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Superior Limbic Keratoconjunctivitis in Contact Lens Wearers
Superior Limbic Keratoconjunctivitis in
Contact Lens Wearers
DEBORAH D. SENDELE, MD, *t* KENNETH R. KENYON, MD, *t* ELEANOR F. MOBILIA, OD,* PERRY ROSENTHAL, MD,* ROGER STEINERT, MD,* LAlLA A. HANNINENt
Abstract: Forty patients with daily wear, cosmetic contact lenses (CL) presented with symptoms of ocular irritation and a keratoconjunctivitis clinically resembling superior limbic keratoconjunctivitis (SLK). Typically the patients were either successful hard CL wearers who changed to soft lenses and used a chemical aseptisizing solution or preserved saline solution, or successful soft CL wearers using salt tablets who switched to a preservative-containing system. In all cases, exposure to thimerosal-preserved solutions was documented. Upon discontinuation of lens wear, all signs and symptoms slowly resolved without permanent sequelae. Positive skin and ocular sensitivity reactions to thimerosal were present in one-third r/,s) of patients tested. Light and transmission electron microscopic examination of conjunctival specimens disclosed intercellular epithelial edema, pseudoepitheliomatous hyperplasia, acute and chronic inflammation, and decreased numbers of goblet cells. Exposure to thimerosal is implicated in the etiology of contact lens-superior limbic keratoconjunctivitis (CL-SLK). [Key words: allergy, contact lens, hypersensitivity, keratitis, superior limbic keratoconjunctivitis, thimerosal, toxic.] Ophthalmology 90:616-622, 1983
As the popularity of contact lenses (CL) increases, so do the problems associated with their wear. In soft CL wearers these problems include subepithelial infiltrates, stromal edema, microbial ulcers, and decreased corneal sensation. I- 4 Several authors have attributed the development of the red eye in hydrogel lens wearers to a hypersensitivity reaction to the thimerosal preservative of chemical cleaning, rinsing, or sterilizing solutions. 5-8 From the Cornea Service, Massachusetts Eye and Ear Infirmary"; the Morphology Unit, Eye Research Institute of Retina Foundationt; and the Department of Ophthalmology, Harvard Medical School.t Supported in part by NEI National Research Service Award EY05479 (Dr. Sendele), NEI Research Grant EY03967, the Research to Prevent Blindness James S. Adams Award and a Fight·for·Sight, Inc., grant·in·aid, New York, New York (Dr. Kenyon). Presented at the Eighty·seventh Annual Meeting of the American Acad· emy of Ophthalmology, San Francisco, California, October 30-November 5, 1982. Reprint requests to Kenneth R. Kenyon, MD, Cornea Service, Massa· chusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114.
616
This paper describes a segment of the CL-wearing population who present corneal and conjunctival changes clinically resembling superior limbic keratoconjunctivitis (SLK) and possibly related to thimerosal exposure. We encourage recognition of this syndrome since discontinuation of lens wear and of associated solutions brings eventual resolution of symptoms and signs without permanent sequelae.
MATERIALS AND METHODS During an 18-month period, 40 contact lens-wearing patients were referred for the evaluation of ocular redness, irritation, and decreased lens tolerance. To elucidate the etiology of this syndrome, one eye of 15 patients was challenged with thimerosal (0.001% and/or 0.01 %) in balanced salt solution after resolution of initial symptoms. For one day, two drops were instilled in the challenged eye every hour the patient was awake. The other eye received one drop of balanced salt solution containing either EDT A (0.1 %) or benzalko-
0161-6420/83/0600/0616/$1.15 © American Academy of Ophthalmology
SENDELE, et al •
SUPERIOR LIMBIC KERATOCONJUNCTIVITIS
Table 1. Hypersensitivity Testing of Patients Ocular test 1. First eye: Instill one drop of balanced salt solution containing 0.001% or 0.01% thimerosal every hour while awake for one day.* 2. Second eye: instill one drop of balanced salt solution containing either 0.1 % EDTA or 0.3% benzalkonium chloride every hour while awake for one day. Occlusive patch test 1. Soak 2 x 2 gauze pad with a. 0.001% thimerosal b. 0.1% EDTA c. 0.3% benzalkonium chloride 2. Apply pad to forearm 3. Examine test sites at 48 and 72 hours Intradermal test 1. Inject 0.01 ml of the above solutions into forearm with tuberculin syringe 2. Examine at 48 and 72 hrs * Fifteen affected patients tested with 0.001% thimerosal. Nine of these patients retested with 0.01% thimerosal. All control patients tested with 0.001% and 0.01% thimerosal.
nium chloride (0.3%) each hour the patient was awake. In addition, the patients were patch tested as outlined ~n Table 1 wi~h those preservatives commonly employed In ophthalmIC products. An intradermal injection of each solution was also performed (Table 1). For comparison, ten soft CL-wearing individuals who used chemical preservatives but showed no ocular irritative signs or symptoms were similarly tested. Also, ten asymptomatic soft CL wearers who had never used chemical preservatives were tested. In five patients, biopsy of the involved superior bulbar conjunctiva was performed, and in one, a corneal epithelial scraping was obtained. For comparison, similar conjunctival biopsies were obtained from five asympTable 2. Patient Data Patients: 40 Male/female: 8/32 Initial visual acuity 20/30 or better 20/40-20/70 Less than 20/70
50% (20/40) 40% (16/40) 10% (4/40)
Type of lenses Bausch and Lomb® Hydrocurve® Polycon®
67% (27/40) 25% (10/40) 8% (3/40)
Power of lenses Myopic, ranging from -2.50D through -19D:80%, -3.0D to -5.0D Sterilization Cold sterilization Preserved saline with heat Unpreserved saline with heat
67% (27/40) 33% (13/40) 0% (0/40)
Table 3. Findings of Ocular Examination Symptoms Foreign body sensation Redness Tearing Photophobia Decreased visual acuity
52% 100% 18% 30% 50%
(21/40) (40/40) (7/40) (12/40) (20/40)
Signs Superior bulbar conjunctival injection Superior limbal epithelial irregularity and pannus Superior corneal sub-epithelial opacity Tarsal conjunctival papillae Filamentary keratitis
100% 100% 100% 25% 13%
(40/40) (40/40) (40/40) (10/40) (5/40)
tomatic soft CL-wearing patients who were not exposed to preservative-containing solutions. The tissues were fixed in glutaraldehyde-formalin and prepared for light and transmission electron microscopy by routine techniques.
