBER-OCTOBER

1979

REVIEW Adverse External Topical

Ocular

Ophthalmic

Effects of

Medications

FREDM. WILSON II, M.D. Cornea1 and External Ocular Disease Service, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana Abstract. Medical and pharmacologic

research of recent years has led to the development of many potent and efficacious topical ophthalmic medications. Unfortunately, many of these drugs are potentially toxic or allergenic, and their adverse effects have themselves become important external ocular diseases. This paper presents a classification of these adverse effects and provides a review of their etiology, pathogenesis, histopathology, diagnosis, and management. It is hoped that this information will be helpful to ophthalmologists in their efforts to anticipate, prevent, recognize, and treat drug-induced ocular problems and that it will serve to emphasize the importance of avoiding the ill-considered use of medications. (SW Ophthalmol 2457-88,

1979)

Key words.

coniunctivitis immunology toxicology

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adverse effects allergy blepharitis dermatitis druas 9 iatrogenic disease irritation - kerat;is . preservatives therapy l

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resent-day ophthalmologists and their patients are fortunate to have available many topical medications for the treatment of a wide variety of ocular disorders, but these drugs should not be regarded as panaceas. Many of the preparations can cause annoying, clinically confusing, and sometimes even serious adverse effects. Rational prescribing that is based on specific diagnosis and indication as opposed to “shotgun therapy” - and careful clinical monitoring of the effects of treatment can minimize the risks, but the indiscriminate use of medications is apt to do more harm than good. This paper reviews the subject of druginduced disorders of the external eye and emphasizes that such disorders themselves

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constitute important diseases. Only the effects of topical drugs on the external eye are considered. Intraocular effects, e.g., glaucoma or cataract from topical corticosteroids, are excluded from consideration, as are systemic reactions to topical drugs and reactions from systemic medications. The paper is divided into three main sections: Eyelids; Conjunctiva; and Cornea. Within each anatomic section the drug reactions are classified according to their known or presumed pathogenetic mechanisms (allergic, toxic, photoallergic, phototoxic, depositional, pigmentary, microbiologic) and according to their clinical appearances (papillary, follicular, cicatrizing, etc.). These subdivisions of the anatomic sections represent, for the most part, the diagnostic 57

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1979

categories into which drug reactions are put in clinical practice. Table 1 provides the reader with an overview of the kinds of adverse reactions that are most likely to be caused by various topical medications.

TABLE I Clinical Features of Common Adverse Reactions to Topical Ophthalmic Medications*

Drug

CDC PK

I. Eyelids A. URTICARIA

AND ANGIOEDEMA

Urticaria (hives or wheals) refers to localized patches of edema in the superficial layers of the skin (epidermidis and dermis), whereas angioedema involves primarily the deeper subcutaneous tissues.134Either may be of immunologic or nonimmunologic origin. 134~175 Most of the immunologic forms are thought to represent type-1 (IgE-mediated) hypersensitivities,“J3 although rare cases of allergic urticaria-angioedema may possibly be caused by IgG or IgM antibodies.‘76*218 The drug-induced urticarial reactions with which we are concerned in this discussion are examples of type-1 hypersensitivities. Such disorders as allergic asthma, allergic rhinitis, hayfever, allergic urticaria from ingestants or inhalants, anaphylaxis, and - at least to some extent - atopic dermatitis and vernal catarrh are also examples of type-1 hypersensitivities. These allergic reactions may be referred to as anaphylactoid or PrausnitzKustner (P-K) reactions* and occur when antigens combine with IgE antibodies that are fixed to mast cells and basophiles. Most drugs act only as partial antigens (haptens) and must combine with tissue proteins (carriers) to form complete antigens (conjugates).13 Nevertheless, these reactions can appear within seconds or minutes after use of a drug if previous sensitization has occurred. P-K reactions are mediated ultimately by vasoactive substances such as histamine, serotonin, slow-reacting substance of anaphylaxis, and various plasma kinins that are released from the granules of mast cells or basophiles following the combination of antigen with antibody.“Js8 Eosinophilic chemotactic factors appear a1so.117J18

*The Prausnitz-Kustner reaction (or phenomenon) originally referred to the passive transfer, by means of serum, of atopic (IgE) antibodies from one individual to another.“’ The term is used in this paper to refer to diseases and clinical manifestations that are mediated by IgE antibodies, as suggested by Weiser et al.22s

Clinical Features

Neomycin Gentamicin Tetracycline Chloramphenicol Iododeoxyuridine Miotics Atropine Vasoconstrictors Preservatives

CC CC OC 0 C R C R RO

PC

C C C 0** O** C C 0*** C*** 0*** 0*** R C 0

FC

CC

NN NN N N C 0 R N N

N N 0 0 N N N

CDC = contact dermatoconjunctivitis; PK = punctate keratopathy; PC = papillary conjunctivitis; FC = follicular conjunctivitis; CC = cicatrizing conjunctivitis and pseudotrachoma; C = common; 0 = occasional; R = rare; N = essentially nonexistent *This Table is based on the personal experience of the author, supplemented by information from certain references cited in this paper.1r~ss~1Tr~1ss~194~ 202.208 **May be caused by preservatives. ***May be caused by irritating products degradation.

of

Allergic urticaria occurs most commonly, but not exclusively, in atopic individuals, i.e., those who have atopic dermatitis or who are prone to develop more than one of the other P-K diseases listed above and who have family histories of P-K diseases.“J3 It is possible for topical agents to produce acute wheals or edema of the eyelids, but such reactions are rare.“’ I have personal knowledge of two cases in which conjunctival instillations of proparacaine hydrochloride were followed in a minute or so by swelling of the eyelids, chemosis, and severe ocular itching. Both patients responded quickly to the use of topical vasoconstricting agents and the application of cold compresses. There were no systemic manifestations in either case. Penicillin is the drug that would seem to be most likely to produce acute ocular urticaria 20~123~156~210 although its topical use is rather ‘infrequent now. It has been estimated that 5-10s of the population of the United States is allergic to penicillin,233 and urticaria is known to be the most common manifestation of such allergy20J38~200 when all routes of

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MEDICATIONS

administration are considered. Use of the drug topically is said to be particularly likely to cause allergic reactions,2*J00Jg*but it is not possible to ascertain from the literature how often these reactions were truly urticarial. Allergic urticaria of the eyelids is caused more commonly by foods, bites or stings of insects, or systemically administered drugs or biologic products. Rarely, inhalants or infectious allergens are at fault. The histopathologic changes of urticaria and angioedema are identical, aside from the differential predilection for the superficial or deep cutaneous tissues, respectively.lg4 There is edema, dilatation of venules and capillaries, and infiltration by lymphocytes and neutrophiles. Eosinophiles appear mainly in atopic individuals and are seen less commonly in reactions of nonatopic patients.12’ Urticaria is typified by a circumscribed plaque of edema with an erythematous margin and a blanched center. Angioedema shows localized dermal edema with an essentially normal epidermis. Diagnosis is made obvious usually by the suddenness of onset following instillation or application of a drug and by the edema and itching. Eosinophiles may be present in conjunctival scrapings.leT The standard clinical test for the diagnosis of urticarial type-1 hypersensitivity is the intradermal skin test. A small amount of the suspected antigen is applied to a cutaneous scratch or is injected intradermally. The rapid appearance, within seconds or minutes, of a wheal and flare indicates a positive reaction. Topical instillations of substances into the conjunctival sac have also been used diagnostically,2g~‘E~2ss a positive response being the nearly immediate onset of swelling of the eyelids, chemosis, hyperemia of the conjunctiva, and itching. It must be realized that these skin and conjunctival tests are not innocuous and that they can cause anaphylaxis in highly susceptible patients. In performing the conjunctival test, therefore, I prefer merely to touch the conjunctiva briefly with a cotton swab that has been moistened with the drug to be tested. The drug can even be diluted by first applying some saline solution to the swab. Only if applications of the swab produce no reaction do I instill a drop of the drug into the conjunctival sac. Unfortunately, a negative skin or conjunctival test does not ensure that a drug can be administered safely. Severe, even fatal, reactions have occurred after negative skin testing.2ss

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Treatments include the systemic administration of antihistaminic agents, epinephrine, or corticosteroids. Cold compresses are of value, but no other local measure is effective for the eyelids. Vasoconstricting agents, and possibly corticosteroids, are of some value topically for conjunctival urticaria (chemosis). Disodium cromoglycate would be expected to be more of prophylactic than therapeutic value, since it acts by inhibiting degranulation of mast cells and basophilese8J80~18s and has no effect on mediators of inflammation that have already been released. Elimination of the cause is most important. P-K allergies often can be treated with “desensitization,” which involves the serial administration of small amounts of the offending allergen. Such treatment presumably results in the production of IgG “blocking” antibodies that interfere with the interaction of the allergen with IgE antibodies. Desensitization for allergy to an ophthalmic drug is theoretically feasible; however, this approach would seldom be chosen in preference to stopping or changing the drug. In any case, desensitization is in the realm of the allergist rather than the ophthalmologist. One highly specific and efficacious mode of therapy is the administration of penicillinase for allergy to penicillin. Havener discusses the subject in some detail.lW The treatment of acute systemic anaphylaxis, a subject beyond the scope of this review, includes the systemic administration of epinephrine, antihistaminic agents, corticosteroids, and oxygen, plus attention to Generalized cardiorespiratory support. anaphylaxis from the ocular instillation of a drug is very rare, but cases have occurred with topical penicillin ointment or drops;SS*144 at least one case had a nearly fatal terminati0n.l” B. ALLERGIC

CONTACT

DERMATOCONJlJNCTIVITIS

This is Theodore’s term for cases of cellmediated contact allergy that involve the conjunctiva in addition to the periocular skin.2o2 The word “dermatoconjunctivitis” may be preferable to “blepharoconjunctivitis,” because the cutaneous reaction may spread from the eyelids to the skin of the forehead, nose, or malar region (Fig. 1). Theodore’s nomenclature is consistent with that used by dermatologists; their official name for contact allergy, regardless of its location, is

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Surv Ophthalmol 24 (2) September-October 1979

“allergic contact eczematous dermatitis.“181 These unwieldy terms can be shortened simply to “contact dermatitis” (or blepharitis, dermatoconjunctivitis, etc.) in everyday usage, although not all contact dermatitis is of an allergic nature. Allergic contact dermatoconjunctivitis, like contact dermatitis elsewhere, is a manifestation of delayed (type-IV) hypersensitivity and is mediated by cellular immunity.41s2aoThe disorder is unrelated to atopy. As mentioned previously, drugs act as haptens’ and must conjugate with proteins before sensitization can occur. The hapten-protein conjugate combines with thymus-derived lymphocytes (T-cells) from the regional lymph nodes. The combination of antigen with T-cell causes the lymphocyte to elaborate various lymphokines which comprise the mediators of the resulting inflammatory response: migration (of macrophages) inhibition factor, macrophage activating factor, macrophage aggregation factor, leukocyte inhibitory factor, neutrophile chemotactic factor, mitogenic factor, factors that enhance or suppress antibody production, cytotoxic factors, skin reactive factor, transfer factor, eosinophile chemotactic factor, and others. Sensitization of the patient’s immune system occurs when a critical, sensitizing dose of antigen reaches the regional lymph nodes.41*67This requires at least live to ten days for strongly sensitizing allergens,” but may require months or years when less potent sensitizers are involved. Following sensitization, the time interval between subsequent exposure to the antigen and the appearance of clinical disease (elicitation phase) is 12-72 (usually 24-48) hours. Once established, sensitivity usually persists throughout the patient’s lifetime. Occasionally, however, the patient “hardens” or loses his sensitivity, and dermatitis ceases despite continuing exposure to the allergen.41~48~1s* The mechanism by which this “hardening” effect occurs is unknown. Because conjugation of hapten with protein appears to take place in the immediately subepidermal dermiss2 (and presumably in the superficial stroma of the conjunctiva), it is necessary that an inciting drug be able to penetrate the epidermis or conjunctival epithelium. The thinness of the conjunctiva and skin of the eyelids may be one factor that makes these tissues more susceptible than many others to the development of contact allergy.4*~‘ggI suspect that other factors might

WILSON

FIG. 1. Eczematoid changes of drug-induced allergic contact dermatoconjunctivitis with involvement of skin of forehead, lateral aspect of nose, and malar region (Courtesy of M Grayson,

