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Delayed Hypersensitivity to Retrobulbar Injections of Methylprednisolone Acetate
DELAYED HYPERSENSITIVITY TO RETROBULBAR INJECTIONS O F METHYLPREDNISOLONE ACETATE C. G. T O B Y M A T H I A S , M.D., H. I. M A I B A C H , M.D., AND M. A. C O N A N T , M.D. San Francisco,
H. B. O S T L E R ,
M.D.,
California
AND W. N E L S O N , Modesto,
System anaphylactoid and cutaneous allergic reactions are rare complications of corticosteroid therapy. 1 - 1 1 Allergic dermatoconjunctivitis has recently been re ported. 12 When delayed hypersensitivity to a corticosteroid is suspected, skin tests may be performed by an occlusive patch test or intradermal injection, and the reac tion evaluated in 48 to 96 hours. Discrep ancies in these two techniques, that is, negative patch test but positive intrader mal test, apparently result from impaired cutaneous penetration, and these differ ences may be overcome by increasing the patch test concentration of the suspected allergen, eliminating the need for intra dermal testing. Alani and Alani 9 and Tegner 7 suggested patch testing with 25% hydrocortisone or enhanced concentra tions of other corticosteroids when de layed hypersensitivity to these agents is suspected. We describe herein a patient with chronic cyclitis who developed a delayed hypersensitivity reaction to a sus pension of methylprednisolone acetate. Despite appropriate patch testing, allergy could only be demonstrated by intrader mal injection. From the Departments of Dermatology (Drs. Mathias, Maibach, and Conant), and Ophthalmology (Dr. Ostler), University of California Medical Cen ter, San Francisco, California; and Modesto, Cali fornia (Dr. Nelson). Reprint request to C. G. Toby Mathias, M.D., Room 342-A, Department of Dermatology, Universi ty of California Medical Center, San Francisco, CA 94943. 816
M.D.
California
CASE REPORT A 35-year old man with a five year history of chronic cyclitis was referred to the Department of Dermatology for suspected hypersensitivity to a methylprednisolone acetate suspension (DepoMedrol). Management of his cyclitis had consisted of various topical corticosteroid ophthalmic drops and periodic retrobulbar injections of methylpredniso lone acetate. For the preceding two years the patient had noted some increase in conjunctival and epi scleral erythema lasting two to three weeks, follow ing retrobulbar injection. Six months before referral, the patient had a severe ocular inflammation after a retrobulbar injection, accompanied by deterioration in his vision. Ocular inflammation decreased and visual acuity improved with a short course of oral prednisone. Subsequently, the patient noted flares of episcleral and conjunctival erythema after topical application of the following ophthalmic corticoster oid preparations: dexamethasone phosphate; prednisolone acetate; a combined preparation of dexa methasone phosphate, neomycin, and polymyxin B; and a combined preparation of prednisolone phos phate, sodium sulfacetamide, and phenylephrine hydroehloride. An ointment containing only dexa methasone phosphate did not evoke ocular inflam mation. Examination revealed visual acuity was R.E.: 6/8 (20/25) and L.E.: 6/15 (20/50). Visual acuity im proved to 6/6 (20/20) in each eye with a pinhole. The eyelids and tarsal conjunctiva were normal. The bulbar conjunctive and episclerae of both eyes were injected, and there was an associated chemosis. A residue of material (Depo-Medrol) was evident underlying the superior temporal conjunctiva of the right eye. The anterior chamber was optically emp ty, and the lens showed early posterior cortical changes. The anterior vitreous of both eyes had 2+ cells and coarse clumps of cellular opacities ("snow balls") were evident inferiorly. The nerve head and vessels were normal. There was no foveal reflex. Patch testing to a routine and preservative screen ing series was performed and graded according to the International Contact Dermatitis Research Group 1 3 ; all tests were negative. Further patch tests were performed to the methylprednisolone acetate suspension (40 ftig/ml), methylprednisolone acetate
AMERICAN JOURNAL O F OPHTHALMOLOGY 86:816-819, 1978
VOL. 86, NO. 6
HYPERSENSITIVITY TO METHYLPREDNISONE