RESULTS Forty patients presented with varying degrees of bilateral ocular redness and irritation while wearing contact lenses (Table 2). All were young adult (15 to 35 years) myopes who used predominantly soft contact lenses (92%) of various manufactures for cosmetic daily wear. All patients used either cold sterilization with a contact lens solution containing thimerosal as the pr~ servative (67%) or preserved saline with heat for disinfecting (33%). No patient had used only unpreserved saline with heat sterilization. Most patients had been successful contact lens wearers for several years, and the onset of signs and symptoms varied from several weeks to many months following exposure to preservative-containing solutions. On ocular examination (Table 3), all patients demonstrated (Fig 1): (I) superior bulbar conjunctival inflammation, usually bilateral and symmetrical, with perilimbal vascular injection and micropannus; (2) irregular thickening and redundancy of the superior bulbar conjunctiva; (3) irregularity of the superior corneal ~pithelium with subepithelial relucent opacity extending In a V-shaped pattern toward the visual axis; and (4) punctate fluorescein staining of the superior bulbar conjunctiva, limbus, and cornea. Filaments were encountered in only five cases (13%). Tarsal conjunctival changes inconsistently included relatively mild papillary response in ten cases (25%). In most cases (75%) the tarsal conjunctiva appeared normal. No other external ocular abnormality, particularly meibomitis or keratoconjunctivitis sicca, was evident in any patient. No nonspecific signs of infectious or aliergic processes were apparent, and nearly all patients demonstrated adequate contact lens fit. Following initial diagnostic evaluation, patients were inst.ru~ted to discontinue contact lens wear immediately. ArtIfiCIal tears and lubricating ointments were pre617
OPHTHALMOLOGY • JUNE 1983 • VOLUME 90 • NUMBER 6
scribed in the majority of patients who complained of a foreign body sensation. Particularly during our early experience with these patients, topical antibiotics and corticosteroids were prescribed, but were subsequently avoided as we later appreciated that these medications did not obviously alter the course of the disorder. In two patients with incapacitating reduction of vision on the basis of corneal epithelial irregularity, removal of the involved superior corneal epithelium by mechanical scraping with a scalpel blade may have hastened visual recovery but did not seem to otherwise affect the ciinical course. Following discontinuation of lens wear, all patients experienced the slow and gradual resolution of signs and symptoms over a period of many weeks to several months, and none developed any permanent sequelae (Fig. I). The visual acuity gradually returned to normal (all correctable to 20/30 or better) as the lirilbal and corneal inflammatory changes subsided. We are as yet unable to judge the ability of these patients to resume successful CL wear. Many patients elected to give up contact lenses altogether. Others, after abstaining from lens wear for as long as a year, have returned without difficulty to use of either hard, gas permeable, or soft CLs; the latter, however, only with the aid of preservative-free saline (eg, salt tablets or Unisol®) and cleaners (eg Pliagel® or Soft Mate®) with heat sterilization. Thirty-three percent f/15) of those patients tested with thimerosal developed a conjunctival inflammatory reaction within 24 hours of ocular challenge. In addition, all these same patients developed a positive patch test and intradermal test consisting of erythematous or vesicular skin reactions within 72 hours. None showed a positive result in any ocular or skin test to benzalkonium chloride or EDT A. In the remaining ten patients tested, none showed signs of ocular redness to the challenge with thimerosal and were negative to all patch and intradermal tests. Among the positive control group (asymptomatic CL wearers using preservatives), none reacted to ocular or skin tests with thimerosal, benzalkonium chloride, or EDTA. Among the negative control group (asymptomatic CL wearers unexposed to preservatives), two subjects (20%) developed positive ocular and skin reactions to thimerosal only.
CASE REPORT One case is detailed as a typical example of the varied clinical situations that can produce diagnostic confusion and hence protracted recovery often encountered in CL-SLK patients. A 26-year-old man who successfully wore hard contact lenses since 1973 changed to Polycon® lenses in 1980. Lens care consisted of storing the lens in Soaklens® solution. After five months, the patient presented with complaints of ocular redness, foreign body sensation, and decreased visual acuity. At that time, visual acuity was correctable to 20/300 right eye and 20/50 left eye. There was a bilateral pannus of the superior peripheral cornea, and the superior bulbar conjunctival epithelium appeared hyperemic, irregular, and thickened. Fluorescein stained the superior cornea and limbus with an over-
618
lying punctate keratitis in both eyes. A subepithelial relucency extended in a V-shaped pattern from the superior limbus toward the visual axis, more severely in the right eye. The central and inferior cornea and conjunctiva appeared normal. The tarsal conjunctiva revealed no papillae or follicles. Biomicroscopy showed adequate fit of the Polycon® lenses and no deposits or abnormalities of the lenses. Giemsa stain of the bulbar and tarsal conjunctival scrapings revealed moderate keratinization of epithelial cells with no inclusion bodies, rare polymorphoilUclearJeukocytes, and no eosinophils. A presumptive diagnosis of inclusion conjunctivitis was considered; the lenses were discontinued and the patient started on tetracycline 250 mgQID. One month later, the superior changes were not completely resolved, and Vasocidin® QID in both eyes was prescribed for one month. At this time, as the corneal and conjunctival changes had cleared with resolution of symptoms, he was allowed to return to new Soflon® lenses with chemical disinfection. He returned two months later with a recurrence of symptoms. At that time visual acuity was 20/30in both eyes; however, the superior conjunctiva was again hyperemic in both eyes and the superior subepithelial haze and pannus had returned. These changes did not extend.into the visual axis. The lenses were again discontinued. Ocular, intradermal, .a nd patch testing were negative. At this time, the diagnosis of CL-SLK was established. Once the symptoms abated, he was refitted with Polycon® lenses using unpreserved saline, and he experienced no further difficulty.