MD). be of equal importance; the extensive lymphatic drainage of the eyelids and conjunctiva should allow for relatively easy sensitization of cells in the regional lymph nodes, while the rich vascular supply probably facilitates the accumulation of cells that mediate the inflammatory response. Epithelial penetration is accomplished most readily by drugs whose molecular weights are under 1,000,22but it is likely that virtually any medicament can cause contact dermatoconjunctivitis.*63 Penetration is enhanced by the effects of drying, maceration from excessive wetness or oiliness, ocular secretions, trauma, or preexisting disease. In fact some drugs, such as sulfonamides, produce contact dermatitis almost exclusively in previously damaged skin.‘OO The major barrier to the percutaneous penetration of drugs is a complex mixture of lipids, proteins, and water in the keratin layer. 27~1ss~140 Clinical observations that ointments and other lipid-soluble preparations are more apt to cause contact allergy than are water-soluble eyedrops may be explained partly by the fact that the barrier is more permeable to lipid-soluble substances.11o *Erythromycin may be an exception. Apparently, it has never been known to cause allergic contact dermatitis, nor has it ever induced a positive patch-test reaction.aS.B4

ADVERSE EFFRCTSOF TOPICAL OPHTHAIMC

MEDICATIONS

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FIG. 2. Histopathology of druginduced allergic contact dermatoconjunctivitis. Acanthosis, hyperkeratosis, parakeratosis, intercellular and intracellular edema, intraepithelial vesicles and edema, and lymphocytic infiltration of epidermis. (Hematoxylin and eosin, 30 X)

Heavy, greasy vehicles also have occlusive properties and produce swelling of the keratin layer by retarding the loss of water;“O the swelling causes separation of keratin librils and enhances the penetrability of drugs.“O Prolonged use of ointments may defat the skin and deprive it of its ability to retain water, resulting in increased penetration of drugs because of dryness, flaking, and scaling.27 By the same mechanisms, a patient may worsen the dermatitis by using soaps, detergents, or fatty cleansers in attempts to cleanse the diseased areas.7gJ74 Certain molecular structures are particularly effective sensitizers, namely ones with an amine or chlorine group at the para position of a benzine ring12s~200~202 (many cosmetics, dyes, synthetic local anesthetics, and other drugs) and ones with pyrimidine nuclei200 (iododeoxyuridine - IDU). In my experience, some other drugs that are likely to cause contact dermatoconjunctivitis are penicillin, neomycin, gentamicin, and atropine. More extensive lists of contact sensitizers are available elsewhere.16J’4J88 It is not always the major pharmacologic component of a preparation that is to blame; preservatives and vehicles may also be at fault.6s~s5 Thimerosal, a mercurial preservative, would be expected to cause contact dermatitis from time to time since mercurial substances are common contact sensitizers.65~78~174 Ethylenediamine tetraacetate (EDTA) is used as a preservative in many topical ophthalmic medications and is used also for the removal by chelation of calcific deposits in the cornea. It occasionally causes contact allergy and can

do so in patients who have been sensitized to ethylenediamine, a closely related substance which is a potent sensitizer and which is of topical prevalent as a stabilizer medications.s2*s5~170 Parabens are preservatives which often are not even mentioned on labels, but which can produce allergic reactions.S,6a*65 Even such a seemingly innocuous vehicle as lanolin can, in some individuals, act as a sensitizer.65 The most common ophthalmic preservative, benzalkonium chloride, causes contact dermatitis rarely.6s The histopathologic features of allergic contact dermatitis (Fig. 2) include intercellular and intracellular edema, intraepithelial vesicles and bullae, lymphocytes and neutrophiles in the epidermis, and hyperemia and edema of the upper dermis 41,22gPerivascular infiltrates, mainly of lymphocytes but with some neutrophiles and a few eosinophiles, also are seen in the dermis. Acanthosis (thickening of the epithelium), parakeratosis (persistence of nuclei in the keratin layer), and hyperkeratosis (increased amounts of keratin) appear later. Contact dermatitis usually affects the epidermis more than the dermis, but “dermal contact allergy” can be caused by neomycin, nickel, or cobalt.55*56This kind of reaction is characterized by erythema and edema without eczematous changes. Topical ophthalmic medications that produce contact blepharitis usually cause first an allergic contact conjunctivitis.202 Contact blepharitis without conjunctivitis, on the other hand, is caused nearly always by a substance that has reached the eyelids without

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1979

having been instilled into the conjunctival sac.202 The earliest clinical signs of allergic dermatoconjunctivitis may be along the course of the natural flow of tears, drugs, and ocular secretions, i.e., the inferior or inferonasal areas of the conjunctiva and the nasal aspect of the lower eyelid (Fig. 3). The remainder of the conjunctiva and lower eyelid, the cornea, the upper eyelid, and even the facial skin may become involved eventually. The cutaneous changes of contact dermatitis are those of eczema (Fig. l), which SulzbergerlBg described as: “A reaction or morbid condition situated principally in the epidermis and characterized grossly by several of the following: erythema, papulation, vesiculation, oozing, crusting, scaling, thickening, pigmentation, itching; and histologically by intraepidermal spongiosis and/or intraepidermal vesiculation.” In my experience a certain puffiness (edema) of the skin is characteristic also. The diagnosis of contact blepharitis is usually made evident by the aforementioned features and by the patient’s complaint of itching; however, in the early phases of the disease, particularly in a darkened examing room, the problem may be overlooked easily. The biomicroscopic finding of small flakes and scales on the periocular skin can alert the ophthalmologist to the possibility of the diagnosis. These flakes and scales are identical in appearance to the classic fibrin collarettes of staphylococcal marginal blepharitis, but are found on the skin of the eyelids away from the marginal lash line. The flakes and scales of contact dermatitis consist of keratin, acanthotic epidermis, and dried fluid from within intraepidermal vesicles. The standard confirmatory test for contact dermatitis is the patch test.lel It should be performed on relatively hairless areas of skin, such as the volar aspect of the forearm or the back. The material to be tested is applied to the skin and is covered by a small piece of impermeable material such as Saran Wrap@ or aluminum foil with overlying tape. Alternatively, the substance may simply be applied under a bandaid if its edges are sealed with tape. Adhesive eye patches which are used for occlusion therapy of amblyopia may also be

used. Readings are taken at 24-48 hours, preferably about 30 minutes after removal of the dressing to allow time for subsidence of pressure-induced effects. A positive reaction shows the same cutaneous changes of contact

FIG. 3. Initial manifestations of allergic contact dermatitis. Patient complains of itching of the eye. Early eczematoid change and mucoid discharge (arrow) on the nasal aspect of the lower eyelid where drugs tend to gravitate.

dermatitis that have been described. The pitfalls of patch testing must be appreciated.80J81 Falsely negative results may occur because the skin of the tested area is relatively resistant to the development of contact dermatitis. Falsely positive tests may result from the application of substances which are too concentrated and which produce eczematous reactions by direct irritation rather than by immunologic hypersensitivity. Detailed information concerning concentrations and vehicles for patch testing is available elsewhere.“,‘6,6S,‘88Since asymptomatic people can show positive patch tests to various substances, a positive test does not necessarily prove the cause of a specific dermatitis. The taking of a careful history is more important than patch testing in pinpointing the cause. Avoidance of the offending substance is the best treatment for contact dermatitis; in many cases no other therapy is required. Mechanical irritation, soaps, and cleansers are to be avoided. Wet dressings of water, Burow’s solution USP (liquid aluminum acetate) 1: 16, or Domeboro@ tablets (aluminum sulfate and calcium acetate) dissolved in water are useful for the acute, weeping stages of the disease and will bring about drying of the dermatitis in a few days, probably by macerating the keratin layer. Creams or ointments containing corticosteroids are helpful in the dry subacute and chronic stages but probably should be avoided in wet dermatitis. Antihistamines

ADVERSE

EFFECTS OF TOPICAL

OPHTHALMIC

MEDICATIONS

have no effect on the immune mechanisms that are operative in contact dermatitis and are highly sensitizing when applied topically;‘W’76 systemically they can provide some antipruritic effect. Systemic corticosteroids are not necessary. Attempts at desensitization to drugs have been largely unrewarding.63 Despite the fact that allergic contact dermatitis is exquisitely responsive to corticosteroids, it can worsen even in the face of steroid therapy if contact with the offending drug continues. This occurred in a patient (Fig. 4) who was referred to me after she had developed a severe dermatoconjunctivitis over the course of several months of treatment with an ophthalmic ointment of neomycinpolymyxin B-hydrocortisone. The history was unequivocally indicative of her having worsened, to the point of developing areas of frank cutaneous ulceration, despite the presence of the steroid. Her allergy was presumably to neomycin since it is a very common cause of contact allergy, but patch

FIG. 4. A: Severe contact dermatoconjunctivitis Bcaused by topical neomycin-polymyxin hydrocortisone, illustrating that contact reactions can occur and worsen despite the presence of corticosteroid if the offending drug (probably neomycin in this case) continues to be used. Ulcerative cutaneous lesions in this patient were a manifestation of secondary infection with Staphylococcus aureus. B: Conjunctival reaction of same patient. No ocular disease was present other than the reaction to the topical medication. C: Complete cure one month following cessation of topical medication. Secondary infection was treated with an oral antibiotic which was selected on the basis of sensitivity studies. Topical corticosteroid therapy for the contact dermatoconjunctivitis was not used.

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testing was not performed. The reaction could have been to any of the other components of the drug, including vehicles or even the steroid. Corticosteroids have been incriminated rarely as causes of contact allergy.63~17g~202Nevertheless, the point remains valid that patients who are using corticosteroids may still develop contact dermatitis. This patient (Fig. 4) was of additional interest in that she developed secondary infection of her dermatitis with Staphylococcus aureus. Secondary infection of contact dermatoconjunctivitis is not uncommon and should be suspected whenever ulceration of the skin is present. Infection with staphylococci or streptococci can produce superimposed bullous impetigo or infectious eczematoid dermatitis,‘” and these cutaneous reactions themselves can resemble contact dermatitis. Any suspicion of infection is cause for taking smears, scrapings, or cultures, especially before starting topical corticosteroid therapy. Secondary infections should be

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1979

treated with systemic antibiotics because of the irritative and sensitizing properties of topical antibiotics. Moreover, cutaneous streptococcal infections must be treated for ten days with systemic penicillin or its equivalent because these infections can lead to erysipelas or to poststreptococcal glomerulonephritis.34~67J21 C. ALLERGIC

CONTACT

DERMATITIS

As has been mentioned, contact blepharitis without conjunctivitis is attributable usually to some substance other than an ophthalmic drug, since ocular medications tend to produce conjunctivitis before they produce dermatitis, A red eye in association with contact blepharitis therefore suggests that an ophthalmic drug is at fault; a white eye, on the other hand, should point the search for etiology in the direction of cosmetics, toiletries, and the like. Substances that should be considered as possible causes of allergic blepharitis include nail polish, perfume, face cream, and lipstick.41 I have found shampoo and eye makeup also to be common offenders. Recall that the eyelids are especially prone to the development of contact dermatitis.‘*Jeg Allergy to shampoo, for example, may affect the eyelids without affecting the scalp. D. PHOTOALLERGIC

CONTACT

DERMATITIS

This is presumed to be an immunologically mediated inflammation that results from the combined effects on tissues of light and drugs or other chemicals.18 Exactly how light, drugs, and host tissues combine to form antigens is not known. It has been postulated that light alters the molecular structures2 or configuration’s7 of the drug, enabling it to combine with tissue proteins so as to form an antigenic conjugate.” The immunologic response appears in some cases to be delayed (type-IV) hypersensitivitys’ and in others to be immediate (type-I) hypersensitivity.13 No photoallergic reactions are recognized for any of the topical ophthalmic drugs, although

*Theodore makes a further distinction between the terms irritative and toxic, using the former to refer to effects of products of degradation of drugs and using the latter to refer to effects of drugs themselves or to effects of microbial contamination of drugs.‘@’Because it is so often difficult or impossible to make such a distinction clinically, I have tended to use the terms synonymously.