0.25% cream, and 25% hydrocortisone in petrola tum. All patch tests were negative. The corticosteroid-containing ophthalmic preparations to which the patient had clinical reactions were not available for testing. A patch test with benzalkonium chloride 0.1% (found as a preservative in the ophthalmic drops to which the patient had clinical reactions) gave a 2+ reaction. This was repeated after a two-month inter val, with identical results. A biopsy of this site was interpreted as compatible with allergic contact der matitis. Intradermal injection of 0.02 ml of the com mercial methylprednisolone acetate suspension (40 mgm/ml) produced a 10 mm erythematous pap ule at 48 hours. Subsequent intradermal tests were performed with 0.02 ml of 0.1%, 0.01%, and 0.001% methylprednisolone acetate powder suspended in normal saline; all produced 5- to 10-mm erythema tous papules which persisted for two weeks. Similar intradermal injections with the 0.1% concentration in three controls produced only vasoconstriction and subsequent atrophy at the test site. Biopsies of two test sites showed a marked perivascular mononuclear infiltrate with numerous eosinophils (Figure). Further patch tests were performed with the remaining constituents of the commercial sus pension; only a nonspecific irritant reaction to myristyl gamma-picolinium chloride (a proprietary quaternary ammonium preservative) was observed. Information obtained from the manufacturer re vealed that the only detectable impurity in meth ylprednisolone acetate was methylprednisolone (ap proximately 3%). To determine the specificity of the reaction, further intradermal tests (0.02 ml) were performed with 0.1% suspensions of methylpred
817
nisolone and prednisolone powder in normal sa line. Methylprednisolone gave a positive reaction (10 mm erythematous papule); prednisolone pro duced an equivocal 2- to 3-mm erythematous pap ule. Simultaneous patch testing was performed with 25% concentrations of methylprednisolone acetate, methylprednisolone, and prednisolone in petrola tum. Patch tests were negative, indicating the inability of this technique to detect corticosteroid hypersensitivity in this patient. Further intradermal tests were performed to com mercial dexamethasone phosphate and triamcinolone acetonide injectable suspensions. The triamcinolone acetonide suspension produced 2- to 3-mm erythematous papule, while dexamethasone phos phate produced no reaction. Erythema around the injection site of triamicinolone acetonide was not observed in the controls. A careful clinical trial of periocular injections of dexamethasone phosphate was begun, and the patient tolerated this prepara tion. DISCUSSION
Adverse cutaneous or systemic re actions may rarely occur to parenteral, intra-articular, or oral preparations of hydrocortisone acetate, 1 hydrocorti sone, 2 prednisone, 3 , 4 prednisolone ace tate, 4 methylprednisolone acetate and methylprednisolone sodium succinate, 5 betamethasone, 6 and dexamethasone. 3 Allergic contact dermatitis from topi cal corticosteroid preparations is more
(Figure). (Mathias and associates). Low and high power magnifications of skin test biopsy, showing marked perivascular lymphocytic infiltrate in dermis, with numerous eosinophils. Mild spongiosis is present in overlying epidermis (left, x 4 0 ; right x250).
818
AMERICAN JOURNAL OF OPHTHALMOLOGY
frequent. 7 - 1 2 Tegner 7 exhaustively re viewed this subject; sensitizers included hydrocortisone, hydrocortisone acetate, hydrocortisone succinate, prednisolone, methylprednisolone, methylprednisolone acetate, triamcinolone, triamcinolone acetonide, fluocinolone acetonide, fluocortilone, betamethasone, and betamethasone valerate. Halcinonide, fluocinonide, and desonide are additionally reported sensi tizers. 8 Alani and Alani 12 reported two cases of allergic dermatoconjunctivitis from betamethasone valerate. Immediate hypersensitivity may be de tected by intradermal injection followed by immediate whealing. 1 ' 5 Delayed hy persensitivity is usually detected by patch testing. Because of occasional false-negative results, patch testing with a 10 to 25% increase over product use con centration has been recommended. 8 ' 9 In tradermal tests, producing erythematous papules at 24 to 48 hours, may also detect delayed hypersensitivity. 1 ' 2 ' 4 ' 10 Simulta neous intradermal and patch tests have been performed in only two instances; in one, only the intradermal test was posi tive, 4 whereas both were positive in the other. 10 Discrepancies between epicutaneous patch and intradermal tests have been documented for several substances. Posi tive patch tests but negative intradermal tests have been observed with nickel, 14 paraphenylenediamine, 1 5 and tubercu lin 16 ; this is known as epidermal hyper sensitivity. Conversely, negative patch tests but positive intradermal tests have been reported with nickel, 14 tuberculin, 1 6 neomycin, 17 and several other chemi cals 14 ; this is known as dermal hyper sensitivity. Histologically, dermal hyper sensitivity produces changes only in the dermis; epidermal changes are minimal or absent. Possible explanations for these observed differences include variable amounts of antigen, impaired cutaneous