HISTOPATHOLOGY Light microscopy of the superior .bulbar conjunctiva was performed on biopsies from five affected patients and five normal controls. Among biopsies of affected patients, keratinization of the epithelium was found in two (Fig 2). Three specimens demonstrated intracellular epithelial edema. In three specimens, striking acanthosis was evident with pseudoepitheliomatous hyperplasia as acute inflaminatory cells were present within both the epithelial and stromal areas (Fig 3). The stroma showed signs of chronic inflammation with plasma cells and mononuclear cells in all five biopsies. No goblet cells were found in four of the biopsies, although in the fifth, the goblet cells appeared to be of normal size and number in comparison to control tissue. . Transmission electron microscopy of the conjunctiva confirmed those abnormalities evident by light microscopy while additionally resolving flattening of,:;uiface microvilli and accumulation of intracytoplasmic keratin filaments plus fibrillogranular inclusions of probable lipoproteinaceous content (Fig 2). The infiltration of polymorphbnuclear leukocytes within the epithelium was particularly striking (Fig 3). Although these evidences of acute and chronic inflammatory response are consistent with typical SLK, the findings of marked epithelial keratinization, nuclear degeneration, and glycogen accumulation said to be associated with SLK9- 12 ~ere not apparent here. The only notable finding in the control conjunctival biopsies was chronic inflammatory cells, which are a usual finding in the conjunctival stroma. The corneal epithelial scraping obtained in the one patient showed no abnormalities by eittier light or electron microscopy.
DISCUSSION In these 40 cosmetic contact lens wearers, a clinical syndrome of superior limbic keratoconjunctivitis is de-
SENDELE, et al •
SUPERIOR LIMBIC KERATOCONJUNCTIVITIS
Fig 1. Clinical manifestations of CL-SLK. Top left, hyperemia of superior bulbar conjunctiva and micropannus of superior limbus. Top right, with fluorescein staining, gelatinous elevation of limbal epithelium and diffuse superficial punctate epithelial changes are evident. Second row left, limbal epithelial elevation, micropannus, and corneal epithelial irregularity are shown. Second row right. with fluorescein staining, superficial punctate epithelial staining is discretely localized to the superior portion of cornea. Third row left. subepithelial opacification is evident as a Vshaped, nebulous relucency in the anterior stroma. Third row right. fluorescein staining of this same patient shows corresponding V-shaped pattern of the corneal epithelium. Bottom left. severe inflammation and superficial neovascularization of the superior cornea. Bottom right. this same patient is shown three months after discontinuation of soft contact lenses to have complete reversal of conjunctival and corneal abnormalities.
scribed. Salient characteristics include: (1) bulbar conjunctival injection most intense at the superior limbal area, (2) a boggy apron of bulbar conjunctiva that often
forms redundant folds over the superior limbus, (3) a fleshy gray thickening of the superior limbal and corneal epithelium, and (4) punctate fluorescein staining of the 619
OPHTHALMOLOGY • JUNE 1983 • VOLUME 90 • NUMBER 6
Fig 2. Morphology of superior bulbar conjunctiva. Inset light photomicrograph shows desquamating keratinized superficial epithelial cells (arrow) and polymorphonuclear neutrophils (circled) within the dilated intercellular spaces (paraphenylenediamine, X I ,000). Main figure transmission electron micrograph of this area demonstrates desquamating degenerate epithelial cells to have decreased surface microvilli and condensed cytoplasm with increased keratin filaments and numerous lipoproteinaceous inclusions (asterisks) (X 18,700).
bulbar conjunctival and corneal epithelium over the involved area. Although these findings are by definition those of a superior limbic keratoconjunctivitis, they should not be confused with the classical form of SLK as described by Theodore. 13- 15 Although the superior limbal and bulbar conjunctival changes are similar in CL-SLK and Theodore's SLK, the latter usually exhibits a diffuse inflammation and papillary reaction of the superior tarsal conjunctiva, seen in CL-SLK only mildly and infrequently (25% of cases). Second, filamentary keratitis, a consistent and important feature of classical SLK, was encountered in only 13% of our CL-SLK cases. Third, corneal epithelial irregularity and punctate keratitis, accounting for substantially reduced vision in 50% of CL-SLK cases, is much more extensive and severe than in Theodore's SLK where significant changes are limited to the limbic region and visual acuity is seldom impaired. Fourth, CL-SLK patients were predominantly younger females with no history of thyroid dysfunction, whereas classical SLK occurs more frequently in older women and is associated with thyroid disorders, particularly hyperthyroidism. Finally, patients with Theodore's SLK often benefit from bandage soft contact lens therapy and frequently require more aggressive treatment including conjunctival cauterization or resection, whereas CL-SLK invariably resolves upon discontinuation of lens wear. 620
The etiology of CL-SLK is difficult to ascertain. All other well known causes of red eyes in soft and hard CL wearers were excluded in these patients. Lenses of several polymers and designs were involved. In none were any physical abnormalities (deposits, edge damage, etc) of the lenses found to account for the ocular irritation. In all, the lens fit was adequate, and lens overwear could be excluded as a cause of ocular hyperemia. Viral and bacterial infections, although not specifically ruled out, were unlikely because of the time sequence of events, the inconsistency of folicular or papillary response, the absence of other clinical bacteriologic or cytologic evidence of an infectious process, and the lack of response to topical antibiotic or corticosteroid therapy. The single consistent feature in all our patients is the exposure to thimerosal in either the cleaning, rinsing, or disinfecting solutions. We have never encountered these findings in patients using unpreserved saline and heat sterilization. Certainly thimerosal is known to cause contact dermatitis (a delayed hypersensitivity reaction) and has also been recently implicated as a cause of delayed hypersensitivity reactions in the eye. 5,7 Among their series of 38 patients with presumed thimerosal sensitivity, Wilson and associates reported a patient (case I) with ocular findings similar to ours and felt the etiology .of the ocular changes was due to thimerosal since the patient exhibited a positive hypersensitivity test re-
SENDELE, et al • SUPERIOR LIMBIC KERATOCONJUNCTIVITIS
Fig 3. Morphology of superior bulbar conjunctiva. Inset light photomicrograph reveals marked acanthosis with pseudoepitheliomatous hyperplasia, as numerous acute inflammatory cells (circled) are evident within the epithelial layers (parapherrylenediamine, X500). Main figure transmission electron micrograph of this tissue specimen confirms presence of numerous polymorphonuclear neutrophils (asterisks) as well as probable lymphocytes within the dilated, edematous intercellular spaces of the epithelial layers (X8,900).