WILSON

hexachlorophene and halogenated salicylanilides in soaps can cause photoallergic blepharitis. Sunscreens containing p-aminobenzoic acid or its esters can, paradoxically, cause photoallergy leading to exaggerated sunburn and eczematous dermatitis.ls3 E. IRRITATIVE

OR TOXIC

CONTACT

DERMATITIS

Toxic means poisonous. A poison may be defined as a substance which, by its chemical action, may cause damage to structure or disturbance of function.’ Irritation is used as a synonym for toxicity except that irritation always connotes inflammatory effects. Mechanical effects also are referred to as irritations rather than toxicities. For practical purposes the words “irritative” and “toxic” may be used interchangeably.* The use of either term implies that immunologic mechanisms are not operative and that effects on tissues are the result of direct chemical action. Some substances, however, can be allergenic in low concentrations and irritative in higher concentrations.‘81J01 Primary irritants include strong acids and alkalis, solvents and oils, some heavy metals, soaps and detergents, pesticides, plastics, and resinsa’ Most occupational dermatoses are irritative, but there are few, if any, examples of irritative blepharitis secondary to ophthalmic drugs. Several drugs are sufficiently irritative to produce conjunctivis (to be discussed later), but drugs so irritative as to produce dermatitis are not marketed or used. One possible exception is the burn of the eyelid that can result from cauterization with solid sticks of silver nitrate. Unless actual burns occur, the clinical appearance of irritative blepharitis is the same as that of allergic contact blepharitis. F. PHOTOTOXIC

DERMATITIS

This seems to differ from photoallergic dermatitis in that the combination of light and drug produces inflammation or noninflammatory hyperpigmentation in the absence of any immunologic response. Phototoxic reactions can occur on the eyelids or other exposed areas following the systemic use of drugs such as sulfonamides, barbiturates, demethylchlortetracycline, phenothiazines, and others; however, phototoxic blepharitis from topical drugs is almost nonexistent. The ophthalmologist might encounter rarely a case of berlock dermatitis of

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MEDICATIONS

become similarly pigmented, as will be discussed later. Dimercaprol, calcium edetate, and penicillamine all have been used with varying success for treating systemic mercurial poisoning, but sodium thiomalate is said to have been more effective experimentally for mercurial pigmentation of the cornea.B4 Argyria (referring to the skin) or argyrosis (referring to the eye) is pigmentation by silver. Discoloration of the eyelids and ocular tissues can occur after chronic local or systemic use of silver preparations, and local absorption of silver can lead to pigmentation G. MISCELLANEOUS CHRONIC IRRITATIONS at distant sites. In severe cases, the skin and AND TOXICITIES mucous membranes of the entire body can These are adverse effects that do not fit show the characteristic slate blue-gray diswell into other categories of classification and coloration. Topical preparations that have that may, until our knowledge is more com- caused argyria or argyrosis include silver nitrate and silver proteinate. Industrial explete, be called irritations (if inflammatory) posures to various silver-containing comor toxicities (if not inflammatory). The chronic cutaneous application of cor- pounds have been responsible for some cases. ticosteroids, particularly fluorinated ones, Argyria from systemic therapy with silver is has been associated with the development of mainly of historic interest. Histopathologstriae and atrophy,S4*148telangiectases,17*~186 ically, the silver granules are found in and purpura and ecchymoses,42*118and rosaceaaround collagenous and elastic fibers, eccrine like135J80or acne-like changes.136 It is said sweat glands, arrector pili muscles, and that the progression of these changes can be vascular basement membranes of the derhalted or reversed by discontinuing the mis.lE2 Involvement of the ocular tissues will be considered later. Argyria is asymptomatic fluorinated steroid or by substituting hydrocortisone,‘7a although abrupt cessation except that it may constitute a significant of the steroid sometimes results in the cosmetic blemish. Thygeson has pointed out, appearance of an intense, pustular, rebound however, that women have sometimes reaction.180 Hydrocortisone probably has no accepted cheerfully the pigmentation of the directly beneficial effect on the cutaneous eyelids from mercury or silver because it complications, but is the steroid least likely to provided them with a sort of permanent produce such problems.“* eyeliner that was considered to be cosmetA case of madarosis (loss of the eyelashes) ically pleasing.210The discoloration of argyria is reported to have occurred following five or argyrosis does not disappear sponof use of topical epinephrine years taneously, but it supposedly can be treated hydrochloride for glaucoma.116 Regrowth of locally with a combination of sodium lashes followed discontinuation of the drug. thiosulfate and potassium ferricyanide injected into the skin or conjunctiva.86~18“

the eyelids. This is a phototoxic hyperpigmentation, with or without inflammatory signs, that occurs in patients who sunbathe after applying perfumes or colognes that contain oil of bergamot. ag This oil contains 5methoxypsoralen, a potent phototoxic agent. Because of the way in which perfume is daubed onto the skin with a sweeping motion of the finger, the area of dermatitis often has a teardrop or pendant shape. This accounts for the names of the disorder: berlock (English), berlocke (German), and berloque (French), all meaning trinket or pendant.lBS

H. CUMULATIVE

DEPOSITION

Pigmentation of the eyelids can result from the cumulative deposition of heavy metals which are present in some ophthalmic medications. This pigmentation (dyschromia) results from impregnation of tissues by particles of the metal itself, rather than from any alteration of melanin content. Blue-gray darkening of the eyelids has occurred with the chronic application of mercurial preparations such as mercuric oxide or ammoniated mercury.82J10 The granules of pigment are found to reside in the superficial dermis.8s Various tissues of the eye may

I. MELANOTIC

HYPERPICMENTATION

OR

HYPOPIGMENTATION

Pigmentary changes may result from the effects of drugs on the metabolism of melanin.13Jsg Numerous systemic medications, with or without the added influence of sunlight, are known to induce increased or decreased production of melanin. Increased pigmentation is called “lentigo” if it is localized, or “melanoderma” if it is more diffuse. Similarly, decreased pigmentation is referred to as “vitiligo” if it is localized or

Surv Ophthalmol 24 (2) September-October 1979

WILSON

patchy, and as “leukoderma” if it is diffuse. Hydroquinone is used topically in dermatology for the therapeutic purpose of lessening abnormal pigmentation, but periocular or ocular changes in melanotic pigmentation from topical ophthalmic medications are uncommon. Thiotepa (triethylenethiophosphoramide), a radiomimetic drug related to nitrogen mustard and used for the prevention or eradication of cornea1 vascularization or for the prevention of recurrence of pterygium, has produced permanent depigmentation of lashes (poliosis) and of periocular skin.10~2s~108~100 The cutaneous depigmentation may not appear, or may progress, for some time after the use of the drug. There were latent periods of one year in two reported caseszsJo8 and a delay of six years in another.“’ The reaction appears to occur mainly in darkly pigmented patients. The mechanism of the depigmentation is not understood, but the drug presumably interferes with the ability of melanocytes to produce melanin. One author thought that exposure to sunlight during treatment may have played a contributory role,‘O but this idea has not been substantiated. Histopathologic examination showed acanthosis, spongiosis (intercellular edema of the epidermis), and absence of melanin in the epidermis.“’ Vitiligo of the eyelids has occurred following the topical use of eserine.“’ All four patients were black, and depigmentation occurred ten months to five years after the beginning of treatment. Two of the patients showed signs of allergy to the drug. Pigmentation returned gradually after discontinuation of the medicine. One case has been recorded of melanotic hyperpigmentation of the eyelids following the chronic application of petroleum jelly for cosmetic purposes.” Hyperpigmentation can appear as a secondary change after allergic contact dermatitis, and this may have been the explanation for this case. There are no other examples of lentigo or melanoderma of the eyelids from topical substances (excluding photoallergic and phototoxic reactions that have been discussed already). Most cases of exogenous melanoderma result from industrial exposures to chemicals such as tars, hydrocarbon oils, and phenol compounds.47

ing with the conjunctiva and cornea, because it is in those tissues that such effects are best understood. The matter is of some importance, however, with regard to the eyelids. From time to time, I have encountered cases of severe meibomitis, marginal blepharitis, or severe and recurrent hordeola and chalazia from which organisms that are not usually found in these disorders can be isolated, e.g., Klebsiella pneumoniae, Proteus spp., Pseudomonas aeruginosa, and Candida spp. I have observed, as have others,15E~210 that such patients have had longterm treatment with multiple antibiotics and corticosteroids. These observations do not prove that the medications led to the appearance of the unusual organisms; it can be argued also that patients with severe and recalcitrant infections are almost certain to be treated with multiple medications over long periods of time. Nevertheless, it cannot do harm to consider the possibility that our drugs may, in some cases, be able to produce such problems, and to remember that the drugs being used by these patients are, at least, frequently providing no benefit. I have the clinical impression that the prolonged use of steroids makes the microbial control of staphylococcal blepharitis more difficult, even though they provide temporary improvement of symptoms by virtue of their antiinflammatory effects. Perhaps others disagree, but there are no longterm studies to lend support to either side of the controversy.

66

J. MICROBIAL

IMBALANCE

The ability of drugs to affect adversely the normal and pathogenic microbial flora of the eye will be discussed later in the sections deal-

K. MISCELLANEOUS

EFFECTS

Topical steroids can produce mild ptosis. In one study the ptosis was attributed to a myopathic effect of the vehicle rather than to the drug itself; the vehicle was a complex mixture of salts, buffers, and preservatives.‘S3 Guanethidine also produces ptosis because of its normal antiadrenergic effect.158

II. Conjunctiva The effects of drugs on the conjunctiva (and cornea) are much the same as those that have just been discussed for the eyelids. Most of the fundamental and general information has been covered and will not be repeated here or in the subsequent section on the cornea. These discussions will be confined largely to the specifics of conjunctival and cornea1 afflictions, although some repetition is unavoidable.

ADVERSE

EFFECTS OF TOPICAL

A. ANAPHYLACTOID

OPHTHALMIC

67

MEDICATIONS

CONJUNCTIVITIS

This is the equivalent of IgE-mediated urticaria or angioedema of the eyelids and represents type-1 hypersensitivity. It may be acute or chronic. Little specific information on these kinds of reactions is available becuase the acute form is rare and the mechanism involved in the chronic form is almost never diagnosed with certainty. In the acute form, the symptoms are of rapid onset and consist of tearing, itching (sometimes with almost frenzied rubbing of the eyes), redness, and burning. The conjunctiva is chemotic and hyperemic. The chemosis may be so prominent as to obscure the hyperemia so that the overall appearance is one of milky edema rather than redness. Mucoid discharge appears rapidly. The chronic form manifests the same symptoms and signs except that they are less impressive. Mild papillary hypertrophy may appear, and the discharge occasionally becomes mildly muc0purulent.ao6 A few eosinophiles are often found in conjunctival scrapings.ao~zoa The chronic form is usually mild, and nonspecificity of its signs is such that it is easily confused with drug-induced irritation. Usually it is unrealistic for the practitioner to hope to differentiate these disorders. As we shall see later, even the presence of eosinophiles may not be conclusive evidence that one is dealing with anaphylactoid conjunctivitis. The most effective treatments, aside from elimination of the cause, are cold compresses and topical vasoconstricting agents. Both of these treatments cause vasoconstriction and a return of vascular permeability toward normal. Epinephrine and other beta-adrenergic agents also produce elevated cellular levels of cyclic adenosine monophosphate (AMP); cyclic AMP, in turn, inhibits the degranulation of mast cells and basophiles so that there is less liberation of inflammatory mediators.‘@ Oral antihistaminic drugs might be indicated occasionally. Topical antihistamines are said not to be particularly effective; the explanation has been that histamine is only one of several vasoactive substances that mediate anaphylactoid conjunctivitis. It is true that several of these mediators are important in the production of asthma and that (systemic) antihistamines are of little value in that disease, but histamine is thought to be the only mediator of cutaneous anaphylactoid reactions in man.22s If this is true for the conjunc-

tiva, perhaps topical ophthalmic antihistamines are worthy of further study. Any such study, however, would be complicated by the fact that two classes of histamine receptors (H, and H,) are now recognized and that some antihistamines act mainly or solely on one kind of receptor; the stimulation of H, receptors, for example, inhibits the release of histamine from basophiles, so that an H, antagonist might actually facilitate the release of histamine.3s Currently available topical ophthalmic antihistamines tend to be allergenic (oddly enough) and irritating.“* Steroids would seldom be indicated and probably are less effective than vasoconstrictars.‘*’ I am unaware of the use of desensitization for drug-induced anaphylactoid conjunctivitis - it is better simply to stop the use of the drug. B. ALLERGIC

CONTACT

(DERMATO)

CONJUNCTIVITIS

Delayed (type-IV) hypersensitivity is a relatively common cause of drug-induced conjunctivitis. If the reaction is sufficiently severe or if the drug is used for a sufficient length of time, contact dermatitis supervenes. Theodore and Schlossman have reviewed in detail the many drugs that can cause contact dermatoconjunctivitis.202 They include antimicrobials, anesthetics, alkaloids, autonomies, antihistaminics, steroids, metals, antiseptics, preservatives, and vehicles - in short, practically anything. The most common causes in my experience have been IDU, gentamicin, atropine, and neomycin. Patients with allergic contact conjunctivitis complain of itching but not so prominently as do those with anaphylactoid reactions. Tearing is common. The conjunctivitis is papillary and is characterized by mucoid or mildly mucopurulent discharge (Figs. 3 and 4B), but the purulence generally is not so severe as to cause sealing of the eyelids in the mornings. Initially the conjunctivitis is worse inferonasally and inferiorly, where drugs tend to accumulate, but it can become diffuse after a time. The cornea usually shows punctate epithelial keratitis and erosions; these changes may be diffuse but are usually worse in the lower two-thirds of the cornea. Allergic contact conjunctivitis often can be differentiated from keratoconjunctivitis sicca by the fact that the former condition shows (in common with toxic or irritative reactions to drugs) punctate staining with fluorescein