DECEMBER, 1978
penetration, formation of different com plete antigens in epidermis or dermis, differences in absolute or threshold con centration of antigen between epidermis and dermis, and rate of antigen removal. Where negative patch tests but positive intradermal tests have been observed, simply increasing the concentration of the allergen will convert a negative patch test to a positive one (neomycin). 17 The need for intradermal tests may be elimi nated by patch testing at higher concen trations of antigen. Our case demonstrates the necessity of intradermal testing for suspected contact hypersensitivity to corticosteroids even when patch tests at enhanced use concen trations are negative. Despite negative patch tests with 25% methylprednisolone acetate, hypersensitivity could be demon strated by intradermal testing with a dilu tion of 0.001%. Although it may be ar gued that methylprednisolone acetate was totally unabsorbed after closed epicutan eous patch test application, we believe this is unlikely. Not only is methylpredni solone acetate clinically effective as a topical anti-inflammatory agent, but at least one case of hypersensitivity with a positive patch test has been reported. 10 Precise identification of the antigenic substance in corticosteroid hypersensi tivity may be difficult. It may be caused by impurities or small amounts of precur sor substances in the final product, 1 1 or to the vehicle itself. 18 The only detectable impurity in methylprednisolone acetate was its precursor, methylprednisolone (approximately 3%); both produced posi tive intradermal reactions. Although puri fied methylprednisolone acetate was not tested, cross-reactivity is likely. Cross-reactivity could not be convinc ingly demonstrated to the structurally similar corticosteroid prednisolone, im plying specificity to the methylpredniso lone molecule. The small erythematous
VOL. 86, NO. 6
HYPERSENSITIVITY TO METHYLPREDNISONE
papule produced by the structurally dis similar triamcinolone acetonide, although only equivocally positive, was surprising; no erythema was observed in controls. Clinically demonstrable cross-reactivity in corticosteroid allergy correlates poorly with structural formulae. Before alterna tive corticosteroids are tried, appropriate testing should be done first. Our patient had a negative intradermal test to dexamethasone phosphate; he has tolerated periocular injections of this preparation without further difficulty. In previously reported cases, concomi tant sensitization to other substances has been common. The clinical adverse reac tions to the topical ophthalmic cortico steroid drops in our case may have repre sented contact hypersensitivity to benzal konium chloride, a preservative found in these preparations. Delayed hypersensi tivity to benzalkonium chloride is un common. While higher concentrations are often irritating, a reproducible positive patch test with 0.1% benzalkonium chlo ride suggests sensitization. Contact hypersensitivity is a rare but recognized complication of corticosteroid therapy. When allergy is suspected, patch testing should be performed with en hanced concentrations 10 to 25% greater than product use concentration. Intrader mal testing with appropriate controls should be performed if appropriate patch tests are negative. SUMMARY
A patient with chronic cyclitis devel oped hyperemia of the episcleral and bulbar conjunctival vessels after retrobulbar injections of methylprednisolone ace tate suspension. Intradermal testing re vealed the responsible allergen to be methylprednisolone acetate; hypersensi tivity could not be demonstrated by patch
819
testing, despite use of increased concen trations. ACKNOWLEDGMENT
Materials for patch testing were supplied by Upjohn Laboratories, Kalamazoo, Michigan.