action.? Our own ocular skin test observations are inconclusive, as only one-third (5 of 15) of affected patients responded to thimerosal, although comparisons to positive control (0% response) and negative control (20% response) groups might prove significant among a larger series of subjects. On the other hand, as Franklin has cautioned, skin tests may not be a sensitive way to test for antibody-mediated response when a small molecule such as thimerosal is involved. 16 Brightbill and associates l ? have presented 20 patients with findings ofCLSLK identical to our own, and have similarly noted a positive skin test reaction to thimerosal in only one of six patients examined. Furthermore, Stenson 18 has recently published four cases of CL-SLK (with clinical features identical to those of our patients), in which three patients had been exposed to preservatives whereas one patient had not. No ocular or skin testing was attempted in these cases.
Pending a definitive resolution of the question ofthimerosal hypersensitivity, the following clinical evidence nonetheless suggests that exposure to thimerosal preservative may be responsible for the observed findings of CL-SLK: 1. All patients had used contact lens solutions containing thimerosal as a preservative. 2. In all cases, the syndrome was bilateral, and no other ocular or contact lens abnormalities could be identified. 3. The clinical signs and symptoms resolved completely upon discontinuation of the contact lenses and preserved solutions. 4. The syndrome recurred if thimerosal-containing solutions were reintroduced when CL wear was resumed. 5. Following complete resolution ofthe syndrome, 621
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most patients could resume contact lens wear without difficulty if thermal disinfection using preservative-free solutions was employed. Thus, irrespective of exact etiology, we emphasize this segment of the CL population who presented with a clinical picture similar to SLK. Prompt recognition of the CL-SLK association should reduce diagnostic confusion (as evidenced in our case report) and facilitate appropriate conservative therapy, thereby lessening patient morbidity and avoiding more significant corneal complications.
ACKNOWLEDGMENT The critical review of Dr. Frederick Theodore is greatly appreciated.
REFERENCES 1. Ruben M. Acute eye disease secondary to contact·lens wear. Report of a census . Lancet 1976; 1:138-40. 2. Morgan JF. Symposium: Contact lenses. Complications associated with contact lens solutions. Ophthalmology 1979; 86: 11 07 -19. 3. Brown SI, Bloomfield S, Pearce DB, Tragakis M. Infections with the therapeutic soft lens. Arch Ophthalmol 1974; 91 :275-7. 4. Dohlman CH, Boruchoff SA, Mobilia EF. Complications in use of soft contact lenses in corneal disease. Arch Ophthalmol 1973; 90:36771.
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5. Mondino BJ, Groden LR. Conjunctival hyperemia and corneal infil· trates with chemically disinfected soft contact lenses. Arch Ophthal· mol 1980; 98:1767-70. 6. Binder PS, Rasmussen OM, Gordon M. Keratoconjunctivitis and soft contact lens solutions. Arch OphthalmoI1981; 99:87-90. 7. Wilson LA, McNatt J, Reitschel R. Delayed hypersensitivity to thi· merosal in soft contact lens wearers. Ophthalmology 1981; 88;804-
8. 8. Mondino BJ, Salamon SM, Zaidman GW. Allergic and toxic reactions of soft contact lens wearers. SUN Ophthalmol 1982; 26:337-44. 9. Theodore FH, Ferry AP. · Superior limbic keratoconjunctivitis; clinical and pathological correlations. Arch Ophthalmol1970; 84:481-4. 10. Cher I. Clinical features of superior limbic keratoconjunctivitis in Aus· tralia; a probable association with thyrotoxicosis. Arch Ophthalmol 1969; 82:580-6. 11. Wright P. Superior limbic keratoconjunctivitis. Trans Ophthalmol Soc UK 1972; 92:555-60. 12. Donshik PC, Collin HB, Foster CS, et aI. Conjunctival resection treat· ment and ultrastructural histopathology of superior limbic keratocon· junctivitis. Am J Ophthalmol 1978; 85:101-10. 13. Theodore FH. Superior limbic keratoconjunctivitis. Eye Ear Nose Throat Mon 1963; 42:25-8. 14. Theodore FH. Further obseNations on superior limbic keratoconjunctivitis. Trans Am Acad Ophthalmol OtolaryngoI1967; 71 :341-51 . 15. Theodore FH. Superior limbic keratoconjunctivitis: further studies. Concilium Ophthalmologicum, 21st, Mexico, 1970. 1971; 1:666-9. 16. Franklin RM. Discussion of paper by Wilson LA, McNatt J, Reitschel R. Ophthalmology 1981; 88:808-9. 17. Brightbill F. Superior limbic keratoconjunctivitis in soft contact lens wearers. Presented at the Ninth National Research Symposium in Contact Lenses, August 28,1981, Dallas, Texas. 18. Stenson S. Superior limbic keratoconjunctivitis associated with soft contact lens wear. Arch Ophthalmol 1983; 101 :402-4.