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Surv Ophthalmol

24 (2) September-October

KEXATOCONJUNCTIVITISSICCA

WILSON

1979

DRUG-INDUCED KERATOCONJUNCTIVITIS

and rose bengal of the areas of the cornea and conjunctiva that lie behind the lower eyelid (Fig. 5) whereas the dry eye shows staining mainly in the interpalpebral area of exposure. In severe cases of contact allergy, the conjunctiva may develop mild keratinization. Punctal edema, stenosis, and occlusion may occur. The punctal occlusion may resolve spontaneously when the drug problem resolves, but three or four months may pass before the punctum opens and epiphora ceases. Dilation of the punctum may hasten recovery, but surgical intervention probably should be avoided until sufficient time has elapsed to allow for spontaneous reopening. When only the conjunctiva is involved, the clinical signs are insufficient to permit the specific diagnosis of delayed hypersensitivity. The exact nature of the reaction becomes evident only when the characteristic contact dermatitis appears. Cytologic study of the conjunctiva reveals mononuclear cells, occasional neutrophiles, and mucus (Fig. 6). Some epithelial cells may be mildly keratinized. Others may show “toxic granules”58 (enlarged organelles?) in the cytoplasm (Fig. 7). Toxic granules are large, basophilic granules unlike the normally small, neutrophilic or red-purple (with Giemsa) cytoplasmic granules. Toxic granules can be seen in mononuclear and polymorphonuclear cells as well as in epithelial cells. These various cytologic features are not specific for allergic contact conjunctivitis and can be seen in various forms of chronic druginduced conjunctivitis, including nonimmunologic irritation. They can occur also in chronic conjunctivitis that is unrelated to drugs. It has been said that eosinophiles are not found in contact dermatoconjunctivitis and that their presence would not be expected since they are characteristic of immediate, rather than delayed, hypersensitivity.‘s5 Theodore and Schlossman, however, found eosinophiles in conjunctival scrapings from patients

FIG. 5. Contrasting patterns of staining in keratoconjunctivitis sicca and drug-induced keratoconjunctivitis. Sicca tends to show staining in the exposed interpalpebral-fissure zone, whereas more inferior and inferonasal staining - where drugs gravitate - is more characteristic of drug-induced problems.

with allergic contact dermatoconjunctivitis,202 and Thygeson found eosinophiles in atropineinduced dermatoconjunctivitis with positive patch tests.21J Recent experimental work in animals and man has shown that one or more eosinophile chemotactic factors can be released from the sensitized lymphocytes that mediate delayed hypersensitivity.37~3*~e1~11g~z17~zz2 For eosinophiles to be attracted - at least in some circumstances - it may be necessary for the factor to be activated by antigenantibody complexes, thus bringing humoral immunity into the sequence of events.117*217 So it is possible that eosinophiles do not appear in drug-induced delayed hypersensitivity unless there is also immune-complex-mediated (type-III) hypersensitivity, although the issue is presently unsettled. Nevertheless, it has become clear that they can be found in some cases (Fig. 7). Whether such cases are characterized by the presence of associated humoral antibody responses would seem to be a moot point insofar as the clinician is concerned. I have found numerous eosinophiles in scrapings from patients with contact allergies to IDU or hyoscine and have found a few in cases of contact allergy to atropine and to neomycin. I have encountered them also in chronic reactions of the conjunctiva to vasoconstrictors, miotics, antibiotics, and the exact immunologic preservatives; mechanisms involved in these cases were not elucidated. In addition to eosinophiles, basophiles are known to appear in some allergic diseases of the eye.*15There is evidence now that delayed hypersensitivity can elicit a basophilic reaction.s0*172This occurs in the early phases of cutaneous delayed hypersensitivity to protein or hapten-protein antigens in animals and previously has been called Jones-Mote hypersensitivity. Because of the prominent basophilic response, the term “cutaneous basophile hypersensitivity” has been suggested.4g~50~172 I have not seen basophiles in conjunctival drug reactions and am not aware

ADVERSE

EFFECTS OF TOPICAL

OPHTHALMIC

MEDICATIONS

69

FIG. 6. Usual cytologic findings in conjunctival scraping from case of chronic drug-induced conjunctivitis. Mononuclear cells (notched arrowheads), occasional neutrophiles (curved arrow), and strands of mucus (block arrow). Eosinophiles appear in some allergic problems (see text). The erythrocytes have no direct relationship to the drug-induced problem and indicate only that bleeding occurred during the taking of the scraping. (Giemsa, 400 X)

FIG. 7. Epithelial “toxic granules” (prominent gray dots in cytoplasm of large cell) in conjunctival scraping from patient with allergic contact dermatoconjunctivitis caused by iododeoxyuridine. Scraping illustrates also that eosinophiles (arrow) can appear in this disease. (Giemsa, 1000 X)

of their having been reported - but perhaps we have not looked. The treatment of allergic contact conjunctivitis is cessation of the causative drug. Other possible measures have been discussed in the section on the eyelid. C. CICATRIZINC

ALLERGIC

CONJUNCTIVITIS

There are no examples of clearly immunologic cicatrizing conjunctivitis from topical drugs. Conjunctival scarring can occur during the use of topical medications, but these reactions are thought to be mainly of toxic or irritative origin and will be discussed later. Two cases of “ocular pseudopemphigoid” from the longterm use of echothiophate iodide have been reported.lE4 There was

strongly suggestive evidence that these reactions were immunologic, but the authors were unwilling to exclude the possibility that the effects were toxic. Each of the cases was unilateral and was associated with use of the drug only in the involved eye. Clinical findings included conjunctival scarring and shrinkage, conjunctival epidermalization, formation of symblepharons, foreshortening of inferior conjunctival fornices, and punctal occlusion. The cornea’ was normal in one patient, but there was an apparently sterile ulcer with cornea1 vascularization in the other Histopathologic examinations patient. revealed subepithelial fibrosis, decreased numbers of goblet cells, and stromal infiltrations of plasma cells and lymphocytes. Immunofluorescent studies of a biopsy from one case showed stromal plasma cells that

70

Surv Ophthalmpl 24 (2) September-October 1979

stained for IgA, IgD, IgE and Cs; there was no epithelial or basement-membrane staining as is seen in pemphigus vulgaris and ocular pemphigoid, respectively. The affected eye of the second case showed plasma-cell staining for IgG, IgD, IgA, and IgE; interepithelial staining for IgG; and basement-membrane staining for IgG. Epithelial and basementmembrane staining disappeared three weeks after stopping the use of the drug. Although it is a systemically administered drug, I should mention that the betaadrenergic blocking agent, practolol, is known to cause an “oculomucocutaneous syndrome.“221 The drug is used in England, Europe, and Australia for angina pectoris, cardiac arrhythmias, and other disorders of abnormal sympathetic activity. It can produce conjunctival scarring and pseudopemphigoid, keratoconjunctivitis sicca, corneal ulceration and opacification, various cutaneous changes, and numerous systemic problems. The conjunctival involvement probably represents immune-complex (type III) hypersensitivity. Progression of the disease ceases, and improvement ensues, when the drug is stopped. D. NONSPECIFIC OR TOXIC

(PAPILLARY)

WILSON

that are compounded by the clinician or his pharmacist for use in the eye and include amphotericin B (along with its solubilizer, sodium desoxycholate) and “fortified”” drops of bacitracin (10,000 units/ml), gentamicin (8-15 mg/ml), and neomycin (5-8 mg/ml). Acetylcysteine is another example; it was used formerly as an eyedrop in a 20% solution as a collagenase inhibitor or as a mucolytic agent, but this concentration is commonly irritating. A 10% solution seems to be equally effective and is much better tolerated. Some commercially available drugs commonly produce signs of irritation after two or three IDU,

weeks’ use: neomycin, gentamicin, chloramphenicol, and even boric acid.

IRRITATIVE

CONJUNCTIVITIS

Some drugs are directly irritating to tissues and can produce inflammation in the absence of any immunologic response. Of course, some substances are capable of eliciting both irritative and allergic responses. Certain features distinguish an irritative reaction from an allergic one. The former can occur with the first exposure to the substance. It is limited to the site of contact, associated with little or no itching, and not associated with a positive patch test unless the substance is highly irritating.2o6 A drug may be inherently irritating or may be so because of pH, tonicity, toxic microbial products from contamination, or the development of toxic degradation products. Numerous drugs are known to cause transient stinging of the eyes after instillation, e.g., cocaine, pontocaine, epinephrine, sulfacetamide 30%, and others; such mild irritation is of little importance. Drugs or concentrations of drugs that regularly cause severe or prolonged irritation tend not to be used except in rather desperate circumstances when no other treatment is adequate or available. Examples in this category usually are nonophthalmic drugs

FIG. 8. Conjunctivitis secondary to the irritative or toxic, rather than allergenic, effects of drugs. Findings are nonspecific, consisting of hyperemia, mild papillary hypertrophy, and watery or mucoid discharge.

FIG. 9. Punctate epithelial keratitis and staining secondary to toxic effects of neomycin.

ADVERSE EFFECTS OF TOPICAL OPHTHALMIC

MEDICATIONS

Immunologic mechanisms seldom can be excluded in these cases. The irritation that occurs with chloramphenicol may be related to preservatives since the drug itself is said to be nontoxic to local tissues.S6,102The same may hold true for gentamicin. One drug that is routinely irritating but that is used commonly is silver nitrate. The 1% solution which is used for Credt prophylaxis can be expected to cause a shortlived conjunctivitis in 50-100% of cases.142 Stronger solutions can be very damaging, and evaporation from bottles of 1% silver nitrate can lead to dangerously high concentrations. Silver nitrate should be stored in wax ampules to prevent evaporative concentration.“’ Another reason for the use of wax ampules is the fact that the alkalinity of glass can cause precipitation of silver, leaving behind nitric acid. The clinician should consider irrigating the eyes of patients who have been treated with 1% silver nitrate (as for superior limbic keratoconjunctivitis) in the hope of minimizing subsequent irritation. Even 0.5% silver nitrate, applied to the eyelids for treatment of blepharitis, can result in two or three days of complaints in patients with keratoconjunctivitis sicca. Irrigation with saline can minimize the toxic, and perhaps the therapeutic, effects of silver nitrate by forming a harmless precipitate of silver chloride. Obviously, the ophthalmic use of solid sticks of silver nitrate must be avoided. Miotic alkaloids, especially pilocarpine and carbachol, are fairly common causes of nonspecific irritative conjunctivitis. This probably relates to the fact that these drugs form toxic degradation products.2”s More potent miotics are likely to cause follicular or cicatrizing forms of irritative conjunctivitis which will be discussed later. Many preservatives are irritating, but their concentrations in proprietary medications are sufficiently low that individual susceptibility may be a critical factor. Benzalkonium seems to be the most potentially irritating preservative of those that are in common use, as will be discussed further in the section on the cornea. Sometimes a compromising factor such as the wearing of hard or soft contact lenses or keratoconjunctivitis sicca has seemed to me to precipitate irritation from preservatives. It has been suggested that sicca patients, particularly when they are wearing soft contact lenses, may benefit from being given a methylcellulose artificial tear without preservative. gg Drops of normal saline solu-

71

tion without preservative may also be used. Diagnosis is nearly always presumptive. Clinical signs are nonspecific, and there are no definitive confirmatory tests. The conjunctival reaction is hyperemic and papillary with watery or mucoid discharge (Fig. 8). Compared to allergic reactions there is less tendency for irritative problems to be diffuse so that the upper bulbar conjunctiva may be spared even in cases of long duration. Punctal stenosis can occur in the absence of any other evidence of conjunctival scarring. Cornea1 involvement is nonspecific, consisting of punctate staining (Fig. 9). Rose bengal may demonstrate similar staining of the conjunctiva. Cytologic findings are the same as those already described for allergic contact conjunctivitis, except that eosinophiles probably do not appear unless there is an allergic component in addition to the toxic one. Very potent irritants such as ipecac, lye, lime, or turpentine are said to produce marked eosinophilic reactions, however.83,206 Such substances are used sometimes by patients for the production of factitious, self-induced conjunctivitis. Final diagnosis of toxic papillary keratoconjunctivitis is largely by exclusion of other possibilities. The treatment is avoidance of the irritating drug. In some cases this may be accomplished merely by giving the patient a fresh preparation that has not undergone degradation. Refrigeration and protection from exposure to light are valuable preventive measures for some drugs. The ability to eliminate the conjunctivitis by substituting a nonirritating preparation of the same drug has been cited as one of the main diagnostic features of irritation.“’ Before leaving this subject, I should mention the sensitivity to cyclopentolate, which has been described by Havener.lo4 The pathogenesis is unknown. I include it here because the onset is rapid (within minutes) following instillat,ion of the drug and because itching is not a significant complaint (suggesting that it may not be an allergy). Havener does, however, refer loosely to the problem as an allergy, and it is possible that it is a type-1 hypersensitivity. No mention was made of the presence or the absence of eosinophiles. The problem occurs each time the affected patient is given cyclopentolate drops for ocular examination. Redness, tearing, and mucoid discharge ensue. The cornea shows punctate staining. One case developed punctal occlusion after numerous insults.

