Superior Limbic Keratoconjunctivitis

Superior Limbic Keratoconjunctivitis A Prognostic Sign for Severe Graves Ophthalmopathy Eddie F. Kadrmas, MD, PhD, George B. Bartley, MD Purpose: To study superior limbic keratoconjunctivitis in a relatively large group of patients and to determine whether a relation exists with thyroid dysfunction. Methods: The medical records of 57 patients with superior limbic keratoconjunctivitis who were examined between 1980 and 1993 were reviewed. Results: Thirty-seven patients (64.9%; 95% confidence interval, 51.1-77.1) had objective evidence of thyroid dysfunction. Of patients with superior limbic keratocon­ junctivitis and thyroid disease, 33 (89.2%) had ophthalmopathy, which in 16 patients (48.5%) was sufficiently severe to require orbital decompression. Conclusion: Superior limbic keratoconjunctivitis is associated with thyroid dys­ function and appears to be a prognostic marker for severe Graves ophthalmopathy. Ophthalmology 1995; 102:1472-1475

Superior limbic keratoconjunctivitis (SLK) is a distinctive chronic and recurrent external ocular inflammatory dis­ ease of unknown cause characterized by inflammation of the superior bulbar and tarsal conjunctiva, proliferation ofsuperior limbus epithelial cells, and fine punctate stain­ ing with filaments adjacent to the superior corneal limbus. Superior limbic keratoconjunctivitis was first described by Theodore 1 in 1961 and was detailed extensively by Theodore and others2- 5 later in the decade, efforts ofwhich culminated in the first review6 of this entity in 1969. Superior limbic keratoconjunctivitis also is character­ ized by a putative association with thyroid dysfunction. In 1968, TenzeC described four patients with thyroid dysOriginally received: March 29, 1995. Revision accepted: May 31, 1995. Department of Ophthalmology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota. Presented in part as a poster at the American Academy ofOphthalmology Annual Meeting, San Francisco, November 1994. Supported in part by an unrestricted grant from Research to Prevent Blindness, Inc, New York, New York, by research grant EY0-8039 from the National Institutes of Health, Bethesda, Maryland, and by the Mayo Foundation, Rochester, Minnesota. Reprint requests to George B. Bartley, MD, Department of Ophthal­ mology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 .

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function and SLK and suggested a possible relation. In the same year, Theodore, 8 commenting on Tenzel's re­ port, noted that some of his own patients had SLK and thyroid dysfunction. Braley and Alexander, 9 in 1953, de­ scribed several cases of "superficial punctate keratitis with filaments" that may have been examples of SLK. Al­ though some of their patients were characterized as "anx­ ious, impatient, and nervous," thyroid dysfunction was not documented. Cher 10 reported that 50% (5 of 10) of patients with SLK had concomitant thyroid dysfunction. Other authors since have reported rates of association ranging from 20% to 50%. 11 - 14 A recent retrospective, population-based study of Graves ophthalmopathy identified SLK in only 4 (3.3%) of 120 incident cases. 15 Because this association seemed relatively infrequent in light of previous assumptions, our specific aim was to study SLK in a relatively large group ofpatients and, if possible, to determine whether a relation exists with thyroid dysfunction.

Materials and Methods The medical records of all patients with the diagnosis of SLK who were examined in the Department of Ophthal­ mology at the Mayo Clinic, Rochester, Minnesota, be­

Kadrmas and Bartley · Superior Limbic Keratoconjunctivitis tween 1980 and 1993, were reviewed. To be included in the study, at least two of the following diagnostic criteria for SLK were necessary: blood vessel dilation of the su­ perior bulbar conjunctiva; papillary inflammation of the upper tarsal conjunctiva; fine punctate rose bengal or flu­ orescein staining of the superior conjunctiva and of the upper cornea, including the limbus; filaments at the su­ perior limbus or upper cornea; superior limbal prolifer­ ation (epithelial thickening of the superior bulbar and limbal conjunctiva); superior micropannus; associated chemosis; or redundancy of the superior bulbar conjunc­ tiva. The presence or absence ofthyroid dysfunction, defined as hyperthyroidism, hypothyroidism, or euthyroid Graves disease (based on the presence of serum thyroid-stimu­ lating immunoglobulins), was determined by thorough review of each patient's medical and laboratory record. The criteria for the diagnosis of Graves ophthalmopathy have been described previously. 15 Follow-up intervals ranged from I to 14 years. All pa­ tients with the diagnosis of Graves ophthalmopathy had follow-up visits at the Mayo Clinic. All except one patient with Graves ophthalmopathy requiring surgical interven­ tion had their procedure(s) performed at our institution. One patient underwent orbital decompression elsewhere but was examined postoperatively at the Mayo Clinic.