Contact Lens Wearers
DEBORAH D. SENDELE, MD, *t* KENNETH R. KENYON, MD, *t* ELEANOR F. MOBILIA, OD,* PERRY ROSENTHAL, MD,* ROGER STEINERT, MD,* LAlLA A. HANNINENt
Abstract: Forty patients with daily wear, cosmetic contact lenses (CL) presented with symptoms of ocular irritation and a keratoconjunctivitis clinically resembling superior limbic keratoconjunctivitis (SLK). Typically the patients were either successful hard CL wearers who changed to soft lenses and used a chemical aseptisizing solution or preserved saline solution, or successful soft CL wearers using salt tablets who switched to a preservative-containing system. In all cases, exposure to thimerosal-preserved solutions was documented. Upon discontinuation of lens wear, all signs and symptoms slowly resolved without permanent sequelae. Positive skin and ocular sensitivity reactions to thimerosal were present in one-third r/,s) of patients tested. Light and transmission electron microscopic examination of conjunctival specimens disclosed intercellular epithelial edema, pseudoepitheliomatous hyperplasia, acute and chronic inflammation, and decreased numbers of goblet cells. Exposure to thimerosal is implicated in the etiology of contact lens-superior limbic keratoconjunctivitis (CL-SLK). [Key words: allergy, contact lens, hypersensitivity, keratitis, superior limbic keratoconjunctivitis, thimerosal, toxic.] Ophthalmology 90:616-622, 1983
As the popularity of contact lenses (CL) increases, so do the problems associated with their wear. In soft CL wearers these problems include subepithelial infiltrates, stromal edema, microbial ulcers, and decreased corneal sensation. I- 4 Several authors have attributed the development of the red eye in hydrogel lens wearers to a hypersensitivity reaction to the thimerosal preservative of chemical cleaning, rinsing, or sterilizing solutions. 5-8 From the Cornea Service, Massachusetts Eye and Ear Infirmary"; the Morphology Unit, Eye Research Institute of Retina Foundationt; and the Department of Ophthalmology, Harvard Medical School.t Supported in part by NEI National Research Service Award EY05479 (Dr. Sendele), NEI Research Grant EY03967, the Research to Prevent Blindness James S. Adams Award and a Fight·for·Sight, Inc., grant·in·aid, New York, New York (Dr. Kenyon). Presented at the Eighty·seventh Annual Meeting of the American Acad· emy of Ophthalmology, San Francisco, California, October 30-November 5, 1982. Reprint requests to Kenneth R. Kenyon, MD, Cornea Service, Massa· chusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114.
616
This paper describes a segment of the CL-wearing population who present corneal and conjunctival changes clinically resembling superior limbic keratoconjunctivitis (SLK) and possibly related to thimerosal exposure. We encourage recognition of this syndrome since discontinuation of lens wear and of associated solutions brings eventual resolution of symptoms and signs without permanent sequelae.
MATERIALS AND METHODS During an 18-month period, 40 contact lens-wearing patients were referred for the evaluation of ocular redness, irritation, and decreased lens tolerance. To elucidate the etiology of this syndrome, one eye of 15 patients was challenged with thimerosal (0.001% and/or 0.01 %) in balanced salt solution after resolution of initial symptoms. For one day, two drops were instilled in the challenged eye every hour the patient was awake. The other eye received one drop of balanced salt solution containing either EDT A (0.1 %) or benzalko-
0161-6420/83/0600/0616/$1.15 © American Academy of Ophthalmology
SENDELE, et al •
SUPERIOR LIMBIC KERATOCONJUNCTIVITIS
Table 1. Hypersensitivity Testing of Patients Ocular test 1. First eye: Instill one drop of balanced salt solution containing 0.001% or 0.01% thimerosal every hour while awake for one day.* 2. Second eye: instill one drop of balanced salt solution containing either 0.1 % EDTA or 0.3% benzalkonium chloride every hour while awake for one day. Occlusive patch test 1. Soak 2 x 2 gauze pad with a. 0.001% thimerosal b. 0.1% EDTA c. 0.3% benzalkonium chloride 2. Apply pad to forearm 3. Examine test sites at 48 and 72 hours Intradermal test 1. Inject 0.01 ml of the above solutions into forearm with tuberculin syringe 2. Examine at 48 and 72 hrs * Fifteen affected patients tested with 0.001% thimerosal. Nine of these patients retested with 0.01% thimerosal. All control patients tested with 0.001% and 0.01% thimerosal.
nium chloride (0.3%) each hour the patient was awake. In addition, the patients were patch tested as outlined ~n Table 1 wi~h those preservatives commonly employed In ophthalmIC products. An intradermal injection of each solution was also performed (Table 1). For comparison, ten soft CL-wearing individuals who used chemical preservatives but showed no ocular irritative signs or symptoms were similarly tested. Also, ten asymptomatic soft CL wearers who had never used chemical preservatives were tested. In five patients, biopsy of the involved superior bulbar conjunctiva was performed, and in one, a corneal epithelial scraping was obtained. For comparison, similar conjunctival biopsies were obtained from five asympTable 2. Patient Data Patients: 40 Male/female: 8/32 Initial visual acuity 20/30 or better 20/40-20/70 Less than 20/70
50% (20/40) 40% (16/40) 10% (4/40)
Type of lenses Bausch and Lomb® Hydrocurve® Polycon®
67% (27/40) 25% (10/40) 8% (3/40)
Power of lenses Myopic, ranging from -2.50D through -19D:80%, -3.0D to -5.0D Sterilization Cold sterilization Preserved saline with heat Unpreserved saline with heat
67% (27/40) 33% (13/40) 0% (0/40)
Table 3. Findings of Ocular Examination Symptoms Foreign body sensation Redness Tearing Photophobia Decreased visual acuity
52% 100% 18% 30% 50%
(21/40) (40/40) (7/40) (12/40) (20/40)
Signs Superior bulbar conjunctival injection Superior limbal epithelial irregularity and pannus Superior corneal sub-epithelial opacity Tarsal conjunctival papillae Filamentary keratitis
100% 100% 100% 25% 13%
(40/40) (40/40) (40/40) (10/40) (5/40)
tomatic soft CL-wearing patients who were not exposed to preservative-containing solutions. The tissues were fixed in glutaraldehyde-formalin and prepared for light and transmission electron microscopy by routine techniques.