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Surv ~Ophthalmol 24 (2) September-October 1979

WILSON

FIG. 10. Follicular conjunctivitis induced by iododeoxyuridine.

FIG. 11. Cornea1 keratinization secondary to many years’ use of echothiophate iodide for glaucoma (Courtesy of M Grayson, MD).

E. FOLLICULAR

could be made to disappear by administration of nonirritating preparations of the same drugs that had induced the follicles.206 Ostler’s patient with atropine-induced follicular conjunctivitis showed no evidence of allergy to atropine.* The follicles are most prominent in the lower tarsal conjunctiva and fornix (Fig. lo), but may develop on the upper tarsal conjunctiva in severe cases. The cytology of toxic follicular conjunctivitis is like that of other drug reactions: mononuclear cells, fewer neutrophiles, and mucus. There is general agreement that eosinophiles do not occur in purely toxic follicular conjunctivitis. A few may be seen in follicular reactions to atropine,s8~21s but atropine is clearly an allergen as well as an irritant. The drug may be acting in both ways when eosinophiles are present, although atropine can cause follicles and eosinophiles in the absence of contact dermatitis.216 Atropine-induced follicles are rather unimpressive in size and number, again suggesting that it may act more as an allergen than as an irritant.

IRRITATIVE

OR TOXIC

CONJUNCTIVITIS

Certain drugs can produce an apparently follicular conjunctivitis, namely physostigmine, echothiophate, diisopropylfluorophosphate, neostigmine, furtrethonium iodide, IDU, pilocarpine, and atropine.206J1s I say that the conjunctivitis is apparently follicular because proof is lacking that these drugs induce the development of’ true lymphoid follicles. Ostler examined histopathologically the conjunctiva from a case of atropine-induced “follicular” conjunctivitis and found focal accumulations of lymphocytes, but these lacked the germinal centers that are found in true, fully developed follicles.* Clinically, however, the reactions are indistinguishable from follicular ones, and it seems reasonable for now to continue to use the traditional designation of follicular conjunctivitis for these reactions. It has been thought that the follicular reactions are irritative rather than allergic because they are not accompanied by itching, conjunctival eosinophilia, or (except occasionally) dermatitis.20s The idea cannot be refuted at the uresent time. because the actual pathogenesis bf follicles ‘is unknown. The similarities of lymph nodes and follicles, with their proliferating lymphocytes and germinal centers, suggest some kind of immune stimulus for follicle formation. To the contrary, ipecac is a pure irritant but has been reported to be able to cause conjunctival follicles.20B Furthermore. Theodore and Schlossman found that drug-induced follicles

F. CICATRIZINC IRRITATIVE

AND KERATINIZINC

OR TOXIC

CONJUNCTIVITIS

The aforementioned follicle-inducing drugs, with the exception of atropine, can also produce keratinization of the conjunctiva or cornea (Fig. 11) and scarring of the conjunctiva (Fig. 12) with prolonged use.21EPunctal, and even canalicular, occlusion can develop. Some cases show cornea1 pannus (Fig. 13) *Ostler HB: Personal communication, 1977

ADVERSE

EFFECTS OF TOPICAL

OPHTHALMIC

MEDICATIONS

FIG. 12. Wispy, but extensive, conjunctival scarring (pale areas in palpebral conjunctiva) after use of iododeoxyuridine for several months. Note also the follicular response and that the cornea1 “herpes” for which the drug was prescribed is obviously an inactive scar.

73

FIG. 13. Iododeoxyuridine-induced pseudotrachoma syndrome showing extensive cornea1 pannus. The drug had also caused follicular conjunctivitis, punctal occlusion, and conjunctival scarring (Courtesy of M Grayson, MD).

and (at least with IDU) preauricular adenopathy, in addition to conjunctival follicles and scarring, and are referred to as “pseudotrachoma syndromes.“21B Upper tarsal follicles and loss of vision can occur. Even limbal follicles, usually considered to be highly suggestive of chlamydial disease, have been reported in one case of IDU toxicity;21e I also have encountered such a case (Fig. 14).

The limbal follicles do not produce the pathognomonic Herbert’s pits of trachoma. The cytology of drug-induced pseudotrachoma is the same as that described in the foregoing section. Neutrophiles are never so prominent as they are in chlamydial infections, and, of course, there are no inclusions. Molluscum contagiosum is another common cause of pseudotrachoma. Mollusca elicit purely mononuclear responses, but it must be remembered that many of these cases have been treated chronically with various drugs. Corticosteroids have little or no effect on toxic follicular and pseudotrachomatous conjunctivitis. There is an interesting historic example of cicatrizing conjunctivitis caused by incompatibility of drugs. It was found that calomel (mercurous chloride) instilled into the eye could react with soluble iodides or bromides that had been given systemically.87 The combination resulted in the production of mercuric iodide or bromide and metallic mercury; the first two compounds are caustic and can produce membranous, purulent, and cicatriz-

FIG. 14. Limbal follicles (arrow and irregular light reflexes) caused by iododeoxyuridine. ing conjunctivitis. G. CUMULATIVE

DEPOSITION

The general and cutaneous aspects of mercurial and silver deposition have been discussed. Granules of mercury are found in the stroma of the bulbar conjunctiva, particularly around blood vessels near the cornea.2*84 In argyrosis, particles of silver are reported to have been found in phagocytes, in reticulin and elastic fibers, and in basement membranes of blood vessels of the conjunctival stroma 1s7~147~230~2s1 as well as in epithelial cells.lo; An ultrastructural study disclosed particles of silver in the conjunctiva only within the connective tissue cells of the stroma.gs The epithelium and mucosal basement membrane of the lacrimal sac may also be involved in argyrosis.2s1 Conjunctival depositions of mercury or silver are asymp-

74

WILSON

Surv Ophthalmol 24 (2) September-October 1979

FIG. 15. Histopathologic appearance of conjunctival “adrenochrome” deposits from the chronic use of epinephrine eyedrops for glaucoma. The deposits are found to reside within conjunctival epithelial cysts. Largest deposit (arrow) consists of a dark brown or black center of oxidized and polymerized epinephrine, surrounded by a lighter pink periphery of less fully polymerized drug. (Hematoxylin and eosin, 100 X)

tomatic except for the blue-gray discoloration, which may be considerable; one patient’s conjunctiva actually became jetblack from argyrosis.147 The most common conjunctival dyschromia is the so-called adrenochrome deposit. These deposits occur in glaucoma patients who have been treated with epinephrine eyedrops. 39 The drug apparently accumulates in preexisting conjunctival cysts, oxidizes and polymerizes, and is converted to a melanin-like pigment (usually said to be adrenochrome) which persists indefinitely.‘“’ Epinephrine in bottles undergoes the same kind of oxidation and darkening. Exposure to light enhances the process, so epinephrine is stored in dark containers.31 Levo-epinephrine is said to resist such decomposition much longer (at least 21 weeks) than epinephrine borate preparations (four weeks),8 but the latter may be much less irritating.lo3 Histopathologically, the deposits are homogenous, pink to dark brown, amorphous clumps (Fig. 15) which have the staining characteristics of melanin in that they stain black with silver stains and are bleached by hydrogen peroxide .2soThe concept that the deposits may actually be melanin, rather than adrenochrome, will be discussed later in the section on the cornea. It is said that a year or more of daily therapy is required for the development of adrenochrome deposits.lo3 Clinically, one sees discrete black or dark brown concretions in the lower, and occasionally the upper, tarsal conjunctiva (Fig. 16). The deposits vary in size from fine granules to one or two millimeters. No inflammation occurs, and the conjunctival deposits are asymptomatic.

Adrenochromes in the nasolacrimal system, however, have caused obstruction.182 Particles of mascara or eyeliner can accumulate in tarsal conjunctiva, producing a similar clinical appearance. They are lighter brown, smaller, usually more numerous, and more prominent in the upper lid than are adrenochrome deposits and seem to elicit a mild follicular response in some patients. Nevertheless, they are asymptomatic. White stonelike concretions of sulfadiazine have been described in cysts of the palpebral conjunctiva.28 The patient had used sulfadiazine eyedrops several times daily for about a year. H. MICROBIAL

IMBALANCE

Many clinicians, including myself, have had clinical impressions that the chronic use of antibiotics or corticosteroids (and possibly antiviral agents) can alter the normal and pathogenic flora of the eyelids and conjunctiva.6~‘~46~152~195~213~225 Impressions that such drugs can alter normal microbial flora in various areas of the body are shared by many of our colleagues in internal medicine,‘O dermato10gy,13Jg2immunology,21 and other fields of medicine. Numerous clinical and experimental references to the adverse effects of antibiotics and corticosteroids on ocular infections have been cited by Bettman et al in their article concerning the use of steroid/ anti-infective combinations.24* Havener also reviews the subject, with commendable objectivity, and cites a number of references.‘O’ *Read the critical comment by Ellis at the end of the article before drawing any conclusions as to the harmlessness of these combinations.

ADVERSE EFFECTS OF TOPICAL OPHTHALMIC

FIG. 16. Clinical

appearance

of

MEDICATIONS

“adreno-

chrome” deposits. It is well known that the chronic use of systemic antibiotics can lead to the overgrowth of organisms (particularly fungi) in the mouth and in the gastrointestinal, respiratory, and genito-urinary tracts.“’ It has been demonstrated rather conclusively also that one of the natural defense mechanisms of the conjunctiva is the production of antibiotics by bacteria of the normal flora.g3*g4 To the contrary, at least one study failed to show alteration of normal ocular flora following the administration of a topical antibiotic.26 There have been very few studies, however, that have dealt with the chronic, rather than the shortterm, use of antibioticsz6 The ability of antibiotics to bring about the emergence of resistant flora by any of several mechanisms is common knowledge.” At the very least, we must keep in mind the fact that we are apt, with the chronic use of antibiotics, to encounter organisms that have become resistant to our therapy. Reevaluation of the effects of therapy and of the results of cultures and sensitivity studies are indicated periodically in the course of any chronic antibiotic usage. There is the feeling, then, among many clinicians that the chronic use of antibiotics tends to convert the normal, predominantly gram-positive flora of the eyelids and conjunctiva to one that contains more gramnegative bacteria and fungi. The ability of corticosteroids to produce alterations in flora is more uncertain, although there is clinical and experimental evidence in support of the contention.24~25~‘01 I.

MISCELLANEOUS

EFFECTS

Patients with nonspecific complaints of ocular irritation frequently use topical vaso-

7s

FIG. 17. Allergic contact keratitis. Marginal cornea1 ulcer as a manifestation of contact allergy to neomycin. constrictors to soothe and whiten the eyes. Some of these preparations can be purchased without prescriptions. Vasoconstriction produces satisfying whitening of vascular congestion, but rebound hyperemia may follow.‘3~‘5 The rebound effect causes the patient to use the drug more and more frequently, thus perpetuating the problem. A similar problem may occur with topical corticosteroids. These agents have been shown to have vasoconstrictive properties, but tachyphylaxis (tolerance) occurs with repeated applications.42 In the skin, at least, vasoconstriction cannot be elicited by these drugs after only a few days’ use. This may explain partly the tendency for many steroidtreated ophthalmic patients to require progressively more steroid as time goes on. III. Cornea A. ANAPHYLACTOID

KERATITIS

Drugs cause keratitis that might be construed as anaphylactoid even less often than they cause anaphylactoid blepharitis or conjunctivitis. The situation is different in other presumably IgE-mediated diseases such as vernal catarrh and atopic dermatitis, each of which can manifest pronounced cornea1 involvement. The response of the cornea to anaphylactoid drug reactions is more like its response to hayfever: usually the cornea is spared, but transient stippling of the epithelium can probably occur occasionally.2o7 A marginal cornea1 delle can be caused by limbal chemosis.pa Exceptionally, transient cornea1 edema has been seen with attacks of urticaria or angioedema, but topical drugs were not implicated.207

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FIG. 18. Toxic effects on cornea1 epithelium of iododeoxyuridine. Heaps and swirls of opaque epithelium. Note also the characteristic inferior location of the drug-induced conjunctival hyperemia.