REFERENCES 1. O'Garra, J. A.: Anaphylactic reactions to hydrocortisone injections. Br. Med. J. 1:615, 1962. 2. King, R. A.: A severe anaphylactoid reaction to hydrocortisone. Lancet 2:1093, 1960. 3. Romankiewicz, J. A., Franklin, J. E.: Allergic reactions to corticosteroid therapy. J. A. M. A. 236: 1939, 1976. 4. Comaish, S.: A case of hypersensitivity to corti costeroid. Br. J. Dermatol. 81:919, 1969. 5. Mendelson, L. M., Meltzer, E. I., and Ham burger, R. N.: Anaphylaxis-like reactions to cortico steroid therapy. J. Allergy Clin. Immunol. 54:125, 1974. 6. Maddin, S.: Urticaria following betamethasone. J. A. M. A. 207:560, 1969. 7. Tegner, E.: Contact allergy to corticosteroids. Int. J. Dermatol. 15:520, 1976. 8. Coskey, R. J.: Contact dermatitis due to multi ple corticosteroid creams. Arch. Dermatol. 114:115, 1978. 9. Alani, M. D., and Alani, S. D.: Allergic contact dermatitis to corticosteroids. Ann. Allergy 30:181, 1972. 10. Coskey, R. J., and Bryan, H. G.: Contact der matitis due to methylprednisolone. J. A. M. A. 199: 136, 1967. 11. Church, R.: Sensitivity to hydrocortisone ace tate ointment. Br. J. Dermatol. 72:341, 1960. 12. Alani, S. D., and Alani, M. D.: Allergic con tact dermatitis and conjunctivitis to corticosteroids. Contact Dermatitis 2:301, 1976. 13. Wilkinson, D. S., Fregert, S., Magnusson, B., Bandmann, H. J., Colnon, C. D., Cronin, E., Hjorth, N., Maibach, H. I., Malten, K. E., Meneghin, C. L., and Pirila, V.: Terminology of contact dermatitis. Acta Derm. Venereol. (Stockh.) 50:287, 1970. 14. Epstein, S.: Contact dermatitis due to nickel and chromate: Observations on dermal delayed (tuberculin-type) sensitivity. Arch. Dermatol. 73: 236, 1956. 15. Blumental, F., and Jaffe, K.: Ekzem and Idiosynkrasie. Berlin, S. Karger, 1933. 16. Sulzberger, M. B.: Dermatologic Allergy. Springfield, Charles C Thomas, 1940, p. 71 (foot note) and p. 227. 17. Epstein, E.: Detection of neomycin sensitivi ty. Arch. Dermatol. 91:50, 1965. 18. Sams, W. M., and Smith, J. G.: Contact der matitis due to hydrocortisone ointment. Report of a case of sensitivity to emulsifying agents in hydrophilic ointment base. J. A. M. A. 164:1212, 1957.
H. B. O S T L E R ,
M.D.,
California
AND W. N E L S O N , Modesto,
System anaphylactoid and cutaneous allergic reactions are rare complications of corticosteroid therapy. 1 - 1 1 Allergic dermatoconjunctivitis has recently been re ported. 12 When delayed hypersensitivity to a corticosteroid is suspected, skin tests may be performed by an occlusive patch test or intradermal injection, and the reac tion evaluated in 48 to 96 hours. Discrep ancies in these two techniques, that is, negative patch test but positive intrader mal test, apparently result from impaired cutaneous penetration, and these differ ences may be overcome by increasing the patch test concentration of the suspected allergen, eliminating the need for intra dermal testing. Alani and Alani 9 and Tegner 7 suggested patch testing with 25% hydrocortisone or enhanced concentra tions of other corticosteroids when de layed hypersensitivity to these agents is suspected. We describe herein a patient with chronic cyclitis who developed a delayed hypersensitivity reaction to a sus pension of methylprednisolone acetate. Despite appropriate patch testing, allergy could only be demonstrated by intrader mal injection. From the Departments of Dermatology (Drs. Mathias, Maibach, and Conant), and Ophthalmology (Dr. Ostler), University of California Medical Cen ter, San Francisco, California; and Modesto, Cali fornia (Dr. Nelson). Reprint request to C. G. Toby Mathias, M.D., Room 342-A, Department of Dermatology, Universi ty of California Medical Center, San Francisco, CA 94943. 816
M.D.