RESULTS Forty patients presented with varying degrees of bilateral ocular redness and irritation while wearing contact lenses (Table 2). All were young adult (15 to 35 years) myopes who used predominantly soft contact lenses (92%) of various manufactures for cosmetic daily wear. All patients used either cold sterilization with a contact lens solution containing thimerosal as the pr~ servative (67%) or preserved saline with heat for disinfecting (33%). No patient had used only unpreserved saline with heat sterilization. Most patients had been successful contact lens wearers for several years, and the onset of signs and symptoms varied from several weeks to many months following exposure to preservative-containing solutions. On ocular examination (Table 3), all patients demonstrated (Fig 1): (I) superior bulbar conjunctival inflammation, usually bilateral and symmetrical, with perilimbal vascular injection and micropannus; (2) irregular thickening and redundancy of the superior bulbar conjunctiva; (3) irregularity of the superior corneal ~pithelium with subepithelial relucent opacity extending In a V-shaped pattern toward the visual axis; and (4) punctate fluorescein staining of the superior bulbar conjunctiva, limbus, and cornea. Filaments were encountered in only five cases (13%). Tarsal conjunctival changes inconsistently included relatively mild papillary response in ten cases (25%). In most cases (75%) the tarsal conjunctiva appeared normal. No other external ocular abnormality, particularly meibomitis or keratoconjunctivitis sicca, was evident in any patient. No nonspecific signs of infectious or aliergic processes were apparent, and nearly all patients demonstrated adequate contact lens fit. Following initial diagnostic evaluation, patients were inst.ru~ted to discontinue contact lens wear immediately. ArtIfiCIal tears and lubricating ointments were pre617
OPHTHALMOLOGY • JUNE 1983 • VOLUME 90 • NUMBER 6
scribed in the majority of patients who complained of a foreign body sensation. Particularly during our early experience with these patients, topical antibiotics and corticosteroids were prescribed, but were subsequently avoided as we later appreciated that these medications did not obviously alter the course of the disorder. In two patients with incapacitating reduction of vision on the basis of corneal epithelial irregularity, removal of the involved superior corneal epithelium by mechanical scraping with a scalpel blade may have hastened visual recovery but did not seem to otherwise affect the ciinical course. Following discontinuation of lens wear, all patients experienced the slow and gradual resolution of signs and symptoms over a period of many weeks to several months, and none developed any permanent sequelae (Fig. I). The visual acuity gradually returned to normal (all correctable to 20/30 or better) as the lirilbal and corneal inflammatory changes subsided. We are as yet unable to judge the ability of these patients to resume successful CL wear. Many patients elected to give up contact lenses altogether. Others, after abstaining from lens wear for as long as a year, have returned without difficulty to use of either hard, gas permeable, or soft CLs; the latter, however, only with the aid of preservative-free saline (eg, salt tablets or Unisol®) and cleaners (eg Pliagel® or Soft Mate®) with heat sterilization. Thirty-three percent f/15) of those patients tested with thimerosal developed a conjunctival inflammatory reaction within 24 hours of ocular challenge. In addition, all these same patients developed a positive patch test and intradermal test consisting of erythematous or vesicular skin reactions within 72 hours. None showed a positive result in any ocular or skin test to benzalkonium chloride or EDT A. In the remaining ten patients tested, none showed signs of ocular redness to the challenge with thimerosal and were negative to all patch and intradermal tests. Among the positive control group (asymptomatic CL wearers using preservatives), none reacted to ocular or skin tests with thimerosal, benzalkonium chloride, or EDTA. Among the negative control group (asymptomatic CL wearers unexposed to preservatives), two subjects (20%) developed positive ocular and skin reactions to thimerosal only.
CASE REPORT One case is detailed as a typical example of the varied clinical situations that can produce diagnostic confusion and hence protracted recovery often encountered in CL-SLK patients. A 26-year-old man who successfully wore hard contact lenses since 1973 changed to Polycon® lenses in 1980. Lens care consisted of storing the lens in Soaklens® solution. After five months, the patient presented with complaints of ocular redness, foreign body sensation, and decreased visual acuity. At that time, visual acuity was correctable to 20/300 right eye and 20/50 left eye. There was a bilateral pannus of the superior peripheral cornea, and the superior bulbar conjunctival epithelium appeared hyperemic, irregular, and thickened. Fluorescein stained the superior cornea and limbus with an over-
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lying punctate keratitis in both eyes. A subepithelial relucency extended in a V-shaped pattern from the superior limbus toward the visual axis, more severely in the right eye. The central and inferior cornea and conjunctiva appeared normal. The tarsal conjunctiva revealed no papillae or follicles. Biomicroscopy showed adequate fit of the Polycon® lenses and no deposits or abnormalities of the lenses. Giemsa stain of the bulbar and tarsal conjunctival scrapings revealed moderate keratinization of epithelial cells with no inclusion bodies, rare polymorphoilUclearJeukocytes, and no eosinophils. A presumptive diagnosis of inclusion conjunctivitis was considered; the lenses were discontinued and the patient started on tetracycline 250 mgQID. One month later, the superior changes were not completely resolved, and Vasocidin® QID in both eyes was prescribed for one month. At this time, as the corneal and conjunctival changes had cleared with resolution of symptoms, he was allowed to return to new Soflon® lenses with chemical disinfection. He returned two months later with a recurrence of symptoms. At that time visual acuity was 20/30in both eyes; however, the superior conjunctiva was again hyperemic in both eyes and the superior subepithelial haze and pannus had returned. These changes did not extend.into the visual axis. The lenses were again discontinued. Ocular, intradermal, .a nd patch testing were negative. At this time, the diagnosis of CL-SLK was established. Once the symptoms abated, he was refitted with Polycon® lenses using unpreserved saline, and he experienced no further difficulty.