FIG. 19. Iododeoxyuridine-induced pseudodendrite. “Y’‘-shaped lesion consisting of heaped, opaque epithelium (near lower right border of pupil).

B. ALLERGIC CONTACT KERATITIS

tual problem medicamentosus.

The cornea is commonly involved in cases of allergic contact dermatoconjunctivitis. Punctate and coarse epithelial keratopathy are the usual findings. Initially these changes tend to be more prominent on the inferior cornea, but they later become disseminated. Much of the epithelium is degenerated but not absent, so staining with rose bengal can be helpful. Rarely, marginal cornea1 ulcers occur.20*~214 They are circumferential with the limbus and are characterized by cellular infiltrate in the superficial stroma, slight edema, and ulceration of the epithelium and superficial stroma (Fig. 17). These ulcers are said to respond to topical steroids,208 but they heal rapidly also with mere discontinuation of the causative drug. C. IRRITATIVE OR TOXIC KERATITIS

Many drugs, preservatives, and vehicles can be irritating to the cornea1 epithelium, including all of the drugs that were previously discussed as being irritants for the conjunctiva. The most common manifestations are coarse and punctate epithelial lesions (Fig. 9). Heaps and swirls of opaque epithelium (Fig. 18) also can appear and can lead to large erosions. Cornea1 keratinization occurs rarely (Fig. 11). “Pseudodendrites” can develop and are important sources of diagnostic confusion (Fig. 19). It is not uncommon for these lesions to be misdiagnosed as herpetic keratitis with the result that topical antiviral therapy is increased or started, thus compounding the ac-

of keratoconjunctivitis occur Pseudodendrites

when opaque, degenerated epithelium fortuitously assumes a linear or dendritiform configuration or when three or four advancing waves of healing epithelium meet. The lesions tend to be linear or “Y”-shaped and are usually oriented horizontally, in the general area of Hudson-StZhli lines. Unlike the true dendrite, the pseudodendrite has no repetitively dichotomous branching and no bulbous terminal erosions. Moreover, the pseudodendrite is composed of heaped, opaque epithelium with a granular appearance rather than absent epithelium; rose bengal may provide more impressive staining than fluorescein. Further evidence that the lesion is not herpetic can be obtained by testing cornea1 sensation and by noting the absence of multinucleated giant cells in scrapings. Virologic studies, of course, are negative. In my experience, IDU has been the most common cause of these changes of heaped, opaque epithelium and pseudodendrites, although I have also seen cases that were caused by neomycin or gentamicin. These manifestations of IDU toxicity, as well as the still more common coarse and punctate staining of the cornea1 epithelium,‘0*146 may be related to irritative products of degradation such as iodurocil.“’ Despite the tendency for IDU to produce such epithelial alterations, it seems not to retard directly the healing of cornea1 epithelium.77*86It does, however, inhibit heal-

ADVERSE EFFECTS OF TOPICAL OPHTHALMIC

MEDICATIONS

77

FIG. 20. A: Iododeoxyuridine-induced pseudogeographic ulcer. The lesion differs from an infectious, herpetic geographic ulcer in that the former has a smoothly undulating border, a rolled-under edge, staining of the bed of the ulcer with rose bengal, and a little-changing appearance over the course of many days. B: Same patient three weeks later showing nearly complete healing of the epithelium after cessation of iododeoxyuridine and the application of a therapeutic soft contact lens.

ing of the cornea1 stroma.8e IDU’s toxic sonal observation). effects on the cornea1 (and conjunctival) Two other antiviral agents, adenine stroma may account for its ability to produce arabinoside and trifluorothymidine, seem to a follicular response (Figs. 10 and 14) and the be able to cause toxic effects similar to those pseudotrachoma syndrome (Figs. 13 and 14), of IDU but may be less likely to do ~0.‘~~ both of which represent primarily subPfister and BursteinlB7 have studied the toxepithelial pathologic changes. ic effects of various topical drugs on the corIDU’s stromal toxicity may account also neal epithelium of the rabbit by scanning elecfor the common clinical observation that in- tron microscopy.167 Single applications of the dolent, postherpetic, sterile, “trophic,” following substances produced no abnorepithelial defects fail to heal as long as IDU malities of the epithelial surface: atropine I%, therapy is continued - epithelial defects tend chloramphenicol 0.5%,epinephryl borate 1% to heal slowly over damaged stroma. These proparacaine 0.5%, tetracaine 0.5% boric “pseudogeographic ulcers,” like pseudodenacid 5%, methylcellulose 0.5% polyvinyl drites, are mistaken frequently for active alcohol 1.6%, saline solution 0.9% replication of herpetic virus in the cornea1 chlorobutanol 0.5%, disodium edetate 0.1% epithelium. It is important for the clinician to and thimerosal 0.01%. Gentamicin 0.3% differentiate these noninfectious and infec- caused the central microvilli of various cells erected. Other substances tious geographic ulcers. A noninfectious one to become (Fig. 20) is characterized by a smoothly un- produced moderate changes with some cells dulating border, a rolled-under edge, rose- showing loss of microvilli and wrinkling of bengal staining of the bed, and a clinical plasma membranes and a few cells showing of plasma membranes and appearance that changes little over the course disruption of several days. An infectious geographic ul- premature desquamation; drugs in this group cer has irregularly heaped edges with ad- were echothiophate 0.25%, pilocarpine 2%, fluorescein 2%, and a commercially available vancing breakdown of epithelium, fluorescein strip staining of the bed, and irregularly geo- fluorescein-impregnated paper moistened with one drop of 0.9% saline solugraphic borders. In the one case IDU therapy should be stopped, while in the other IDU tion. A third group of substances produced may be begun or increased. The toxicity of significant changes consisting of complete IDU on the cornea1 stroma has been loss of microvilli, wrinkling of plasma memsuspected of aggravating or causing sub- branes, and premature desquamation of the epithelial “ghost” scars beneath herpetic den- top layer of epithelium: cocaine 4% and a drites,lsl beneath the epithelial lesions of mixture of neomycin-gramicidin-polymyxin superficial ._ punctate . _ keratitis of Thygeson,* . . . _ *Thvzeson P: Personal communication. 1972 and in epidemic keratoconjunctivitis (per-

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24 (2) September-October

1979

WILSON

FIG. 2 1. Toxic keratoconjunctivitis

from chronic use of topical anesthetic eyedrops. Papillary conjunctivitis with mucopurulent exudate, chronic epithelial defect with rolled edge, circular stromal infiltrate (small asterisk) without stromal ulceration, and endothelial plaque of inflammatory cells (large asterisk).

B without benzalkonium (BAK). Severe changes of loss of microvilli, disruption of plasma membranes, and desquamation of the top two layers of cells were produced by BAK 0.01% alone or in combination with pilocarpine 2% or gentamicin 0.3%. The authors went so far as to suggest that the ophthalmic use of BAK should be reviewed critically and perhaps even curtailed in favor of less cytotoxic preservatives. BAK 0.01% is used in many currently as a preservative ophthalmic drugs, including a number of artificial tears and many “over-the-counter” preparations. Another study found that BAK 1% produced necrosis and severe hyperemia of the conjunctiva, excessive mucus, cornea1 clouding, and almost total destruction of the cornea1 epithelium and endothelium.‘s No changes were produced by 1% thimerosal or chlorobutanol. BAK has been found also to produce solubilization of epithelial intercellular cement. The cytotoxic effects of antiglaucoma medications on cornea1 epithelium in tissue culture have been studied.125 Cytotoxicities were rated in the following order, beginning with the most toxic drug and proceeding to the least toxic one: neostigmine, carbachol, epinephrine, echothiophate, guanethidine, pilocarpine combined with epinephrine, demecarium, and pilocarpine. Toxic effects from the prolonged use of topical anesthetic agents can be serious. These drugs can produce alteration or destruction of epithelial mitochondria, endoplasmic reticulum, intracellular proteins, tonotibrils, desmosomes, and microvilli.gs~133

Topical anesthetics interfere also with cellmembrane permeability, osmotic stability, glycolysis, and oxygen consumption of There is inhibition of epithelial cells. 30~83~106~154 cellular mitosis and migration,“’ and decreased cornea1 sensation contributes to drying and exposure. Spotty drying of the cornea1 epithelium is seen commonly after the instillation of a topical anesthetic if the patient fails to blink. The ocular syndrome of topical anesthetic abuse is characteristic.30~53~14g*17’ Pain becomes severe and may lead to the use of narcotics, retrobulbar alcohol, or hospitalization. Discomfort increases and is relieved for progressively shorter periods of time as use of the drug is continued. Clinical findings include severe conjunctival hyperemia, chronic epithelial defect with rolled edges, decreased or absent cornea1 sensation, pannus, stromal infiltrate without loss of substance, white infiltrates resembling “immune (Wessely) rings” in the stroma and on the endothelium, and striate keratopathy (Fig. 21). Hypopyon and hyphema can occur. Cytologic examinations show mononuclear and neutrophilic cells with severe degenerative changes of epithelial cells. Cornea1 stippling and conjunctival irritation commonly result from the topical use of amphotericin B. Eyedrops are made in concentrations of 0.1% to 0.5% from amphotericin B that is marketed for parenteral use. Definite irritation occurs with solutions of 0.3% or greater and has been attributed to the sodium desoxycholate which is added to make the drug soluble in water.226

ADVERSE

EFFECTS OF TOPICAL

OPHTHALMIC

MEDICATIONS

79

FIG. 22. Toxic calcific band keratopathy secondary to the preservative phenylmercuric nitrate in topical ophthalmic medication (sulfisoxasole diolamine). A: Finely granular opacities of calcium at the

level of Bowman’s layer in the paracentral cornea (extending down and left, and to the right, from the lower aspect of the light reflex). Note also the deposition of mercury itself (rather than calcium) in the central aspect of the anterior lens capsule (mercurialentis; edge of this deposition is visible near upper left edge of pupil). B: Another patient who had used topical sulfisoxisole diolamine with phenylmercuric nitrate for several years, manifesting finely granular peripheral cornea1 deposits of calcium in Bowman’s

layer. Nearly all of the other polyene antifungal agents are somewhat irritating to the eye.“* Of those that have been used clinically (nystatin, pimaricin, dermostatin, amphotericin A and B, candicidin, and trichomycin), pimaricin is the least toxic and most stable. I have used pimaricin 5% in several cases and have observed no adverse effects. The imidazole antifungals - clotrimazole, miconazole, econazole, and thiabendazole appear to be relatively nonirritating.“* The cases in which I have used clotrimazole ointment 1% showed no signs of toxicity. Topical flucytosine 1.5% is completely nonirritating.“* One more mention should be made of the danger of using sticks of solid silver nitrate. A case was reported of complete opacification of the cornea, requiring keratoplasty, following cauterization of a chalazion with such a stick.@’ Mechanical “irritation” might be considered here. It has been suggested for years that ophthalmic ointments retard the healing of wounds* and that globules of ointment can become entrapped within cornea1 tissues. Recent studies indicate that ointments do not impede healing of cornea1 wounds and that *The effects of drugs on wound healing is an important subject about which much has been written 11.17.‘18.86,88,105,1z1L31.116.1BB.111 However detailed discussion of this subject is beyond thk scope of this review.

entrapment

is unlikely.71~e5 Entrapment

oc-

curs mainly when the ointment is surrounded completely by stroma, as in a slanting, flaplike laceration.‘* In any case, entrapped ointment elicits no significant reaction in the tissues and disappears eventually.‘* Particles of corticosteroid suspensions can become enmeshed among the giant papillae of vernal catarrh and can produce cornea1 irritation.l13 Steroid solutions avoid this problem.“3 Additional discussion of toxic and irritative effects of drugs was provided in the section on the conjunctiva. Most of the conjunctival effects apply equally to the cornea. D. PHOTOTOXIC KERATITIS Proflavine, neutral red, and other photoactive substances have been used topically, in conjunction with exposure to various kinds of light, to induce phototoxic damage to herpesvirus in cornea1 infections. The phototoxicity can affect the eye as well. Epithelial keratitis, anterior uveitis, and even hypopyon have been reported.16’ In fact, some observations have suggested that phototherapy with proflavine or neutral red may act mainly by the production of phototoxic “debridement” of the epithelium.62 E. TOXIC CALCIFIC BAND KERATOPATHY

keratopathy (CBSK) Calcific band-shaped can result from the chronic use of pilocarpine