Results Fifty-seven patients had SLK during the period studied. Nine (15.8%) had unilateral disease and 48 (84.2%) had bilateral disease at initial examination. Twelve (21.1%) patients were male, and 45 (78.9%) were female (female: male ratio, 3.7: 1.0). All were white. The mean age at pre­ sentation was 50.6 years (range, 20-79 years). Several clinical characteristics in these patients were noteworthy. Thirty (52.6%) patients had eyelid retraction at the time of diagnosis of SLK, and all of these patients had evidence of thyroid dysfunction. Twenty-six patients (45.6%) had normal eyelid position, and one (1.8%) had blepharoptosis. Proptosis, as defined by Krahn or Hertel exophthalmometry measurements greater than 20 mm, 15 was documented in 21 (36.8%) patients, all ofwhom had thyroid dysfunction. Lid lag and lagophthalmos were present in 27 (47.4%) and 11 (19.3%) patients, respectively, at the time of diagnosis of SLK. Similarly, all of these patients had evidence of thyroid dysfunction. Patients with the diagnosis of SLK were characterized further by association with other disease states (Table 1). Thirty-seven patients (64.9%; 95% confidence interval, 51.1-77 .I) had objective evidence of thyroid disease or Graves ophthalmopathy (including patients who were eu­ thyroid but who had ophthalmopathy and elevated levels of thyroid-stimulating immunoglobulin). Two patients (3.5%) had evidence of other autoimmune disorders (rheumatoid arthritis and Sjogren syndrome), and six pa­ tients (10.5%) had SLK in association with contact lens wear. Eighteen (31.6%) patients had no associated medical abnormalities.

The average age at initial examination for patients with SLK and thyroid dysfunction was 52.6 years (range, 21­ 79 years). Four of these patients (10.8%) were male, and 33 (89.2%) were female (female:male ratio, 8.3:1.0). In this group, the mean vertical eyelid fissure was 11.9 mm (range, 7.5-17 mm), and the average degree of upper eye­ lid retraction was 1.8 mm (range, 0-5.5 mm). In contrast, all patients with SLK who did not demonstrate evidence for thyroid dysfunction or Graves ophthalmopathy had normal eyelid positions. The thyroid status of patients with SLK and evidence for thyroid dysfunction or Graves ophthalmopathy was further classified (Table 2). Hyperthyroidism was docu­ mented in 32 (86.5%) 6fthese patients: 9 were hyperthy­ roid at the time of diagnosis ofSLK; 21 (20 ofwhom had undergone radioablative 131 iodine treatment) were euthy­ roid while receiving hormone replacement therapy at the time of diagnosis of SLK; 1 patient was hypothyroid after 131 iodine treatment, the result of inadequate replacement therapy; and I had Hashimoto thyroiditis. Primary hy­ pothyroidism was diagnosed in three patients (8.1% ): two were euthyroid while receiving thyroid hormone replace­ ment, and one was overmedicated. Two patients (5.4%) had euthyroid Graves disease. Thirty-three patients with SLK had evidence ofGraves ophthalmopathy (Table 3). They represented 89.2% of patients with thyroid dysfunction and 57.9% ofall patients with a diagnosis of SLK. Eighteen (54.5%) of these 33 patients required some form of surgical intervention for ophthalmopathy during the course of their follow-up: 11 (33.3%) underwent orbital decompression alone, 5 (15.2%) underwent orbital decompression and eyelid retraction repair, and 2 (6.1%) had eyelid retraction repair alone. Sixteen (48.5%) ofthe 33 patients, therefore, required or­ bital decompression. Indications for orbital decompres­ sion included optic neuropathy, severe orbital inflam­ mation that was not responsive to systemic corticosteroids, exposure keratopathy, or in preparation for strabismus surgery (recession procedures that would exacerbate pro­ ptosis).