HISTOPATHOLOGY Light microscopy of the superior .bulbar conjunctiva was performed on biopsies from five affected patients and five normal controls. Among biopsies of affected patients, keratinization of the epithelium was found in two (Fig 2). Three specimens demonstrated intracellular epithelial edema. In three specimens, striking acanthosis was evident with pseudoepitheliomatous hyperplasia as acute inflaminatory cells were present within both the epithelial and stromal areas (Fig 3). The stroma showed signs of chronic inflammation with plasma cells and mononuclear cells in all five biopsies. No goblet cells were found in four of the biopsies, although in the fifth, the goblet cells appeared to be of normal size and number in comparison to control tissue. . Transmission electron microscopy of the conjunctiva confirmed those abnormalities evident by light microscopy while additionally resolving flattening of,:;uiface microvilli and accumulation of intracytoplasmic keratin filaments plus fibrillogranular inclusions of probable lipoproteinaceous content (Fig 2). The infiltration of polymorphbnuclear leukocytes within the epithelium was particularly striking (Fig 3). Although these evidences of acute and chronic inflammatory response are consistent with typical SLK, the findings of marked epithelial keratinization, nuclear degeneration, and glycogen accumulation said to be associated with SLK9- 12 ~ere not apparent here. The only notable finding in the control conjunctival biopsies was chronic inflammatory cells, which are a usual finding in the conjunctival stroma. The corneal epithelial scraping obtained in the one patient showed no abnormalities by eittier light or electron microscopy.
DISCUSSION In these 40 cosmetic contact lens wearers, a clinical syndrome of superior limbic keratoconjunctivitis is de-
SENDELE, et al •
SUPERIOR LIMBIC KERATOCONJUNCTIVITIS
Fig 1. Clinical manifestations of CL-SLK. Top left, hyperemia of superior bulbar conjunctiva and micropannus of superior limbus. Top right, with fluorescein staining, gelatinous elevation of limbal epithelium and diffuse superficial punctate epithelial changes are evident. Second row left, limbal epithelial elevation, micropannus, and corneal epithelial irregularity are shown. Second row right. with fluorescein staining, superficial punctate epithelial staining is discretely localized to the superior portion of cornea. Third row left. subepithelial opacification is evident as a Vshaped, nebulous relucency in the anterior stroma. Third row right. fluorescein staining of this same patient shows corresponding V-shaped pattern of the corneal epithelium. Bottom left. severe inflammation and superficial neovascularization of the superior cornea. Bottom right. this same patient is shown three months after discontinuation of soft contact lenses to have complete reversal of conjunctival and corneal abnormalities.
scribed. Salient characteristics include: (1) bulbar conjunctival injection most intense at the superior limbal area, (2) a boggy apron of bulbar conjunctiva that often
forms redundant folds over the superior limbus, (3) a fleshy gray thickening of the superior limbal and corneal epithelium, and (4) punctate fluorescein staining of the 619
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Fig 2. Morphology of superior bulbar conjunctiva. Inset light photomicrograph shows desquamating keratinized superficial epithelial cells (arrow) and polymorphonuclear neutrophils (circled) within the dilated intercellular spaces (paraphenylenediamine, X I ,000). Main figure transmission electron micrograph of this area demonstrates desquamating degenerate epithelial cells to have decreased surface microvilli and condensed cytoplasm with increased keratin filaments and numerous lipoproteinaceous inclusions (asterisks) (X 18,700).
bulbar conjunctival and corneal epithelium over the involved area. Although these findings are by definition those of a superior limbic keratoconjunctivitis, they should not be confused with the classical form of SLK as described by Theodore. 13- 15 Although the superior limbal and bulbar conjunctival changes are similar in CL-SLK and Theodore's SLK, the latter usually exhibits a diffuse inflammation and papillary reaction of the superior tarsal conjunctiva, seen in CL-SLK only mildly and infrequently (25% of cases). Second, filamentary keratitis, a consistent and important feature of classical SLK, was encountered in only 13% of our CL-SLK cases. Third, corneal epithelial irregularity and punctate keratitis, accounting for substantially reduced vision in 50% of CL-SLK cases, is much more extensive and severe than in Theodore's SLK where significant changes are limited to the limbic region and visual acuity is seldom impaired. Fourth, CL-SLK patients were predominantly younger females with no history of thyroid dysfunction, whereas classical SLK occurs more frequently in older women and is associated with thyroid disorders, particularly hyperthyroidism. Finally, patients with Theodore's SLK often benefit from bandage soft contact lens therapy and frequently require more aggressive treatment including conjunctival cauterization or resection, whereas CL-SLK invariably resolves upon discontinuation of lens wear. 620
The etiology of CL-SLK is difficult to ascertain. All other well known causes of red eyes in soft and hard CL wearers were excluded in these patients. Lenses of several polymers and designs were involved. In none were any physical abnormalities (deposits, edge damage, etc) of the lenses found to account for the ocular irritation. In all, the lens fit was adequate, and lens overwear could be excluded as a cause of ocular hyperemia. Viral and bacterial infections, although not specifically ruled out, were unlikely because of the time sequence of events, the inconsistency of folicular or papillary response, the absence of other clinical bacteriologic or cytologic evidence of an infectious process, and the lack of response to topical antibiotic or corticosteroid therapy. The single consistent feature in all our patients is the exposure to thimerosal in either the cleaning, rinsing, or disinfecting solutions. We have never encountered these findings in patients using unpreserved saline and heat sterilization. Certainly thimerosal is known to cause contact dermatitis (a delayed hypersensitivity reaction) and has also been recently implicated as a cause of delayed hypersensitivity reactions in the eye. 5,7 Among their series of 38 patients with presumed thimerosal sensitivity, Wilson and associates reported a patient (case I) with ocular findings similar to ours and felt the etiology .of the ocular changes was due to thimerosal since the patient exhibited a positive hypersensitivity test re-
SENDELE, et al • SUPERIOR LIMBIC KERATOCONJUNCTIVITIS
Fig 3. Morphology of superior bulbar conjunctiva. Inset light photomicrograph reveals marked acanthosis with pseudoepitheliomatous hyperplasia, as numerous acute inflammatory cells (circled) are evident within the epithelial layers (parapherrylenediamine, X500). Main figure transmission electron micrograph of this tissue specimen confirms presence of numerous polymorphonuclear neutrophils (asterisks) as well as probable lymphocytes within the dilated, edematous intercellular spaces of the epithelial layers (X8,900).