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24 (2) September-October

or other drops containing phenylmercuric nitrate (PMN) as a preservative (Fig. 22). 120~121 It is the mercury in the preservative, and not the pilocarpine, that has been incriminated as leading to the development of the CBSK. It has been known for many years that people who are exposed to mercurial vapors (workers in the manufacture of thermometers, felt hats, batteries; occasionally dentists) can develop band keratopathy.13,74 These opacities, and those associated with PMN, are known now to consist of calcium rather than mercury. The mercury seems to act as a denaturant of proteins, and the resulting devitalization of tissues promotes the deposition of calcium.7s There is no histopathologic difference between mercury-induced and other CBSK. Some of the mercurial cases have shown small amounts of iron, perhaps accounting for the fact that some of the hands have brown tints. In most cases the CBSK from PMN develops only after several years’ use of the drops, but it appeared within seven or eight months in a couple of cases. It not infrequently begins in the paracentral or central cornea (Fig. 22A), unlike other forms of CBSK. Finely granular, gray, subepithelial flecks appear and spread later to the limbus and sometimes to the pupillary area. In other cases the deposits may begin near the limbus (Fig. 22B). In addition to CBSK, PMN can be a source of the deposition of mercury itself in other parts of the eye,74 and these deposits can be of help in clinical diagnosis. Cornea1 deposition of mercury can produce a goldenbrown sheen at the level of Descemet’s membrane, particularly in the periphery. Pupillary dilatation may make evident a similar pink to golden-brown discoloration of the central aspect of the anterior lens capsule (mercurialentis) (Fig. 22A). There have been two known cases of mercurialentis from sulfisoxazole with PMN.74 Mercurialentis has been associated also with the use of epinephryl borate drops containing phenylmercuric acetate (PMA) as a preservative.74 The PMN-containing pilocarpine and the PMA-containing epinephrine have been withdrawn from the market because of the reports of CBSK and mercurialentis, but some other proprietary preparations containing these oreservatives are still available. 1

WILSON

1979

Treatment of mercury-induced CBSK is by debridement, chelation with disodium ethylenediamine tetraacetate and the cessation of mercury-containing ophthalmic drugs. F. PSEUDOTRACHOMA

Pseudotrachoma was discussed in the section dealing with the conjunctiva. G. CUMULATIVE

DEPOSITION

Mercurial discoloration of the deep cornea was mentioned above. Cornea1 deposition of silver in argyrosis is characterized first by gray or gray-blue mottled discoloration of Descemet’s membrane in the cornea1 periphery.85*g2*gs Later the discoloration may spread to involve central Descemet’s membrane and all layers of the cornea1 stroma. Simple cornea1 argyrosis, in the absence of caustic burns, does not affect vision. Conjunctival deposits of the oxidative breakdown products of epinephrine have been discussed. Topical epinephrine can produce the same kind of black or dark brown discoloration of the corneaeoJ43J71or of soft contact lenses,151except that these discolorations can be diffuse. The involved cornea or contact lens may appear to have turned totally black. Even an ocular prosthesis has been known to develop such pigmentation.s1 The cornea1 pigmentation occurs in diseased corneas, usually ones with hullous keratopathy, and is located primarily between Bowman’s layer and the epithelium. As mentioned previously, such deposits have been called adrenochromes. A recent study of a “black cornea” concluded, however, that the dark material probably represented actual melanin rather than its red, water-soluble precursor, adrenochrome.143 Cessation of the drug does not cure black cornea, but a black hydrophilic contact lens can be cleared by placing it in 3% hydrogen peroxide for several hours.151 H. MICROBIAL

IMBALANCE

That steroids can possibly alter the ocular flora has already been discussed. More widely held is the belief that steroids enhance the virulence and proliferation of organisms (bacterial, but especially viral and fungal) that are already present, probably mainly by virtue of their well known immunosuppressive effects on the host’s defense mechanisms. Steroid-treated animals are more susceptible to virtually every infectious .._ ~_ agent.110 There is evidence also that steroids

ADVERSE

EFFECTS OF TOPICAL

OPHTHALMIC

MEDICATIONS

can enhance in vitro the metabolic activity and virulence of fungil Steroids are generally considered to be contraindicated in keratomycosis,1s2 which appears to have been a very rare disease before these drugs became available for topical ophthalmic use in 195 1. Since then the incidence of the problem has increased almost explosively, and the arguments are persuasive that many, if not most, of these infections would not have occurred if corneas with epithelial defects had not been treated in-. discriminately with steroids.218 Keratomycosis is nearly always caused by opportunistic and so-called saprophytic fungi of relatively low pathogenicity. It is likely that most of these organisms, unless they are inoculated in unusually large numbers, are unable to cause serious cornea1 infection without the antiinflammatory and immunosuppressive effects of steroids. It is possible, too, that the chronic use of broad-spectrum antibiotics has contributed to the increased incidence of keratomycosis.213 There is wide agreement that steroids are contraindicated in epithelial keratitis caused by Herpesvirus hominis,la2 but they continue to enjoy widespread use for treating herpetic disciform keratitis because they bring about rapid improvement of the cornea1 edema and the associated iridocyclitis. It is said that disciform keratitis was a relatively mild and selflimited disease prior to the advent of topical ophthalmic steroids, but that steroids have greatly prolonged the duration of the disease in many cases - apparently by interfering with the patient’s immunologic mechanisms that are responsible for ultimate healing.lB1 Whether the prolonged course itself can cause greater scarring is not known, but it is clear that many patients must use the steroids for long periods of time - months or even years - with the result that steroid-related morbidity can ensue, namely enhanced viral replication, secondary infection with bacteria or fungi, gluacoma, or cataract. If abrupt cessation of the steroids is attempted, usually because of the appearance of an epithelial dendrite, rebound inflammation can occur. This inflammation can be so severe as to be characterized by intolerable pain, fibrin in the anterior chamber, and hypopyon. Still another problem with the use of steroids for herpetic disciform keratitis is that their use usually calls for the prescribing of an antiviral agent also in the hope that it will offer some protection against steroid-induced enhance-

81

ment of viral replication; the chronic use of the antiviral agent renders the patient susceptible to all of its adverse effects in addition to those of steroids. Like steroids, IDU is known to have immunosuppressive pr0perties.161*212It appears to be capable of promoting secondary opportunistic infections, particularly with Staphylococcus aureus and Streptococcus viridans, when it is applied chronically to bare cornea1 stroma. Cytosine arabinoside also has been found to be immunosuppressive, but adenine arabinoside has shown no such effect.2s2 Biotropism is drug-induced reactivation of latent infection.13v’50Very little is known of the mechanisms by which these reactivations occur, but a few possible examples are known: reactivation by steroids of latent candida or dermatophyte infections in man,13 by epinephrine of herpetic infections in animals,l%l26 and perhaps by steroids of herpetic infections in marP and animals.51 Topical ophthalmic medications of every variety, with or without antibiotics or preservatives, can become contaminated with bacteria or fungi and can act as sources of infections for patients, 5s*2M Similar contamination of eye makeup is commonplace.’ Users of contaminated medications or cosmetics may have the same contaminant organism, primarily Pseudomonas aeruginosa, in their conjunctival sacs or in infected cornea1 ulcers. 1. MISCELLANEOUS

EFFECTS

Experimentally, steroids enhance the activity of collagenase and can stimulate its production by cornea1 tibroblasts.2s There are untold numbers of cases in which cornea1 “melts” of various kinds have been thought clinically to have perforated because of steroid-aggravated lysis of cornea1 collagen.

IV. Summary Topical ophthalmic medications can have adverse effects on the external eye by means of a variety of mechanisms: immunologic, photoimmunologic or phototoxic, irritative or toxic, cumulative deposition, alteration of melanotic pigmentation, and microbial imbalance, among others. The ocular or adnexal tissues can respond to these insults by manifesting cutaneous changes; papillary, follicular, keratinizing, or cicatrizing conjunctivitis; epithelial, ulcerative, vascularizing, or cicatrizing keratitis; hyperpigmenta-

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tion or hypopigmentation; and infectious complications. We, as clinicians, must maintain a constant awareness of these problems and of the possibility that our therapy may produce iatrogenic disease. This review has been presented in the hope that it will facilitate better prevention, recognition, and treatment of the adverse effects of topical ophthalmic medications.

14.

15.

16.

References 1. Abel R Jr: The danger of accidental cornea1 trauma from cosmetic applicators: Mascara use and abuse. Ann Ophthalmol 9:348, 1977 2. Abramowicz I: Deposition of mercury in the eye. Br J Ophthalmol 30:696-697, 1946 3. Aeling JL, Nuss DD: Systemic eczematous “contact-type” dermatitis medicamentosa caused by parabens. Arch Dermatol 110:640, 1974 4. Allansmith MR: Allergy of the lids, in Golden B (ed): Ocular Inflammatory Disease. Springfield, Ill, Charles C Thomas, 1974, pp 25 l-264 5. Allansmith MR: Ocular allergy - diagnosis and management, in Golden B (ed): Ocular Inflammatory Disease. Springfield, Ill, Charles C Thomas, 1974, pp 14-27 6. Allen HF: Prevention of infection in the ophthalmologic office, in Dunlap EA (ed): Gordon’s Medical Management of Ocular Disease. Hagerstown, Md, Harper and Row, 1976, ed 2, pp l-5 7. Allen HF: Antimicrobial therapy, in Dunlap EA (ed): Gordon’s Medical Management of Ocular Disease. Hagerstown, Md, Harper and Row, 1976, ed 2, pp 16-35 8. Allergan Research Memo: Comparison of the relative stability of epinephrine formulations under simulated use conditions. Irvine, California, Allergan Pharmaceuticals, 1976 9. Arey LB, Burrows W, Greenhill JP, et al (eds): Dorland’s Illustrated Medical Dictionary. Philadelphia, WB Saunders, 1959, ed 23, p 1079 10. Asregadoo ER: Surgery, thio-tepa and corticosteroid in the treatment of pterygium. Am J Ophthalmol 74:960-963, 1972 11. Austen KF, Sheffer AL: Vascular responses: The anaphylactic syndrome, in Fitzpatrick TB, Arndt KA, Clark WH Jr, et al (eds): Dermatology in General Medicine. New York, McGraw-Hill, 1971, pp 1244-1261 12. Baer RL, Harber LC: Photosensitivity induced by drugs. JAMA 192:989-990, 1965 13. Baer RL, Levine BB: Adverse cutaneous reactions to drugs, in Fitzpatrick TB, Arndt KA, Clark WH Jr, et al (eds): Dermatology

17.

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21. 22. 23.

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26.

27. 28.

29. 30. 31. 32.

in General Medicine. New York, McGrawHill, 1971, pp 1281-1313 Baer RL, Serri F, Weissenbach-Vial C: Studies on allergic sensitization to certain topical therapeutic agents. Arch Dermatol 71:19-23, 1955 Baer RL, Witten VH: Allergic eczematous contact dermatitis: A review of selected aspects for the practitioner, in Year Book of Dermatology. Chicago, Year Book Medical Publishers, 1956-1957, pp 7-38 (part I) and 1957-1958, pp 7-46 (part II) Bartlett RE: Generalized argyrosis with lens involvement. Am J Ophthalmol 38:402-403, 1954 Basu PK: Effect of different steroids on the healing of nonperforating cornea1 wounds in rabbits. Arch Ophthalmol 59:657-664, 1958 Basu PK: Experimental oculomycosis. (abstract of paper presented at University of Toronto Annual Research Meeting, May 1971) Am J Ophthalmol 72:653, 1971 Beaven MA: Histamine and its participation in dermatological disorders. Part II. Its role in pathological reactions and diseases. Progr Dermatol 11:23-30, 1977 Beigelman MN: Vernal Conjunctivitis. Los Angeles, University of Southern California Press, 1950, p 141 Ballanti JA: Immunology. Philadelphia, WB Saunders, 1971, pp 161-162, 290, 320 Ibid., p 220 Berkow JW, Gill JP Jr, Wise JB: Depigmentation of eyelids after topically administered thiotepa. Arch Ophthalmol82:415-420, 1969 Bettman JW, Aronson SB, Kagawa CM, et al: The incidence of adverse reactions from steroid/antiinfective combinations. Surv Ophthalmol 20:28 l-290, 1976 Binder PS, Abel RA Jr, Kaufman HE: The effect of chronic administration of a topical antibiotic on the conjunctival flora. Ann Ophthalmol 7:1429-1435, 1975 Bloomfield SE, Brown SE: Treatment of corneal ulcers with collagenase inhibitors. Int Ophthalmol Clin 13:225-234, 1973 Bluefarb SM: Scope Monograph on Dermatology. Kalamazoo, Mich, Upjohn, 1972, P5 Boettner EA, Fralick FB, Wolter JR: Conjunctival concretions of sulfadiazine. An unusual clinical problem solved with modern analytical techniques. Arch Ophthalmol 92: 446-448, 1974 Brown EA: Reactions to penicillin. A review of the literature, 1943-1948. Ann Allergy 6:723-746, 1948 Bryant JA: Local and topical anesthetics in ophthalmology. Surv Ophthalmol 13: 263-283, 1969 Bullock JD: Epinephrine pigmentation. Arch Ophthalmol I&546, 1970 Burckhardt W: Largactilekzeme mit

ADVERSE EFFECTS OF TOPICAL OPHTHALMIC

33.