California
CASE REPORT A 35-year old man with a five year history of chronic cyclitis was referred to the Department of Dermatology for suspected hypersensitivity to a methylprednisolone acetate suspension (DepoMedrol). Management of his cyclitis had consisted of various topical corticosteroid ophthalmic drops and periodic retrobulbar injections of methylpredniso lone acetate. For the preceding two years the patient had noted some increase in conjunctival and epi scleral erythema lasting two to three weeks, follow ing retrobulbar injection. Six months before referral, the patient had a severe ocular inflammation after a retrobulbar injection, accompanied by deterioration in his vision. Ocular inflammation decreased and visual acuity improved with a short course of oral prednisone. Subsequently, the patient noted flares of episcleral and conjunctival erythema after topical application of the following ophthalmic corticoster oid preparations: dexamethasone phosphate; prednisolone acetate; a combined preparation of dexa methasone phosphate, neomycin, and polymyxin B; and a combined preparation of prednisolone phos phate, sodium sulfacetamide, and phenylephrine hydroehloride. An ointment containing only dexa methasone phosphate did not evoke ocular inflam mation. Examination revealed visual acuity was R.E.: 6/8 (20/25) and L.E.: 6/15 (20/50). Visual acuity im proved to 6/6 (20/20) in each eye with a pinhole. The eyelids and tarsal conjunctiva were normal. The bulbar conjunctive and episclerae of both eyes were injected, and there was an associated chemosis. A residue of material (Depo-Medrol) was evident underlying the superior temporal conjunctiva of the right eye. The anterior chamber was optically emp ty, and the lens showed early posterior cortical changes. The anterior vitreous of both eyes had 2+ cells and coarse clumps of cellular opacities ("snow balls") were evident inferiorly. The nerve head and vessels were normal. There was no foveal reflex. Patch testing to a routine and preservative screen ing series was performed and graded according to the International Contact Dermatitis Research Group 1 3 ; all tests were negative. Further patch tests were performed to the methylprednisolone acetate suspension (40 ftig/ml), methylprednisolone acetate
AMERICAN JOURNAL O F OPHTHALMOLOGY 86:816-819, 1978
VOL. 86, NO. 6
HYPERSENSITIVITY TO METHYLPREDNISONE
0.25% cream, and 25% hydrocortisone in petrola tum. All patch tests were negative. The corticosteroid-containing ophthalmic preparations to which the patient had clinical reactions were not available for testing. A patch test with benzalkonium chloride 0.1% (found as a preservative in the ophthalmic drops to which the patient had clinical reactions) gave a 2+ reaction. This was repeated after a two-month inter val, with identical results. A biopsy of this site was interpreted as compatible with allergic contact der matitis. Intradermal injection of 0.02 ml of the com mercial methylprednisolone acetate suspension (40 mgm/ml) produced a 10 mm erythematous pap ule at 48 hours. Subsequent intradermal tests were performed with 0.02 ml of 0.1%, 0.01%, and 0.001% methylprednisolone acetate powder suspended in normal saline; all produced 5- to 10-mm erythema tous papules which persisted for two weeks. Similar intradermal injections with the 0.1% concentration in three controls produced only vasoconstriction and subsequent atrophy at the test site. Biopsies of two test sites showed a marked perivascular mononuclear infiltrate with numerous eosinophils (Figure). Further patch tests were performed with the remaining constituents of the commercial sus pension; only a nonspecific irritant reaction to myristyl gamma-picolinium chloride (a proprietary quaternary ammonium preservative) was observed. Information obtained from the manufacturer re vealed that the only detectable impurity in meth ylprednisolone acetate was methylprednisolone (ap proximately 3%). To determine the specificity of the reaction, further intradermal tests (0.02 ml) were performed with 0.1% suspensions of methylpred
817
nisolone and prednisolone powder in normal sa line. Methylprednisolone gave a positive reaction (10 mm erythematous papule); prednisolone pro duced an equivocal 2- to 3-mm erythematous pap ule. Simultaneous patch testing was performed with 25% concentrations of methylprednisolone acetate, methylprednisolone, and prednisolone in petrola tum. Patch tests were negative, indicating the inability of this technique to detect corticosteroid hypersensitivity in this patient. Further intradermal tests were performed to com mercial dexamethasone phosphate and triamcinolone acetonide injectable suspensions. The triamcinolone acetonide suspension produced 2- to 3-mm erythematous papule, while dexamethasone phos phate produced no reaction. Erythema around the injection site of triamicinolone acetonide was not observed in the controls. A careful clinical trial of periocular injections of dexamethasone phosphate was begun, and the patient tolerated this prepara tion. DISCUSSION
Adverse cutaneous or systemic re actions may rarely occur to parenteral, intra-articular, or oral preparations of hydrocortisone acetate, 1 hydrocorti sone, 2 prednisone, 3 , 4 prednisolone ace tate, 4 methylprednisolone acetate and methylprednisolone sodium succinate, 5 betamethasone, 6 and dexamethasone. 3 Allergic contact dermatitis from topi cal corticosteroid preparations is more
(Figure). (Mathias and associates). Low and high power magnifications of skin test biopsy, showing marked perivascular lymphocytic infiltrate in dermis, with numerous eosinophils. Mild spongiosis is present in overlying epidermis (left, x 4 0 ; right x250).