action.? Our own ocular skin test observations are inconclusive, as only one-third (5 of 15) of affected patients responded to thimerosal, although comparisons to positive control (0% response) and negative control (20% response) groups might prove significant among a larger series of subjects. On the other hand, as Franklin has cautioned, skin tests may not be a sensitive way to test for antibody-mediated response when a small molecule such as thimerosal is involved. 16 Brightbill and associates l ? have presented 20 patients with findings ofCLSLK identical to our own, and have similarly noted a positive skin test reaction to thimerosal in only one of six patients examined. Furthermore, Stenson 18 has recently published four cases of CL-SLK (with clinical features identical to those of our patients), in which three patients had been exposed to preservatives whereas one patient had not. No ocular or skin testing was attempted in these cases.
Pending a definitive resolution of the question ofthimerosal hypersensitivity, the following clinical evidence nonetheless suggests that exposure to thimerosal preservative may be responsible for the observed findings of CL-SLK: 1. All patients had used contact lens solutions containing thimerosal as a preservative. 2. In all cases, the syndrome was bilateral, and no other ocular or contact lens abnormalities could be identified. 3. The clinical signs and symptoms resolved completely upon discontinuation of the contact lenses and preserved solutions. 4. The syndrome recurred if thimerosal-containing solutions were reintroduced when CL wear was resumed. 5. Following complete resolution ofthe syndrome, 621
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most patients could resume contact lens wear without difficulty if thermal disinfection using preservative-free solutions was employed. Thus, irrespective of exact etiology, we emphasize this segment of the CL population who presented with a clinical picture similar to SLK. Prompt recognition of the CL-SLK association should reduce diagnostic confusion (as evidenced in our case report) and facilitate appropriate conservative therapy, thereby lessening patient morbidity and avoiding more significant corneal complications.
ACKNOWLEDGMENT The critical review of Dr. Frederick Theodore is greatly appreciated.
REFERENCES 1. Ruben M. Acute eye disease secondary to contact·lens wear. Report of a census . Lancet 1976; 1:138-40. 2. Morgan JF. Symposium: Contact lenses. Complications associated with contact lens solutions. Ophthalmology 1979; 86: 11 07 -19. 3. Brown SI, Bloomfield S, Pearce DB, Tragakis M. Infections with the therapeutic soft lens. Arch Ophthalmol 1974; 91 :275-7. 4. Dohlman CH, Boruchoff SA, Mobilia EF. Complications in use of soft contact lenses in corneal disease. Arch Ophthalmol 1973; 90:36771.
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5. Mondino BJ, Groden LR. Conjunctival hyperemia and corneal infil· trates with chemically disinfected soft contact lenses. Arch Ophthal· mol 1980; 98:1767-70. 6. Binder PS, Rasmussen OM, Gordon M. Keratoconjunctivitis and soft contact lens solutions. Arch OphthalmoI1981; 99:87-90. 7. Wilson LA, McNatt J, Reitschel R. Delayed hypersensitivity to thi· merosal in soft contact lens wearers. Ophthalmology 1981; 88;804-
8. 8. Mondino BJ, Salamon SM, Zaidman GW. Allergic and toxic reactions of soft contact lens wearers. SUN Ophthalmol 1982; 26:337-44. 9. Theodore FH, Ferry AP. · Superior limbic keratoconjunctivitis; clinical and pathological correlations. Arch Ophthalmol1970; 84:481-4. 10. Cher I. Clinical features of superior limbic keratoconjunctivitis in Aus· tralia; a probable association with thyrotoxicosis. Arch Ophthalmol 1969; 82:580-6. 11. Wright P. Superior limbic keratoconjunctivitis. Trans Ophthalmol Soc UK 1972; 92:555-60. 12. Donshik PC, Collin HB, Foster CS, et aI. Conjunctival resection treat· ment and ultrastructural histopathology of superior limbic keratocon· junctivitis. Am J Ophthalmol 1978; 85:101-10. 13. Theodore FH. Superior limbic keratoconjunctivitis. Eye Ear Nose Throat Mon 1963; 42:25-8. 14. Theodore FH. Further obseNations on superior limbic keratoconjunctivitis. Trans Am Acad Ophthalmol OtolaryngoI1967; 71 :341-51 . 15. Theodore FH. Superior limbic keratoconjunctivitis: further studies. Concilium Ophthalmologicum, 21st, Mexico, 1970. 1971; 1:666-9. 16. Franklin RM. Discussion of paper by Wilson LA, McNatt J, Reitschel R. Ophthalmology 1981; 88:808-9. 17. Brightbill F. Superior limbic keratoconjunctivitis in soft contact lens wearers. Presented at the Ninth National Research Symposium in Contact Lenses, August 28,1981, Dallas, Texas. 18. Stenson S. Superior limbic keratoconjunctivitis associated with soft contact lens wear. Arch Ophthalmol 1983; 101 :402-4.