34. 35. 36.

37.

38.

39.

40.

41.

42.

43.

44. 45.

MEDICATIONS

photoallergischer Komponente. Dermatologica (Basel) 113:307-308, 1956 Burdick KH, Hanover NH: Phototoxicity of Shalimar perfume. Arch Dermatol 93: 424-425, 1966 Callaway JL, Gilgor RS: Pyoderma and nephritis. Progr Dermatol 2: 11-l 5, 1967 Carter ES Jr, Cope CB: Anaphylaxis due to topical penicillin. J Allergy 25:270-27 I, 1954 Chand N, Eyre P: Classification and biological distribution of histamine receptor sub-types. Agents and Actions 5:277-295, 1975 Cohen S, Ward PA: In vitro and in vivo activity of a lymphocyte and immune complexdependent chemotactic factor for eosinophils. J Exp Med 133:133-146, 1971 Colley DG: Eosinophils and immune mechanisms. 1. Eosinophil stimulation promoter (ESP): A lymphokine induced by specific antigen or phytohemagglutinin. J Immunol 110:1419-1423, 1973 Corwin ME, Spencer WH: Conjunctival melanin deposits. Arch Ophthalmol 69: 317-321, 1963 Dale DC, Petersdorf RG: Corticosteroids and infectious diseases. Med Clin N Amer 57:1277-1287, 1973 de Week AL: Contact eczematous dermatitis, in Fitzpatrick TB, Arndt KA, Clark WH Jr, et al (eds): Dermatology in General Medicine. New York, McGraw-Hill, 1971, pp 669-679 du Vivier A: Tachyphylaxis to topically applied steroids. Arch Dermatol 112: 1245-1248, 1976 Duke-Edler S: System of Ophthalmology. The Foundations of Ophthalmology. Pathology, Diagnosis, and Heredity, Therapeutics, Vol VII. St. Louis, CV Mosby, 1962, pp 571-577 Ibid., pp 640-643 Duke-Elder S: System of Ophthalmology. Diseases of the Outer Eye. Conjunctiva, Vol VIII, Part 1. St Louis, CV Mosby, 1965, pp 143, 150, 385-386

46. Ibid., p 436 47. Duke-Elder S, MacFaul

PA: System of The Ocular Adnexa. Ophthalmology. Diseases of the Eyelids, Vol XIII, Part 1. St Louis, CV Mosby, 1974, p 367 48. Ibid., p 59 49. Dvorak HF, Dvorak AM, Simpson BA, et al: Cutaneous basophil hypersensitivity. II. Light and electron microscopic description. J Exp Med 132:558-582, 1970 50. Dvorak HF, Simpson BA, Bast RC Jr, et al: Cutaneous basophil hypersensitivity. III. Participation of the basophil in hypersensitivity to antigen-antibody complexes, delayed hypersensitivity, and contact allergy. Passive transfer. J Immunol 107:138-148,

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1971 5 1. Easterbrook M, Wilkie J, Coleman V, et al: The effect of topical corticosteroids on the susceptibility of immune animals to reinoculation with Herpes simplex. Invest Ophthalmol 12:181-184, 1973 52. Eisen HN, Tabachnick M: Elicitation of allergic contact dermatitis in the guinea pig: The distribution of bound dinitrobenzene groups within the skin and quantitative determination of the extent of combination of 2,4dinitrochlorobenzene with epidermal protein in vivo. J Exp Med 108:773-796, 1958 53. Epstein DL, Paton D: Keratitis from misuse of cornea1 anesthetics. N Eng J Med 279:396-399, 1968 54. Epstein NN, Epstein WL, Epstein JH: Atrophic striae in patients with inguinal intertrigo: pathogenesis. Arch Dermatol 87: 450-457, 1963 55. Epstein S: Epidermal and dermal reactions in a case of sensitivity to nickel. J Invest Dermatol 38:37-40, 1962 56. Epstein S: The antigen-antibody reaction in contact dermatitis: A hypothesis and review. Ann Allergy 10:633-652, 1952 57. Epstein WL, Kligman AM, Seneca1 IP: Role of regional lymph nodes in contact sensitization. Arch Dermatol g&789-792, 1963 58. Fedukowicz H, Wise GN, Zaret MM: Toxic conjunctivitis due to antibiotics. Am J Ophthalmol 40:849-856, 1955 59. Feinstein N: Robert R Feinstein 1912-1959 (obituary). Ann Ophthalmol 7:1271-1273, 1975 60. Ferry AP, Zimmerman LE: Black cornea: A complication of topical use of epinephrine. Am J Ophthalmol 58:205-210, 1964 61. Ferry JF: Black prosthesis: A complication of the topical use of epinephrine. Am J Ophthalmol 64: 162, 1967 62. Fife T, Cesario TC, Tilles JG: Effect of neutral red and light on herpesvirus hominis type I in cell culture. J Infect Dis 134: 324-327, 1976 63. Fisher AA: Contact Dermatitis. Philadelphia, Lea and Febiger, 1973, 2nd ed, pp 39-70 64. Fisher AA: Erythromycin: A nonsensitizing topical antibiotic. Arch Dermatol 112:732, 1976 65. Fisher AA, Pascher F, Kanof NB: Allergic contact dermatitis due to ingredients of vehicles. A “vehicle tray” for patch testing. Arch Dermatol 104:286-290, 197 1 66. Fisher AA, Stillman MA: Allergic contact sensitivity to benzalkonium chloride (BAK). Cutaneous, ophthalmic and general medical imolications. Arch Dermatol 106:169-171. i9j2

67. Fisher M, Wittner M: Bacterial Infections of the Skin. Impetigo, Furunculosis, Cellulitis,

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85

Dermatol 93:450-453, 1966 129. Landsteiner K, Jacobs J: Studies on the sensitization of animals with simple chemical compounds. J Exp Med 61:643-656, 1935 130. Lavin N, Rachelefsky GS, Kaplan SA: An action of disodium cromoglycate: Inhibition of cyclic 3’,5’ AMP phosphodiesterase. J Allergy CIin Immunol 57:80-88, 1976 131. Lemp MA, Roddy M: The effect of acetylcysteine (Mucomyst) on reepithelialization of the cornea. Ann Ophthalmol 6:893-895, 1974 132. Leopold IH: Clinical use of corticosteroids in anterior segment inflammatory disease initiated by replicating agents. Trans Am Acad Ophthalmol Otolaryngol 79:117-127, 1975 133. Leuenberger PM: Ultrastructure of cornea1 epithelium after topical anesthetics. Albrecht von Graefe’s Arch Klin Exp Ophthaimoi l&73-90, 1973 134. Lever WF: Histopathology of the Skin. Philadelphia, JB Lippincott, 1961, ed 3, p 114 135. Leyden JJ, Thew M, Kligman AM: Steroid rosacea. Arch Dermatol 110:619-622, 1974 136. Long JC, Danielson RW: Mercurial discoloration of the eyelids. Am J Ophthalmol 34:753-756, 195 1 137. Lowenstein A: Argyrosis of conjunctiva, cornea and tear-sac. Br J Ophthahnol 25: 360-369, 1941 138. Lyons C: Penicillin therapy of surgical infections in US Army. JAMA 123:1007-1018, 1943 139. Malkinson FD: Permeability of the stratum corneum, in Montagna W, Lobitz WC Jr (eds): The Epidermis. New York, Academic Press, 1964, pp 435-452 140. Malkinson FD, Gehlmann L: Factors affecting percutaneous absorption, in Drill VA, Lazar P (eds): Cutaneous Toxicity. New York, Academic Press, 1977, pp 63-81 141. Maloney ED, Kaufman HE: Antagonism and toxicity of IDU by its degradation products. Invest OphthaImol 2:55-57, 1963 142. Mathieu PL Jr: Comparison study of silver nitrate and oxytetracycline in newborn eyes. J Dis Child 95:609-611, 1958 143. McCarthy RW, LeBlanc R: A black cornea secondary to topical epinephrine. Can J Ophthalmol 11:336-340, 1976 144. McCuiston CF: Penicillin-sensitivity test. N Engl J Med 25:1114, 1957 145. McDonald TO, Borgmann AR, Roberts MD, et al: Cornea1 wound healing. I. Inhibition of stromal healing by three dexamethasone derivatives. Invest Ophthalmoi 9:703-709, 1970 FT, Jones^ BR: 146. McGill J, Fraunfelder _ Current and proposed management of ocular herpes simplex. Surv Ophthalmol 20: 358-365, 1976 147. McKee SH: Severe argyrosis of the conjunctiva. Can Med Assoc J 39:474, 1938

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204. 205. 206. 207. 208.

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Medicine and Related Sciences. Philadelphia, Lea and Febiger, 1970, pp 163-169 Wheeler M: Discoloration of the eyelids from prolonged use of ointment containing mercury. Am J Ophthalmol 31:441-444, 1948 White JH, Cinotti AA: Experimental fungal contamination of the conjunctiva. EENT Monthly 50:441-443, 1971 Wood TO, Williford W: Treatment of keratomycosis with amphotericin B 0.15%. Am J Ophthalmol 81:847-849, 1976 Wright P, Fraunfelder FT: Practolol-induced oculomucocutaneous syndrome, in Leopold, IH, Burns RP (eds): Symposium on Ocular Therapy, Vol 9. New York, John Wiley and Sons, 1976, pp 97-110 Wyngaarden VB, Seevers MH: Toxic effects of antihistamine drugs. JAMA 145:277-282, 1951 Yanoff M, Fine BS: Ocular Pathology. A Text and Atlas. Hagerstown, Maryland, Harper and Row, 1975, pp 194-195 Ibid., p 246-247 Yanoff M, Scheie HG: Argyrosis of the conjunctiva and lacrimal sac. Arch Ophthalmol 72:57-58, 1964 Zam ZS, Centifanto YM, Kaufman HE: Failure of systemically administered adenine arabinoside to affect humoral and cellmediated immunity. Am J Ophthalmol 81:502-505, 1976 Zimmerman MC: The prophylaxis and treatment of penicillin reactions with penicillinase. Clin Med 5:305-311, 1958 Zuckerman BD: Conjunctiva pigmentation due to cosmetics. Am J Ophthalmol 62:672-676, 1966

This work was supported in part by a grant from Research to Prevent Blindness, Inc., New York. This paper was presented in part at the Third Annual Proctor Fellows Meeting, Francis I. Proctor Foundation for Research in Ophthalmology, University of California, San Francisco, June 16, 1977; at the University of Illinois Eye and Ear Infirmary, Chicago, September 1, 1977; and at a meeting of the Columbus Ophthalmologic and

Otolaryngologic Society, Columbus, Ohio, October 2, 1978. Requests for reprints should be addressed to Fred M. Wilson II, M.D., Department of Ophthalmology, Indiana University School of Medicine, 1100 West Michigan Street, Indianapolis, Indiana 46202. Outline I. Eyelids A. Urticaria and angioedema B. Allergic contact dermatoconjunctivitis C. Allergic contact dermatitis D. Photoallergic contact dermatitis E. Irritative or toxic contact dermatitis F. Phototoxic dermatitis G. Miscellaneous chronic irritations and toxicities H. Cumulative deposition I. Melanotic hyperpigmentation or hypopigmentation J. Microbial imbalance K. Miscellaneous effects II. Coniunctiva A. knaphylactoid conjunctivitis Allergic contact (dermato) conjunctivitis :: Cicatrizing allergic conjunctivitis D. Nonspecific (papillary) irritative or toxic conjunctivitis E. Follicular irritative or toxic conjunctivitis F. Cicatrizing and keratinizing irritative or toxic conjunctivitis (including pseudotrachoma) G. Cumulative deposition H. Microbial imbalance I. Miscellaneous effects III. Cornea A. Anaphylactoid keratitis B. Allergic contact keratitis C. Irritative or toxic keratitis D. Phototoxic keratitis E. Toxic calcific band keratopathy F. Pseudotrachoma G. Cumulative deposition H. Microbial imbalance I. Miscellaneous effects IV. Summary