Discussion The frequency of SLK in an incidence cohort of patients with Graves ophthalmopathy was relatively low (4 [3.3%] of 120 patients)Y The converse relation, the presence of thyroid dysfunction in patients with SLK, has ranged from 20% to 50% in published reports 10- 14 (Table 4) and was 64.9% in the patients we studied. 16 •17 Of the patients with SLK and thyroid disease described herein, approximately 90% had ophthalmopathy, which was sufficiently severe to require orbital decompression in 49% of patients. Su­ perior limbic keratoconjunctivitis may be a prognostic marker for severe Graves ophthalmopathy. The population from which the patients we studied were drawn was not population-based and is subject to referral bias, in that our institution is a tertiary-care center where the physicians have a longstanding interest in thy­ roid disease and Graves ophthalmopathy. This bias may

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Ophthalmology

Volume 102, Number 10, October 1995

Table 1. Conditions Associated with Superior Limbic Keratoconjunctivitis in 57 Patients Condition

No. of Patients*

(%)

37

(64.9) (95% Cl, 51.1-77.1) (1.8) (1.8) (10.5) (31.6)

Objective evidence of thyroid disease or Graves ophthalmopathy Rheumatoid arthritis Sjogren syndrome Contact lens wear No associated diseases CI

=

1 6 18

confidence interval.

• Some patients had more than one condition.

explain, at least in part, the predominant association with thyroid disease in patients with SLK, the frequent finding of ophthalmopathy in patients with thyroid dysfunction, and the common occurrence (in 55% of patients) of sur­ gical intervention and, in particular, orbital decompres­ sion. In contrast, an incidence study of Graves ophthal­ mopathy in the county in which our institution is located demonstrated that 20% of patients in the cohort under­ went surgery for ophthalmopathy and 7% required orbital decompression. 15 The precise cause ofSLK remains unknown, although several theories of pathogenesis have been proposed. Ev­ idence for an infectious cause is lacking, 14• 18 in that cul­ tures for bacteria, fungi, viruses, and chlamydial agents are routinely negative or noncontributory. Antimicrobial therapy is typically without value. Corticosteroid agents also are of minimal, if any, help. Wright 11 postulated a mechanical cause for SLK, not­ ing that most patients appear to have loose and redundant superior bulbar conjunctiva, which often rubs against the superior palpebral conjunctiva and limbus. This mechan­ ical effect may disrupt cellular membranes, resulting in a loss of cyclic adenosine monophosphate, which, in turn, can cause increased rates of mitosis and of maturation that appear as acanthosis and keratinization histologically. Table 2. Classification of Thyroid Status in 37 Patients with Superior Limbic Keratoconjunctivitis Classification Hyperthyroidism Hyperthyroid at diagnosis of SLK Euthyroid at diagnosis of SLK Hypothyroid after 1311 therapy Hashimoto thyroiditis Primary hypothyroidism Euthyroid on hormone replacement Overmedicated Euthyroid Graves disease SLK

=

1474

superior limbic keratoconjunctivitis.

No. of Patients 32 9 21

(%)

(86.5)

1

1 3 2 1 2

Wright also suggested that the palpebral conjunctiva may be responsible for initiating the pathologic process in a susceptible eye, noting that a chronically inflamed upper eyelid might cause a disturbance in the normal maturation ofcells ofthe bulbar conjunctiva, allowing them to persist long enough to keratinize. Factors such as tight upper eyelids, prominent globes, and thyroid eye disease might act to initiate tissue contact and conjunctival redundancy, which could be self-perpetuating. This hypothesis has been supported by others. 18• 19 Cher 10 noted that all of his pa­ tients with SLK and thyroid dysfunction had eyelid re­ traction and postulated that upper eyelid retraction of any type may cause SLK by changing the microenviron­ ment at the superior limbus, mechanically, chemically, or thermally. Cher also postulated a possible autoimmune mechanism for SLK based on several observations, in­ cluding the predominantly female incidence, the tendency for spontaneous remission and exacerbation, and the as­ sociation with thyroid dysfunction. Further support for the mechanical hypothesis comes from the finding by Wilson and Ostler 18 of one patient with temporally ec­ centric SLK in an esotropic eye. In the current study, 52.6% of patients with SLK had eyelid retraction and 47.4% had lid lag. No data exist for comparison because previous studies have not reported similar findings. Whether eyelid retraction is causative or merely associated is unclear. That SLK regressed or re­ solved after eyelid retraction repair or orbital decompres­ sion in several of the patients we studied may lend some support to the mechanical theory of SLK causation.