818
AMERICAN JOURNAL OF OPHTHALMOLOGY
frequent. 7 - 1 2 Tegner 7 exhaustively re viewed this subject; sensitizers included hydrocortisone, hydrocortisone acetate, hydrocortisone succinate, prednisolone, methylprednisolone, methylprednisolone acetate, triamcinolone, triamcinolone acetonide, fluocinolone acetonide, fluocortilone, betamethasone, and betamethasone valerate. Halcinonide, fluocinonide, and desonide are additionally reported sensi tizers. 8 Alani and Alani 12 reported two cases of allergic dermatoconjunctivitis from betamethasone valerate. Immediate hypersensitivity may be de tected by intradermal injection followed by immediate whealing. 1 ' 5 Delayed hy persensitivity is usually detected by patch testing. Because of occasional false-negative results, patch testing with a 10 to 25% increase over product use con centration has been recommended. 8 ' 9 In tradermal tests, producing erythematous papules at 24 to 48 hours, may also detect delayed hypersensitivity. 1 ' 2 ' 4 ' 10 Simulta neous intradermal and patch tests have been performed in only two instances; in one, only the intradermal test was posi tive, 4 whereas both were positive in the other. 10 Discrepancies between epicutaneous patch and intradermal tests have been documented for several substances. Posi tive patch tests but negative intradermal tests have been observed with nickel, 14 paraphenylenediamine, 1 5 and tubercu lin 16 ; this is known as epidermal hyper sensitivity. Conversely, negative patch tests but positive intradermal tests have been reported with nickel, 14 tuberculin, 1 6 neomycin, 17 and several other chemi cals 14 ; this is known as dermal hyper sensitivity. Histologically, dermal hyper sensitivity produces changes only in the dermis; epidermal changes are minimal or absent. Possible explanations for these observed differences include variable amounts of antigen, impaired cutaneous
DECEMBER, 1978
penetration, formation of different com plete antigens in epidermis or dermis, differences in absolute or threshold con centration of antigen between epidermis and dermis, and rate of antigen removal. Where negative patch tests but positive intradermal tests have been observed, simply increasing the concentration of the allergen will convert a negative patch test to a positive one (neomycin). 17 The need for intradermal tests may be elimi nated by patch testing at higher concen trations of antigen. Our case demonstrates the necessity of intradermal testing for suspected contact hypersensitivity to corticosteroids even when patch tests at enhanced use concen trations are negative. Despite negative patch tests with 25% methylprednisolone acetate, hypersensitivity could be demon strated by intradermal testing with a dilu tion of 0.001%. Although it may be ar gued that methylprednisolone acetate was totally unabsorbed after closed epicutan eous patch test application, we believe this is unlikely. Not only is methylpredni solone acetate clinically effective as a topical anti-inflammatory agent, but at least one case of hypersensitivity with a positive patch test has been reported. 10 Precise identification of the antigenic substance in corticosteroid hypersensi tivity may be difficult. It may be caused by impurities or small amounts of precur sor substances in the final product, 1 1 or to the vehicle itself. 18 The only detectable impurity in methylprednisolone acetate was its precursor, methylprednisolone (approximately 3%); both produced posi tive intradermal reactions. Although puri fied methylprednisolone acetate was not tested, cross-reactivity is likely. Cross-reactivity could not be convinc ingly demonstrated to the structurally similar corticosteroid prednisolone, im plying specificity to the methylpredniso lone molecule. The small erythematous
VOL. 86, NO. 6
HYPERSENSITIVITY TO METHYLPREDNISONE