(8.1)

(5.4)

Table 3. Graves Ophthalmopathy and Superior Limbic Keratoconjunctivitis in 33 Patients 33 patients had Graves ophthalmopathy 89.2% with thyroid dysfunction 57.9% with SLK 18 (54.5%) of 33 patients required surgical intervention 11 (33.3%): orbital decompression alone 5 (15.2%): orbital decompression and eyelid retraction repair 2 (6.1%): eyelid retraction repair alone

Kadrmas and Bartley · Superior Limbic Keratoconjunctivitis Table 4. Summary of Clinical Findings in Patients with Superior Limbic Keratoconjunctivitis

Findings No. of patients Age 30-55 yrs (no.)* Female (no.) Bilateral (no.) Thyroid dysfunction (%) ND

=

Corwin, 16 Cher, 10 Wright/ 1

1968

1969

1972

22 19 18 ND ND

10 8 8 5 50

23.0 ND 8.0 19.0 26.1

Passons and Wood, 12 Udell et al, 17 Ohashi et al, 13 Nelson, 14 Current 1986 1984 1988 1989 Study

10 8 8 9 50

11 ND 7 3 ND

12 12 11 ND 25

5 5 5 5 20

57.0 29.0 45.0 48.0 64.9

not determined.

* Age range chosen for comparison with other studies. 15

References 1. Theodore FH. The Collected Letters of the International Correspondence Society of Ophthalmologists and Otolar­ yngologists 1961 ;6:89. 2. Thygeson P. Further observations on superficial punctate keratitis. Arch Ophthalmol 1961 ;66: 158-62. 3. Thygeson P, Kimura SJ. Chronic conjunctivitis. Trans Am Acad Ophthalmol Otolaryngol 1963;67:494-517. 4. Theodore FH. Superior limbic keratoconjunctivitis. Eye Ear Nose Throat Monthly 1963;42:25-8. 5. Theodore FH. Further observations on superior limbic ker­ atoconjunctivitis. Trans Am Acad Ophthalmol Otolaryngol 1967;71 :341-51. 6. Theodore FH. Diagnostic dyes in superior limbic kerato­ conjunctivitis and other superficial entities. In: Turtz AI, ed. Proceedings of the Centennial Symposium, Manhattan Eye, Ear and Throat Hospital, vol 1. St. Louis: CV Mosby, 1969;260-66. 7. Tenzel RR. Comments on superior l~mbic filamentous ker­ atitis: Part 2 [letter]. Arch Ophthalmol 1968;79:508. 8. Theodore FH. Comments on findings of elevated protein­ bound iodine in superior limbic keratoconjunctivitis: Part 1 [letter]. Arch Ophthalmol 1968;79:508. 9. Braley AE, Alexander RC. Superficial punctate keratitis. Isolation of a virus. Arch Ophthalmol 1953;50:147-54. 10. Cher I. Clinical features of superior limbic keratoconjunc­

11. 12. 13. 14. 15.

16. 17.

18. 19.

tivitis in Australia. A probable association with thyrotoxi­ cosis. Arch Ophthalmol 1969;82:580-6. Wright P. Superior limbic keratoconjunctivitis. Trans Ophthalmol Soc UK 1972;92:555-60. Passons GA, Wood TO. Conjunctival resection for superior limbic keratoconjunctivitis. Ophthalmology 1984;91 :966-8. Ohashi Y, Watanabe H, Kinoshita S, et al. Vitamin A eye­ drops for superior limbic keratoconjunctivitis. Am J Ophthalmol 1988;105:523-7. Nelson JD. Superior limbic keratoconjunctivitis (SLK). Eye 1989;3: 180-9. Bartley GB. The epidemiologic characteristics and clinical course of ophthalmopathy associated with autoimmune thyroid disease in Olmsted County, Minnesota. Trans Am Ophthalmol Soc 1994;92:477-588. Corwin ME. Superior· limbic keratoconjunctivitis. Am J Ophthalmol 1968;66:338-40. Udell IJ, Kenyon KR, Sawa M, Dohlman CH. Treatment of superior limbic keratoconjunctivitis by thermocauteri­ zation of the superior bulbar conjunctiva. Ophthalmology 1986;93: 162-6. Wilson FM II, Ostler HB. Superior limbic keratoconjunc­ tivitis. Int Ophthalmol Clin 1986;26:99-112. Ostler HB. Suspected infectious etiology. In: Smolin G, Thoft RA, eds. The Cornea: Scientific Foundations and Clinical Practice, 2nd ed. Boston: Little, Brown and Com­ pany, 1987;296-8.

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