papule produced by the structurally dis similar triamcinolone acetonide, although only equivocally positive, was surprising; no erythema was observed in controls. Clinically demonstrable cross-reactivity in corticosteroid allergy correlates poorly with structural formulae. Before alterna tive corticosteroids are tried, appropriate testing should be done first. Our patient had a negative intradermal test to dexamethasone phosphate; he has tolerated periocular injections of this preparation without further difficulty. In previously reported cases, concomi tant sensitization to other substances has been common. The clinical adverse reac tions to the topical ophthalmic cortico steroid drops in our case may have repre sented contact hypersensitivity to benzal konium chloride, a preservative found in these preparations. Delayed hypersensi tivity to benzalkonium chloride is un common. While higher concentrations are often irritating, a reproducible positive patch test with 0.1% benzalkonium chlo ride suggests sensitization. Contact hypersensitivity is a rare but recognized complication of corticosteroid therapy. When allergy is suspected, patch testing should be performed with en hanced concentrations 10 to 25% greater than product use concentration. Intrader mal testing with appropriate controls should be performed if appropriate patch tests are negative. SUMMARY
A patient with chronic cyclitis devel oped hyperemia of the episcleral and bulbar conjunctival vessels after retrobulbar injections of methylprednisolone ace tate suspension. Intradermal testing re vealed the responsible allergen to be methylprednisolone acetate; hypersensi tivity could not be demonstrated by patch
819
testing, despite use of increased concen trations. ACKNOWLEDGMENT
Materials for patch testing were supplied by Upjohn Laboratories, Kalamazoo, Michigan.
REFERENCES 1. O'Garra, J. A.: Anaphylactic reactions to hydrocortisone injections. Br. Med. J. 1:615, 1962. 2. King, R. A.: A severe anaphylactoid reaction to hydrocortisone. Lancet 2:1093, 1960. 3. Romankiewicz, J. A., Franklin, J. E.: Allergic reactions to corticosteroid therapy. J. A. M. A. 236: 1939, 1976. 4. Comaish, S.: A case of hypersensitivity to corti costeroid. Br. J. Dermatol. 81:919, 1969. 5. Mendelson, L. M., Meltzer, E. I., and Ham burger, R. N.: Anaphylaxis-like reactions to cortico steroid therapy. J. Allergy Clin. Immunol. 54:125, 1974. 6. Maddin, S.: Urticaria following betamethasone. J. A. M. A. 207:560, 1969. 7. Tegner, E.: Contact allergy to corticosteroids. Int. J. Dermatol. 15:520, 1976. 8. Coskey, R. J.: Contact dermatitis due to multi ple corticosteroid creams. Arch. Dermatol. 114:115, 1978. 9. Alani, M. D., and Alani, S. D.: Allergic contact dermatitis to corticosteroids. Ann. Allergy 30:181, 1972. 10. Coskey, R. J., and Bryan, H. G.: Contact der matitis due to methylprednisolone. J. A. M. A. 199: 136, 1967. 11. Church, R.: Sensitivity to hydrocortisone ace tate ointment. Br. J. Dermatol. 72:341, 1960. 12. Alani, S. D., and Alani, M. D.: Allergic con tact dermatitis and conjunctivitis to corticosteroids. Contact Dermatitis 2:301, 1976. 13. Wilkinson, D. S., Fregert, S., Magnusson, B., Bandmann, H. J., Colnon, C. D., Cronin, E., Hjorth, N., Maibach, H. I., Malten, K. E., Meneghin, C. L., and Pirila, V.: Terminology of contact dermatitis. Acta Derm. Venereol. (Stockh.) 50:287, 1970. 14. Epstein, S.: Contact dermatitis due to nickel and chromate: Observations on dermal delayed (tuberculin-type) sensitivity. Arch. Dermatol. 73: 236, 1956. 15. Blumental, F., and Jaffe, K.: Ekzem and Idiosynkrasie. Berlin, S. Karger, 1933. 16. Sulzberger, M. B.: Dermatologic Allergy. Springfield, Charles C Thomas, 1940, p. 71 (foot note) and p. 227. 17. Epstein, E.: Detection of neomycin sensitivi ty. Arch. Dermatol. 91:50, 1965. 18. Sams, W. M., and Smith, J. G.: Contact der matitis due to hydrocortisone ointment. Report of a case of sensitivity to emulsifying agents in hydrophilic ointment base. J. A. M. A. 164:1212, 1957.